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Sample records for vahur pik saima

  1. Vahur Kraft / Vahur Kraft ; interv. Tiina Jõgeda

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2004-01-01

    Eesti Panga president õpingutest Tartu Ülikooli majandusteaduskonnas, tööst Mererajooni hoiukassade peavalitsuse osakonnajuhatajana ja Eesti Pangas, väärtushinnangutest, rahareformist. Lisatud Vahur Krafti olulisemad eluloolised andmed

  2. Elamu Pirital / Vahur Sova

    Index Scriptorium Estoniae

    Sova, Vahur

    1998-01-01

    Tellija soovis eestiaegset maja, millest õhkuks harmooniat, väärikust, turvalisust. Majas on üle 400 mø, kuid tube ainult kolm, bassein. Projekteerija: M. Pressi Arhitektuuribüroo. Arhitekt Vahur Sova. Ehitus: AS TTP. Projekt 1997, valmis 1998.

  3. Vahur Kraft soovitab elektritootmise erastada / Vahur Kraft ; interv. Vallo Toomet

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2003-01-01

    Eesti Panga president Vahur Kraft soovitab seoses Iraagi sõja ja ebakindlusega maailmas suhtuda ettevaatlikult majanduskasvu prognoosi ning näeb maksureformi läbiviimiseks vajaliku kokkuhoiu võimalusi hariduse, tervishoiu ja sotsiaalkindlustuse reformimisel. Diagramm. Tabel. Vt. samas: Andrus Säälik. Tulude alla jõuavad ka toetused

  4. Kraft kasvatab Nordea haaret Eestis / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2006-01-01

    Avades lähikuudel seitse uut harukontorit, toimub Nordea Panga juhatuse esimehe Vahur Krafti juhtimisel suurim laienemine ettevõtte ajaloos. Ühtlasi peab Kraft jätkuvalt oluliseks internetipanga ja teiste elektrooniliste teenuste arendamist

  5. Vahur Kraft kraamis eile oma sahtlid Eesti Pangas tühjaks / Urmas Tooming

    Index Scriptorium Estoniae

    Tooming, Urmas

    2005-01-01

    6. juunil oli Vahur Krafti viimane tööpäev Eesti Panga presidendina. Lisad: CV; Keskpanga ekspresident Vahur Kraft juhtis 10 aastat Eesti pangandust. Kommenteerivad Eesti Panga endine asepresident Heldur Meerits ja endine Hansapanga juht Indrek Neivelt

  6. Võlakoorem tuhmistab Eesti võimalusi / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2003-01-01

    Eesti Panga president Vahur Kraft hoiatab liiga kergekäelise laenuvõtmise eest. Tema sõnul on Eesti Pank valmis vajaduse korral kasutama võimalusi nii laenuandjate kui ka -võtjate mõjutamiseks. Riigi stabiliseerimisreservist

  7. Zr and REE mineralization in sodic lujavrite from the Saima alkaline complex, northeastern China: A mineralogical study and comparison with potassic rocks

    Science.gov (United States)

    Wu, Bin; Wang, Ru-Cheng; Yang, Jin-Hui; Wu, Fu-Yuan; Zhang, Wen-Lan; Gu, Xiang-Ping; Zhang, Ai-Cheng

    2016-10-01

    The Triassic Saima alkaline complex on the Liaodong Peninsula, northeastern China, consists mainly of potassic phonolite, nepheline syenite, and sodic lujavrite. The lujavrite shows significant Zr-REE mineralization, which is present in the form of early magmatic, Zr-REE-enriched clinopyroxene (30%-40%), titanite (5%), and loparite-(Ce), and late magmatic to hydrothermal wadeite, widespread eudialyte group minerals (5%-10%), and catapleiite. Ultimately, the fractionation of the alkaline magma leads to the crystallization of mosandrite and hezuolinite. Textural relations and compositional variation among the characteristic Zr-REE-bearing minerals record that both Zr and REEs were strongly incompatible in the sodic melt, but that Zr mineralization preceded REE mineralization. The main Zr-REE mineralization in the Saima lujavrite resulted from the high peralkalinity, Na/K ratio and HFSE content, low oxygen fugacity, and the intensive activity of water and volatiles of its evolving magma. The discontinuous and abrupt changes in melt composition and mineral assemblage from the potassic nepheline syenite of the complex to the sodic lujavrite suggest that their magma was derived from different episodes of magmatic activity with different physico-chemical characteristics, rather than from the continuous evolution of a single magmatic event.

  8. Millisele õpetajale kingiksite imerohu? / Karl Martin Sinijärv, Vahur Keller, Kaarel Tarand ... [jt.

    Index Scriptorium Estoniae

    2010-01-01

    Küsimusele vastavad: Eesti kirjanike liidu esimees Karl Martin Sinijärv, nuku- ja noorsooteatri lavastaja Vahur Keller, Sirbi peatoimetaja Kaarel Tarand, kirjanik Andrus Kivirähk, ajakirjanik Juhani Püttsepp

  9. Ere täht Britta / Britta Vahur ; interv. Jüri Muttika

    Index Scriptorium Estoniae

    Vahur, Britta, 1984-

    2006-01-01

    Rubriigis "elu ühes päevas" TV 3 uues telesarjas "Helena" peaosalist kehastav Britta Vahur endast. Lisaks sarja stsenaristi Marko Lillemägi kirjutatud "Seriaalikangelanna Helena Haas (23)", mis kirjeldab seriaali Helena päeva

  10. Somatic PIK3CA mutations in seven patients with PIK3CA-related overgrowth spectrum.

    Science.gov (United States)

    Yeung, Kit San; Ip, Janice Jing Kun; Chow, Chin Pang; Kuong, Evelyn Yue Ling; Tam, Paul Kwong-Hang; Chan, Godfrey Chi-Fung; Chung, Brian Hon-Yin

    2017-04-01

    Somatic mutations in PIK3CA cause many overgrowth syndromes that have been recently coined the "PIK3CA-Related Overgrowth Spectrum." Here, we present seven molecularly confirmed patients with PIK3CA-Related Overgrowth Spectrum, including patients with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal syndrome, Klippel-Trenaunay syndrome, lymphatic malformation and two with atypical phenotypes that cannot be classified into existing disease categories. The literature on PIK3CA-Related Overgrowth Spectrum, suggests that PIK3CA c.1258T>C; p.(Cys420Arg), c.1624G>A; p.(Glu542Lys), c.1633G>A; p.(Glu545Lys), c.3140A>G; p.(His1047Arg), and c.3140A>T; p.(His1047Leu) can be identified in approximately 90% of patients without brain overgrowth. Therefore, droplet digital polymerase chain reaction targeting these mutation hotspots could be used as the first-tier genetic test on patients with PIK3CA-Related Overgrowth Spectrum who do not have signs of overgrowth in their central nervous system. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  11. Lihtne, keeruline : elamu Rohuneemes = Simple, Complicated : Residence in Rohuneeme / Vahur Sova

    Index Scriptorium Estoniae

    Sova, Vahur

    2001-01-01

    Krundi asukohta ja ilmakaari arvestav mereäärne eramu. Maja ruumid ei ole neljakandilised. Tellija soovidest. Projekteerija Teigar. Tork. Sova Arhitektibüroo. Arhitekt Vahur Sova, sisearhitekt Aita Teigar, konstruktor Mart Tamm. Projekt 1998, valmis 2000. 9 ill.: I ja II korruse plaan, välis- ja sisevaated

  12. Treff tähistab sünnipäeva enneolematu kavaga / Vahur Keller ; intervjueerinud Heili Sibrits

    Index Scriptorium Estoniae

    Keller, Vahur, 1976-

    2011-01-01

    Etenduskunstide festivali Treff kunstilise juhi Vahur Kelleri mõtteid 28. maist 1. juunini Tallinnas ja 25.-27. maini Viljandis toimuvast Eesti Nukuteatri korraldatud rahvusvahelisest festivalist "Tallinn Treff"

  13. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

    Science.gov (United States)

    Ilic, Nina; Birsoy, Kıvanç; Aguirre, Andrew J.; Kory, Nora; Pacold, Michael E.; Singh, Shambhavi; Moody, Susan E.; DeAngelo, Joseph D.; Spardy, Nicole A.; Freinkman, Elizaveta; Weir, Barbara A.; Cowley, Glenn S.; Root, David E.; Asara, John M.; Vazquez, Francisca; Widlund, Hans R.; Sabatini, David M.; Hahn, William C.

    2017-01-01

    Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate–aspartate shuttle, which is important for cytoplasmic NAD+ regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate–aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD+/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene. PMID:28396387

  14. SANA - project results and PIK contributions

    Energy Technology Data Exchange (ETDEWEB)

    Bellmann, K.; Erhard, M.; Flechsig, M.; Grote, R.; Suckow, F.

    1998-03-01

    This report includes the final project results of the two groups at PIK, involved in the project: Firstly, the newly developed physiologically-based forest growth model FORSANA was applied for the first time to three pine stands, which differed largely in their air pollution and deposition history. (The evaluation of the model is presented in PIK Report 32). The model was able to explain the growth during the last decades of at least two of the three stands from the climatic and deposition conditions at the sites. The third site was shown to be exceptional with respect to its relation between dimension and age, and was supposed to be exposed to major disturbances in the past, which could not be accounted for by the model. To extrapolate from the stand level to the regional level, FORSANA was initialised with spatially explicit data from forestry inventory and soil maps. Simulations were executed with measured weather records and regional distributions of deposition and air pollution, which were estimated on the basis of emission inventories and wind directions. Different assumptions about the development of air pollution had been applied to investigate different pollution abatement strategies. The results showed that a positive effect can be expected from the actual emission reductions close the main centres of emission, but showed also that this effect is decreasing with increasing distance from the emission source. (orig./KW)

  15. Mutations of PIK3CA in gastric adenocarcinoma

    Directory of Open Access Journals (Sweden)

    So Samuel

    2005-03-01

    Full Text Available Abstract Background Activation of the phosphatidylinositol 3-kinase (PI3K through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110α catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation. Methods Based on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM, we further searched for genes that show correlating expression with PIK3CA. Results We have identified PIK3CA mutations in 4 cases (4.3%, all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p PIK3CA. Conclusion Our data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency.

  16. Analysis of PIK3CA mutations in breast cancer subtypes.

    Science.gov (United States)

    Arsenic, Ruza; Lehmann, Annika; Budczies, Jan; Koch, Ines; Prinzler, Judith; Kleine-Tebbe, Anke; Schewe, Christiane; Loibl, Sibylle; Dietel, Manfred; Denkert, Carsten

    2014-01-01

    Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) is a central element of a signaling pathway involved in cell proliferation, survival, and growth. Certain mutations in this pathway result in enhanced PI3K signaling, which is associated with oncogenic cellular transformation and cancer. The aims of this study were to characterize different types of PIK3CA mutations in exons 9 and 20 in a series of primary breast carcinomas and to correlate the results with clinicopathologic parameters and survival. We used frozen tissue samples and sequenced exons 9 and 20 for a series of 241 patients with a diagnosis of breast carcinoma. We found that 15.8% of the primary breast carcinomas possessed PIK3CA mutations in either exon 9 or exon 20. The rate of PIK3CA mutations was increased in HR(+)/HER2(-) tumors (18.6%), but this difference did not reach a statistical significance. The lowest rate of mutations was observed in HR(+)/HER2(+) tumors (5.3%). No statistically significant association was found between the presence of PIK3CA mutations and the prognostic/clinical features of breast cancer, including histologic subtype, Her2 status, axillary lymph node involvement, tumor grade, and tumor stage. However, the presence of the H1047R mutation in 10 samples was associated with a statistically significantly worse overall survival. PIK3CA mutation was found to be a frequent genetic change in all breast cancer subtypes but occurred with the highest rate in HR(+)/HER2(-) tumors. Further studies are needed to validate the prognostic impact of different PIK3CA mutations.

  17. Lasteaed ja lihtsad asjad : lasteaed "Naba" Pirital = Kindergarten and Simple Things : the NABA Kindergarten at Pirita / Vahur Sova

    Index Scriptorium Estoniae

    Sova, Vahur

    2005-01-01

    Projekteerija: Teigar.Sova.Arhitektid. Autorid: Vahur Sova, Lauri Saar. Sisekujundaja Mari Tosmin. Konstruktor Tõnu Peipman (Inseneribüroo Peipman). Projekt: 2001-2003, valmis: 2004-2005. Ill.: 4 värv. välis- ja 2 sisevaadet, I korruse plaan

  18. Kas tõesti viimane liivlane elab Kanadas? / Alo Lõhmus ; kommenteerinud Vahur Laiapea ja Tiit-Rein Viitso

    Index Scriptorium Estoniae

    Lõhmus, Alo

    2010-01-01

    Režissöör Vahur Laiapea plaanist teha liivi keele teemaline film läänemeresoome keelte emeriitprofessorist Tiit-Rein Viitsost. Tegevuse käigus leiti Kanadast teadaolevalt vanim liivi keelt emakeelena kõnelev liivlanna Grizelda Kristina

  19. PIK-20 and LRV Vehicles Parked on Ramp

    Science.gov (United States)

    1981-01-01

    This photo shows NASA's PIK-20 motor-glider sailplane on the ramp at the Dryden Flight Research Center, Edwards, California. Next to the PIK-20 is the Low Reynolds Number Vehicle (LRV) remotely-piloted research vehicle. The PIK-20E was a sailplane flown at NASA's Ames-Dryden Flight Research Facility (now Dryden Flight Research Center, Edwards, California) beginning in 1981. The vehicle, bearing NASA tail number 803, was used as a research vehicle on projects calling for high lift-over-drag and low-speed performance. Later NASA used the PIK-20E to study the flow of fluids over the aircraft's surface at various speeds and angles of attack as part of a study of airflow efficiency over lifting surfaces. The single-seat aircraft was used to begin developing procedures for collecting sailplane glide performance data in a program carried out by Ames-Dryden. It was also used to study high-lift aerodynamics and laminar flow on high-lift airfoils. Built by Eiri-Avion in Finland, the PIK-20E is a sailplane with a two-cylinder 43-horsepower, retractable engine. It is made of carbon fiber with sandwich construction. In this unique configuration, it takes off and climbs to altitude on its own. After reaching the desired altitude, the engine is shut down and folded back into the fuselage and the aircraft is then operated as a conventional sailplane. Construction of the PIK-20E series was rather unusual. The factory used high-temperature epoxies cured in an autoclave, making the structure resistant to deformation with age. Unlike today's normal practice of laying glass over gelcoat in a mold, the PIK-20E was built without gelcoat. The finish is the result of smooth glass lay-up, a small amount of filler, and an acrylic enamel paint. The sailplane was 21.4 feet long and had a wingspan of 49.2 feet. It featured a wooden, fixed-pitch propeller, a roomy cockpit, wingtip wheels, and a steerable tailwheel.

  20. Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer

    DEFF Research Database (Denmark)

    Palimaru, Irina; Brügmann, Anja; Wium-Andersen, Marie Kim

    2013-01-01

    PURPOSE: High activity of the intracellular phosphatidylinositol-3 kinase (PI3K) pathway is common in breast cancer. Here, we explore differences in expression of important PI3K pathway regulators: the activator, phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA), and the tumour...

  1. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma

    Directory of Open Access Journals (Sweden)

    Bardeesy Nabeel

    2011-02-01

    Full Text Available Abstract Background The genetics of advanced biliary tract cancers (BTC, which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined. Methods To better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases. Results Mutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%. KRAS mutations were identified in 3 (13% intra-hepatic cholangiocarcinomas and 1 (33% perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma. Conclusions The presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.

  2. Somatic mutations of PIK3R1 promote gliomagenesis.

    Directory of Open Access Journals (Sweden)

    Steven N Quayle

    Full Text Available The phosphoinositide 3-kinase (PI3K pathway is targeted for frequent alteration in glioblastoma (GBM and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.

  3. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in Breast Cancer

    DEFF Research Database (Denmark)

    Dupont Jensen, Jeanette; Laenkholm, Anne-Vibeke; Knoop, Ann

    2011-01-01

    PURPOSE: PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available the objective was to assess changes...... recurrence than wild type cases (p=0.03). CONCLUSIONS: PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary...... metastatic breast tumors. Samples were analysed for PIK3CA mutations (exon 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER and HER2. RESULTS: PIK3CA mutation was detected in 45 % of the primary tumors. Overall there was a net gain in mutation in metastatic disease, to 53...

  4. PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations

    Directory of Open Access Journals (Sweden)

    Katsuhiko Nosho

    2008-06-01

    Full Text Available Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN. Microsatellite instability (MSI and CpG island methylator phenotype (CIMP are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15% of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight. PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR = 2.44], KRAS mutation (P < .0001; OR = 2.68, CIMP-high (P = .03; OR = 2.08, phospho–ribosomal protein S6 expression (P = .002; OR = 2.19, and FASN expression (P = .02; OR = 1.85 and inversely with p53 expression (P = .01; OR = 0.54 and β-catenin (CTNNB1 alteration (P = .004; OR = 0.43. In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24 but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.

  5. Gain of Function Mutations of PIK3CD as a Cause of Primary Sclerosing Cholangitis.

    Science.gov (United States)

    Hartman, Heather N; Niemela, Julie; Hintermeyer, Mary K; Garofalo, Mary; Stoddard, Jennifer; Verbsky, James W; Rosenzweig, Sergio D; Routes, John M

    2015-01-01

    Gain of function (GOF) mutation in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) is the cause of a primary immunodeficiency (PID) characterized by recurrent sinopulmonary infections and lymphoproliferation. We describe a family of two adults and three children with GOF mutation in PIK3CD, all with recurrent sinopulmonary infections and varied infectious and non-infectious complications. The two adults have Primary Sclerosing Cholangitis (PSC) without evidence of Cryptosporidium parvum infection and have required liver transplantation. PSC is a novel phenotype of GOF mutation in PIK3CD.

  6. Oncogenic PIK3CA Mutation and Dysregulation in Human Salivary Duct Carcinoma

    Directory of Open Access Journals (Sweden)

    Wanglong Qiu

    2014-01-01

    Full Text Available Salivary duct carcinoma (SDC is an aggressive malignant tumor with a high mortality, which resembles high-grade breast ductal carcinoma in morphology. The parotid gland is the most common location. Its molecular genetic characteristics remain largely unknown. We have previously reported high incidence of PIK3CA somatic mutations in head and neck squamous cell carcinoma, particularly in pharyngeal cancers. Here we examined the PIK3CA gene expression status and hotspot mutations in six cases of SDC by immunohistochemistry and genomic DNA sequencing. Immunohistochemistry showed that PIK3CA expression was elevated in all six patients with SDC. By DNA sequencing, two hotspot mutations of the PIK3CA gene, E545K (exon 9 and H1047R (exon 20, were identified in two of the six cases. Our results support that oncogenic PIK3CA is upregulated and frequently mutated in human SDC, adding evidence that PIK3CA oncogenic pathway is critical in the tumorigenesis of SDC, and may be a plausible drug target for this rare disease.

  7. Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer.

    Science.gov (United States)

    Dirican, Ebubekir; Akkiprik, Mustafa; Özer, Ayşe

    2016-06-01

    Breast cancer (BCa) is the most common cancer and the second cause of death among women. Phosphoinositide 3-kinase (PI3K) signaling pathway has a crucial role in the cellular processes such as cell survival, growth, division, and motility. Moreover, oncogenic mutations in the PI3K pathway generally involve the activation phosphatidylinositol-4,5-bisphosphate 3-kinase-catalytic subunit alpha (PIK3CA) mutation which has been identified in numerous BCa subtypes. In this review, correlations between PIK3CA mutations and their clinicopathological parameters on BCa will be described. It is reported that PIK3CA mutations which have been localized mostly on exon 9 and 20 hot spots are detected 25-40 % in BCa. This relatively high frequency can offer an advantage for choosing the best treatment options for BCa. PIK3CA mutations may be used as biomarkers and have been major focus of drug development in cancer with the first clinical trials of PI3K pathway inhibitors currently in progress. Screening of PIK3CA gene mutations might be useful genetic tests for targeted therapeutics or diagnosis. Increasing data about PIK3CA mutations and its clinical correlations with BCa will help to introduce new clinical applications in the near future.

  8. Tree-level ({pi},K) amplitude and analyticity

    Energy Technology Data Exchange (ETDEWEB)

    Vereshagin, V.V. [Theoretical Physics Department, Institute of Physics, St. Petersburg State University, 198904 St. Petersburg (Russia)

    1997-05-01

    I consider the tree-level amplitude describing all three channels of the binary ({pi},K) reaction, as a meromorphic, polynomially bounded function of three dependent complex variables. Using the Mittag-Leffler theorem, I construct three convergent partial fraction expansions, each one being applied in the corresponding domain. Noting that the mutual intersections of those domains are nonempty, I employ analytical continuation. It is shown that the necessary conditions to make such a continuation feasible are the following: (1) The only parameters completely determining the amplitude are the on-shell couplings and masses; (2) these parameters are restricted by a certain (infinite) system of bootstrap equations; (3) the full cross-symmetric amplitude takes the dual form even when the Pomeron contribution is taken into account; (4) this latter contribution corresponds to a nonresonant background which, in turn, is expressed in terms of cross-channel resonance parameters. Also, it is demonstrated that chiral symmetry provides a unique scale for the mentioned parameters, the resonance saturation effect appearing as a direct consequence of the above results. {copyright} {ital 1997} {ital The American Physical Society}

  9. Program for studying fundamental interactions at the PIK reactor facilities

    Science.gov (United States)

    Serebrov, A. P.; Vassiljev, A. V.; Varlamov, V. E.; Geltenbort, P.; Gridnev, K. A.; Dmitriev, S. P.; Dovator, N. A.; Egorov, A. I.; Ezhov, V. F.; Zherebtsov, O. M.; Zinoviev, V. G.; Ivochkin, V. G.; Ivanov, S. N.; Ivanov, S. A.; Kolomensky, E. A.; Konoplev, K. A.; Krasnoschekova, I. A.; Lasakov, M. S.; Lyamkin, V. A.; Martemyanov, V. P.; Murashkin, A. N.; Neustroev, P. V.; Onegin, M. S.; Petelin, A. L.; Pirozhkov, A. N.; Polyushkin, A. O.; Prudnikov, D. V.; Ryabov, V. L.; Samoylov, R. M.; Sbitnev, S. V.; Fomin, A. K.; Fomichev, A. V.; Zimmer, O.; Cherniy, A. V.; Shoka, I. V.

    2016-05-01

    A research program aimed at studying fundamental interactions by means of ultracold and polarized cold neutrons at the GEK-4-4' channel of the PIK reactor is presented. The apparatus to be used includes a source of cold neutrons in the heavy-water reflector of the reactor, a source of ultracold neutrons based on superfluid helium and installed in a cold-neutron beam extracted from the GEK-4 channel, and a number of experimental facilities in neutron beams. An experiment devoted to searches for the neutron electric dipole moment and an experiment aimed at a measurement the neutron lifetime with the aid of a large gravitational trap are planned to be performed in a beam of ultracold neutrons. An experiment devoted to measuring neutron-decay asymmetries with the aid of a superconducting solenoid is planned in a beam of cold polarized neutrons from the GEK-4' channel. The second ultracold-neutron source and an experiment aimed at measuring the neutron lifetime with the aid of a magnetic trap are planned in the neutron-guide system of the GEK-3 channel. In the realms of neutrino physics, an experiment intended for sterile-neutrino searches is designed. The state of affairs around the preparation of the experimental equipment for this program is discussed.

  10. PIK3CD promoted proliferation in diffuse large B cell lymphoma through upregulation of c-myc.

    Science.gov (United States)

    Cui, Wenli; Zheng, Shutao; Li, Xinxia; Ma, Yuqing; Sang, Wei; Liu, Ming; Zhang, Wei; Zhou, Xiaoyan

    2016-09-01

    Despite PIK3CD has been extensively reported in cancers, however, little evidence has been available regarding its role in the setting of diffuse large B cell lymphoma (DLBCL). In the present study, to investigate the role of PIK3CD in DLBCL, relevant experiments were carried out on both in vivo clinical tissue level and in vitro cell line level. Prognostic and clinicopathological significance were analyzed after immunohistochemical assay of PIK3CD expression on DLBCL tissue microarray. MTT assay and flow cytometry were employed to evaluate the proliferative variation, cell cycle, and apoptosis. Athymic nude mice xenografted with DLBCL cell line were employed to confirm the role of PIK3CD. It was found that there was a significant difference between expression of PIK3CD and international prognosis index (IPI), performance state (PS), and inferior overall prognosis. Furthermore, PIK3CD can promote proliferation and prevent apoptosis in DLBCL cells in vitro through upregulation of c-myc and p-AKT and in contrast downregulation of p21 and p27. In nude mice model, knock-down of PIK3CD was shown to be able to suppress the proliferation of DLBCL but not significantly compared with control group. Taken together, our study showed that PIK3CD can promote proliferation of DLBCL cells both in vitro and in vivo, suggesting that PIK3CD could be druggable in the therapy of DLBCL.

  11. Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Paolo Cossu-Rocca

    Full Text Available Triple Negative Breast Cancer (TNBC accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

  12. Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas

    Energy Technology Data Exchange (ETDEWEB)

    Murat, C.B.; Braga, P.B.S.; Fortes, M.A.H.Z. [Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Bronstein, M.D. [Unidade de Neuroendocrinologia, Serviço de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Corrêa-Giannella, M.L.C.; Giorgi, R.R. [Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-07-13

    The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-α catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number ≥4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland.

  13. The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses.

    Science.gov (United States)

    Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

    2015-04-01

    The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1-CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  14. Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer

    National Research Council Canada - National Science Library

    Arsenic, Ruza; Treue, Denise; Lehmann, Annika; Hummel, Michael; Dietel, Manfred; Denkert, Carsten; Budczies, Jan

    2015-01-01

    Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PIK3CA, is one of the most frequently mutated genes in breast cancer, and the mutation status of PIK3CA has clinical relevance...

  15. Mutación del gen PIK3CA en el carcinoma epidermoide oral

    OpenAIRE

    Pombo Castro, María

    2017-01-01

    PIK3CA es uno de los genes más frecuentemente alterados en el carcinoma epidermoide oral (CEO), por lo que podría considerarse una posible diana terapéutica. Nuestro objetivo es averiguar la frecuencia de mutación y amplificación de PIK3CA en el CEO en nuestra población, y si existe alguna relación entre este hecho y las variables clínicas o la supervivencia. Se incluyeron 98 pacientes (31 lesiones precancerosas y 67 carcinomas). El porcentaje de mutaciones fue 18.5% en carcinomas y 22,6...

  16. Relationship of KRAS and PIK3CA gene mutation in colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Fan-Bao Yao; Qian-Yi Kuang; Xi Fu; Shi-Yao Huang

    2016-01-01

    Objective:To analyze the relationship between KRAS/PIK3CA gene mutation and clinicopathologic characteristics such as gender, age, tumor location, pathological pattern, histological grade, TNM stage and lymph node metastasis, especially the relationship with distant metastasis of colorectal cancer.Methods:A total of94 cases of colorectal cancer samples surgically resected in Gastrointestinal Surgery Department of our hospital from January 2012 to August 2015 were collected, DNA was extracted and then KRAS and PIK3CA gene sequencing was carried out; their clinicopathologic characteristics (gender, age, tumor location, pathological pattern, histological grade, TNM stage, lymph node metastasis and distant metastasis) were analyzed, the relationship between KRAS/PIK3CA gene mutation and above factors, especially distant metastasis was analyzed, and statistical analysis processing was conducted; patients received 3-year follow-up, distant metastasis and recurrence were observed, and the number of their cases was counted, statistically analyzed and processed.Results:KRAS gene mutation was not associated with gender, age, tumor location, pathological pattern and histological grade, and significantly associated with distant metastasis, lymph node metastasis and TNM stage; PIK3CA was not associated with gender, age, tumor location, pathological pattern and histological grade, and associated with TNM stage, lymph node metastasis and distant metastasis; 7 cases (7.4%) were with mutation of both KRAS and PIK3CA (double positive), and 55 cases (57.4%) were with no mutation at all (double negative); in double positive cases, 5 cases were with distant metastasis, metastasis rate was 71.4% and higher than that of double negative (16/55, 29.1%), and there were statistical differences; it was found in follow-up that metastasis rate of KRAS mutant type was higher than that of wild type, and differences were statistically significant; recurrence rates of KRAS and PIK3CA mutant type

  17. Genetic alterations of the PIK3CA oncogene in human oral squamous cell carcinoma in an Indian population.

    Science.gov (United States)

    Shah, Sejal; Shah, Siddharth; Padh, Harish; Kalia, Kiran

    2015-11-01

    The phosphatidylinositol 3-kinase (PIK3) genes, which code for heterodimeric lipid kinases, consist of a catalytic subunit, p110α (PIK3CA), which regulates cell proliferation, apoptosis, and metastasis. Recently, a high frequency of somatic mutations was observed in the PIK3CA gene in various cancer types, including oral squamous cell carcinoma (OSCC). This study aimed to determine the frequency of oncogenic hotspot mutations in exons 9 and 20 of the PIK3CA gene and its correlation with the clinical characteristics of OSCC patients in an Indian population. We analyzed exons 9 and 20 of the PIK3CA gene using polymerase chain reaction (PCR) and direct genomic sequencing of 50 OSCC primary tumors. We observed two hotspot oncogenic mutations (E542 K, E545 K) in exon 9 and two synonymous mutations (A994 A, T1025 T) in exon 20. Moreover, we identified two single nucleotide polymorphisms (SNPs), rs114587137 (C>T) and rs17849071 (T>G), in intron 9 of the PIK3CA gene. Both oncogenic hotspot mutations were reported primarily in patients with advanced-stage cancer of the buccal mucosa. We have observed a 4% oncogenic mutation frequency of the PIK3CA gene, which plays a minor role in the development of OSCC in an Indian population. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Expression of activated PIK3CA in ovarian surface epithelium results in hyperplasia but not tumor formation.

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    Shun Liang

    Full Text Available The Phosphatidylinositol 3'-kinase is a key regulator in various cancer-associated signal transduction pathways. Genetic alterations of its catalytic subunit alpha, PIK3CA, have been identified in ovarian cancer. Our in vivo data suggests that PIK3CA activation is one of the early genetic events in ovarian cancer. However, its role in malignant transformation of ovarian surface epithelium (OSE is largely unclear.Using the Müllerian inhibiting substance type II receptor (MISIIR promoter, we generated transgenic mice that expressed activated PIK3CA in the Müllerian epithelium. Overexpression of PIK3CA in OSE induced remarkable hyperplasia, but was not able to malignantly transform OSE in vivo. The consistent result was also observed in primary cultured OSEs. Although enforced expression of PIK3CA could not induce OSE anchorage-independent growth, it significantly increased anchorage-independent growth of OSE transformed by mutant K-ras.While PIK3CA activation may not be able to initiate OSE transformation, we conclude that activation of PIK3CA may be an important molecular event contributing to the maintenance of OSE transformation initiated by oncogenes such as K-ras.

  19. MicroRNA-375 inhibits colorectal cancer growth by targeting PIK3CA

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yihui [Department of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, 150 Haping Road, 150081 Harbin (China); Tang, Qingchao [Cancer Center, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, 150086 Harbin (China); Li, Mingqi; Jiang, Shixiong [Department of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, 150 Haping Road, 150081 Harbin (China); Wang, Xishan, E-mail: wxshan12081@163.com [Cancer Center, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, 150086 Harbin (China)

    2014-02-07

    Highlights: • miR-375 is downregulated in colorectal cancer cell lines and tissues. • miR-375 inhibits colorectal cancer cell growth by targeting PIK3CA. • miR-375 inhibits colorectal cancer cell growth in xenograft nude mice model. - Abstract: Colorectal cancer (CRC) is the second most common cause of death from cancer. MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by triggering RNA degradation or interfering with translation. Aberrant miRNA expression is involved in human disease including cancer. Herein, we showed that miR-375 was frequently down-regulated in human colorectal cancer cell lines and tissues when compared to normal human colon tissues. PIK3CA was identified as a potential miR-375 target by bioinformatics. Overexpression of miR-375 in SW480 and HCT15 cells reduced PIK3CA protein expression. Subsequently, using reporter constructs, we showed that the PIK3CA untranslated region (3′-UTR) carries the directly binding site of miR-375. Additionally, miR-375 suppressed CRC cell proliferation and colony formation and led to cell cycle arrest. Furthermore, miR-375 overexpression resulted in inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. SiRNA-mediated silencing of PIK3CA blocked the inhibitory effect of miR-375 on CRC cell growth. Lastly, we found overexpressed miR-375 effectively repressed tumor growth in xenograft animal experiments. Taken together, we propose that overexpression of miR-375 may provide a selective growth inhibition for CRC cells by targeting PI3K/Akt signaling pathway.

  20. Segmental overgrowth syndrome due to an activating PIK3CA mutation identified in affected muscle tissue by exome sequencing

    DEFF Research Database (Denmark)

    Rasmussen, Maria; Sunde, Lone; Weigert, Karen Petra

    2014-01-01

    Mosaic PIK3CA-mutations have been described in an increasing number of overgrowth syndromes. We describe a patient with a previously unreported segmental overgrowth syndrome with the mutation, PIKCA3 c.3140A>G (p.His1047Arg) in affected tissue diagnosed by exome sequencing. This PIK3CA-associated......-associated segmental overgrowth syndrome overlaps with CLOVES syndrome and fibroadipose hyperplasia but is distinct from each of these entities....

  1. An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

    2008-05-06

    Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

  2. The Inhibitory Effect of PIK-75 on Inflammatory Mediator Response Induced by Hydrogen Peroxide in Feline Esophageal Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Jun Yeong Jeong

    2014-01-01

    Full Text Available Isoform-selective inhibitors of phosphoinositide 3-kinase (PI3K activation have an anti-inflammatory effect by reducing proinflammatory cytokines. Cultured feline esophageal epithelial cells (EEC of passages 3~4 were treated with hydrogen peroxide and PIK-75. The cell viability was measured by a MTT incorporation assay. The distribution of PI3K isoforms, p-Akt, IL-1β, and IL-8 was inferred from Western blots. The release of IL-6 was determined by ELISA. The cell morphology was not considerably different from nontreated cells if the cells were pretreated with PIK-75 and treated with 300 μM hydrogen peroxide. The density of p110α of PI3K was increased, but that of other types was not affected after the treatment with hydrogen peroxide. The density of p-Akt, when the cells were exposed to PIK-75 and hydrogen peroxide, was diminished dose dependently more than that of hydrogen peroxide treatment only. The decrease of p-Akt showed an inhibition of PI3K by PIK-75. PIK-75 dose dependently reduced the expression of IL-1β, IL-8, and the level of IL-6 compared with hydrogen peroxide treatment only. These results suggest evidence that p110α mediates esophageal inflammation and that PIK-75 has an anti-inflammatory effect by reducing proinflammatory cytokines on feline esophageal epithelial cultured cells.

  3. Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway.

    Science.gov (United States)

    Lou, Hong; Villagran, Guillermo; Boland, Joseph F; Im, Kate M; Polo, Sarita; Zhou, Weiyin; Odey, Ushie; Juárez-Torres, Eligia; Medina-Martínez, Ingrid; Roman-Basaure, Edgar; Mitchell, Jason; Roberson, David; Sawitzke, Julie; Garland, Lisa; Rodríguez-Herrera, Maria; Wells, David; Troyer, Jennifer; Pinto, Francisco Castillo; Bass, Sara; Zhang, Xijun; Castillo, Miriam; Gold, Bert; Morales, Hesler; Yeager, Meredith; Berumen, Jaime; Alvirez, Enrique; Gharzouzi, Eduardo; Dean, Michael

    2015-12-01

    Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. ©2015 American Association for Cancer Research.

  4. Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway

    Science.gov (United States)

    Lou, Hong; Villagran, Guillermo; Boland, Joseph F.; Im, Kate M.; Polo, Sarita; Zhou, Weiyin; Odey, Ushie; Juárez-Torres, Eligia; Medina-Martínez, Ingrid; Roman-Basaure, Edgar; Mitchell, Jason; Roberson, David; Sawitzke, Julie; Garland, Lisa; Rodríguez-Herrera, Maria; Wells, David; Troyer, Jennifer; Pinto, Francisco Castillo; Bass, Sara; Zhang, Xijun; Castillo, Miriam; Gold, Bert; Morales, Hesler; Yeager, Meredith; Berumen, Jaime; Alvirez, Enrique; Gharzouzi, Eduardo; Dean, Michael

    2015-01-01

    Purpose Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing over 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. Experimental Design We performed HPV typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. Results Cervical cancer cases in Guatemala and Venezuela have an average age-of-diagnosis of 50 years, and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other phosphatidyl inositol (PI3K)/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types, and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after age 50. Frequent gain of chromosome 3q was found and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. Conclusions PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. PMID:26080840

  5. Prognostic role of PIK3CA mutations of cell-free DNA in early-stage triple negative breast cancer.

    Science.gov (United States)

    Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Inao, Toko; Sueta, Aiko; Fujiwara, Saori; Omoto, Yoko; Iwase, Hirotaka

    2015-11-01

    PIK3CA is an oncogene that encodes the p110α component of phosphatidylinositol 3-kinase (PI3K); it is the second most frequently mutated gene following the TP53 gene. In the clinical setting, PIK3CA mutations may have favorable prognostic value for hormone receptor-positive breast cancer patients and, during the past few years, PIK3CA mutations of cell-free DNA (cfDNA) have attracted attention as a potential noninvasive biomarker of cancer. However, there are few reports on the clinical implications of PIK3CA mutations for TNBC patients. We investigated the PIK3CA major mutation status of cfDNA as a noninvasive biomarker of cancer using droplet digital polymerase chain reaction (ddPCR), which has high level sensitivity and specificity for cancer mutation, in early-stage 49 triple negative breast cancer (TNBC) patients. A total of 12 (24.4%) of 49 patients had PIK3CA mutations of cfDNA. In a median follow up of 54.4 months, the presence of PIK3CA mutations of cfDNA had significant impacts on relapse-free survival (RFS; P = 0.0072) and breast cancer-specific survival (BCSS; P = 0.016), according to the log-lank test. In a Cox proportional hazards model, the presence of PIK3CA mutations of cfDNA had significant prognostic value in the univariate and multivariate analysis. Additionally, the presence of PIK3CA mutations of cfDNA was significantly correlated with positive androgen receptor phosphorylated form depending on PI3K signaling pathway (pAR) which is independent favorable prognostic factors of TNBC. We demonstrated that the presence of PIK3CA major mutations of cfDNA could be a discriminatory predictor of RFS and BCSS in early-stage TNBC patients and it was associated with PI3K pathway-dependent AR phosphorylation. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  6. Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer*

    Science.gov (United States)

    Young, Christian D.; Zimmerman, Lisa J.; Hoshino, Daisuke; Formisano, Luigi; Hanker, Ariella B.; Gatza, Michael L.; Morrison, Meghan M.; Moore, Preston D.; Whitwell, Corbin A.; Dave, Bhuvanesh; Stricker, Thomas; Bhola, Neil E.; Silva, Grace O.; Patel, Premal; Brantley-Sieders, Dana M.; Levin, Maren; Horiates, Marina; Palma, Norma A.; Wang, Kai; Stephens, Philip J.; Perou, Charles M.; Weaver, Alissa M.; O'Shaughnessy, Joyce A.; Chang, Jenny C.; Park, Ben Ho; Liebler, Daniel C.; Cook, Rebecca S.; Arteaga, Carlos L.

    2015-01-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR. PMID:25953087

  7. Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.

    Science.gov (United States)

    Young, Christian D; Zimmerman, Lisa J; Hoshino, Daisuke; Formisano, Luigi; Hanker, Ariella B; Gatza, Michael L; Morrison, Meghan M; Moore, Preston D; Whitwell, Corbin A; Dave, Bhuvanesh; Stricker, Thomas; Bhola, Neil E; Silva, Grace O; Patel, Premal; Brantley-Sieders, Dana M; Levin, Maren; Horiates, Marina; Palma, Norma A; Wang, Kai; Stephens, Philip J; Perou, Charles M; Weaver, Alissa M; O'Shaughnessy, Joyce A; Chang, Jenny C; Park, Ben Ho; Liebler, Daniel C; Cook, Rebecca S; Arteaga, Carlos L

    2015-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1.

    Directory of Open Access Journals (Sweden)

    Gottfrid Sjödahl

    Full Text Available BACKGROUND: Urothelial carcinoma (UC is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g., PIK3CA, AKT1, and RAS. Most mutation studies of UCs have been focused on single or a few genes at the time or been performed on small sample series. This has limited the possibility to investigate co-occurrence of mutations. METHODOLOGY/PRINCIPAL FINDINGS: We performed mutation analyses of 16 genes, FGFR3, PIK3CA, PIK3R1 PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, TSC1, TSC2, APC, CTNNB1, and TP53, in 145 cases of UC. We show that FGFR3 and PIK3CA mutations are positively associated. In addition, we identified PIK3R1 as a target for mutations. We demonstrate a negative association at borderline significance between FGFR3 and RAS mutations, and show that these mutations are not strictly mutually exclusive. We show that mutations in BRAF, ARAF, RAF1 rarely occurs in UC. Our data emphasize the possible importance of APC signaling as 6% of the investigated tumors either showed inactivating APC or activating CTNNB1 mutations. TSC1, as well as TSC2, that constitute the mTOR regulatory tuberous sclerosis complex were found to be mutated at a combined frequency of 15%. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a significant association between FGFR3 and PIK3CA mutations in UC. Moreover, the identification of mutations in PIK3R1 further emphasizes the importance of the PI3-kinase pathway in UC. The presence of TSC2 mutations, in addition to TSC1 mutations, underlines the involvement of mTOR signaling in UC.

  9. PIK3CB and K-ras in oral squamous Cell carcinoma. A possible cross-talk!

    Directory of Open Access Journals (Sweden)

    Natheer H Al-Rawi

    2014-01-01

    Full Text Available Background: PIK3 and K-ras are signal transducing proteins involved and mediating many responses related to cell cycle growth regulation. Until date, there has been only limited evidence about the expression of K-ras and PKI3CB in oral squamous cell carcinoma (OSCC. AIMS : This study aimed to examine both proteins in OSCC and their relation to clinic- pathological findings. Setting and Design: A total of 31 formalin-fixed paraffin-embedded specimens of OSCC were selected in this study. PIK3CB and K-ras expressions were detected using standard immunohistochemical techniques. Materials and Methods: PIK3CB and k-ras immune reactivity was semi-quantitatively evaluated in at least five representative fields at 400X magnification and recorded as percentage of PIK3CB and k-ras positive tumor cells over the total number of cells examined in the same area. Results and Conclusion: All examined specimens of OSCC were positive for monoclonal antibodies directed against PIK3CB and K-ras proteins especially at advanced stage of the disease. No significant relation was observed between the tested proteins and the clinic-pathological findings of OSCC; however a highly significant direct relationship was observed between K-ras and PIK3CB. This lead to conclusion that both K-ras and PIK3CB signaling pathway were activated in the advanced stage of OSCC, and possibly a cross-talk between them. This could make these mutant proteins a potential target for an effective molecular therapy.

  10. UCN sources at external beams of thermal neutrons. An example of PIK reactor

    Energy Technology Data Exchange (ETDEWEB)

    Lychagin, E.V., E-mail: lychag@nf.jinr.ru [Joint Institute for Nuclear Research, 6 Joliot-Curie, Dubna 141980 (Russian Federation); Mityukhlyaev, V.A., E-mail: victim@pnpi.spb.ru [Petersburg Nuclear Physics Institute, Orlova Roscha, Gatchina 188300 (Russian Federation); Muzychka, A.Yu., E-mail: muz@nf.jinr.ru [Joint Institute for Nuclear Research, 6 Joliot-Curie, Dubna 141980 (Russian Federation); Nekhaev, G.V., E-mail: grigorijnekhaev@yandex.ru [Joint Institute for Nuclear Research, 6 Joliot-Curie, Dubna 141980 (Russian Federation); Nesvizhevsky, V.V., E-mail: nesvizhevsky@ill.eu [Institut Max von Laue – Paul Langevin, 71 Avenue des Martyrs, Grenoble 38042 (France); Onegin, M.S., E-mail: oneginm@gmail.com [Petersburg Nuclear Physics Institute, Orlova Roscha, Gatchina 188300 (Russian Federation); Sharapov, E.I., E-mail: sharapov@nf.jinr.ru [Joint Institute for Nuclear Research, 6 Joliot-Curie, Dubna 141980 (Russian Federation); Strelkov, A.V., E-mail: str@jinr.ru [Joint Institute for Nuclear Research, 6 Joliot-Curie, Dubna 141980 (Russian Federation)

    2016-07-01

    We consider ultracold neutron (UCN) sources based on a new method of UCN production in superfluid helium ({sup 4}He). The PIK reactor is chosen as a perspective example of application of this idea, which consists of installing {sup 4}He UCN source in the beam of thermal or cold neutrons and surrounding the source with moderator-reflector, which plays the role of cold neutron (CN) source feeding the UCN source. CN flux in the source can be several times larger than the incident flux, due to multiple neutron reflections from the moderator–reflector. We show that such a source at the PIK reactor would provide an order of magnitude larger density and production rate than an analogous source at the ILL reactor. We estimate parameters of {sup 4}He source with solid methane (CH{sub 4}) or/and liquid deuterium (D{sub 2}) moderator–reflector. We show that such a source with CH{sub 4} moderator–reflector at the PIK reactor would provide the UCN density of ~1·10{sup 5} cm{sup −3}, and the UCN production rate of ~2·10{sup 7} s{sup −1}. These values are respectively 1000 and 20 times larger than those for the most intense UCN user source. The UCN density in a source with D{sub 2} moderator-reflector would reach the value of ~2·10{sup 5} cm{sup −3}, and the UCN production rate would be equal ~8·10{sup 7} s{sup −1}. Installation of such a source in a beam of CNs would slightly increase the density and production rate.

  11. Oncogenic mutations of PIK3CA and HRAS in carcinoma of cervix in South Indian women

    Directory of Open Access Journals (Sweden)

    Geetha kumari Konathala

    2017-12-01

    Full Text Available Carcinoma of the cervix is the second most successive reason of female cancer which remains an imperative medical issue in women around the world. Mutations are normally dissected by tissue biopsy which is intrusive, costly and possibly subjective. However, detection of mutations from blood is a non-invasive procedure. However, detection of mutations from blood is a non-invasive procedure. It would offer several advantages, including greater speed and cheap at a cost such that the family members can likewise be screened. Repeated tests after surgery provide an early cautioning for the disease recurrence. The present work aimed to assess the frequency of PIK3CA and HRAS mutations in cervical cancer patients using peripheral blood. This study includes 210 cases presenting cervical cancer and 210 age and sex-matched healthy controls. Genomic DNA was isolated from peripheral blood. The PCR-CTPP method was performed for screening of exons 9 and 20 of PIK3CA and exon 34 HRAS mutations. Sequencing of PIK3CA and of HRAS genes was done for further confirmation. Out of eight mutations studied, no clear disease causing mutations were noticed in any of the cervical cancer patients in the present investigation. Cervical cancer harbors excessive rates of targetable oncogenic mutations. We couldn't find any changes in our investigation. If a connection amongst tissue and non-tissue mutations could be shown, the probability of a basic blood test to distinguish possibility for anticancer treatment comes a bit nearer. Repeated blood tests after surgery provide an early cautioning for disease recurrence. Therefore, in future evaluation of a larger data set and cases with progressive tumor (Stage III–IV will be required to approve these findings.

  12. p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC.

    Science.gov (United States)

    Kidacki, Michal; Lehman, Heather L; Green, Michelle V; Warrick, Joshua I; Stairs, Douglas B

    2017-10-01

    Despite recent improvements in treatment for head and neck squamous cell carcinoma (HNSCC), half of all patients with a regional or advanced disease will die within 5 years from diagnosis. Therefore, identification of mechanisms driving the aggressive behavior of HNSCC is of utmost importance. Because p120-catenin (CTNND1/P120CTN) downregulation and PIK3CA mutations are commonly found in HNSCC, the objective of this study was to identify their impact on fundamental processes of metastasis, specifically, migration and invasion. Furthermore, this study aimed to identify the key effector proteins regulated by P120CTN downregulation and PIK3CA mutations. Studies using oral keratinocytes demonstrated that P120CTN downregulation and PIK3CA mutations increased migration and invasion. In addition, P120CTN downregulation and PIK3CA mutations resulted in elevated matrix metallopeptidase 1 (MMP1) levels. Inhibition of MMP1 resulted in decreased invasion, suggesting that MMP1 plays a critical role in HNSCC invasion. Moreover, analysis of HNSCC patient specimens from The Cancer Genome Atlas confirmed these findings. Tumors with low P120CTN and PI3K pathway mutations have higher levels of MMP1 compared to tumors with high P120CTN and no PI3K pathway mutations. In conclusion, this study demonstrates that P120CTN downregulation and PIK3CA mutations promote MMP1-driven invasion, providing a potential novel target for limiting metastasis in HNSCC.Implications: Because of its role in invasion, MMP1 represents a novel, potential target for limiting metastasis in a subset of HNSCCs with P120CTN downregulation and PIK3CA mutations. Mol Cancer Res; 15(10); 1398-409. ©2017 AACR. ©2017 American Association for Cancer Research.

  13. Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC

    Directory of Open Access Journals (Sweden)

    Shi Bingyin

    2011-04-01

    Full Text Available Abstract Background Lung cancer is the leading cause of cancer-related death worldwide. Genetic and epigenetic alterations have been identified frequently in lung cancer, such as promoter methylation, gene mutations and genomic amplification. However, the interaction between genetic and epigenetic events and their significance in lung tumorigenesis remains poorly understood. Methods We determined the promoter methylation of 6 genes and PIK3CA amplification using quantitative methylation-specific PCR (Q-MSP and real-time quantitative PCR, respectively, and explore the association of promoter methylation with PIK3CA amplification in a large cohort of clinically well-characterized non-small cell lung cancer (NSCLC. Results Highly frequent promoter methylation was observed in NSCLC. With 100% diagnostic specificity, excellent sensitivity, ranging from 45.8 to 84.1%, was found for each of the 6 genes. The promoter methylation was associated with histologic type. Methylation of CALCA, CDH1, DAPK1, and EVX2 was more common in squamous cell carcinomas (SCC compared to adenocarcinomas (ADC. Conversely, there was a trend toward a higher frequency of RASSF1A methylation in ADC than SCC. In addition, PIK3CA amplification was frequently found in NSCLC, and was associated with certain clinicopathologic features, such as smoking history, histologic type and pleural indentation. Importantly, aberrant promoter methylation of certain genes was significantly associated with PIK3CA amplification. Conclusions Our data showed highly frequent promoter methylation and PIK3CA amplification in Chinese NSCLC population, and first demonstrated the associations of gene methylation with PIK3CA amplification, suggesting that these epigenetic events may be a consequence of overactivation of PI3K/Akt pathway.

  14. PRKCI negatively regulates autophagy via PIK3CA/AKT–MTOR signaling

    Energy Technology Data Exchange (ETDEWEB)

    Qu, Liujing; Li, Ge; Xia, Dan; Hongdu, Beiqi; Xu, Chentong; Lin, Xin [Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, Beijing (China); Peking University Center for Human Disease Genomics, Peking University, Beijing (China); Chen, Yingyu, E-mail: yingyu_chen@bjmu.edu.cn [Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, Beijing (China); Peking University Center for Human Disease Genomics, Peking University, Beijing (China)

    2016-02-05

    The atypical protein kinase C isoform PRKC iota (PRKCI) plays a key role in cell proliferation, differentiation, and carcinogenesis, and it has been shown to be a human oncogene. Here, we show that PRKCI overexpression in U2OS cells impaired functional autophagy in normal or cell stress conditions, as characterized by decreased levels of light chain 3B-II protein (LC3B-II) and weakened degradation of endogenous and exogenous autophagic substrates. Conversely, PRKCI knockdown by small interference RNA resulted in opposite effects. Additionally, we identified two novel PRKCI mutants, PRKCI{sup L485M} and PRKCI{sup P560R}, which induced autophagy and exhibited dominant negative effects. Further studies indicated that PRKCI knockdown–mediated autophagy was associated with the inactivation of phosphatidylinositol 3-kinase alpha/AKT–mammalian target of rapamycin (PIK3CA/AKT–MTOR) signaling. These data underscore the importance of PRKCI in the regulation of autophagy. Moreover, the finding may be useful in treating PRKCI-overexpressing carcinomas that are characterized by increased levels of autophagy. - Highlights: • The atypical protein kinase C iota isoform (PRKCI) is a human oncogene. • PRKCI overexpression impairs functional autophagy in U2OS cells. • It reduces LC3B-II levels and weakens SQSTM1 and polyQ80 aggregate degradation. • PRKCI knockdown has the opposite effect. • The effect of PRKCI knockdown is related to PIK3CA/AKT–MTOR signaling inactivation.

  15. The Potsdam Parallel Ice Sheet Model (PISM-PIK – Part 1: Model description

    Directory of Open Access Journals (Sweden)

    R. Winkelmann

    2011-09-01

    Full Text Available We present the Potsdam Parallel Ice Sheet Model (PISM-PIK, developed at the Potsdam Institute for Climate Impact Research to be used for simulations of large-scale ice sheet-shelf systems. It is derived from the Parallel Ice Sheet Model (Bueler and Brown, 2009. Velocities are calculated by superposition of two shallow stress balance approximations within the entire ice covered region: the shallow ice approximation (SIA is dominant in grounded regions and accounts for shear deformation parallel to the geoid. The plug-flow type shallow shelf approximation (SSA dominates the velocity field in ice shelf regions and serves as a basal sliding velocity in grounded regions. Ice streams can be identified diagnostically as regions with a significant contribution of membrane stresses to the local momentum balance. All lateral boundaries in PISM-PIK are free to evolve, including the grounding line and ice fronts. Ice shelf margins in particular are modeled using Neumann boundary conditions for the SSA equations, reflecting a hydrostatic stress imbalance along the vertical calving face. The ice front position is modeled using a subgrid-scale representation of calving front motion (Albrecht et al., 2011 and a physically-motivated calving law based on horizontal spreading rates. The model is tested in experiments from the Marine Ice Sheet Model Intercomparison Project (MISMIP. A dynamic equilibrium simulation of Antarctica under present-day conditions is presented in Martin et al. (2011.

  16. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies

    Science.gov (United States)

    Hanker, Ariella B.; Pfefferle, Adam D.; Balko, Justin M.; Kuba, María Gabriela; Young, Christian D.; Sánchez, Violeta; Sutton, Cammie R.; Cheng, Hailing; Perou, Charles M.; Cook, Rebecca S.; Arteaga, Carlos L.

    2013-01-01

    Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2+/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2+/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2+/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CAH1047R accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies. PMID:23940356

  17. PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors.

    Science.gov (United States)

    Dueñas, Marta; Martínez-Fernández, Mónica; García-Escudero, Ramón; Villacampa, Felipe; Marqués, Miriam; Saiz-Ladera, Cristina; Duarte, José; Martínez, Victor; Gómez, M José; Martín, M Luisa; Fernández, Manoli; Castellano, Daniel; Real, Francisco X; Rodriguez-Peralto, Jose L; De La Rosa, Federico; Paramio, Jesús M

    2015-07-01

    Bladder cancer (BC) is the fifth most common cancer in the world, being the non-muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment. © 2013 Wiley Periodicals, Inc.

  18. Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer.

    Science.gov (United States)

    Arsenic, Ruza; Treue, Denise; Lehmann, Annika; Hummel, Michael; Dietel, Manfred; Denkert, Carsten; Budczies, Jan

    2015-01-01

    Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PIK3CA, is one of the most frequently mutated genes in breast cancer, and the mutation status of PIK3CA has clinical relevance related to response to therapy. The aim of our study was to investigate the mutation status of PIK3CA gene and to evaluate the concordance between NGS and SGS for the most important hotspot regions in exon 9 and 20, to investigate additional hotspots outside of these exons using NGS, and to correlate the PIK3CA mutation status with the clinicopathological characteristics of the cohort. In the current study, next-generation sequencing (NGS) and Sanger Sequencing (SGS) was used for the mutational analysis of PIK3CA in 186 breast carcinomas. Altogether, 64 tumors had PIK3CA mutations, 55 of these mutations occurred in exons 9 and 20. Out of these 55 mutations, 52 could also be detected by Sanger sequencing resulting in a concordance of 98.4 % between the two sequencing methods. The three mutations missed by SGS had low variant frequencies below 10 %. Additionally, 4.8 % of the tumors had mutations in exons 1, 4, 7, and 13 of PIK3CA that were not detected by SGS. PIK3CA mutation status was significantly associated with hormone receptor-positivity, HER2-negativity, tumor grade, and lymph node involvement. However, there was no statistically significant association between the PIK3CA mutation status and overall survival. Based on our study, NGS is recommended as follows: 1) for correctly assessing the mutation status of PIK3CA in breast cancer, especially for cases with low tumor content, 2) for the detection of subclonal mutations, and 3) for simultaneous mutation detection in multiple exons.

  19. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG Study.

    Directory of Open Access Journals (Sweden)

    George Papaxoinis

    Full Text Available The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9 and kinase (exon 20 domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR. PIK3CA mutations were analyzed by Sanger sequencing (exon 20 and qPCR (exon 9 (Sanger/qPCR mutations. In 610 cases, next generation sequencing (NGS PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC were analyzed in luminal tumors (ER and/or PgR positive, molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive and hormone receptor (ER/PgR/AR negative tumors.PIK3CA mutations were detected in 235/1008 tumors (23% with Sanger/qPCR and in 149/610 tumors (24% with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82. Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel, while luminal B with kinase domain mutations (PIK3CAkin. The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004. Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer

  20. {pi}K interaction effects on CP violation in B (right arrow) K {pi} {sup + }{pi}{ sup -} decays.

    Energy Technology Data Exchange (ETDEWEB)

    Loiseau, B.; El-Bennich, B.; Furman, A.; Kaminski, R.; Lesniak, L.; Moussallam, B.; Physics; LPNHE, Univ. Pierre et Marie Curie; The Henryk Niewodniczanski Inst. of Nucler Physics; IPN, CNRS/Univ. Paris; ul.Bronowicka 85/26

    2009-04-30

    The authors apply QCD factorization to the quasi two-body B {yields} (K{pi}){pi} decays where the (K{pi})-pair effective mass is limited to 1.8 GeV. Our strong interaction phases constrained by theory and {pi}K experimental data yield useful information for studies of CP violation.

  1. EGFR gene copy number predicts response to anti-EGFR treatment in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer.

    Science.gov (United States)

    Ålgars, Annika; Sundström, Jari; Lintunen, Minnamaija; Jokilehto, Terhi; Kytölä, Soili; Kaare, Milja; Vainionpää, Reetta; Orpana, Arto; Österlund, Pia; Ristimäki, Ari; Carpen, Olli; Ristamäki, Raija

    2017-02-15

    Anti-EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti-EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti-EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses. EGFR GCN was analysed by EGFR immunohistochemistry guided automated silver in situ hybridisation. Increased EGFR GCN (≥4.0) predicted a better response and prolonged progression free survival in anti-EGFR treated RAS/BRAF/PIK3CA wild type patients (Log-rank test, p = 0.0004). In contrast, survival of RAS/BRAF/PIK3CA wild type, EGFR GCN below 4.0 patients did not differ from patients with mutant RAS, BRAF or PIK3CA. Our study indicates that EGFR GCN predicts anti-EGFR treatment efficacy in patients with RAS/BRAF/PIK3CA wt metastatic CRC. Tumours with EGFR GCN below 4.0 appear to be as refractory to anti-EGFR treatment as tumours with mutation in any of the RAS/RAF/PIK3CA pathway genes. © 2016 UICC.

  2. High-density ultracold neutron sources for the WWR-M and PIK reactors

    Energy Technology Data Exchange (ETDEWEB)

    Serebrov, A. P., E-mail: serebrov@pnpi.spb.ru; Fomin, A. K.; Kharitonov, A. G.; Lyamkin, V. A.; Prudnikov, D. V.; Ivanov, S. A.; Erykalov, A. N.; Onegin, M. S. [National Research Centre “Kurchatov Institute”, Petersburg Nuclear Physics Institute (Russian Federation); Gridnev, K. A. [St. Petersburg State University (Russian Federation)

    2016-01-15

    It is proposed to equip the PIK and WWR-M research reactors at the Petersburg Nuclear Physics Institute (PNPI) with high-density ultracold neutron (UCN) sources, where UCNs will be obtained based on the effect of their accumulation in superfluid helium (due to the specific features of this quantum fluid). The maximum UCN storage time in superfluid helium is obtained at temperatures on the order of 1 K. These sources are expected to yield UCN densities of 10{sup 3}–10{sup 4} cm{sup –3}, i.e., approximately three orders of magnitude higher than the density from existing UCN sources throughout the world. The development of highest intensity UCN sources will make PNPI an international center of fundamental UCN research.

  3. Prognostic role of KRAS, NRAS, BRAF and PIK3CA mutations in advanced colorectal cancer.

    Science.gov (United States)

    Foltran, Luisa; De Maglio, Giovanna; Pella, Nicoletta; Ermacora, Paola; Aprile, Giuseppe; Masiero, Elena; Giovannoni, Mariella; Iaiza, Emiliana; Cardellino, Giovanni Gerardo; Lutrino, Stefania Eufemia; Mazzer, Micol; Giangreco, Manuela; Pisa, Federica Edith; Pizzolitto, Stefano; Fasola, Gianpiero

    2015-01-01

    To explore the prognostic value of extended mutational profiling for metastatic colorectal cancer (mCRC). We retrospectively reviewed survival results of 194 mCRC patients that were assigned to four molecular subgroups: BRAF mutated; KRAS mutated codons 12-13 only; any of KRAS codons 61-146, PIK3CA or NRAS mutations and all wild-type. Point mutations were investigated by pyrosequencing. BRAF (5.2%) and KRAS 12-13 (31.9%) mutations were associated with poorer survival (HR 2.8 and 1.76, respectively). Presenting with right-sided colon cancer, not resected primary tumor, WBC >10 × 10(9)/l, receiving less chemotherapy or no bevacizumab were all associated with inferior outcome. The all-wild-type subgroup (39.2%) reported the longest survival. Extended mutational profile combined with clinical factors may impact on survival in mCRC.

  4. Dual HER2\\PIK3CA targeting overcomes single-agent acquired resistance in HER2 amplified uterine serous carcinoma cell lines in vitro and in vivo

    Science.gov (United States)

    Lopez, Salvatore; Cocco, Emiliano; Black, Jonathan; Bellone, Stefania; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Schwab, Carlton L.; English, Diana P.; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; Terranova, Corrado; Angioli, Roberto; Santin, Alessandro D.

    2015-01-01

    HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC), and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA mutated and PIK3CA-wild type HER2/neu amplified USC cell lines. Cell viability and cell cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC-xenografts. We found both single agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long lasting growth inhibition in both USC xenografts when compared to single agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA or pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild type PIK3CA resistant to chemotherapy. PMID:26333383

  5. PIK3CA C2 domain deletions hyperactivate phosphoinositide 3-kinase (PI3K), generate oncogene dependence and are exquisitely sensitive to PI3Kα inhibitors.

    Science.gov (United States)

    Croessmann, Sarah; Sheehan, Jonathan H; Lee, Kyung-Min; Sliwoski, Gregory R; He, Jie; Nagy, Rebecca J; Riddle, David A; Mayer, Ingrid A; Balko, Justin M; Lanman, Richard B; Miller, Vincent; Cantley, Lewis C; Meiler, Jens; Arteaga, Carlos L

    2017-12-28

    We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER+ breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446-460 of the C2 domain, suggesting these residues are critical for p110α function.   Design: A computational structural model of PIK3CAdelP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and PIK3CAH450_P458del were used to understand the phenotype of C2 domain deletions.  Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Co-immunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared to wild type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor-independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK and S6 compared to parental MCF10A cells. All these changes were ablated by alpelisib treatment. C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Copyright ©2017, American Association for Cancer Research.

  6. Unilateral vestibular schwannoma and meningiomas in a patient with PIK3CA-related segmental overgrowth: Co-occurrence of mosaicism for 2 rare disorders.

    Science.gov (United States)

    Mills, J R; Moyer, A M; Kipp, B R; Poplawski, A B; Messiaen, L M; Babovic-Vuksanovic, D

    2018-01-01

    A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. These results suggest that the patient has 2 different mosaic disorders, NF2 and PIK3CA-related overgrowth. The PIK3CA mutation was also present in the VS. Confirmation of the clinical diagnosis of mosaic NF2 in this patient has implications for monitoring and highlights the possibility of co-occurrence of mosaicism for multiple rare disorders in a single patient. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Analytical complex at the PIK reactor for studying the supra-atomic structure and dynamics of materials by neutron scattering

    Energy Technology Data Exchange (ETDEWEB)

    Lebedev, V. M., E-mail: lebedev@pnpi.spb.ru; Lebedev, V. T.; Ivanova, I. N.; Orlova, D. N. [Russian Academy of Sciences, St. Petersburg Nuclear Physics Institute (Russian Federation)

    2011-12-15

    A project of the center for studying reactor materials and solving problems of materials science is presented which will be equipped with the following neutron instruments: a small-angle Membrana diffractometer, a spin-echo spectrometer, and a time-of-flight spectrometer. It is proposed to irradiate materials in the PIK reactor core and use neutron-scattering tools to analyze the structure and dynamics of these materials and investigate radiative defects in the complete experimental cycle (initial material-irradiation-strength tests, thermal loads, and other effects) using materials science techniques.

  8. Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia.

    Science.gov (United States)

    Palomba, Grazia; Colombino, Maria; Contu, Antonio; Massidda, Bruno; Baldino, Giovanni; Pazzola, Antonio; Ionta, MariaTeresa; Capelli, Francesca; Trova, Vittorio; Sedda, Tito; Sanna, Giovanni; Tanda, Francesco; Budroni, Mario; Palmieri, Giuseppe; Cossu, Antonio; Contu, Marta; Cuccu, Angelo; Farris, Antonio; Macciò, Antonio; Mameli, Giuseppe; Olmeo, Nina; Ortu, Salvatore; Petretto, Elisabetta; Pusceddu, Valeria; Virdis, Luciano

    2012-08-29

    Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. Overall, KRAS tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation in BRAF gene; PIK3CA was found mutated in 67 (17%) patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern vs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. Our findings support the hypothesis that differences in patients' origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

  9. Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia

    Directory of Open Access Journals (Sweden)

    Palomba Grazia

    2012-08-01

    Full Text Available Abstract Background Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. Methods From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478 were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. Results Overall, KRAS tumour mutation rate was 30% (145/478 positive cases. Distribution of mutation carriers was surprisingly different within the island: 87/204 (43% in North Sardinia vs. 58/274 (21% in Middle-South Sardinia (pBRAF gene; PIK3CA was found mutated in 67 (17% patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10% cases from northern vs. 48/201 (24% cases from central-southern island (pKRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. Conclusions Our findings support the hypothesis that differences in patients’ origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

  10. Molecular and Functional Characterization of Three Different Postzygotic Mutations in PIK3CA-Related Overgrowth Spectrum (PROS Patients: Effects on PI3K/AKT/mTOR Signaling and Sensitivity to PIK3 Inhibitors.

    Directory of Open Access Journals (Sweden)

    Daria C Loconte

    Full Text Available PIK3CA-related overgrowth spectrum (PROS include a group of disorders that affect only the terminal portion of a limb, such as type I macrodactyly, and conditions like fibroadipose overgrowth (FAO, megalencephaly-capillary malformation (MCAP syndrome, congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES syndrome and Hemihyperplasia Multiple Lipomatosis (HHML. Heterozygous postzygotic PIK3CA mutations are frequently identified in these syndromes, while timing and tissue specificity of the mutational event are likely responsible for the extreme phenotypic variability observed.We carried out a combination of Sanger sequencing and targeted deep sequencing of genes involved in the PI3K/AKT/mTOR pathway in three patients (1 MCAP and 2 FAO to identify causative mutations, and performed immunoblot analyses to assay the phosphorylation status of AKT and P70S6K in affected dermal fibroblasts. In addition, we evaluated their ability to grow in the absence of serum and their response to the PI3K inhibitors wortmannin and LY294002 in vitro.Our data indicate that patients' cells showed constitutive activation of the PI3K/Akt pathway. Of note, PI3K pharmacological blockade resulted in a significant reduction of the proliferation rate in culture, suggesting that inhibition of PI3K might prove beneficial in future therapies for PROS patients.

  11. Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin

    Science.gov (United States)

    Cufí, Sílvia; Corominas-Faja, Bruna; Lopez-Bonet, Eugeni; Bonavia, Rosa; Pernas, Sonia; López, Isabel álvarez; Dorca, Joan; Martínez, Susana; López, Norberto Batista; Fernández, Severina Domínguez; Cuyàs, Elisabet; Visa, Joana; Rodríguez-Gallego, Esther; Quirantes-Piné, Rosa; Segura-Carretero, Antonio; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A.

    2013-01-01

    Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing

  12. Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CA (H1047R) in HER2/ER-positive breast cancer.

    Science.gov (United States)

    Cheng, Feixiong; Zhao, Junfei; Hanker, Ariella B; Brewer, Monica Red; Arteaga, Carlos L; Zhao, Zhongming

    2016-12-01

    Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti-estrogen receptor (ER) agents in HER2 or ER positive (HER2(+)/ER(+)) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2(+)/ER(+) breast cancer would provide novel insights into elucidating resistance to anti-HER2/ER therapies. In this study, we systematically investigated the biological consequences of PIK3CA (H1047R) in HER2(+)/ER(+) breast cancer by uniquely incorporating mRNA transcriptomic data from The Cancer Genome Atlas and proteomic data from reverse-phase protein arrays. Our integrative bioinformatics analyses revealed that several important pathways such as STAT3 and VEGF/hypoxia were selectively altered by PIK3CA (H1047R) in HER2(+)/ER(+) breast cancer. Protein differential expression analysis indicated that an elevated eIF4G might promote tumor angiogenesis and growth via regulation of the hypoxia-activated switch in HER2(+) PIK3CA (H1047R) breast cancer. We observed hypo-phosphorylation of EGFR in HER2(+) PIK3CA (H1047R) breast cancer versus HER2(+)PIK3CA(wild-type) (PIK3CA (WT)). In addition, ER and PIK3CA (H1047R) might cooperate to activate STAT3, MAPK, AKT, and Hippo pathways in ER(+) PIK3CA (H1047R) breast cancer. A higher YAPpS127 level was observed in ER(+) PIK3CA (H1047R) patients than that in an ER(+) PIK3CA (WT) subgroup. By examining breast cancer cell lines having both microarray gene expression and drug treatment data from the Genomics of Drug Sensitivity in Cancer and the Stand Up to Cancer datasets, we found that the elevated YAP1 mRNA expression was associated with the resistance of BCL-2 family inhibitors, but with the sensitivity to MEK/MAPK inhibitors in breast cancer cells. In summary, these findings shed light on the functional consequences of PIK3CA (H1047R)-driven breast

  13. Mutational analysis of PIK3CA, JAK2, BRAF, FOXL2, IDH1, AKT1 and EZH2 oncogenes in sarcomas.

    Science.gov (United States)

    Je, Eun M; An, Chang H; Yoo, Nam J; Lee, Sug H

    2012-08-01

    Recent studies have revealed several recurrent mutations in oncogenes that could not only be underlying mechanisms of tumorigenesis, but also be potential targets for cancer therapies. Compared to carcinomas, genetic alterations of sarcomas are relatively unknown. To see whether recurrent oncogenes discovered in non-sarcomatous malignancies are present in sarcomas as well, we analyzed oncogenes with known mutations in various types of sarcomas. We performed mutational analysis of recurrent mutation sites of PIK3CA (exons 9 and 20), JAK2 (exon 14), BRAF (exon 15), FOXL2 (exon 1), IDH1 (exon 4), AKT1 (exon 3), and EZH2 (exon 16) genes in 108 sarcomas by single- strand conformation polymorphism and DNA sequencing. The sarcomas consisted of malignant fibrous histiocytomas, rhabdomyosarcomas, osteosarcomas, malignant peripheral nerve sheath tumors, leiomyosarcomas, synovial sarcomas, liposarcomas, angiosarcomas, chondrosarcomas, and Ewing sarcomas. Overall, we detected the two PIK3CA mutations and one JAK2 mutation (total: 3/108: 2.8%). Two rhabdomyosarcomas (16.7%) and one angiosarcoma (16.7%) harbored the mutations, whereas other sarcomas harbored none. The PIK3CA mutations were novel missense mutations that had not been detected in other cancers. The JAK2 mutation was an intron mutation. This study demonstrated that the somatic mutations of PIK3CA and JAK2 occurred in a small fraction of the sarcomas and that these mutations may not play a principal role in the development of sarcomas. © 2012 The Authors APMIS © 2012 APMIS.

  14. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer

    NARCIS (Netherlands)

    Majewski, Ian J; Nuciforo, Paolo; Mittempergher, Lorenza; Bosma, Astrid J; Eidtmann, Holger; Holmes, Eileen; Sotiriou, Christos; Fumagalli, Debora; Jimenez, Jose; Aura, Claudia; Prudkin, Ludmila; Díaz-Delgado, Maria Carmen; de la Peña, Lorena; Loi, Sherene; Ellis, Catherine; Schultz, Nikolaus; de Azambuja, Evandro; Harbeck, Nadia; Piccart-Gebhart, Martine; Bernards, René|info:eu-repo/dai/nl/070416990; Baselga, José

    2015-01-01

    PURPOSE: We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer. PATIENTS AND METHODS:

  15. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

    Directory of Open Access Journals (Sweden)

    Schmitt Fernando

    2008-09-01

    Full Text Available Abstract Background BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC. In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP, MLH1 methylation and microsatellite instability (MSI. We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Methods Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. Results KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112, but statistically different from what is found in microsatellite stable (MSS tumours (P = 0.0191. Conclusion Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal

  16. Relative quantification of PIK3CA gene expression level in fine-needle aspiration biopsy thyroid specimens collected from patients with papillary thyroid carcinoma and non-toxic goitre by real-time RT-PCR

    Directory of Open Access Journals (Sweden)

    Wojciechowska-Durczyńska Katarzyna

    2010-08-01

    Full Text Available Abstract Background Recent studies have shown that the phosphatidylinositol 3-kinase (PI3K signaling pathway is important regulator of many cellular events, including apoptosis, proliferation and motility. PI3K pathway alterations (PIK3CA gene mutations and/or amplification have been observed in various human tumours. In the majority of diagnosed cases, mutations are localized in one of the three "hot spots" in the gene, responsible for coding catalytic subunit α of class I PI3K (PIK3CA. Mutations and amplification of PIK3CA gene are characteristic for thyroid cancer, as well. Methods The aim of our study was to examine a gene expression level of PIK3CA in fine-needle aspiration biopsy (FNAB thyroid specimens in two types of thyroid lesions, papillary thyroid carcinoma (PTC and non-toxic goitre (NTG. Following conventional cytological examination, 42 thyroid FNAB specimens, received from patients with PTC (n = 20 and NTG (n = 22, were quantitatively evaluated regarding PIK3CA expression level by real-time PCR in the ABI PRISM® 7500 Sequence Detection System. Results Significantly higher expression level (RQ of PIK3CA in PTC group has been noted in comparison with NTG group (p Conclusion These observations may suggest role of PIK3CA alterations in PTC carcinogenesis.

  17. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors

    Directory of Open Access Journals (Sweden)

    Mitrou Panagiota N

    2011-04-01

    Full Text Available Abstract Background The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. Methods 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Results Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05. PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04. Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02 and poor differentiation (p PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55. Conclusion These data demonstrated the frequent occurrence (34.9% of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.

  18. PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.

    Science.gov (United States)

    Silva, Jillian M; Deuker, Marian M; Baguley, Bruce C; McMahon, Martin

    2017-05-01

    Malignant conversion of BRAF- or NRAS-mutated melanocytes into melanoma cells can be promoted by PI3'-lipid signaling. However, the mechanism by which PI3'-lipid signaling cooperates with mutationally activated BRAF or NRAS has not been adequately explored. Using human NRAS- or BRAF-mutated melanoma cells that co-express mutationally activated PIK3CA, we explored the contribution of PI3'-lipid signaling to cell proliferation. Despite mutational activation of PIK3CA, melanoma cells were more sensitive to the biochemical and antiproliferative effects of broader spectrum PI3K inhibitors than to an α-selective PI3K inhibitor. Combined pharmacological inhibition of MEK1/2 and PI3K signaling elicited more potent antiproliferative effects and greater inhibition of the cell division cycle compared to single-agent inhibition of either pathway alone. Analysis of signaling downstream of MEK1/2 or PI3K revealed that these pathways cooperate to regulate cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Although PI3K inhibition resulted in cytostatic effects on xenografted NRASQ61H /PIK3CAH1047R melanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression. This study provides insights as to how mutationally activated PIK3CA acts in concert with MEK1/2 signaling to cooperatively regulate mTORC1/2 to sustain PIK3CA-mutated melanoma proliferation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Ernst Julius Öpik's (1916) note on the theory of explosion cratering on the Moon's surface—The complex case of a long-overlooked benchmark paper

    Science.gov (United States)

    Racki, Grzegorz; Koeberl, Christian; Viik, Tõnu; Jagt-Yazykova, Elena A.; Jagt, John W. M.

    2014-10-01

    High-velocity impact as a common phenomenon in planetary evolution was ignored until well into the twentieth century, mostly because of inadequate understanding of cratering processes. An eight-page note, published in Russian by the young Ernst Julius Öpik, a great Estonian astronomer, was among the key selenological papers, but due to the language barrier, it was barely known and mostly incorrectly cited. This particular paper is here intended to serve as an explanatory supplement to an English translation of Öpik's article, but also to document an early stage in our understanding of cratering. First, we outline the historical-biographical background of this benchmark paper, and second, a comprehensive discussion of its merits is presented, from past and present perspectives alike. In his theoretical research, Öpik analyzed the explosive formation of craters numerically, albeit in a very simple way. For the first time, he approximated relationships among minimal meteorite size, impact energy, and crater diameter; this scaling focused solely on the gravitational energy of excavating the crater (a "useful" working approach). This initial physical model, with a rational mechanical basis, was developed in a series of papers up to 1961. Öpik should certainly be viewed as the founder of the numerical simulation approach in planetary sciences. In addition, the present note also briefly describes Nikolai A. Morozov as a remarkable man, a forgotten Russian scientist and, surprisingly, the true initiator of Öpik's explosive impact theory. In fact, already between 1909 and 1911, Morozov probably was the first to consider conclusively that explosion craters would be circular, bowl-shaped depressions even when formed under different impact angles.

  20. Investigating the Structure and Dynamics of the PIK3CA Wild-Type and H1047R Oncogenic Mutant

    Science.gov (United States)

    Pavlaki, Maria; Lazani, Vasiliki; Christoforidis, Savvas; Agianian, Bogos; Cournia, Zoe

    2014-01-01

    The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kα inhibitors that exploit the altered mutant conformation. PMID:25340423

  1. Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients.

    Science.gov (United States)

    Nakayama, Izuma; Shinozaki, Eiji; Matsushima, Tomohiro; Wakatsuki, Takeru; Ogura, Mariko; Ichimura, Takashi; Ozaka, Masato; Takahari, Daisuke; Suenaga, Mitsukuni; Chin, Keisho; Mizunuma, Nobuyuki; Yamaguchi, Kensei

    2017-01-09

    After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer. Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status. The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab. Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type

  2. mTOR complex-2 stimulates acetyl-CoA and de novo lipogenesis through ATP citrate lyase in HER2/PIK3CA-hyperactive breast cancer.

    Science.gov (United States)

    Chen, Yaqing; Qian, Jianchang; He, Qun; Zhao, Hui; Toral-Barza, Lourdes; Shi, Celine; Zhang, Xuesai; Wu, Jiang; Yu, Ker

    2016-05-03

    The mechanistic target of rapamycin (mTOR) is a major regulator of cell growth and is frequently dysregulated in cancer. While mTOR complex-1 (mTORC1) is a validated cancer target, the role of mTOR complex-2 (mTORC2) remains less defined. Here, we reveal mTORC2 as a critical regulator of breast cancer metabolism. We showed that hyperphosphorylation in ATP citrate lyase (ACL) occurs frequently in human breast tumors and correlates well with HER2+ and/or PIK3CA-mutant (HER2+/PIK3CAmut) status in breast tumor cell lines. In HER2+/PIK3CAmut cells, mTORC2 controls Ser-455 phosphorylation of ACL thereby promoting acetyl-CoA production, de novo lipogenesis and mitochondrial physiology, all of which were inhibited by an mTORC1/mTORC2 kinase inhibitor (mTOR-KI) or cellular depletion of mTORC2 or ACL. mTOR-KI but not rapamycin blocked the IGF-1-induced ACL phosphorylation and glucose to lipid conversion. Depletion of mTORC2 but not mTORC1 specifically inhibited the ACL-dependent acetyl-CoA production. In the HER2+/PIK3CAmut MDA361, MDA453, BT-474 and T47D cells, depletion of mTORC2 or ACL led to growth inhibition and mitochondrial hyperpolarization, which were partially rescued by an alternate source of acetyl-CoA. These same changes were not apparent in mTORC2- or ACL-depleted HER2-/PIK3CAwt MDA231 and HCC1806 cells, highlighting a differential dependence of mTORC2-ACL for survival in these two cell types. Moreover, ACL Ser-455 mutants S455E (phosphomimetic) and S455A (non-phosphorylatable) each increased or decreased, respectively, the acetyl-CoA production, mitochondrial homeostasis and survival in ACL-depleted MDA453 cells. These studies define a new and rapamycin-resistant mechanism of mTORC2-ACL in lipogenesis and acetyl-CoA biology and provide a rationale for targeting of mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.

  3. Vahur Kraft soovitab segadused unustada / Vahur Kraft ; interv. Argo Ideon

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2000-01-01

    Eesti Panga president ei näe vajadust lasta riigikontrolli ametnikke uuesti keskpanka. Kommenteerivad: Juhan Parts, Villu Reiljan, Mati Meos ja Kalle Jürgenson. Parlamendisaadik (V. Reiljan, K. Jürgenson)

  4. Eesti plaanib tankiostu / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Kaitseminister Jaak Aaviksoo tutvustas valmivat kaitseväe arengukava aastani 2018, mille järgi olulisim on luure- ja seirevõime ning sidesüsteemide areng. Kava näeb ette ka võimaluse osta tanke või jalaväe lahingumasinaid, transpordikoptereid ja keskmaa õhutõrjesüsteeme

  5. Head uut euroaastat? / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2006-01-01

    Nordea Panga Eesti filiaali juhatuse esimees käsitleb eurole üleminekuga seotud probleeme ning on seisukohal, et kui Eestil ei õnnestu sise- või välispoliitiliste tingimuste tõttu 2007. aasta 1. jaanuaril eurot kasutusele võtta, võiks võtta euro vabatahtlikku kasutusse igapäevastes tehingutes

  6. Mutations of KRAS, NRAS, BRAF, EGFR, and PIK3CA genes in urachal carcinoma: Occurence and prognostic significance.

    Science.gov (United States)

    Módos, Orsolya; Reis, Henning; Niedworok, Christian; Rübben, Herbert; Szendröi, Attila; Szász, Marcell A; Tímár, József; Baghy, Kornélia; Kovalszky, Ilona; Golabek, Tomasz; Chlosta, Piotr; Okon, Krzysztof; Peyronnet, Benoit; Mathieu, Romain; Shariat, Shahrokh F; Hollósi, Péter; Nyirády, Péter; Szarvas, Tibor

    2016-06-28

    Targeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma (UrC). The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer. Mutational hot-spots of selected genes were tested in 22 UrC samples by pyrosequencing. Mutational patterns were compared to those published for colorectal and urothelial cancers. Furthermore, we sought correlations between mutations and clinicopathological and follow-up data. We found 11 mutations in 10 of 22 (45%) patients. The most frequently mutated gene was KRAS (27%) followed by BRAF (18%) and NRAS (5%), while no mutations were detected in the EGFR and PIK3CA genes. No correlation was found between the mutation status and clinicopathological parameters (Sheldon/Mayo stage, tumor grade, metastases). Furthermore, none of the mutations correlated with progression-free or overall survival. The mutation pattern of UrC is more similar to colorectal than to urothelial cancer. However, the mutation characteristics of UrC seems to be unique suggesting that clinical decision-making for UrC cannot be simply adopted from urothelial or colorectal carcinoma. The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC.

  7. PIK3CA and TP53 gene mutations in human breast cancer tumors frequently detected by ion torrent DNA sequencing.

    Science.gov (United States)

    Bai, Xusheng; Zhang, Enke; Ye, Hua; Nandakumar, Vijayalakshmi; Wang, Zhuo; Chen, Lihong; Tang, Chuanning; Li, Jianhui; Li, Huijin; Zhang, Wei; Han, Wei; Lou, Feng; Zhang, Dandan; Sun, Hong; Dong, Haichao; Zhang, Guangchun; Liu, Zhiyuan; Dong, Zhishou; Guo, Baishuai; Yan, He; Yan, Chaowei; Wang, Lu; Su, Ziyi; Li, Yangyang; Jones, Lindsey; Huang, Xue F; Chen, Si-Yi; Gao, Jinglong

    2014-01-01

    Breast cancer is the most common malignancy and the leading cause of cancer deaths in women worldwide. While specific genetic mutations have been linked to 5-10% of breast cancer cases, other environmental and epigenetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive breast cancer molecular profile is needed to develop more effective target therapies. Until recently, identifying genetic cancer mutations via personalized DNA sequencing was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 105 human breast cancer samples. The sequencing analysis revealed missense mutations in PIK3CA, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations.

  8. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.

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    Lucie C Kompier

    Full Text Available BACKGROUND: Fifty percent of patients with muscle-invasive bladder cancer (MI-BC die from their disease and current chemotherapy treatment only marginally increases survival. Novel therapies targeting receptor tyrosine kinases or activated oncogenes may improve outcome. Hence, it is necessary to stratify patients based on mutations in relevant oncogenes. Patients with non-muscle-invasive bladder cancer (NMI-BC have excellent survival, however two-thirds develop recurrences. Tumor specific mutations can be used to detect recurrences in urine assays, presenting a more patient-friendly diagnostic procedure than cystoscopy. METHODOLOGY/PRINCIPAL FINDINGS: To address these issues, we developed a mutation assay for the simultaneous detection of 19 possible mutations in the HRAS, KRAS, and NRAS genes. With this assay and mutation assays for the FGFR3 and PIK3CA oncogenes, we screened primary bladder tumors of 257 patients and 184 recurrences from 54 patients. Additionally, in primary tumors p53 expression was obtained by immunohistochemistry. Of primary tumors 64% were mutant for FGFR3, 11% for RAS, 24% for PIK3CA, and 26% for p53. FGFR3 mutations were mutually exclusive with RAS mutations (p = 0.001 and co-occurred with PIK3CA mutations (p = 0.016. P53 overexpression was mutually exclusive with PIK3CA and FGFR3 mutations (p≤0.029. Mutations in the RAS and PIK3CA genes were not predictors for recurrence-free, progression-free and disease-specific survival. In patients presenting with NMI-BC grade 3 and MI-BC, 33 and 36% of the primary tumors were mutant. In patients with low-grade NMI-BC, 88% of the primary tumors carried a mutation and 88% of the recurrences were mutant. CONCLUSIONS/SIGNIFICANCE: The mutation assays present a companion diagnostic to define patients for targeted therapies. In addition, the assays are a potential biomarker to detect recurrences during surveillance. We showed that 88% of patients presenting with low-grade NMI

  9. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.

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    Kompier, Lucie C; Lurkin, Irene; van der Aa, Madelon N M; van Rhijn, Bas W G; van der Kwast, Theo H; Zwarthoff, Ellen C

    2010-11-03

    Fifty percent of patients with muscle-invasive bladder cancer (MI-BC) die from their disease and current chemotherapy treatment only marginally increases survival. Novel therapies targeting receptor tyrosine kinases or activated oncogenes may improve outcome. Hence, it is necessary to stratify patients based on mutations in relevant oncogenes. Patients with non-muscle-invasive bladder cancer (NMI-BC) have excellent survival, however two-thirds develop recurrences. Tumor specific mutations can be used to detect recurrences in urine assays, presenting a more patient-friendly diagnostic procedure than cystoscopy. To address these issues, we developed a mutation assay for the simultaneous detection of 19 possible mutations in the HRAS, KRAS, and NRAS genes. With this assay and mutation assays for the FGFR3 and PIK3CA oncogenes, we screened primary bladder tumors of 257 patients and 184 recurrences from 54 patients. Additionally, in primary tumors p53 expression was obtained by immunohistochemistry. Of primary tumors 64% were mutant for FGFR3, 11% for RAS, 24% for PIK3CA, and 26% for p53. FGFR3 mutations were mutually exclusive with RAS mutations (p = 0.001) and co-occurred with PIK3CA mutations (p = 0.016). P53 overexpression was mutually exclusive with PIK3CA and FGFR3 mutations (p≤0.029). Mutations in the RAS and PIK3CA genes were not predictors for recurrence-free, progression-free and disease-specific survival. In patients presenting with NMI-BC grade 3 and MI-BC, 33 and 36% of the primary tumors were mutant. In patients with low-grade NMI-BC, 88% of the primary tumors carried a mutation and 88% of the recurrences were mutant. The mutation assays present a companion diagnostic to define patients for targeted therapies. In addition, the assays are a potential biomarker to detect recurrences during surveillance. We showed that 88% of patients presenting with low-grade NMI-BC are eligible for such a follow-up. This may contribute to a reduction in the number

  10. BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis.

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    Soo Kyung Nam

    Full Text Available Anti-EGFR antibody-based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC; despite this, several mutations--including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification--are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.KRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.Mutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%, 6 (3.1%, and 25 (13.1% cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6% and 16 (8.4% cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3% than KRAS wild type (6.9% (P = 0.020. In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively. In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004. When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7% CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%.KRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

  11. Mutations in FGFR3 and PIK3CA, singly or combined with RAS and AKT1, are associated with AKT but not with MAPK pathway activation in urothelial bladder cancer.

    Science.gov (United States)

    Juanpere, Nuria; Agell, Laia; Lorenzo, Marta; de Muga, Silvia; López-Vilaró, Laura; Murillo, Raquel; Mojal, Sergi; Serrano, Sergio; Lorente, José A; Lloreta, Josep; Hernández, Silvia

    2012-10-01

    Different members of the phosphoinositide 3 kinase--serine threonine protein kinase (PI3K-AKT) pathway are altered in bladder cancer. Fibroblast growth factor receptor 3 (FGFR3) mutations characterize the low-grade tumors, and RAS genes are mutated in approximately 13% of all bladder tumors. Interestingly, a percentage of bladder tumors have alterations in more than 1 PI3K-AKT or rat sarcoma viral oncogene homolog-RAF mitogen activated protein kinase (RAS-MAPK) pathway gene or their upstream regulators, but some combinations are mutually exclusive. We analyzed mutations in FGFR3, phosphoinositide 3 kinase catalytic alpha polypeptide (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) in 88 urothelial cell carcinomas and the immunohistochemical expression of phospho-v-akt murine thymoma viral oncogene homolog (AKT) and mitogen-activated protein kinase 1 and 2 (pERK1/2) in 80 and 77 urothelial cell carcinomas, respectively. Approximately 43% and 20.5% of tumors presented 1 and 2 mutated genes, respectively. FGFR3 mutations were more frequent alone, whereas PIK3CA mutations were associated with another mutated gene (FGFR3 and KRAS). Overall, mutated FGFR3 (FGFR3(mut)) and mutated FGFR3 (FGFR3(mut))-mutated PIK3CA (PIK3CA(mut)) genotypes were associated with low-grade bladder tumors and mutated PIK3CA (PIK3CA(mut))-mutated KRAS (KRAS(mut)) and mutated AKT1 (AKT1(mut)) were only present in high-grade tumors. There are no mutated FGFR3 (FGFR3(mut))-mutated RAS (RAS(mut)) nor mutated PIK3CA (PIK3CA(mut))-mutated AKT1 (AKT1(mut)) combinations. Fifty percent and 56% of tumors showed high levels of pAKT and pERK1/2, respectively. High levels of pAKT were associated with total mutations, FGFR3(mut), and PIK3CA(mut) tumors but not with tumor grade or stage. Wild-type tumors presented

  12. Frequency of mesenchymal-epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer.

    Science.gov (United States)

    Gonzalez-Angulo, Ana M; Chen, Huiqin; Karuturi, Meghan S; Chavez-MacGregor, Mariana; Tsavachidis, Spyrus; Meric-Bernstam, Funda; Do, Kim-Anh; Hortobagyi, Gabriel N; Thompson, Patricia A; Mills, Gordon B; Bondy, Melissa L; Blumenschein, George R

    2013-01-01

    The current study was conducted to determine the frequency and association between recurrence-free survival (RFS) and MET and catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevations in patients with early stage breast cancer. Tumor DNA was extracted from 971 formalin-fixed, paraffin-embedded early breast cancers for molecular inversion probes arrays. Data were segmented using the single-nucleotide polymorphism (SNP)-FASST2 segmentation algorithm. Copy number gains were called when the copy number of each segment was greater than 2.3 or 1.7, respectively. RFS was estimated by the Kaplan-Meier method. Cox proportional hazards models were fit to determine independent associations between copy number and RFS. Of the 971 tumors studied, 82 (8.44%) and 134 (13.8%) had an elevation of the MET or PIK3CA copy number, respectively, and 25.6% of tumors with a MET copy number elevation had a PIK3CA copy number elevation. Patients with either a MET or PI3KCA high copy number tended to have poorer prognostic features (larger tumor size, higher tumor grade, and hormone receptor negativity). Both MET and PIK3CA high copy numbers were more likely to occur in patients with triple receptor-negative disease (P = .019 and P number and MET normal/low copy number, respectively (P = .06) and 73.1%, and 82.3% for PIK3CA high copy number and PIK3CA normal/low copy number, respectively (P = .15). A high copy number for either gene was not found to be an independent predictor of RFS. A high copy number of MET or PIK3CA was found to be associated with poorer prognostic features and triple receptor-negative disease. Coamplification was frequent. Patients with tumors with high MET copy numbers tended to have a worse RFS. Copyright © 2012 American Cancer Society.

  13. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts

    Science.gov (United States)

    Li, S; Li, L; Zhu, Y; Huang, C; Qin, Y; Liu, H; Ren-Heidenreich, L; Shi, B; Ren, H; Chu, X; Kang, J; Wang, W; Xu, J; Tang, K; Yang, H; Zheng, Y; He, J; Yu, G; Liang, N

    2014-01-01

    Background: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study. Methods: Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis. Results: EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments. Conclusions: EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment. PMID:24743704

  14. Mutation analysis of CTNNB1 gene and the ras pathway genes KRAS, NRAS, BRAF, and PIK3CA in eyelid sebaceous carcinomas.

    Science.gov (United States)

    Kwon, Mi Jung; Nam, Eun Sook; Cho, Seong Jin; Park, Hye-Rim; Min, Soo Kee; Seo, Jinwon; Choe, Ji-Young

    2017-06-01

    Sebaceous carcinoma (SC) represents a rare, aggressive eyelid malignancy with poor prognosis and is a possible component of Muir-Torre syndrome. However, genetic features as driver mutations or potential therapeutic targets are not fully elucidated. Recent a few studies have shown that SCs have concurrently multiple mutations including RAS/RAF/MAPK and PI3K/Akt pathways via next-generation sequencing in western population. Because we recently demonstrated absence of KRAS mutations in Korean eyelid SCs, we extended our previous study to the analysis of NRAS, BRAF, PIK3CA, and CTNNB1 mutations, and the examination of related protein expressions in 15 eyelid SCs. Repeated molecular analysis by peptide nucleic acid-mediated PCR clamping method, PNA clamping-assisted fluorescence melting curve analysis, and direct sequencing revealed that all eyelid SCs had wild type alleles of NRAS, BRAF, and PIK3CA in hotspot exon locations. Only silent mutations in the CTNNB1 gene (p.Q61Q) were identified. Using immunohistochemistry and microsatellite instability analysis, they harbored all intact mismatch repair gene proteins with microsatellite stability. Membranous and cytoplasmic β-catenin staining was found in all tumors, whereas the one third of those tumors showed cyclin D1 overexpression, of which 40% and 80% showed p53 expression and p16 expression, respectively. The lack of KRAS, NRAS, BRAF, and PIK3CA mutation in our study may suggest that a subset of eyelid SCs is unlike that of eyelid SCs of western countries. The mismatch repair gene proteins and microsatellite instability analysis as a screening test for Muir-Torre syndrome may be limited in the Korean eyelid SCs. Copyright © 2017 Elsevier GmbH. All rights reserved.

  15. PIK3CG single nucleotide polymorphisms are associated with poor responsiveness to clopidogrel and increased risk of ischemia in patients with coronary heart disease.

    Science.gov (United States)

    Li, Ke-Cheng; Yu, Shu-Hong; Zhuge, Bao-Zhong

    2017-09-01

    This study explores the associations between PIK3CG single nucleotide polymorphisms (SNPs, rs1129293 and rs17398575) and patient responsiveness to clopidogrel to evaluate the risks of ischemia in patients with coronary heart disease (CHD). The study consisted of 513 CHD patients who received clopidogrel as part of antiplatelet therapy, after percutaneous coronary intervention. According to the patient responsiveness to clopidogrel, the subjects were assigned to either clopidogrel-resistant (CR) or clopidogrel-sensitive (CS) groups. CR group was determined by patients' platelet aggregation rate of ≥70% and poor responsiveness to clopidogrel, and CS group by patients' platelet aggregation rates of clopidogrel. Polymerase chain reaction using TaqMan probe was employed to detect PIK3CG polymorphism. Haplotype and linkage disequilibrium analyses were performed. Prognosis analysis was performed using the Kaplan-Meier curve. Significant difference was found in genotype and rs1129293 and rs17398575 allele frequency between the CR and CS groups. Haplotype analysis indicated that the frequency of TG allele was higher in the CR group compared with the CS group, and the frequency of CA allele was lower in the CR group compared with the CS group. Patients with rs1129293 CT + TT genotype and T allele, rs1129293 AG + GG genotype and G allele exhibited an increased CR risk. Logistic regression analysis determined hypertension history as an independent risk factor for CR. The Kaplan-Meier curve suggests that distribution curve of cumulative probability nonischemic events was different between patients with rs1129293 and rs17398575 alleles. Stable CHD patients with TT genotype of rs1129293 allele and GG genotype of rs17398575 allele showed poorer prognosis compared to those with other genotypes and patients with acute coronary syndromes. A positive correlation may exist between PIK3CG SNPs (rs1129293 and rs17398575) and patients with poor responsiveness to clopidogrel. These

  16. A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer.

    Science.gov (United States)

    Ma, Cynthia X; Suman, Vera; Goetz, Matthew P; Northfelt, Donald; Burkard, Mark E; Ademuyiwa, Foluso; Naughton, Michael; Margenthaler, Julie; Aft, Rebecca; Gray, Richard; Tevaarwerk, Amye; Wilke, Lee; Haddad, Tufia; Moynihan, Timothy; Loprinzi, Charles; Hieken, Tina; Barnell, Erica K; Skidmore, Zachary L; Feng, Yan-Yang; Krysiak, Kilannin; Hoog, Jeremy; Guo, Zhanfang; Nehring, Leslie; Wisinski, Kari B; Mardis, Elaine; Hagemann, Ian S; Vij, Kiran; Sanati, Souzan; Al-Kateb, Hussam; Griffith, Obi L; Griffith, Malachi; Doyle, Laurence; Erlichman, Charles; Ellis, Matthew J

    2017-09-05

    Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER(+)) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER(+) breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER(+) breast cancer.Experimental Design: Potential eligible patients with clinical stage II/III ER(+)/HER2(-) breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER(+) breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 1-10. ©2017 AACR. ©2017 American Association for Cancer Research.

  17. Promoter Variant of PIK3C3 Is Associated with Autoimmunity against Ro and Sm Epitopes in African-American Lupus Patients

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    Silvia N. Kariuki

    2010-01-01

    Full Text Available The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-α. Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR=2.24 (1.34–3.73, P=2.0×10−3]. This autoantibody profile was associated with higher serum IFN-α (P=7.6×10−6. In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P=2.0×10−5, which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients.

  18. Effective use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib to treat PIK3CA mutant ovarian cancer

    Science.gov (United States)

    Wang, Dong; Wang, Min; Jiang, Nan; Zhang, Yuan; Bian, Xing; Wang, Xiaoqing; Roberts, Thomas M.; Zhao, Jean J.; Liu, Pixu; Cheng, Hailing

    2016-01-01

    Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition. PMID:26909613

  19. Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

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    Minchul Kim

    2016-09-01

    Full Text Available ARID1A is frequently mutated in ovarian clear cell carcinoma (OCCC and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here, we established an in vitro model of OCCC by introducing ARID1A knockdown and mutant PIK3CA into a normal human ovarian epithelial cell line, resulting in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while the PIK3CA mutation releases RelA from IκB, leading to cytokine gene activation. We show that an NF-κB inhibitor partly attenuates the proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and in a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC and suggests that NF-κB inhibition could be a potential therapeutic option.

  20. Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients.

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    Zacharenia Saridaki

    2011-01-01

    Full Text Available To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC patients treated with cetuximab containing salvage chemotherapy.Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded.KRAS, BRAF and PIK3CA mutations were present in 37 (33%, 8 (7.2% and 11 (9.8% cases, respectively, PTEN was lost in 21 (19.8% cases, AREG and EREG were overexpressed in 48 (45% and 51 (49% cases. In the whole study population, time to tumor progression (TTP and overall survival (OS was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively or BRAF (p = 0.001 and p<0.0001, respectively mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively or EREG (p = 0.002 and p = 0.004, respectively and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively. In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively or EREG (p = 0.0001 and p<0.0001, respectively and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively. TTP was significantly lower in patients with PIK3CA mutations (p = 0.01 or lost PTEN (p = 0.002. Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001, BRAF mutation (HR: 5.1, p<0.0001, EREG low expression (HR: 1.6, p = 0.021 and absence of severe/moderate skin rash (HR: 4.0, p<0.0001 as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01, BRAF mutation (HR: 3.0, p = 0.001, EREG low expression (HR: 1.7, p = 0.021, absence of severe/moderate skin rash (HR: 3.7, p<0.0001 and the presence of undifferantited tumours (HR: 2.2, p = 0.001 were revealed as independent prognostic factors for decreased OS.These results underscore that KRAS-BRAF mutations and EREG

  1. Computational Analysis of mRNA Expression Profiles Identifies the ITG Family and PIK3R3 as Crucial Genes for Regulating Triple Negative Breast Cancer Cell Migration

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    Sukhontip Klahan

    2014-01-01

    Full Text Available Triple-negative breast cancer (TNBC is an aggressive type of breast cancer that does not express estrogen receptor (ER, progesterone receptor (PR, and human epidermal growth factor receptor (Her2/neu. TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926 and non-Asian populations (GSE46581 to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes, PIK3R3, ITGB1, ITGAL, and ITGA6, were involved in the regulation of actin cytoskeleton. Our results indicated potential genes that link to TNBC migration. This study may help identify novel therapeutic targets for drug development in cancer therapy.

  2. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Bergmann, Troels K; Henrichsen-Schnack, Tine

    2014-01-01

    BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK a......BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS......-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. METHODS: In total, 22 studies that include 2395 patients...

  3. Impact of KRAS, BRAF, PIK3CA Mutations, PTEN, AREG, EREG Expression and Skin Rash in ≥2nd Line Cetuximab-Based Therapy of Colorectal Cancer Patients

    Science.gov (United States)

    Saridaki, Zacharenia; Tzardi, Maria; Papadaki, Chara; Sfakianaki, Maria; Pega, Fraga; Kalikaki, Aristea; Tsakalaki, Eleftheria; Trypaki, Maria; Messaritakis, Ippokratis; Stathopoulos, Efstathios; Mavroudis, Dimitris; Georgoulias, Vassilis; Souglakos, John

    2011-01-01

    Background To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy. Methods Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded. Results KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absecence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as

  4. Correlation of extended RAS and PIK3CA gene mutation status with outcomes from the phase III AGITG MAX STUDY involving capecitabine alone or in combination with bevacizumab plus or minus mitomycin C in advanced colorectal cancer.

    Science.gov (United States)

    Price, T J; Bruhn, M A; Lee, C K; Hardingham, J E; Townsend, A R; Mann, K P; Simes, J; Weickhardt, A; Wrin, J W; Wilson, K; Gebski, V; Van Hazel, G; Robinson, B; Cunningham, D; Tebbutt, N C

    2015-03-17

    Mutations affecting RAS genes are now established predictive markers of nonresponse to anti-EGFR antibodies in advanced CRC. This analysis assessed the prognostic and predictive impact of extended RAS and PIK3CA gene mutation status in patients receiving capecitabine plus or minus bevacizumab (±mitomycin C) in the randomised phase III MAX study. DNA was extracted from archival macrodissected formalin-fixed paraffin-embedded tumour tissue. Mutation status was determined using pyrosequencing, confirmed with Sanger sequencing (for equivocal RAS) and correlated with efficacy outcomes. Predictive analyses were undertaken using a test for interaction involving both C vs CB+CBM. Of the available 280 of the 471 (59.4%) patients, mutations in KRAS exons 2, 3 and 4 and NRAS 2, 3 and 4 were as follows: 32%, 2.9%, 2.2%, 1.4%, 0.7% and 0% (total RAS MT 39%). The PIK3CA MT rate was 7.5% exon 9 and 3.6% exon 20. Extended RAS gene mutation status (WT vs MT) had no prognostic impact for PFS (HR 0.91 (0.71-1.17)) or OS (HR 0.95 (0.71-1.25)). The RAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS (HR 0.56 (0.37-0.85) for RAS MT and HR 0.69 (0.5-0.97) for RAS WT; P for interaction 0.50). The PIK3CA mutation was neither predictive for bevacizumab effect nor prognostic. Of KRAS exon 2 WT patients, 10% had additional RAS mutations. Neither all RAS gene mutation status nor PIK3CA mutation status was prognostic for PFS or OS, or predictive of bevacizumab outcome in patients with advanced CRC.

  5. PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab

    DEFF Research Database (Denmark)

    Jensen, J D; Knoop, Ann; Laenkholm, A V

    2012-01-01

    BACKGROUND: This study was conducted to determine the frequency of PIK3CA mutations and human epidermal growth factor receptor-2 (HER2) phosphorylation status (pHER2-Tyr(1221/1222)) and if PIK3CA, phosphatase and tensin homolog (PTEN), or pHER2 has an impact on outcome in HER2-positive early......-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) before administration...... of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent...

  6. Patient harboring a novel PIK3CA point mutation after acquired resistance to crizotinib in an adenocarcinoma with ROS1 rearrangement: A case report and literature review.

    Science.gov (United States)

    Xu, Chun-Wei; Wang, Wen-Xian; Huang, Rong-Fang; He, Cheng; Liao, Xing-Hui; Zhu, You-Cai; Du, Kai-Qi; Zhuang, Wu; Chen, Yan-Ping; Chen, Gang; Fang, Mei-Yu

    2017-11-01

    ROS1 rearrangement occurs in 1-2% of non-small cell lung cancer (NSCLC) cases. These patients would benefit from treatment with the anaplastic lymphoma kinase inhibitor, crizotinib; however, resistance to crizotinib inevitably develops in such patients despite an initial response. The mechanism of acquired resistance to crizotinib in patients with NSCLC with ROS1 rearrangement has not yet been identified. Herein, we report a case of a 66-year-old woman diagnosed with adenocarcinoma. PCR revealed no EGFR or ALK mutations. After the patient underwent several rounds of chemotherapy, crizotinib was administered. The disease explosively progressed six months later. A novel PIK3CA gene point mutation (p.L531P) was detected by next generation sequencing. This case is the second report of bypass activation conferred crizotinib resistance in a patient with NSCLC with ROS1-rearrangement, but is the first to confirm that activation of the mTOR signaling pathway leads to acquired crizotinib resistance. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  7. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Jatin Roper

    Full Text Available To examine the in vitro and in vivo efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type colorectal cancer (CRC.PIK3CA mutant and wild-type human CRC cell lines were treated in vitro with NVP-BEZ235, and the resulting effects on proliferation, apoptosis, and signaling were assessed. Colonic tumors from a genetically engineered mouse (GEM model for sporadic wild-type PIK3CA CRC were treated in vivo with NVP-BEZ235. The resulting effects on macroscopic tumor growth/regression, proliferation, apoptosis, angiogenesis, and signaling were examined.In vitro treatment of CRC cell lines with NVP-BEZ235 resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (median IC(50 = 9.0-14.3 nM. Similar effects were seen in paired isogenic CRC cell lines that differed only in the presence or absence of an activating PIK3CA mutant allele. In vivo treatment of colonic tumor-bearing mice with NVP-BEZ235 resulted in transient PI3K inhibition and sustained blockade of mTORC1/mTORC2 signaling. Longitudinal tumor surveillance by optical colonoscopy demonstrated a 97% increase in tumor size in control mice (p = 0.01 vs. a 43% decrease (p = 0.008 in treated mice. Ex vivo analysis of the NVP-BEZ235-treated tumors demonstrated a 56% decrease in proliferation (p = 0.003, no effects on apoptosis, and a 75% reduction in angiogenesis (p = 0.013.These studies provide the preclinical rationale for studies examining the efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in treatment of PIK3CA wild-type CRC.

  8. Ansipi optimism on haihtumas / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 31 märts lk. 6. Suurepärast maksulaekumist toonitanud peaminister Andrus Ansip tunnistas siiski, et sügisel võib tulla negatiivne lisaeelarve ning rahandusminister Ivari Padari sõnul tuleb riigil hakata kulusid kokku hoidma. Lisa: Käibemaks

  9. Eestlased tahavad Gruusiale appi minna / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Eesti reservohvitserid ja kaitseministeeriumile alluva Laidoneri muuseumi direktor Indrek Tarand otsivad vabatahtlikke, et minna appi Gruusiale sõjas Venemaaga. Lisa: Reservohvitseride Kogu maililistist levima hakanud kiri Eesti vabatahtlike leidmiseks

  10. Kotkapoja sünd / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-2017

    2008-01-01

    Autor leiab Kosovo iseseisvumisega seoses, et on kujunemas uus rahvusvahelise poliitika arusaam, mille kohaselt sõltub iseseisvumise edukus eelkõige sellest, kes selle taga seisab. Kosovo iseseisvumine on tõenäoliselt edukas, sest seda toetab USA koos EL-i ja NATO-ga. Eesti-poolne Kosovo iseseisvuse tunnustamine tugevdab EL-i välispoliitilist üksmeelt

  11. Kunstikoguja surub teoseid Kumu saalidesse / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Oyvind Dino Hjulmand, kes ostis Jüri Palmi maalid kunstniku leselt, soovib laenata need KUMU püsiekspositsioonis eksponeerimiseks. Ruumipuudusel ettepanekut vastu ei võetud. Kommentaarid Marika Valgult ja Mai Levinilt

  12. Pole demokraatiat, pole probleemi / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-2017

    2005-01-01

    Rets. rmt.: Fareed Zakaria. Vabaduse tulevik. Mitteliberaalse demokraatia ohud tänapäeva maailmas. Raamatu sisu võib kokku võtta lausega - tänapäeva poliitika vajab mitte rohkem, vaid vähem demokraatiat. Raamat jaguneb tinglikult kaheks, üks osa sisaldab Zakaria maailmaajaloolisi ja globaalseid spekulatsioone demokraatia ja vabaduse teemal, teises osas käsitletakse USA sisepoliitilisi arengusuundi

  13. Subtypes of HPV-positive head and neck cancers are associated with HPV characteristics, copy number alterations, PIK3CA mutation, and pathway signatures

    Science.gov (United States)

    Zhang, Yanxiao; Koneva, Lada A.; Virani, Shama; Arthur, Anna E.; Virani, Alisha; Hall, Pelle B.; Warden, Charles D.; Carey, Thomas E.; Chepeha, Douglas B.; Prince, Mark E.; McHugh, Jonathan B.; Wolf, Gregory T.; Rozek, Laura S.; Sartor, Maureen A.

    2016-01-01

    Structured Abstract Purpose There is substantial heterogeneity within human papillomavirus (HPV) associated head and neck cancer (HNC) tumors that predispose them to different outcomes, however the molecular heterogeneity in this subgroup is poorly characterized due to various historical reasons. Experimental Design We performed unsupervised gene expression clustering on deeply-annotated (transcriptome and genome) HPV(+) HNC samples from two cohorts (84 total primary tumors), including 18 HPV(−) HNC samples, to discover subtypes and characterize the differences between subgroups in terms of their HPV characteristics, pathway activity, whole-genome somatic copy number alterations and mutation frequencies. Results We identified two distinct HPV(+) subtypes (namely HPV-KRT and HPV-IMU). HPV-KRT is characterized by elevated expression of genes in keratinocyte differentiation and oxidation-reduction process, whereas HPV-IMU has strong immune response and mesenchymal differentiation. The differences in expression are likely connected to the differences in HPV characteristics and genomic changes. HPV-KRT has more genic viral integration, lower E2/E4/E5 expression levels and higher ratio of spliced to full length HPV oncogene E6 than HPV-IMU; the subgroups also show differences in copy number alterations and mutations, in particular the loss of chr16q in HPV-IMU and gain of chr3q and PIK3CA mutation in HPV-KRT. Conclusion Our characterization of two subtypes of HPV(+) HNC tumors provides valuable molecular level information that point to two main carcinogenic paths. Together, these results shed light on stratifications of the HPV(+) HNCs and will help to guide personalized care for HPV(+) HNC patients. PMID:27091409

  14. Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation.

    Directory of Open Access Journals (Sweden)

    Douglas D Fang

    Full Text Available PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K/mammalian target of rapamycin (mTOR pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT (S473, a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

  15. Une « huile » végétale aux multiples usages dans la région du fleuve Sépik (Papouasie Nouvelle-Guinée)

    OpenAIRE

    Coiffier, Christian

    2008-01-01

    L’exsudat d’un arbre du genre Campnosperma est collecté dans une grande partie du bassin du fleuve Sépik. Cet exsudat constitue un liquide huileux utilisé localement pour de très nombreux usages rituels. Sa représentation locale comme substance vitale en fait un produit qui participe à divers types d’échanges. The exudation of trees, Campnosperma species, is gathered on a large part of the Sepik River Valley basin. This exultation is on oily liquid that is used locally for many rituals. Be...

  16. Effective lifetime measurements in the $B_{s}^{0} \\rightarrow K^{+}K^{-}$, $B^{0} \\rightarrow K^{+}\\pi^{-}$ and $B_{s}^{0} \\rightarrow \\pi^{+}K^{-}$ decays

    CERN Document Server

    INSPIRE-00258707; Adeva, B.; Adinolfi, M.; Affolder, A.; Ajaltouni, Z.; Albrecht, J.; Alessio, F.; Alexander, M.; Ali, S.; Alkhazov, G.; Alvarez Cartelle, P.; Alves Jr, A.A.; Amato, S.; Amerio, S.; Amhis, Y.; An, L.; Anderlini, L.; Anderson, J.; Andreassen, R.; Andreotti, M.; Andrews, J.E.; Appleby, R.B.; Aquines Gutierrez, O.; Archilli, F.; Artamonov, A.; Artuso, M.; Aslanides, E.; Auriemma, G.; Baalouch, M.; Bachmann, S.; Back, J.J.; Badalov, A.; Balagura, V.; Baldini, W.; Barlow, R.J.; Barschel, C.; Barsuk, S.; Barter, W.; Batozskaya, V.; Bauer, Th.; Bay, A.; Beddow, J.; Bedeschi, F.; Bediaga, I.; Belogurov, S.; Belous, K.; Belyaev, I.; Ben-Haim, E.; Bencivenni, G.; Benson, S.; Benton, J.; Berezhnoy, A.; Bernet, R.; Bettler, M.O.; van Beuzekom, M.; Bien, A.; Bifani, S.; Bird, T.; Bizzeti, A.; Bjornstad, P.M.; Blake, T.; Blanc, F.; Blouw, J.; Blusk, S.; Bocci, V.; Bondar, A.; Bondar, N.; Bonivento, W.; Borghi, S.; Borgia, A.; Borsato, M.; Bowcock, T.J.V.; Bowen, E.; Bozzi, C.; Brambach, T.; van den Brand, J.; Bressieux, J.; Brett, D.; Britsch, M.; Britton, T.; Brook, N.H.; Brown, H.; Bursche, A.; Busetto, G.; Buytaert, J.; Cadeddu, S.; Calabrese, R.; Calvi, M.; Calvo Gomez, M.; Camboni, A.; Campana, P.; Campora Perez, D.; Carbone, A.; Carboni, G.; Cardinale, R.; Cardini, A.; Carranza-Mejia, H.; Carson, L.; Carvalho Akiba, K.; Casse, G.; Cassina, L.; Garcia, L.Castillo; Cattaneo, M.; Cauet, Ch.; Cenci, R.; Charles, M.; Charpentier, Ph.; Cheung, S.F.; Chiapolini, N.; Chrzaszcz, M.; Ciba, K.; Cid Vidal, X.; Ciezarek, G.; Clarke, P.E.L.; Clemencic, M.; Cliff, H.V.; Closier, J.; Coco, V.; Cogan, J.; Cogneras, E.; Collins, P.; Comerma-Montells, A.; Contu, A.; Cook, A.; Coombes, M.; Coquereau, S.; Corti, G.; Corvo, M.; Counts, I.; Couturier, B.; Cowan, G.A.; Craik, D.C.; Cruz Torres, M.; Cunliffe, S.; Currie, R.; D'Ambrosio, C.; Dalseno, J.; David, P.; David, P.N.Y.; Davis, A.; De Bruyn, K.; De Capua, S.; De Cian, M.; de Miranda, J.M.; De Paula, L.; De Silva, W.; De Simone, P.; Decamp, D.; Deckenhoff, M.; Del Buono, L.; Deleage, N.; Derkach, D.; Deschamps, O.; Dettori, F.; Di Canto, A.; Dijkstra, H.; Donleavy, S.; Dordei, F.; Dorigo, M.; Dosil Suarez, A.; Dossett, D.; Dovbnya, A.; Dupertuis, F.; Durante, P.; Dzhelyadin, R.; Dziurda, A.; Dzyuba, A.; Easo, S.; Egede, U.; Egorychev, V.; Eidelman, S.; Eisenhardt, S.; Eitschberger, U.; Ekelhof, R.; Eklund, L.; El Rifai, I.; Elsasser, Ch.; Esen, S.; Evans, T.; Falabella, A.; Farber, C.; Farinelli, C.; Farley, N.; Farry, S.; Ferguson, D.; Fernandez Albor, V.; Ferreira Rodrigues, F.; Ferro-Luzzi, M.; Filippov, S.; Fiore, M.; Fiorini, M.; Firlej, M.; Fitzpatrick, C.; Fiutowski, T.; Fontana, M.; Fontanelli, F.; Forty, R.; Francisco, O.; Frank, M.; Frei, C.; Frosini, M.; Fu, J.; Furfaro, E.; Gallas Torreira, A.; Galli, D.; Gallorini, S.; Gambetta, S.; Gandelman, M.; Gandini, P.; Gao, Y.; Garofoli, J.; Garra Tico, J.; Garrido, L.; Gaspar, C.; Gauld, R.; Gavardi, L.; Gersabeck, E.; Gersabeck, M.; Gershon, T.; Ghez, Ph.; Gianelle, A.; Giani', S.; Gibson, V.; Giubega, L.; Gligorov, V.V.; Gobel, C.; Golubkov, D.; Golutvin, A.; Gomes, A.; Gordon, H.; Gotti, C.; Grabalosa Gandara, M.; Graciani Diaz, R.; Granado Cardoso, L.A.; Grauges, E.; Graziani, G.; Grecu, A.; Greening, E.; Gregson, S.; Griffith, P.; Grillo, L.; Grunberg, O.; Gui, B.; Gushchin, E.; Guz, Yu.; Gys, T.; Hadjivasiliou, C.; Haefeli, G.; Haen, C.; Haines, S.C.; Hall, S.; Hamilton, B.; Hampson, T.; Han, X.; Hansmann-Menzemer, S.; Harnew, N.; Harnew, S.T.; Harrison, J.; Hartmann, T.; He, J.; Head, T.; Heijne, V.; Hennessy, K.; Henrard, P.; Henry, L.; Hernando Morata, J.A.; van Herwijnen, E.; Hess, M.; Hicheur, A.; Hill, D.; Hoballah, M.; Hombach, C.; Hulsbergen, W.; Hunt, P.; Hussain, N.; Hutchcroft, D.; Hynds, D.; Idzik, M.; Ilten, P.; Jacobsson, R.; Jaeger, A.; Jalocha, J.; Jans, E.; Jaton, P.; Jawahery, A.; Jezabek, M.; Jing, F.; John, M.; Johnson, D.; Jones, C.R.; Joram, C.; Jost, B.; Jurik, N.; Kaballo, M.; Kandybei, S.; Kanso, W.; Karacson, M.; Karbach, T.M.; Kelsey, M.; Kenyon, I.R.; Ketel, T.; Khanji, B.; Khurewathanakul, C.; Klaver, S.; Kochebina, O.; Kolpin, M.; Komarov, I.; Koopman, R.F.; Koppenburg, P.; Korolev, M.; Kozlinskiy, A.; Kravchuk, L.; Kreplin, K.; Kreps, M.; Krocker, G.; Krokovny, P.; Kruse, F.; Kucharczyk, M.; Kudryavtsev, V.; Kurek, K.; Kvaratskheliya, T.; La Thi, V.N.; Lacarrere, D.; Lafferty, G.; Lai, A.; Lambert, D.; Lambert, R.W.; Lanciotti, E.; Lanfranchi, G.; Langenbruch, C.; Langhans, B.; Latham, T.; Lazzeroni, C.; Le Gac, R.; van Leerdam, J.; Lees, J.P.; Lefevre, R.; Leflat, A.; Lefrancois, J.; Leo, S.; Leroy, O.; Lesiak, T.; Leverington, B.; Li, Y.; Liles, M.; Lindner, R.; Linn, C.; Lionetto, F.; Liu, B.; Liu, G.; Lohn, S.; Longstaff, I.; Lopes, J.H.; Lopez-March, N.; Lowdon, P.; Lu, H.; Lucchesi, D.; Luo, H.; Lupato, A.; Luppi, E.; Lupton, O.; Machefert, F.; Machikhiliyan, I.V.; Maciuc, F.; Maev, O.; Malde, S.; Manca, G.; Mancinelli, G.; Manzali, M.; Maratas, J.; Marchand, J.F.; Marconi, U.; Benito, C.Marin; Marino, P.; Marki, R.; Marks, J.; Martellotti, G.; Martens, A.; Martin Sanchez, A.; Martinelli, M.; Martinez Santos, D.; Martinez Vidal, F.; Martins Tostes, D.; Massafferri, A.; Matev, R.; Mathe, Z.; Matteuzzi, C.; Mazurov, A.; McCann, M.; McCarthy, J.; McNab, A.; McNulty, R.; McSkelly, B.; Meadows, B.; Meier, F.; Meissner, M.; Merk, M.; Milanes, D.A.; Minard, M.N.; Moggi, N.; Molina Rodriguez, J.; Monteil, S.; Moran, D.; Morandin, M.; Morawski, P.; Morda, A.; Morello, M.J.; Moron, J.; Mountain, R.; Muheim, F.; Muller, K.; Muresan, R.; Mussini, M.; Muster, B.; Naik, P.; Nakada, T.; Nandakumar, R.; Nasteva, I.; Needham, M.; Neri, N.; Neubert, S.; Neufeld, N.; Neuner, M.; Nguyen, A.D.; Nguyen, T.D.; Nguyen-Mau, C.; Nicol, M.; Niess, V.; Niet, R.; Nikitin, N.; Nikodem, T.; Novoselov, A.; Oblakowska-Mucha, A.; Obraztsov, V.; Oggero, S.; Ogilvy, S.; Okhrimenko, O.; Oldeman, R.; Onderwater, G.; Orlandea, M.; Otalora Goicochea, J.M.; Owen, P.; Oyanguren, A.; Pal, B.K.; Palano, A.; Palombo, F.; Palutan, M.; Panman, J.; Papanestis, A.; Pappagallo, M.; Parkes, C.; Parkinson, C.J.; Passaleva, G.; Patel, G.D.; Patel, M.; Patrignani, C.; Pazos Alvarez, A.; Pearce, A.; Pellegrino, A.; Pepe Altarelli, M.; Perazzini, S.; Perez Trigo, E.; Perret, P.; Perrin-Terrin, M.; Pescatore, L.; Pesen, E.; Petridis, K.; Petrolini, A.; Picatoste Olloqui, E.; Pietrzyk, B.; Pilar, T.; Pinci, D.; Pistone, A.; Playfer, S.; Plo Casasus, M.; Polci, F.; Poluektov, A.; Polycarpo, E.; Popov, A.; Popov, D.; Popovici, B.; Potterat, C.; Powell, A.; Prisciandaro, J.; Pritchard, A.; Prouve, C.; Pugatch, V.; Puig Navarro, A.; Punzi, G.; Qian, W.; Rachwal, B.; Rademacker, J.H.; Rakotomiaramanana, B.; Rama, M.; Rangel, M.S.; Raniuk, I.; Rauschmayr, N.; Raven, G.; Reichert, S.; Reid, M.M.; dos Reis, A.C.; Ricciardi, S.; Richards, A.; Rihl, M.; Rinnert, K.; Rives Molina, V.; Roa Romero, D.A.; Robbe, P.; Rodrigues, A.B.; Rodrigues, E.; Rodriguez Perez, P.; Roiser, S.; Romanovsky, V.; Vidal, A.Romero; Rotondo, M.; Rouvinet, J.; Ruf, T.; Ruffini, F.; Ruiz, H.; Valls, P.Ruiz; Sabatino, G.; Saborido Silva, J.J.; Sagidova, N.; Sail, P.; Saitta, B.; Salustino Guimaraes, V.; Sanchez Mayordomo, C.; Sanmartin Sedes, B.; Santacesaria, R.; Santamarina Rios, C.; Santovetti, E.; Sapunov, M.; Sarti, A.; Satriano, C.; Satta, A.; Savrie, M.; Savrina, D.; Schiller, M.; Schindler, H.; Schlupp, M.; Schmelling, M.; Schmidt, B.; Schneider, O.; Schopper, A.; Schune, M.H.; Schwemmer, R.; Sciascia, B.; Sciubba, A.; Seco, M.; Semennikov, A.; Senderowska, K.; Sepp, I.; Serra, N.; Serrano, J.; Sestini, L.; Seyfert, P.; Shapkin, M.; Shapoval, I.; Shcheglov, Y.; Shears, T.; Shekhtman, L.; Shevchenko, V.; Shires, A.; Coutinho, R.Silva; Simi, G.; Sirendi, M.; Skidmore, N.; Skwarnicki, T.; Smith, N.A.; Smith, E.; Smith, E.; Smith, J.; Smith, M.; Snoek, H.; Sokoloff, M.D.; Soler, F.J.P.; Soomro, F.; Souza, D.; Souza De Paula, B.; Spaan, B.; Sparkes, A.; Spinella, F.; Spradlin, P.; Stagni, F.; Stahl, S.; Steinkamp, O.; Stenyakin, O.; Stevenson, S.; Stoica, S.; Stone, S.; Storaci, B.; Stracka, S.; Straticiuc, M.; Straumann, U.; Stroili, R.; Subbiah, V.K.; Sun, L.; Sutcliffe, W.; Swientek, K.; Swientek, S.; Syropoulos, V.; Szczekowski, M.; Szczypka, P.; Szilard, D.; Szumlak, T.; T'Jampens, S.; Teklishyn, M.; Tellarini, G.; Teubert, F.; Thomas, C.; Thomas, E.; van Tilburg, J.; Tisserand, V.; Tobin, M.; Tolk, S.; Tomassetti, L.; Tonelli, D.; Topp-Joergensen, S.; Torr, N.; Tournefier, E.; Tourneur, S.; Tran, M.T.; Tresch, M.; Tsaregorodtsev, A.; Tsopelas, P.; Tuning, N.; Garcia, M.Ubeda; Ukleja, A.; Ustyuzhanin, A.; Uwer, U.; Vagnoni, V.; Valenti, G.; Vallier, A.; Vazquez Gomez, R.; Vazquez Regueiro, P.; Vazquez Sierra, C.; Vecchi, S.; Velthuis, J.J.; Veltri, M.; Veneziano, G.; Vesterinen, M.; Viaud, B.; Vieira, D.; Vieites Diaz, M.; Vilasis-Cardona, X.; Vollhardt, A.; Volyanskyy, D.; Voong, D.; Vorobyev, A.; Vorobyev, V.; Voss, C.; Voss, H.; de Vries, J.A.; Waldi, R.; Wallace, C.; Wallace, R.; Walsh, J.; Wandernoth, S.; Wang, J.; Ward, D.R.; Watson, N.K.; Websdale, D.; Whitehead, M.; Wicht, J.; Wiedner, D.; Wilkinson, G.; Williams, M.P.; Williams, M.; Wilson, F.F.; Wimberley, J.; Wishahi, J.; Wislicki, W.; Witek, M.; Wormser, G.; Wotton, S.A.; Wright, S.; Wu, S.; Wyllie, K.; Xie, Y.; Xing, Z.; Xu, Z.; Yang, Z.; Yuan, X.; Yushchenko, O.; Zangoli, M.; Zavertyaev, M.; Zhang, F.; Zhang, L.; Zhang, W.C.; Zhang, Y.; Zhelezov, A.; Zhokhov, A.; Zhong, L.; Zvyagin, A.

    2014-01-01

    Measurements of the effective lifetimes in the $B_{s}^{0} \\rightarrow K^{+}K^{-}$, $B^{0} \\rightarrow K^{+}\\pi^{-}$ and $B_{s}^{0} \\rightarrow \\pi^{+}K^{-}$ decays are presented using $1.0~\\mathrm{fb^{-1}}$ of $pp$ collision data collected at a centre-of-mass energy of 7 TeV by the LHCb experiment. The analysis uses a data-driven approach to correct for the decay time acceptance. The measured effective lifetimes are $\\tau_{B_{s}^{0} \\rightarrow K^{+}K^{-}}$ = $1.407~\\pm~0.016~\\pm~0.007~\\mathrm{ps}$, $\\tau_{B^{0} \\rightarrow K^{+}\\pi^{-}}$ = $1.524~\\pm~0.011~\\pm~0.004~\\mathrm{ps}$, $\\tau_{B_{s}^{0} \\rightarrow \\pi^{+}K^{-}}$ = $1.60~\\pm~0.06~\\pm~0.01~\\mathrm{ps}$. This is the most precise determination to date of the effective lifetime in the $B_{s}^{0} \\rightarrow K^{+}K^{-}$ decay and provides constraints on contributions from physics beyond the Standard Model to the $B_{s}^{0}$ mixing phase and the width difference $\\Delta\\Gamma_{s}$.

  17. Identification of E545k mutation in plasma from a PIK3CA wild-type metastatic breast cancer patient by array-based digital polymerase chain reaction: Circulating-free DNA a powerful tool for biomarker testing in advance disease.

    Science.gov (United States)

    Romero, Atocha; Acosta-Eyzaguirre, Daniel; Sanz, Julián; Moreno, Fernando; Serrano, Gloria; Díaz-Rubio, Eduardo; Caldés, Trinidad; Garcia-Saenz, José Á

    2015-12-01

    PIK3CA gene is frequently mutated in patients with breast cancer and it has been the focus of intense research. Inhibitors of PI3K pathway are being evaluated in ongoing clinical trials but the impact of PIKC3A mutation status on tumor response is yet uncertain. In the metastatic setting, several studies are evaluating the predictive value of PIK3CA mutations. However, results could be biased by biopsy localization. Digital polymerase chain reaction is a new technology that enables detection and quantification of cancer DNA molecules from peripheral blood and can potentially overcome such situation. As a proof of the concept, we present the case of a metastatic patient with a PIK3CA wild-type primary tumor in which the PIK3CA E545K mutation was identified in both the circulating-free DNA obtained from a peripheral blood sample and in the formalin-fixed, paraffin-embedded liver metastasis. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Ansip : Vash opross, vashi kommentarii / Andrus Ansip ; interv. Vahur Koorits

    Index Scriptorium Estoniae

    Ansip, Andrus, 1956-

    2008-01-01

    Intervjuu peaminister Andrus Ansipiga avaliku elu tegelaste populaarsuse edetabelist. Vt. samas: Parteide populaarsus kasvas; Diagramm: Toetus erakondadele kasvas, Ansip on populaarseim avaliku elu tegelane

  19. Juncker kehutab ühiselt Venemaa vastu seisma / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Luksemburgi peaminister Jean-Claude Juncker külastas Eestit ja lausus intervjuus Postimehele, et väikeriikide loobumine oma vetoõigusest EL-i välispoliitikas aitaks vältida üksikute liikmesriikide kahepoolseid tehinguid Venemaaga. Välisminister Urmas Paeti ja Välispoliitika Instituudi direktori Andres Kasekampi arvamusest. Vt. samas intervjuud Jean-Claude Junckeriga: Luksemburgi peaminister toetab enamushääletust

  20. Aasta pärast mais? / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2009-01-01

    Nordea Eesti juht avaldab arvamust, et peaksime tõsiselt läbi mõtlema, kas oleme ise valmis ja soovime euroga liituda ning kas meil on piisavalt mõjukaid toetajaid, kes hääletaksid meid eurotsooni liikmeks. Autor pakub välja mõtte teise pensionisamba sissemaksete mõlemapoolsest vähendamisest ja investeerimisreeglite muutmisest

  1. Rohelised mõõtsid surnud kanade temperatuuri / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Roheliste erakonda kuuluvad Riigikogu liikmed Marek Strandberg ja Mart Jüssi korraldasid Talleggi Newcastle tõve tõttu hukatud kanade matmispaigas Lagedil mõõteaktsiooni. Kaart: Kanakalmistu. Vt. samas: Strandbergi süüdistati omakasu püüdmises

  2. Minjust probivajet zakonoprojekt o kamerah slezhenija / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Justiitsministeeriumi põhiseadusevastasest seaduseelnõust kiiruskaamerate kasutamiseks autode kiiruse määramise, rikkujate kindlakstegemise ning trahvimise kohta. Kommenteerivad põhiseaduskomisjoni esimees Väino Linde ja Riigikohtu nõunik Sten Lind

  3. Prantsusmaa tähistas Bastille' vallutamist paraadiga / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2004-01-01

    Prantsusmaa tähtsaima riigipüha tähistamisest. Sõjaväeparaadist, president Jaques Chiraci teleintervjuust ja rahvapidustustest. Lisa: Bastille kindluse vallutamine 1789. Vt. samas: Prantsusmaa paneb Euroopa põhiseaduse rahvahääletusele

  4. Vene sõdurid matsid Eestisse ohtralt pomme / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Demineerijad leidsid 2007. aastal viis lõhkekehade matmispaika ja tegid kahjutuks 6413 pärast sõda lõhkamata jäetud lõhkekeha. Vt. samas: Kuidas me salaja pomme matsime; Kampaania tõi kilode kaupa lõhkematerjali

  5. Kaitseministeerium paneb tuulikuprojektidele käe ette / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Kaitseministeerium ei kooskõlasta Ida-Virumaal asuvate Purtse, Varja ja Sirgala tuuleparkide planeeringuid, kuna tuulikud jääksid Lääne-Virumaal Kellaveres oleva kaitseväe radari ja Venemaa vahele ning segaksid radaripilti. Sonda vallavanema sõnul ei tähenda mittekooskõlastamine tuuleparkide rajamise keeldu. Kaart

  6. Eesti kutsuti rikaste riikide majandusklubi liikmeks / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Eesti sai kutse liituda maailma kõige rikkamaid riike ühendava Majandusliku Koostöö ja Arengu Organisatsiooni ehk OECD-ga. Liitumisläbirääkimistele said kutse ka Venemaa, Iisrael, Sloveenia ja Tšiili. Lisa: Mis on OECD

  7. Päästeameti imevits osutus petukaubaks / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 26. aug. lk. 5. Päästeamet kasutab lõhkekehade avastamiseks endiselt nõiavitsa Sniffex, kuigi see ei toimi ning selle tootjale esitas USA börsijärelevalveorgan SEC süüdistuse börsipettuses. Lisa: Sniffex

  8. Eesti saadab EXPO-le hoiupõrsad / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    2010. aasta EXPO toimub Hiinas Shanghais, teemaks "Parem linn, parem elu". Eesti paviljoni ideekonkursi võitis Illimar Truverki, Andres Labi, Janno Roosi, Ionel Lehari, Priit Hameri ja Kristian Paljasma töö "Savecity.org"

  9. Ozhidanije sluzhbõ snizhajet bojevoi duhh / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ekspertide arvates ei näita ajateenistusest vabastatud noormeeste suur protsent Eestis mitte kutsealuste kehva tervist, vaid pigem neile esitatavaid kõrgeid norme. Tabel: Ajateenistus Eestis ja Soomes. Jaak Aaviksoo arvamus

  10. Osaline ajateenistus kisub Eesti meestel moraali alla / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ekspertide arvates ei näita ajateenistusest vabastatud noormeeste suur protsent Eestis mitte kutsealuste kehva tervist, vaid pigem neile esitatavaid kõrgeid norme. Tabel: Ajateenistus Eestis ja Soomes; Vt. samas: Ajateenistuse edasilükkamine Eestis; Ajateenistuse lõpetamine Lätis; Ajateenistus Iisraelis; Ajateenistus Saksamaal; Ajateenistus Soomes; Lühiintervjuu Jaak Aaviksooga

  11. Aidsiepideemia on teinud tiiru ümber maailma / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2004-01-01

    Aids on tänaseks tõusnud maailmas täiskasvanute peamiseks surmapõhjuseks ja selle levik on endiselt pidurdamatu, nenditi rahvusvahelisel konverentsil Bangkokis. Vt. samas ka "Mida tähendab HI-viirus ja AIDS?" Lisa: HIV/AIDS maailmas ja Eestis

  12. Gazprom tõrjub võimalikku konkurenti / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Eesti põhjarannikule kavandatud veeldatud maagaasi ehk LNG terminali ees seisab rida takistusi, suurimaks probleemiks on Gazprom. Vt. samas: Veeldatud maagaasi terminal annaks sõltumatuse Gazpromist

  13. Keskpanga ja rahaliitude roll stabiilses majanduses / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2004-01-01

    Keskpankade rollist ajaloos ja tänapäeval, Ladina ja Skandinaavia rahaliitudest, Euroopa Majandus- ja Rahaliidust, rahapoliitika koordineerimise vajaduses, Eesti Pangast valuutakomitee funktsioonidest, euroala rahapoliitikast, Euroopa Keskpankade Süsteemist ning Eesti Panga rollist tulevikus. Tabel: Maastrichti kriteeriumid

  14. Resonances in pi-K scattering

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, David J. [Old Dominion University, Norfolk, VA

    2014-06-23

    We have obtained clear signals of resonances in coupled-channel pi K - eta K scattering. Using distillation and a large basis of operators we are able to extract a precise spectrum of energy levels using the variational method. These energies are analysed using inelastic extensions of the Luescher method to obtain scattering amplitudes that clearly describe S, P and D wave resonances, corresponding to the physical K_0^*(1430), the K^*(892) and the K_2^*(1430).

  15. Haṭhapradīpikā

    DEFF Research Database (Denmark)

    Olesen, Bjarne Wernicke; Einarsen, Silje Lyngar; , .

    ), prāṇāyāma (åndedrætsteknikker), mudrā (yogiske teknikker) og samādhi (meditative indsigter). Dertil er HYP et encyklopædisk værk (formodentligt sammensat af mere end 20 forskellige yogaskrifter) fra haṭhayogaens klassisk-formative fase, hvorfor værket tillige udgør en forståelsesnøgle til yoga, tantra og...

  16. An improved $\\pi$K atom lifetime measurement

    CERN Document Server

    Yazkov, V

    2016-01-01

    This note describes details of analysis of data samples collected by DIRAC experiment on a Pt target in 2007 and Ni targets in 2008–2010 in order to estimate the lifetime of πK atoms. Experimental results consist of eight distinct data samples: both charge combinations ( π + K − and K + π − atoms) obtained in different experimental conditions corresponding to each year of data taking. Estimations of systematic errors are presented. Taking into account both statistical and systematic uncertainties, the lifetime of πK atoms is estimated by the maximum likelihood method. The above sample comprises the total statistics, available for the analysis, thus the improvement over the previous estimation [1,3] of the πK atom lifetime is achieved.

  17. First observation of $\\pi^{-}K^+$ and $\\pi^{+}K^-$ atoms, their lifetime measurement and $\\pi K$ scattering lengths evaluation

    CERN Document Server

    Afanasyev, Leonid

    2016-01-01

    The Low Energy QCD allows to calculate the ππ and π K scattering lengths with high precision. There are accurate relations between these scattering lengths and π + π − , π − K + , π + K − atoms lifetimes. The experiment on the first observation of π − K + and π + K − atoms is described. The atoms were generated in Nickel and Platinum targets hit by the PS CERN proton beam with momentum of 24 GeV/ c . Moving in the target, part of atoms break up producing characteristic π K pairs (atomic pairs) with small relative momentum Q in their c.m.s. In the experiment, we detected n A = 349 ± 62 (5.6 standard deviations) π − K + and π + K − atomic pairs. The main part of π K pairs are produced in free state. The majority of such particles are generated directly or from short-lived sources as ρ , ω and similar resonances. The electromagnetic interactions in the final state create Coulomb pairs with a known sharp dependence on Q . This effect allows to evaluate the number of these Coulomb pai...

  18. Herman Simm on varemgi oma tegudega kummastust tekitanud / Vahur Koorits, Kristi Leppik, Dagne Hanschmidt

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 23. sept. 2008, lk. -5. Endine kaitseministeeriumi ametnik Herman Simm vahistati kahtlustatuna Venemaale salajase info loovutamises. Vt. samas: Arvatava reeturi tabamise uudis jõudis maailma; Sõjaeelne riigireetur maksis joomavõlgasid. Kommenteerivad: Urmas Paet, Jürgen Ligi, Tarmo Kõuts, Jaak Aaviksoo, Koit Pikaro, Leo Kunnas, Ain Seppik, Andrus Ansip

  19. Türgi politsei süüdistab kurdidest inimõiguslasi / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2004-01-01

    Türgi politsei ja võimud süüdistavad vanglast vabanenud kurdi parlamendisaadikuid separatistlikes kihutuskõnedes ning kurdi keele rääkimises. Üks süüdistatu Leyla Zana on saanud 1995. aastal Andrei Zahharovi nimelise inimõiguste preemia

  20. Euro on sama tähtis kui NATO ja Euroopa Liit / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2005-01-01

    Ilmunud ka: Severnoje Poberezhje 3. juuni lk 2. Eesti Panga presidendi sõnul on euro aluseks oleva majandus- ja rahaliidu peamisteks eesmärkideks stabiilne majanduskasv ja madal inflatsioon. Väljavõte esinemisest Riigikogus

  1. Kraft ootab noorelt valitsuselt jõulisi majandusotsuseid / Vahur Kraft ; interv. Andrus Karnau

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2007-01-01

    Nordea Eesti juht vastab küsimustele, mis puudutavad majanduse ülekuumenemist ja selle lahendamist, Läti valitsuse käitumist inflatsiooni ohjeldamisel, Eesti valitsuse käitumist avaliku sektori palkade kujundamisel ning pronkssõdurit

  2. Vikergallup : eesti kirjandus 2014 / Vahur Afanasjev, Sirel Heinloo, Peeter Helme ... [jt.

    Index Scriptorium Estoniae

    2015-01-01

    Kriitikute arvamus 2014. aastal Eestis ilmunud nüüdiskirjandusest. Aasta parimaks uudisteoseks nimetati Hasso Krulli luuleraamat "Kui kivid olid veel pehmed", parimaks debüüdiks Kristjan Haljaku luulekogu "Palavik", parimate tõlkeraamatutena tõsteti esile Elena Ferrante romaan "Üksilduse päevad", Konstantinos Petrou Kavafise "Kogutud luuletusi" ja Ivan Turgenevi "Senilia"

  3. Seesmise põlemisega kirjutatud näidendid noortelt autoritelt / Vahur Keller ; interv. Merit Kask

    Index Scriptorium Estoniae

    Keller, Vahur, 1976-

    2007-01-01

    Eesti Nukuteatris korraldatud laste ja noorte näidendivõistlusest "Pööning", mille tulemusena jõuab 1. märtsil esietenduseni teiste hulgas ka Kristiina Jalasto näidend "Kui mind ei oleks, oleks maailm teine". Etendus koosneb kolmest lühinäidendist koondnimetusega "Põlev pööning"

  4. Vikergallup : eesti kirjandus 2012 / Vahur Afanasjev, Joanna Ellmann, Peeter Helme ... [jt.

    Index Scriptorium Estoniae

    2013-01-01

    Erinevate kriitikute arvamus 2012. aastal Eestis ilmunud nüüdiskirjandusest. Aasta parimaks uudisteoseks nimetati Peeter Sauteri "Märkmeid vaeste kirjanike majast", parimaks debüüdiks Mait Vaigu luulekogu "Kõigil on alati õigus", parimaks tõlkeraamatuks Georges Pereci romaan "Elu, kasutusjuhend" ja Pentti Saarikoski koondkogu "Luuletused"

  5. Vikergallup : eesti kirjandus 2011 / Vahur Afanasjev, Janar Ala, Joanna Ellmann ... [jt.

    Index Scriptorium Estoniae

    2012-01-01

    Erinevate arvustajate arvamus 2011. aastal Eestis ilmunud ilukirjandusest. Aasta parimaks uudisteoseks nimetati Andrei Hvostovi "Sillamäe passioon", parimateks debüütideks Margus Tamme proosaraamatut "Unesnõiduja" ja Kaur Riismaa luulekogu "Me hommikud, me päevad, õhtud, ööd" ning parimaks tõlkeraamatuks Harald Rajametsa postuumselt ilmunud Dante-tõlget "Jumalik komöödia. Põrgu"

  6. FBI direktor : ametnike korruptsioon on ohtlik / Robert Mueller ; interv. Vahur Koorits, Rasmus Kagge

    Index Scriptorium Estoniae

    Mueller, Robert

    2007-01-01

    Ilmunud ka: Postimees : na russkom jazõke 21. sept. lk. 9. USA föderaalse juurdlusbüroo direktor vastab küsimustele, mis puudutavad küberkuritegevuse ohtu Eestis, FBI ja Eesti politsei koostööd organiseeritud kuritegevuse vastases võitluses, Balkani ja Aasia vägivaldse organiseeritud kuritegevuse imbumist EL-i uutesse riikidesse, suurimaid ohte Eestile ja Euroopale

  7. Urve Palo : vabad lasteaiakohad on saavutatavad / Urve Palo ; interv. Vahur Koorits

    Index Scriptorium Estoniae

    Palo, Urve, 1972-

    2007-01-01

    Rahvastikuminister Urve Palo vastab küsimustele, mis puudutavad pronkssõduri äraviimist ja hukkunute säilmete ümbermatmist, uute töötajate otsimist büroosse, integratsiooniprogrammi, tööd rahvastikuvaldkonnas, pereväärtusi ja lasteaiakohti. Kommenteerib Paul-Eerik Rummo. Lisa: Urve Palo

  8. Väikegaleriid jäeti salaja toetusrahata / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Eesti Kultuuriministeerium andis kogu kunstigaleriide toetamiseks ettenähtud raha Eesti Kunstnike Liidule kuuluvatele Draakoni, Hobusepea, Vabaduse ja Hop galeriile. Rahapuudusel sulges uksed Rael Artel Gallery Tartus ja Pärnus

  9. Hollandi heategija ei soovita igasugust raha vastu võtta / Octave Regout ; Interv. Vahur Koorits

    Index Scriptorium Estoniae

    Regout, Octave, 1935-

    2007-01-01

    President Toomas Hendrik Ilveselt Eesti Punase Risti III klassi ordeni pälvinud Hollandi heategevusfondi Eesti koordinaator leiab, et ebaeetiliselt teenitud raha ei tohiks heategevusorganisatsioonid annetajatelt vastu võtta. Vt. samas: Toetus. 1992. aastast on heategevad Hollandi fondid toetanud Eestis 670 projekti kokku 66 miljoni krooniga. 2007. a. jaanuaris loodi SA Eesti-Hollandi Heategevusfond Päikeselill, mis peab jätkama sama tööd Eestis edaspidi juba kohalike annetuste abil

  10. Naastrehve võib maksulisa tõttu tabada hinnatõus / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Majandus- ja kommunikatsiooniministeeriumi kavast maksustada naastrehvid, et inimesed kasutaksid rohkem teid säästvaid lamellrehve. Lisa: Rehvide hinnavõrdlus; Naastrehvide kasutusaeg põhjamaades. Vt. samas: Rehvid, mis lõhuvad teid, säästavad inimelusid. Kommenteerib Indrek Madar

  11. Kemplus võidusamba pärast kogub aina tuure / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Kaitseministeerium süüdistab Tallinna linnavalitsust vabadussamba ehitusloa väljastamisega venitamises. Linnavalitsus tahab enne ehitusloa andmist samba projekti näha ja nõuab kolmemõõtmelise maketi tegemist

  12. Kõrged maksud paisutavad mõttetult töötukasa reserve / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2010-01-01

    Sotsiaalministri ja Töötukassa nõukogu esimehe Hanno Pevkuri sõnul tuleks kaaluda töötuskindlustuse makse langetamist 2012. aastast, töötukassa nõukogus ametiühinguid esindava Harri Taliga arvates võiks töötuskindlustuse makseid vähendada juba 2011. aastal, tööandjaid esindava Tarmo Kriisi arvates võiks maksemäära alles paari aasta pärast arutama hakata. Graafik

  13. Vastab Joan Baixas / Joan Baixas ; intervjueerinud, tõlkinud ja litereerinud Vahur Keller

    Index Scriptorium Estoniae

    Baixas, Joan, 1946-

    2010-01-01

    Maalikunstnik, näitekirjanik, lavastaja, õppejõud Barcelona Teatriinstituudis ja Barcelona Rahvusvahelise nukuteatrifestivali kunstiline juht J. Baixas visuaalteatrist, nukuteatri olemusest, nüüdiskunstist, Joan Mirost, tööst erinevates kultuurides, kunsti eesmärgist

  14. Mihkelson : ENPA juhil Venemaal ärihuvid / Vahur Koorits, Ingvar Bärenklau, Igor Taro

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Ilmunud ka: Postimees : na russkom jazõke, 9. okt. 2007, lk. 3. Eestit teravalt kritiseerinud Euroopa Nõukogu Parlamentaarse Assamblee president Rene van der Linden on Vene meedia andmetel miljardeid kroone Venemaale investeeriva firma nõukogu esimees. Riigikogu liikme Andres Herkeli tähelepanekuid van der Lindeni Venemaasse suhtumise muutuste kohta ning Marko Mihkelsoni süüdistusi van der Lindeni ärihuvide kohta Venemaal. Lisa: Teateid seostest. Kaart: Sobinsk

  15. Petukahtlusega firma müüb juba uusi reise / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 30. sept. lk. 2. Kliendid raha ja reisideta jätnud Line Cross OÜ müüb juba uusi puhkusereise, kuigi pole vanu võlgu ära maksnud. Vt. samas: Rein Kalda ärid

  16. Eurohirm võib nurjata pensionitõusu / Vahur Koorits, Andrus Karnau

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Euroopa Komisjoni rahandusvolinik Joaquin Almunia ei usu, et Eesti suudaks majanduskriisi tingimustes hoida oma eelarvedefitsiiti alla kolme protsendi SKT-st. Erinevaid eksperthinnaguid. Graafik: Inflatsioon ja majanduskasv

  17. Väidetav piraat oli Krossi firma üürnik / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Kaubalaeva Arctic Sea kaaperdamises süüdistatava Dmitrijs Savinsi seotusest endise luurekoordinaatori Eerik-Niiles Krossiga. Arctic Sea kaaperdamisjuhtumiga seoses on välismeedia tähelepanu pööranud ka riigikogulase Tarmo Kõutsi kommentaaridele. Vt. samas: Kaubalaevaga Arctic Sea seotud sündmused

  18. Tippspetsialist valib hoolikalt, kelle heaks tööle hakkab / Agu Vahur

    Index Scriptorium Estoniae

    Vahur, Agu

    2006-01-01

    Ilmunud ka: Delovõje Vedomosti 29. nov. lk. 34. Tippspetsialistid otsivad ettevõtet, mis toetaks tööalast arengut, isiklikku identiteeti ja eetilisi tõekspidamisi ning ühtlasi aitaks luua isiklikku edulugu ja imagot. Vt. samas: Juhilt saadud emotsioon mõjutab tööotsijat

  19. Vikergallup : eesti kirjandus 2009 / Vahur Afanasjev, Ott Heinapuu, Peeter Helme... [jt.

    Index Scriptorium Estoniae

    2010-01-01

    24 arvustaja vastus küsimusele, milline oli 2009. aasta parim uudisteos ja debüüt. Parimaks debüüdina nimetati enim Mart Kanguri luulekogu "Kuldne põli" ja Triin Tasuja luulekogu "Provintsiluule", samuti märgiti mitme arvustaja poolt ära Jüri Kolgi luulekogu "Barbar Conan peeglitagusel maal" ning Birgit Renseri ja Terje Toomistu reisiromaan "Seitse maailma". Parima uudisteosena nimetati enim Jan Kausi romaani "Hetk" ning Hasso Krulli luulekogu "Neli korda neli"

  20. Presidentidest usaldas rahvas kõige enam Arnold Rüütlit / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Kaitseministeeriumi korraldatud institutsioonide usaldusväärsuse küsitlusest selgus, et president Arnold Rüütlit usaldas tema ametiajal keskmiselt 79 % Eesti inimestest. President Toomas Hendrik Ilves pälvis 73 % vastanute usalduse ja president Lennart Meri usaldas tema viimasel ametiaastal 70 % küsitletutest. Lisatud joonis: Usaldus taasiseseisvuseaegsete presidentide vastu (aastatel 2001-2008). Arvamust avaldavad president Arnold Rüütel, Postimehe kolumnist Enn Soosaar, uuringufirma Saar Poll juhataja Andrus Saar ja president T. H. Ilvese avalike suhete nõunik Toomas Sildam

  1. Soomussõidukipark ootab tublit täiendust / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Kaitseväe arengukava aastani 2018 näeb ette, kui palju ja milliseid soomustatud transpordivahendeid Eesti endale 10 aasta jooksul ostab. Kaitseministeeriumi pressiesindaja Peeter Kuimeti selgitusi. Lisa: Soomustatud masinad

  2. Esimene väitekiri Jaan Krossist / Cornelius Hasselblatt ; saksa keelest tõlkinud Vahur Aabrams

    Index Scriptorium Estoniae

    Hasselblatt, Cornelius, 1960-

    2015-01-01

    Wagner, Kerttu. Die historischen Romane von Jaan Kross : am Beispiel einer Untersuchung der deutschen und englischen Übersetzungen von "Professor Martensi ärasõit" (1984). Frankfurt/M : P. Lang, 2001.

  3. Edward Lucas: ajaloorindel ei ole Venemaa võitmas / Edward Lucas ; interv. Vahur Koorits

    Index Scriptorium Estoniae

    Lucas, Edward

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 29. apr. lk. 2-3. Ajakirja Economist ajakirjanik vastab küsimustele, mis puudutavad Eesti valitsuse ja peaminister Andrus Ansipi käitumist pronksiööde ajal, välisministeeriumi tööd, Eesti poliitilist kapitali ja välispoliitikat, lääneriikide suhtumist ajaloosündmustesse ja Venemaa ajaloonägemust. Vt. samas: Erinevad arvamused; Anna Levandi. Pronkssõduri teisaldamise viis jättis suhu paha maigu

  4. Kalapüük ja -varud : [2000-2005 Eestis] / Vahur Võrel

    Index Scriptorium Estoniae

    Võrel, Vahur

    2005-01-01

    Ilmunud ka: Agriculture and the development of rural life : overview 2004/2005. - Tallinn, 2005, lk. 47-49. Kalapüügi mahust enamiku ehk 75% moodustab Läänemere kalapüük. Diagramm: Kalapüügi ja kalakasvatuse struktuur 2003. a (% kogumahust). Tabelid: Püügikogused ja väärtused 2000-2002; Läänemere püügikvoodid

  5. Vikergallup : eesti kirjandus 2013 / Vahur Afanasjev, Joanna Ellmann, Peeter Helme ... [jt.

    Index Scriptorium Estoniae

    2014-01-01

    Kriitikute arvamus 2013. aastal Eestis ilmunud nüüdiskirjandusest. Aasta parimaks uudisteoseks nimetati Valdur Mikita "Lingvistiline mets", parimaks debüüdiks Sveta Grigorjeva luulekogu "Kes kardab Sveta Grigorjevat?", parima tõlkeraamatuna tõsteti esile Michel Houellebeqi romaan "Kaart ja territoorium" ning Andrei Ivanovi romaan "Harbini ööliblikad"

  6. McDonald's läks maja pärast kohtusse / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 13. veebr. 2008, lk. 3. McDonaldþsi toidukohti pidava firma Premier Restaurants Eesti AS arvates on tal õigus küsida teistelt samas majas paiknevatelt asutustelt üüri ning nõuab saamata jäänud raha eest üle 8 miljoni krooni kahjutasu. Vt. samas: Viru 24; Lao tõstis McDonaldsi töötajad tänavale

  7. Karistuste karmistamine pole liiklusõnnetusi vähendanud / Vahur Koorits, Agnes Kuus

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Ilmunud ka: Postimees : na russkom jazõke 25. sept. lk. 4. Politsei on avastanud kaheksa kuuga 47% enam väärtegusid ja karmistanud karistusi, kuid vigastatute ja hukkunute arvu pole see vähendanud. Siseministri Jüri Pihli väljakuulutatud kampaaniast liiklussurmade vähendamiseks. Lisa: Nädalavahetuse must statistika

  8. U voennõh invalidov net sredstv pogashat kredit / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Afganistanis missioonil jala kaotanud Andrei Vesterineni murest kodulaenu tasumisel. Kaitseväeteenistuse seaduse muudatustest, mis sätestavad toetused ja sotsiaalsed tagatised välismissioonil haigestunud või hukkunud kaitseväelastele ja nende omastele. Lisatud: missioonil hukkunud omastele makstav toetus

  9. Eesti ja USA juhtide kohtumiste peateema on NATO ja demokraatia / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    USA presidendi George W. Bushi visiidi ajal toimuvatel USA ja Eesti riigijuhtide kohtumistel räägitakse NATO ja demokraatia tulevikust, samuti tulevad kõne alla missioonid Afganistanis ja Iraagis ning eestlaste viisavabadus USA-sse reisimisel. Lisa: Millest kavatsevad riigijuhid kohtumistel rääkida: Ansip, Ilves, Bush. Vt. samas: Bushi visiidi ajal vilksatab Eesti üheks õhtuks ameeriklaste teleekraanidel

  10. Imar Raag : miks rekordpalka nautiv Vahtur Kersna ETVd põhjab? / Kaspar Käänik

    Index Scriptorium Estoniae

    Käänik, Kaspar

    2007-01-01

    ETV endine juht arvustab teleajakirjanik Vahur Kersna avalikku kriitikat oma tööandja aadressil. Artiklis tsiteeritakse Ilmar Raagi 25. sept. ajalehes Postimees ilmunud artiklit "Huvide konflikt : Vahur Kersna näide"

  11. "Tallinn Treff" - maailma lavade uus põlvkond Tallinnas / Meelis Pai, Vahur Keller, Reeda Toots ; intervjueerinud Margot Visnap

    Index Scriptorium Estoniae

    Pai, Meelis, 1968-

    2009-01-01

    30. maist 6. juunini toimuvast rahvusvahelisest nukuteatrifestivalist "Tallinn Treff" ning selle alafestivalist "Noor vaim" annavad ülevaate festivali peakorraldaja Meelis Pai, kusntiline juht Vahut Keller ja "Noor vaimu" juht Reeda Toots

  12. Vikergallup: eesti kirjandus 2003 : [vastused Vikerkaare küsimustele] / Vahur Afanasjev, Indrek Hargla, Peeter Helme ... [jt.

    Index Scriptorium Estoniae

    2004-01-01

    2003. a. parima uudisraamatu tiitli pälvis Kivisildniku "Päike, mida sa õhtul teed"; parima esikraamatu tiitlit jagasid Asko Künnapi "Ja sisalikud vastasid (kolmes kirjas)" ning Erkki Luugi "Ornitoloogi meelespea"

  13. Jaht Saddamile / Abdel Bari Atwan ; interv. Christopher Dickey, tõlk. Vahur Kuusk, tõlk. Silva Jõulu

    Index Scriptorium Estoniae

    Atwan, Abdel Bari

    2002-01-01

    Väljavõtteid intervjuust Londonis ilmuva ajalehe Al Quds al-Arabi toimetajaga, kes vastab küsimustele Saddam Husseini, tema väljavahetamise, USA võimaliku Iraagi ründamise ja selle tagajärgede ning Osama bin Ladeni kohta

  14. Laaneots võtab sõja korral püssi alla 30 000 meest / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2010-01-01

    Kaitseväe mobilisatsiooniplaanist. Kaitseväe juhataja Ants Laaneots teeb ettevalmistusi mobilisatsiooniks, et sõjaohu korral püssi alla võtta 30 000 meest. Eesti suudaks mobiliseerida Lätist ja Leedust palju rohkem mehi. Diagramm

  15. Komparativistlikke ja kultuuriteaduslikke ärgitusi Baltimaade germanistikale / Michael Schwidtal ; saksa keelest tõlkinud Vahur Aabrams

    Index Scriptorium Estoniae

    Schwidtal, Michael

    2001-01-01

    3. - 5. sept. 2001 toimus Riias sümpoosion "Unter diesem braunen Himmel. Jakob Michael Reinhold Lenz und die deutsche Literatur des Baltikums", 7. - 9. sept. Tartus "Torm ja tung Liivimaal. Mässu mudelid", pühendatud J. M. R. Lenzi ja Kristian Jaak Petersoni loomingule. Ülevaade

  16. Las koerad hauguvad, karavan liigub ikka edasi ehk Maanteeamet ja MTA "ruulivad" vaatamata Riigikohtu juhistele edasi / Vahur Kivistik, Janar Urres

    Index Scriptorium Estoniae

    Kivistik, Vahur

    2016-01-01

    Riigikohtu lahendist 3-3-1-69-15 seoses Maksu- ja Tolliameti (MTA) ja Maanteeameti (MNT) koostööga eesmärgiga pidurdada 2009. a toodetud ja uuemate autode maaletoomisel toimuvaid käibemaksupettusi

  17. Veebist, ülepildistamisest, muuseumiaastast ja rahvast ehk teeme ometi talgud ja jätame jalgratta leiutamata! / Vahur Puik

    Index Scriptorium Estoniae

    Puik, Vahur

    2008-01-01

    Ajalooliste kohafotode väärtusest, nende ülepildistamisest, veebikeskkonda laadimisest, mäluasutuste tööst selles vallas. Fotojagamiskeskkonnas Flickr on loodud mäluasutuste jaoks alajaotus "the Commons", mille eesmärk on kaasata inimesi avalike fotokogude kirjeldamisse

  18. The estimation of production rates of $\\pi^+K^-, \\pi^-K^+$ and $\\pi^+\\pi^-$ atoms in proton-nucleus interactions at 450 GeV/c

    CERN Document Server

    Gorchakov, O

    2015-01-01

    Short-lived (τ ∼ 3 × 10 − 15 s) π+ K− , K+ π− and π+ π− atoms as well as long- lived (τ ≥ 1 × 10 − 11 s) π+ π− atoms produced in proton-nucleus interactions at 24 GeV/c are observed and studied in the DIRAC experiment at the CERN PS. The purpose of this paper is to show that the yields of the short-lived π+ K−, K+ π− and π+ π− atoms in proton-nucleus interactions at 450 GeV/c and θ lab = 4◦ are estimated to be, respectively, 17, 38 and 16 times higher per time unit. This may allow significantly improving the precision of their lifetime measurement and ππ and πK scattering length combinations |a0 − a2| and |a 1/2 − a3/2| . The yields of the long-lived π+ K− , K+ π− and π+ π− atoms at 450 GeV/c are estimated to be 370, 1600 and 750 times higher than at 24 GeV/c. This may allow the resonance method to be used for measuring the Lamb shift in the ππ atom and a new ππ scattering length combination 2 a0 + a2 to be obtained.

  19. Particle identification aerogel counter with n=1.13 for {pi}/K separation

    Energy Technology Data Exchange (ETDEWEB)

    Barnyakov, A.Yu.; Barnyakov, M.Yu. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Beloborodov, K.I., E-mail: K.I.Beloborodov@inp.nsk.s [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Novosibirsk State University, 2, Pirogova Street, Novosibirsk 630090 (Russian Federation); Bobrovnikov, V.S.; Buzykaev, A.R. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Danilyuk, A.F. [Boreskov Institute of Catalysis, 5, akademika Lavrentieva prospect, Novosibirsk 630090 (Russian Federation); Golubev, V.B. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Novosibirsk State University, 2, Pirogova Street, Novosibirsk 630090 (Russian Federation); Kirillov, V.L. [Boreskov Institute of Catalysis, 5, akademika Lavrentieva prospect, Novosibirsk 630090 (Russian Federation); Kononov, S.A. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Kravchenko, E.A. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Novosibirsk State University, 2, Pirogova Street, Novosibirsk 630090 (Russian Federation); Onuchin, A.P. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Martin, K.A. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Novosibirsk State Technical University, 20, Karl Marx prospect, Novosibirsk 630092 (Russian Federation); Serednyakov, S.I. [Budker Institute of Nuclear Physics, 11, akademika Lavrentieva prospect, Novosobirsk 630090 (Russian Federation); Novosibirsk State University, 2, Pirogova Street, Novosibirsk 630090 (Russian Federation)

    2010-11-01

    The paper is devoted to the cosmic muon tests of particle identification system for the SND detector at the new VEPP-2000 e{sup +}e{sup -} collider. The goal of the tests is to measure average signal for the relativistic particles. The measurements of the average signal were done at five different points of the counter. Obtained values of the signal are close to 10 photoelectrons. Preliminary results for misidentification probability for {pi} and K mesons with the energy of 1000 MeV are presented.

  20. New POLDI - project of reincarnation of a polarized neutron diffractometer at the reactor PIK

    Science.gov (United States)

    Zobkalo, I.; Gavrilov, S.; Matveev, V.; Fenske, J.

    2017-06-01

    The project of a considerable modernization of the polarized neutron diffractometer POLDI is discussed. It assumes the adoption of POLDI to a broader range of magnetic investigations such as determination of magnetic structures, detailed investigation of complex magnetic structures, studies of magnetic domains, study of the magnetization density maps, magnetic form-factor particularities, local susceptibility, etc. The flexible construction should permit to use either spherical neutron polarimetry technique or flipping ratio technique. Different types of polarization system were analyzed. Original focusing fan-like bender is proposed as polarizer unit. Our simulations give evidence that for the wavelength range 1.3 - 3 Å and with suitable size, such a device can give much better efficiency than 3He cells, which are often in use. The higher flux at the sample position of a factor of at least 3.3, with lower divergence and good polarization degree from 98% (1.3 Å) to above 94% (3 Å) makes the bender set-up favorable over the layout with a 3He-cell.

  1. Measurement of Pi-K Ratios from the NuMI Target

    Energy Technology Data Exchange (ETDEWEB)

    Seun, Sin Man [Harvard Univ., Cambridge, MA (United States)

    2007-07-01

    Interactions of protons (p) with the NuMI (Neutrinos at the Main Injector) target are used to create the neutrino beam for the MINOS (Main Injector Neutrino Oscillation Search) Experiment. Using the MIPP (Main Injector Particle Production) experimental apparatus, the production of charged pions and kaons in p+NuMI interactions is studied. The data come from a sample of 2 x 106 events obtained by MIPP using the 120 GeV/c proton beam from the Main Injector at Fermi National Accelerator Laboratory in Illinois, USA. Pions and kaons are identified by measurement in a Ring Imaging Cherenkov detector. Presented are measurements of π-+, K-/K+, π+/K+ and π-/K- production ratios in the momentum range pT < 2 GeV/c transversely and 20 GeV/c < pz < 90 GeV/c longitudinally. Also provided are detailed comparisons of the MIPP NuMI data with the MIPP Thin Carbon data, the MIPP Monte Carlo simulation and the current MINOS models in the relevant momentum ranges.

  2. Optimization of a polarizer device for SANS-2 instrument at the PIK reactor

    Science.gov (United States)

    Pavlov, K. A.; Konik, P. I.; Syromyatnikov, V. G.; Grigoriev, S. V.; Moskvin, E. V.

    2017-06-01

    A polarizer of V-cavity type for small angle diffractometer was considered. The device performance was simulated using McStas ray tracing package with the input parameters for supermirrors of PNPI home production (CoFe/TiZr, m = 2.13). Two replaceable devices with lengths 0.75 m and 1.8 m are proposed to cover the wavelength range 4-25 Å with beam polarization not less than 95%.

  3. Tunnustame tõenduspõhise õendusabi edendajaid / Ester Öpik, Ilme Aro

    Index Scriptorium Estoniae

    Öpik, Ester

    2014-01-01

    Tunnustati meditsiiniõdesid Tiina Freimanni, Reet Urbanit, Marika Asbergi, Tiina Tõemetsa, Kersti Viitkarit ja Ireen Bruusi Eesti Õdede Liidu poolt 2011. aastani kaitstud õendusteaduslike uurimistööde eest

  4. Võttetrupp jootis meid iga päev viina ja õllega! / Oliver Rand

    Index Scriptorium Estoniae

    Rand, Oliver, 1971-

    2007-01-01

    Sulev Keeduse dokumentaalfilm "Jonathan Austraaliast" pahandas Mustjala vallavanemat Kalle Kolterit, vallavolikogu esimeest Toivo Lõhmust ja sotsiaaltöötajat Saima Lõhmust. Süüdistustele vastab võttegrupi assistent Salme Poopuu

  5. Välispoliitika võimalustest julgeoleku kadudes : 1920.-1930. aastate Eesti välispoliitika ja konkureerivad maailmakorrad / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-2017

    2008-01-01

    Balti riikidest kui süsteemivälistest väikeriikidest. Balti koostööst ja Eesti orientatsioonidest. Murrangust Balti riikide süsteemikuuluvuses, mis saabus 1940. aastal, kui Balti riigid said oma iseseisvusele suurriigist toetaja USA näol.

  6. Töölepingu ülesütlemine majanduslikel põhjustel : töötaja tagatised / Vahur-Peeter Liin

    Index Scriptorium Estoniae

    Liin, Vahur-Peeter, 1983-

    2009-01-01

    Töötajate valiku kriteeriumitest, töölepingu ülesütlemise piirangutest ja teise töö pakkumise kohustusest enne töölepingu ülesütlemist. Etteteatamistähtajast ja rahalisest hüvitisest töölepingu ülesütlemisel

  7. MediANA - interaktiivne tööriist kommunikatsioonijuhtidele / Akvilė Katilienė ; intervjueerinud Kaidi Balder, Vahur Orrin

    Index Scriptorium Estoniae

    Katilienė, Akvilė

    2013-01-01

    BNS-i grupi peaanalüütik Balti riikides Akvilė Katilienė selgitab intervjuus, kuidas aitab ETA Monitooringu interaktiivne kommunikatsioonijuhtimise ja analüüsi keskkond mediANA tõhustada kommunikatsioonijuhi tööd

  8. Dokumente ja materjale Tartu saksa ülikooli kohta aastast 1918 / Reinhold Zilch ; [inglise keelest] tõlkinud Vahur Aabrams ; kommenteerinud Sirje Tamul

    Index Scriptorium Estoniae

    Zilch, Reinhold, 1952-

    2010-01-01

    Tartu saksa ülikool eksisteeris 15. septembrist kuni 1. detsembrini 1918. Valimik tähtsamaid dokumente. Keskset rolli Tartu saksa ülikooli ülesehitamisel mängis Hans Helfritz. Dokumendid kajastavad Preisi haridusministeeriumi võitlust mõju pärast ülikoolis

  9. Precise excision of IS5 from the intergenic region between the fucPIK and the fucAO operons and mutational control of fucPIK operon expression in Escherichia coli.

    Science.gov (United States)

    Zhang, Zhongge; Yen, Ming Ren; Saier, Milton H

    2010-04-01

    Excision of transposable genetic elements from host DNA occurs at low frequencies and is usually imprecise. A common insertion sequence element in Escherichia coli, IS5, has been shown to provide various benefits to its host by inserting into specific sites. Precise excision of this element had not previously been demonstrated. Using a unique system, the fucose (fuc) regulon, in which IS5 insertion and excision result in two distinct selectable phenotypes, we have demonstrated that IS5 can precisely excise from its insertion site, restoring the wild-type phenotype. In addition to precise excision, several "suppressor" insertion, deletion, and point mutations restore the wild-type Fuc(+) phenotype to various degrees without IS5 excision. The possible bases for these observations are discussed.

  10. The estimation of production rates of $\\pi^+K^-, \\pi^-K^+$ and $\\pi^+\\pi^-$ atoms in proton-Ni interactions at proton momentum of 450 GeV/c

    CERN Document Server

    Gorchakov, O

    2015-01-01

    In the DIRAC experiment at CERN the π+ K− , K+ π− and π+ π− atoms generated in proton-nucleus interaction at proton momentum Pp = 24 GeV/c were investigated. This work shows that the yields of π+ K− , K+ π− and π+ π− atoms in the p-nucleus interactions at Pp = 450 GeV/c and θ lab = 4◦ are 17, 38 and 16 times more than the one in the DIRAC experiment. The increased yields of the short-lived ππ ( πK ) atoms with minimum lifetime τ th = 2.9 . 10 − 15 s ( τ th = 3.5 . 10 − 15 s ) allows to improve the precisions of their lifetime measurement and ππ ( πK ) scattering length combinations | a 0 − a 2 | ( | a 1 / 2 − a 3/2 | ). In the DIRAC experiment the long-lived ππ atoms( τ th ≥ 1.2 . 10 − 11 s) were observed also. It was detected n A = 436 ± 61 π + π − pairs(atomic pairs) originating in the breakup of long-lived ππ atoms in the Pt foil with probability more than 90%. After the change of experiment scheme the number of produced long-lived π+ π− , π+ K− a...

  11. Production rates for $\\pi^+K^-, \\pi^-K^+$ and $\\pi^+\\pi^-$ atoms in $p$-Ni interactions at proton momentum 24 and 450 GeV/c

    CERN Document Server

    Gorchakov, O

    2015-01-01

    The results of performed analysis show that the yield of π+ K− , K+ π− and π+ π− atoms in the p-nucleus interactions increases significantly at change of proton momentum Pp from 24 up to 450 GeV/c. The yield of these dimesoatoms at Pp = 450 GeV/c and θ lab = 4◦ is more than on the order of magnitude more than the one at DIRAC experiment conditions: Pp = 24 GeV/c and θ lab = 5.7◦ . The large yield of dimesoatoms allows to improve their lifetime measuremen t and to investigate long-lived π+ π− atoms significantly.

  12. NPP Multi-Biome: PIK Data for Northern Eurasia, 1940-1988 (Based on Bazilevich), R1

    Data.gov (United States)

    National Aeronautics and Space Administration — There is one comma-separated (.csv) data file and one text (.txt) file (bibliographic information) with this data set. This data set provides above-ground net...

  13. NPP Multi-Biome: PIK Data for Northern Eurasia, 1940-1988 (Based on Bazilevich), R1

    Data.gov (United States)

    National Aeronautics and Space Administration — ABSTRACT: There is one comma-separated (.csv) data file and one text (.txt) file (bibliographic information) with this data set. This data set provides above-ground...

  14. Kaameraga veere pääl / Arp Müller

    Index Scriptorium Estoniae

    Müller, Arp

    2005-01-01

    Dokumentaalfilm "Vahtsõ ilma veere pääl" : idee Vahur Laiapea : autorid Silvia Karro, Peeter Brambat : režissöör Peeter Brambat : operaator Arvo Vilu : muusika Ardo R. Varres, Tõnu Kõrvits : produtsent Vahur Laiapea : Ikoon, AD Oculos Film 2004

  15. Dokfilm Mustjalast tõi võttegrupile ärakasutamissüüdistuse / Oliver Rand

    Index Scriptorium Estoniae

    Rand, Oliver, 1971-

    2007-01-01

    Sulev Keeduse dokumentaalfilmi "Jonathan Austraaliast" on Mustjalas puhkenud pahameeletorm. Nördimust avaldavad valla sotsiaaltöötaja Saima Lõhmus, vallavanem Kalle Kolter, vallavolikogu esimees Toivo Lõhmus, kui ka üks filmis osaleja Toomas Mõttus. Süüdistusi eitavad režissöör S. Keedus ja assistent Salme Poopuu

  16. 1. X toimus Hanila Muuseumi Seltsi pidulik koosolek... / Laine Vesker

    Index Scriptorium Estoniae

    Vesker, Laine

    2005-01-01

    Anti üle tunnistused seltsi auliikmetele, kelleks on Lennart Meri, Heinz Valk, Saima Mägi, Lily Kocins, Helmut Polberg, Mai Schröder, Eimar Kaasik, Hermi Vain, Elmar Vesker, Õie Pärna, Marju Heldema, Piret Leiumaa ja Salme Valdmets

  17. Homology modeling of ɣ-aminobutyrate- aminotransferase, a ...

    African Journals Online (AJOL)

    Jane

    2011-06-29

    Jun 29, 2011 ... enzyme of Homo sapiens: Molecular modeling approach to rational drug design against epilepsy. Hina Naz Khan1, Hamid Rashid1*and Saima Kulsoom2. 1Department of Bioinformatics, Mohammad Ali Jinnah University, Islamabad, Pakistan. 2Department of Chemistry, Quaid-e-Azam University, Pakistan.

  18. Rotary klubi tuli rannarahvale appi / Anu Jürisson

    Index Scriptorium Estoniae

    Jürisson, Anu

    2005-01-01

    Tallinna Vanalinna Rotary klubi kinkis kolmele Rannametsa perele kümme tuhat krooni jaanuaritormi kahjustuste likvideerimiseks. Klubi presidendiks on Allan Martinson, nimekirjas ka Tõnis Palts, Toomas Hendrik Ilves, Rein Kilk, Hans H. Luik, Vahur Kraft jt.

  19. Laulvad kirjanikud Juuksuris / Irja Tähismaa

    Index Scriptorium Estoniae

    Tähismaa, Irja, 1977-

    2007-01-01

    20. aprillil esitleti Tallinna klubis Juuksur heliplaati "Laulvad kirjanikud". Esitajad: Lauri Sommer, Jüri Kaldmaa, Aapo Ilves, Jan Rahman, Merca, Jaan Pehk, Aleksander Müller, Jürgen Rooste, Vahur Afanasjev

  20. 19. IV avati Y-galeriis Andreas W kureeritud näitus "Puudumise kohalolu : the presence of absence"

    Index Scriptorium Estoniae

    2005-01-01

    Osalevad kunstnikud Kaisa Eiche, Toomas Kalve, Alan Proosa, Maari Ross, Riho Peiker, Anna Hints, Siim Vahur, Katz, Alan Ross, Jaan Sokk, Andreas W, Taavi Piibemann ja Kalev Vapper on Tartu Kõrgemast Kunstikoolist või sellega seotud

  1. Huilun jäljillä / Hilkka Eklund

    Index Scriptorium Estoniae

    Eklund, Hilkka

    2006-01-01

    W. A. Mozarti "Võluflööt" Von Krahli Teatris (lavastuse kontseptsioon ja lavastus Peeter Jalakalt, tantsude seade Sasha Pepeljajevilt), Vahur Kelleri "Võluflöödi" lavastus Eesti Nukuteatris ja Jussi Tapola lavastus Soome Rahvusooperis

  2. "Rohkem naisest kui näitlejast..." / Meelis Kapstas

    Index Scriptorium Estoniae

    Kapstas, Meelis, 1963-

    2006-01-01

    Ilmus Ita Everi elulooraamat "Ita Ever. Elu suuruses". Näitlejannad Viire Valdma, Mari-Liis Lill, Ülle Kaljuste, Britta Vahur, Elina Reinold, Kersti Kreismann, Merle Palmiste ja Ülle Ulla avaldavad oma esmamulje raamatust

  3. Zolotaja medal za upakovku

    Index Scriptorium Estoniae

    2006-01-01

    Eesti pakenditootja AS Cista võitis kuldmedali Moskvas toimunud pakendikonkursil "Venemaa tähed 2006". Pakendi autor on eesti kunstnik Andres Palopääl. Kommenteerib firma juhatuse esimees Vahur Käärik

  4. Vahva notsu ja nähtamatu ämblik / Pille-Riin Purje

    Index Scriptorium Estoniae

    Purje, Pille-Riin, 1963-

    2000-01-01

    Elwyn Brooks White'i lasteraamatu ainetel valminud lavalugu lastele "Charlotte koob võrku", lavastaja EMA Kõrgema Lavakunstikooli XIX lennu lavastaja-diplomand Vahur Keller. Esietendus Vanemuises 8. jaan

  5. Charlotte koob Vanemuises võrku / Jaanika Juhanson

    Index Scriptorium Estoniae

    Juhanson, Jaanika, 1977-

    2000-01-01

    Elwyn Brooks White'i lasteraamatu ainetel valminud lavalugu lastele "Charlotte koob võrku", lavastaja EMA Kõrgema Lavakunstikooli XIX lennu lavastaja-diplomand Vahur Keller. Esietendus Vanemuises 8. jaan

  6. Vesilinnu teekonnalt maailma otsa / Juhani Püttsepp

    Index Scriptorium Estoniae

    Püttsepp, Juhani, 1964-

    2011-01-01

    Vassili Sarana dokumentaalfilmidest "Suur jõgi: Retk Leena lättele" ja "Delta", produtsent, helioperaator, jutustaja Riho Västrik ja monteerija Liina Triškina. Vestlusest dokumentalist Vahur Laiapeaga

  7. Tuuletul minestusjärvel rulluvat lainet püüdes / Kalle Mälberg

    Index Scriptorium Estoniae

    Mälberg, Kalle, 1948-

    2010-01-01

    Vahur Laiapea dokumnetaalfilmid "Arnold Rüütel. Lõpetamata lause" (2006), "Teisel pool pidalitõbe" (2006), "Film minu emast" (2007), "Ilusad inimesed" (2008), "Krimmi õpetaja" (2009), "Eric. Tule laps" (2009) ja "Doktor Grossmanni jumalate maa" (2009)

  8. Kelgu uued koerad / Inge Pitsner

    Index Scriptorium Estoniae

    Pitsner, Inge

    2007-01-01

    Eesti omamaise krimiseriaali võtetel Pirital. Osalevad produtsent Toomas Kirss, näitlejad Ivo Uukkivi, Madis Milling, Mait Malmsten, Karin Rask, Britta Vahur. Lisatud lühiintervjuud Karin Raski ja Britta Vahuriga

  9. Leviv HI-viirus suurendab Eestis tuberkuloosiohtu / Agnes Kuus

    Index Scriptorium Estoniae

    Kuus, Agnes

    2005-01-01

    Põhja-Eesti Regionaalhaigla tuberkuloosiregistri juhataja Vahur Hollo tõdes, et tuberkuloosiga nakatanute koguarvu on keeruline määrata, sest suur osa viirusekandjaist ei haigestu kunagi. Lisa: Tuberkuloos

  10. Kohtuotsus on õige : ['Siioni tarkade protokolli' eesti tõlke hävitamine] / Ain Kaalep

    Index Scriptorium Estoniae

    Kaalep, Ain, 1926-

    1995-01-01

    Vastukaja : Tärni, Aulis. Tuleriit kohalikust punasest kütusest // Postimees. - 1995. - 24.nov. - Lk.6; Kalmre, Vahur. Raamatute kaitseks // Postimees. - 1995. - 27.nov. - Lk. 6; Langemets, Andres. Eesti ja juudi // Postimees. - 1995. - 30.nov. - Lk.8

  11. FGFR3, HRAS, KRAS, NRAS AND PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy

    NARCIS (Netherlands)

    L.C. Kompier (Lucie); I. Lurkin (Irene); M.M.N. van der Aa (Madelon); B.W.G. van Rhijn (Bas); Th.H. van der Kwast (Theo); E.C. Zwarthoff (Ellen)

    2010-01-01

    textabstractBackground: Fifty percent of patients with muscle-invasive bladder cancer (MI-BC) die from their disease and current chemotherapy treatment only marginally increases survival. Novel therapies targeting receptor tyrosine kinases or activated oncogenes may improve outcome. Hence, it is

  12. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis

    DEFF Research Database (Denmark)

    De Roock, Wendy; Claes, Bart; Bernasconi, David

    2010-01-01

    Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients...... with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre...

  13. PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway

    Directory of Open Access Journals (Sweden)

    Wei Zhang

    2014-12-01

    Full Text Available PCI-24781 is a novel histone deacetylase inhibitor that inhibits tumor proliferation and promotes cell apoptosis. However, it is unclear whether PCI-24781 inhibits Enhancer of Zeste 2 (EZH2 expression in malignant gliomas. In this work, three glioma cell lines were incubated with various concentrations of PCI-24781 (0, 0.25, 0.5, 1, 2.5 and 5 M and analyzed for cell proliferation by the MTS 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium assay and colony formation, and cell cycle and apoptosis were assessed by flow cytometry. The expression of EZH2 and apoptosis-related proteins was assessed by western blotting. Malignant glioma cells were also transfected with EZH2 siRNA to examine how PCI-24781 suppresses tumor cells. EZH2 was highly expressed in the three glioma cell lines. Incubation with PCI-24781 reduced cell proliferation and increased cell apoptosis by down-regulating EZH2 in a concentration-dependent manner. These effects were simulated by EZH2 siRNA. In addition, PCI-24781 or EZH2 siRNA accelerated cell apoptosis by down-regulating the expression of AKT, mTOR, p70 ribosomal protein S6 kinase (p70s6k, glycogen synthase kinase 3A and B (GSK3a/b and eukaryotic initiation factor 4E binding protein 1 (4E-BP1. These data suggest that PCI-24781 may be a promising therapeutic agent for treating gliomas by down-regulating EZH2 which promotes cell apoptosis by suppressing the phosphatidylinositol 3-kinase (PI3K/Akt/mammalian target of the rapamycin (mTOR pathway.

  14. University of Texas MD Anderson: Phenotypic Examination of PIK3CA Allelic Series using In Vitro/In Vivo Sensor Platforms | Office of Cancer Genomics

    Science.gov (United States)

    The CTD2 Center at the University of Texas MD Anderson Cancer Center utilized an established and operational MCF10A normal breast epithelial cell model to assess the ability of candidate driver aberrations to promote cell grow in anchorage-independent conditions (soft agar assay) and proliferate in the absence of insulin and epidermal growth factor (EGF).

  15. Wave spectral response to sudden changes in wind direction in finite depth waters

    Science.gov (United States)

    2015-11-14

    Virtual Special Issue Ocean Surface Waves Wave spectral response to sudden changes in wind direction in finite -depth waters Saima Aijaz a , ∗, W...exact solutions of the nonlinear term n two-dimensional models, in particular for finite -depth waters. In ddition to the complexities of shallow water...vary in time. This study seeks to investigate the wave response in finite -depth aters due to sudden changes in wind by conducting numerical imulations

  16. The Mediating Effects of Hardiness on Resilience in Repatriated Vietnam-Era Prisoners of War

    Science.gov (United States)

    2015-11-30

    The Mediating Effects of Hardiness on Resilience in Repatriated Vietnam-Era Prisoners of War Saima S. Raza, LT, MSC, USN Jeffrey L. Moore, Ph.D...optimism, emotional regulation, impulse control, empathy, causal analysis, self-efficacy, and reaching out (social support). More recently, Southwick and...models, maintaining physical fitness, learning cognitive and emotional flexibility, and having a growth-promoting sense of meaning and purpose in

  17. Davaite budem nemnogo glupõmi / Luiza Mishina

    Index Scriptorium Estoniae

    Mishina, Luiza

    1996-01-01

    Nagibin, Juri. Tma v kontse tunnelja. Moja zolotaja teshtsha : Povesti. Moskva : PIK, 1994; Nagibin, Juri. Dafnis i Hloja epohhi kulta litshnosti, voljuntarisma i zastoja : Istorija odnoi ljubvi. Moskva : PIK, 1995

  18. Measurements of the Branching Fractions of B0 --> K^*0K+K-, B0 --> K^*0pi+K-, B0 --> K*0K+pi-, and B0 --> K*0pi+pi-

    CERN Document Server

    Aubert, B; Karyotakis, Yu; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Graugès-Pous, E; López, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes-Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabé, T; Wenzel, W A; Del Amo-Sánchez, P; Hawkes, C M; Watson, A T; Koch, H; Schröder, T; Walker, D; Asgeirsson, D J; Çuhadar-Dönszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Vitug, G M; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, C; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; De Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro-Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Bequilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Sacco, R; Cowan, G; Flächer, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Bailey, D; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; Mclachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, Gallieno; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; LoSecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Sekula, S J; Wong, Q K; Blount, N L; Brau, J E; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; De La Vaissière, C; Hamon, O; Leruste, P; Malcles, J; Ocariz, J; Pérez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Biesiada, J; Elmer, P; Lau, Y P; Lü, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Röthel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yéche, C; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; White, R M; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Lüth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Müller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Vavra, J; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Ziegler, V; Burchat, P R; Edwards, A J; Majewski, S A; Miyashita, T S; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martínez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-01-01

    Branching fraction and asymmetry measurements of charmless $B^0\\to K^{*0}h^+_1h^-_2$ ($h_{1,2}$ = $K$, $\\pi$) decays are presented, using a data sample of 383 million $\\Upsilon(4S) \\to$ $B\\bar{B$} decays collected with the BaBar detector at the PEP-II asymmetric-energy $B$-meson factory at SLAC. The results are: ${\\cal B}$($B^0 \\to K^{*0}K^+ K^-)$ = (27.5 $\\pm$ 1.3 $\\pm$ 2.2) $\\times$ 10$^{-6}$, ${\\cal B}$($B^0$ $\\to$ $K^{*0}\\pi^+ K^-$) = (4.6 $\\pm$ 1.1 $\\pm$ 0.8) $\\times$ 10$^{-6}$ and ${\\cal B}$($B^0$ $\\to$ $K^{*0}\\pi^+\\pi^-$) = (54.5 $\\pm$ 2.9 $\\pm$ 4.3) $\\times$ 10$^{-6}$. The first errors quoted are statistical and the second are systematic. An upper limit is set for ${\\cal B}$($B^0$ $\\to$ $K^{*0}K^+ \\pi^-$) $<$ 2.2 $\\times$ 10$^{-6}$ at 90% confidence level.

  19. Measurements of $\\Lambda_c^+ \\to p K^-K^+$, $\\Lambda_c^+ \\to p \\pi^-\\pi^+$ and $\\Lambda_c^+ \\to p \\pi^-K^+$ branching ratios

    CERN Document Server

    Aaij, Roel; LHCb Collaboration; Adinolfi, Marco; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Alfonso Albero, Alejandro; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Andreassi, Guido; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Archilli, Flavio; d'Argent, Philippe; Arnau Romeu, Joan; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Babuschkin, Igor; Bachmann, Sebastian; Back, John; Badalov, Alexey; Baesso, Clarissa; Baker, Sophie; Balagura, Vladislav; Baldini, Wander; Baranov, Alexander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Baryshnikov, Fedor; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Beiter, Andrew; Bel, Lennaert; Beliy, Nikita; Bellee, Violaine; Belloli, Nicoletta; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Beranek, Sarah; Berezhnoy, Alexander; Bernet, Roland; Berninghoff, Daniel; Bertholet, Emilie; Bertolin, Alessandro; Betancourt, Christopher; Betti, Federico; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bezshyiko, Iaroslava; Bifani, Simone; Billoir, Pierre; Birnkraut, Alex; Bitadze, Alexander; Bizzeti, Andrea; Bjørn, Mikkel; Blake, Thomas; Blanc, Frederic; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Boettcher, Thomas; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Bordyuzhin, Igor; Borgheresi, Alessio; Borghi, Silvia; Borisyak, Maxim; Borsato, Martino; Bossu, Francesco; Boubdir, Meriem; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Braun, Svende; Britton, Thomas; Brodzicka, Jolanta; Brundu, Davide; Buchanan, Emma; Burr, Christopher; Bursche, Albert; Buytaert, Jan; Byczynski, Wiktor; Cadeddu, Sandro; Cai, Hao; Calabrese, Roberto; Calladine, Ryan; Calvi, Marta; Calvo Gomez, Miriam; Camboni, Alessandro; Campana, Pierluigi; Campora Perez, Daniel Hugo; Capriotti, Lorenzo; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carniti, Paolo; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cavallero, Giovanni; Cenci, Riccardo; Chamont, David; Chapman, Matthew George; Charles, Matthew; Charpentier, Philippe; Chatzikonstantinidis, Georgios; Chefdeville, Maximilien; Chen, Shanzhen; Cheung, Shu Faye; Chitic, Stefan-Gabriel; Chobanova, Veronika; Chrzaszcz, Marcin; Chubykin, Alexsei; Ciambrone, Paolo; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Cogan, Julien; Cogneras, Eric; Cogoni, Violetta; Cojocariu, Lucian; Collins, Paula; Colombo, Tommaso; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombs, George; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Costa Sobral, Cayo Mar; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Crocombe, Andrew; Cruz Torres, Melissa Maria; Currie, Robert; D'Ambrosio, Carmelo; Da Cunha Marinho, Franciole; Dall'Occo, Elena; Dalseno, Jeremy; Davis, Adam; De Aguiar Francisco, Oscar; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Serio, Marilisa; De Simone, Patrizia; Dean, Cameron Thomas; Decamp, Daniel; Del Buono, Luigi; Dembinski, Hans Peter; Demmer, Moritz; Dendek, Adam; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Dey, Biplab; Di Canto, Angelo; Di Nezza, Pasquale; Dijkstra, Hans; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Douglas, Lauren; Dovbnya, Anatoliy; Dreimanis, Karlis; Dufour, Laurent; Dujany, Giulio; Durante, Paolo; Dzhelyadin, Rustem; Dziewiecki, Michal; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Ebert, Marcus; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Farley, Nathanael; Farry, Stephen; Fazzini, Davide; Federici, Luca; Ferguson, Dianne; Fernandez, Gerard; Fernandez Declara, Placido; Fernandez Prieto, Antonio; Ferrari, Fabio; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fini, Rosa Anna; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fleuret, Frederic; Fohl, Klaus; Fontana, Marianna; Fontanelli, Flavio; Forshaw, Dean Charles; Forty, Roger; Franco Lima, Vinicius; Frank, Markus; Frei, Christoph; Fu, Jinlin; Funk, Wolfgang; Furfaro, Emiliano; Färber, Christian; Gabriel, Emmy; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; Garcia Martin, Luis Miguel; García Pardiñas, Julián; Garra Tico, Jordi; Garrido, Lluis; Garsed, Philip John; Gascon, David; Gaspar, Clara; Gavardi, Laura; Gazzoni, Giulio; Gerick, David; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianì, Sebastiana; Gibson, Valerie; Girard, Olivier Göran; Giubega, Lavinia-Helena; Gizdov, Konstantin; Gligorov, Vladimir; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gorelov, Igor Vladimirovich; Gotti, Claudio; Govorkova, Ekaterina; Grabowski, Jascha Peter; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graverini, Elena; Graziani, Giacomo; Grecu, Alexandru; Greim, Roman; Griffith, Peter; Grillo, Lucia; Gruber, Lukas; Gruberg Cazon, Barak Raimond; Grünberg, Oliver; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Göbel, Carla; Hadavizadeh, Thomas; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hamilton, Brian; Han, Xiaoxue; Hancock, Thomas Henry; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; Hasse, Christoph; Hatch, Mark; He, Jibo; Hecker, Malte; Heinicke, Kevin; Heister, Arno; Hennessy, Karol; Henrard, Pierre; Henry, Louis; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hombach, Christoph; Hopchev, Plamen Hristov; Huard, Zachary; Hulsbergen, Wouter; Humair, Thibaud; Hushchyn, Mikhail; Hutchcroft, David; Ibis, Philipp; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jalocha, Pawel; Jans, Eddy; Jawahery, Abolhassan; Jiang, Feng; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kandybei, Sergii; Karacson, Matthias; Kariuki, James Mwangi; Karodia, Sarah; Kazeev, Nikita; Kecke, Matthieu; Kelsey, Matthew; Kenzie, Matthew; Ketel, Tjeerd; Khairullin, Egor; Khanji, Basem; Khurewathanakul, Chitsanu; Kirn, Thomas; Klaver, Suzanne; Klimaszewski, Konrad; Klimkovich, Tatsiana; Koliiev, Serhii; Kolpin, Michael; Komarov, Ilya; Kopecna, Renata; Koppenburg, Patrick; Kosmyntseva, Alena; Kotriakhova, Sofia; Kozeiha, Mohamad; Kravchuk, Leonid; Kreps, Michal; Krokovny, Pavel; Kruse, Florian; Krzemien, Wojciech; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kuonen, Axel Kevin; Kurek, Krzysztof; Kvaratskheliya, Tengiz; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lanfranchi, Gaia; Langenbruch, Christoph; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; Leflat, Alexander; Lefrançois, Jacques; Lefèvre, Regis; Lemaitre, Florian; Lemos Cid, Edgar; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Pei-Rong; Li, Tenglin; Li, Yiming; Li, Zhuoming; Likhomanenko, Tatiana; Lindner, Rolf; Lionetto, Federica; Lisovskyi, Vitalii; Liu, Xuesong; Loh, David; Loi, Angelo; Longstaff, Iain; Lopes, Jose; Lucchesi, Donatella; Lucio Martinez, Miriam; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Lusiani, Alberto; Lyu, Xiao-Rui; Machefert, Frederic; Maciuc, Florin; Macko, Vladimir; Mackowiak, Patrick; Maddrell-Mander, Samuel; Maev, Oleg; Maguire, Kevin; Maisuzenko, Dmitrii; Majewski, Maciej Witold; Malde, Sneha; Malinin, Alexander; Maltsev, Timofei; Manca, Giulia; Mancinelli, Giampiero; Manning, Peter Michael; Marangotto, Daniele; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marinangeli, Matthieu; Marino, Pietro; Marks, Jörg; Martellotti, Giuseppe; Martin, Morgan; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massacrier, Laure Marie; Massafferri, André; Matev, Rosen; Mathad, Abhijit; Mathe, Zoltan; Matteuzzi, Clara; Mauri, Andrea; Maurice, Emilie; Maurin, Brice; Mazurov, Alexander; McCann, Michael; McNab, Andrew; McNulty, Ronan; Mead, James Vincent; Meadows, Brian; Meaux, Cedric; Meier, Frank; Meinert, Nis; Melnychuk, Dmytro; Merk, Marcel; Merli, Andrea; Michielin, Emanuele; Milanes, Diego Alejandro; Millard, Edward James; Minard, Marie-Noelle; Minzoni, Luca; Mitzel, Dominik Stefan; Mogini, Andrea; Molina Rodriguez, Josue; Mombächer, Titus; Monroy, Igancio Alberto; Monteil, Stephane; Morandin, Mauro; Morello, Michael Joseph; Morgunova, Olga; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Mulder, Mick; Müller, Dominik; Müller, Janine; Müller, Katharina; Müller, Vanessa; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nandi, Anita; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Thi Dung; Nguyen-Mau, Chung; Nieswand, Simon; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Nogay, Alla; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Ogilvy, Stephen; Oldeman, Rudolf; Onderwater, Gerco; Ossowska, Anna; Otalora Goicochea, Juan Martin; Owen, Patrick; Oyanguren, Maria Aranzazu; Pais, Preema Rennee; Palano, Antimo; Palutan, Matteo; Papanestis, Antonios; Pappagallo, Marco; Pappalardo, Luciano; Parker, William; Parkes, Christopher; Passaleva, Giovanni; Pastore, Alessandra; Patel, Mitesh; Patrignani, Claudia; Pearce, Alex; Pellegrino, Antonio; Penso, Gianni; Pepe Altarelli, Monica; Perazzini, Stefano; Perret, Pascal; Pescatore, Luca; Petridis, Konstantinos; Petrolini, Alessandro; Petrov, Aleksandr; Petruzzo, Marco; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pikies, Malgorzata; Pinci, Davide; Pisani, Flavio; Pistone, Alessandro; Piucci, Alessio; Placinta, Vlad-Mihai; Playfer, Stephen; Plo Casasus, Maximo; Polci, Francesco; Poli Lener, Marco; Poluektov, Anton; Polyakov, Ivan; Polycarpo, Erica; Pomery, Gabriela Johanna; Ponce, Sebastien; Popov, Alexander; Popov, Dmitry; Poslavskii, Stanislav; Potterat, Cédric; Price, Eugenia; Prisciandaro, Jessica; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Pullen, Hannah Louise; Punzi, Giovanni; Qian, Wenbin; Quagliani, Renato; Quintana, Boris; Rachwal, Bartlomiej; Rademacker, Jonas; Rama, Matteo; Ramos Pernas, Miguel; Rangel, Murilo; Raniuk, Iurii; Ratnikov, Fedor; Raven, Gerhard; Ravonel Salzgeber, Melody; Reboud, Meril; Redi, Federico; Reichert, Stefanie; dos Reis, Alberto; Remon Alepuz, Clara; Renaudin, Victor; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vicente; Robbe, Patrick; Robert, Arnaud; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Lopez, Jairo Alexis; Rodriguez Perez, Pablo; Rogozhnikov, Alexey; Roiser, Stefan; Rollings, Alexandra Paige; Romanovskiy, Vladimir; Romero Vidal, Antonio; Ronayne, John William; Rotondo, Marcello; Rudolph, Matthew Scott; Ruf, Thomas; Ruiz Valls, Pablo; Ruiz Vidal, Joan; Saborido Silva, Juan Jose; Sadykhov, Elnur; Sagidova, Naylya; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santimaria, Marco; Santovetti, Emanuele; Sarpis, Gediminas; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrina, Darya; Schael, Stefan; Schellenberg, Margarete; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmelzer, Timon; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schreiner, HF; Schubert, Konstantin; Schubiger, Maxime; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Sepulveda, Eduardo Enrique; Sergi, Antonino; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Siddi, Benedetto Gianluca; Silva Coutinho, Rafael; Silva de Oliveira, Luiz Gustavo; Simi, Gabriele; Simone, Saverio; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Eluned; Smith, Iwan Thomas; Smith, Jackson; Smith, Mark; Soares Lavra, Lais; Sokoloff, Michael; Soler, Paul; Souza De Paula, Bruno; Spaan, Bernhard; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Stefko, Pavol; Stefkova, Slavomira; Steinkamp, Olaf; Stemmle, Simon; Stenyakin, Oleg; Stepanova, Margarita; Stevens, Holger; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Stramaglia, Maria Elena; Straticiuc, Mihai; Straumann, Ulrich; Sun, Jiayin; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Syropoulos, Vasileios; Szczekowski, Marek; Szumlak, Tomasz; Szymanski, Maciej Pawel; T'Jampens, Stephane; Tayduganov, Andrey; Tekampe, Tobias; Tellarini, Giulia; Teubert, Frederic; Thomas, Eric; van Tilburg, Jeroen; Tilley, Matthew James; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Toriello, Francis; Tourinho Jadallah Aoude, Rafael; Tournefier, Edwige; Traill, Murdo; Tran, Minh Tâm; Tresch, Marco; Trisovic, Ana; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tully, Alison; Tuning, Niels; Ukleja, Artur; Usachov, Andrii; Ustyuzhanin, Andrey; Uwer, Ulrich; Vacca, Claudia; Vagner, Alexander; Vagnoni, Vincenzo; Valassi, Andrea; Valat, Sebastien; Valenti, Giovanni; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vecchi, Stefania; van Veghel, Maarten; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Venkateswaran, Aravindhan; Verlage, Tobias Anton; Vernet, Maxime; Vesterinen, Mika; Viana Barbosa, Joao Vitor; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Viemann, Harald; Vilasis-Cardona, Xavier; Vitti, Marcela; Volkov, Vladimir; Vollhardt, Achim; Voneki, Balazs; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; de Vries, Jacco; Vázquez Sierra, Carlos; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wang, Jianchun; Ward, David; Wark, Heather Mckenzie; Watson, Nigel; Websdale, David; Weiden, Andreas; Whitehead, Mark; Wicht, Jean; Wilkinson, Guy; Wilkinson, Michael; Williams, Mark Richard James; Williams, Matthew; Williams, Mike; Williams, Timothy; Wilson, Fergus; Wimberley, Jack; Winn, Michael Andreas; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wraight, Kenneth; Wyllie, Kenneth; Xie, Yuehong; Xu, Zhirui; Yang, Zhenwei; Yang, Zishuo; Yao, Yuezhe; Yin, Hang; Yu, Jiesheng; Yuan, Xuhao; Yushchenko, Oleg; Zarebski, Kristian Alexander; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Yanxi; Zhelezov, Alexey; Zheng, Yangheng; Zhu, Xianglei; Zhukov, Valery; Zonneveld, Jennifer Brigitta; Zucchelli, Stefano

    2017-01-01

    The ratios of the branching fractions of the decays $\\Lambda_{c}^{+} \\rightarrow p \\pi^{-} \\pi^{+}$, $\\Lambda_{c}^{+} \\rightarrow p K^{-} K^{+}$, and $\\Lambda_{c}^{+} \\rightarrow p \\pi^{-} K^{+}$ with respect to the Cabibbo-favoured $\\Lambda_{c}^{+} \\rightarrow p K^{-} \\pi^{+}$ decay are measured using proton-proton collision data collected with the LHCb experiment at a 7 TeV centre-of-mass energy and corresponding to an integrated luminosity of 1.0 fb$^{-1}$: \\begin{align*} \\frac{\\mathcal{B}(\\Lambda_{c}^{+} \\rightarrow p \\pi^{-} \\pi^{+})}{\\mathcal{B}(\\Lambda_{c}^{+} \\rightarrow p K^{-} \\pi^{+})} & = (7.44 \\pm 0.08 \\pm 0.18)\\,\\%, \\\\ \\frac{\\mathcal{B}(\\Lambda_{c}^{+} \\rightarrow p K^{-} K^{+})}{\\mathcal{B}(\\Lambda_{c}^{+} \\rightarrow p K^{-} \\pi^{+})} &= (1.70 \\pm 0.03 \\pm 0.03)\\,\\%, \\\\ \\frac{\\mathcal{B}(\\Lambda_{c}^{+} \\rightarrow p \\pi^{-} K^{+})}{\\mathcal{B}(\\Lambda_{c}^{+} \\rightarrow p K^{-} \\pi^{+})} & = (0.165 \\pm 0.015 \\pm 0.005 )\\,\\%, \\end{align*} where the...

  20. PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery

    Science.gov (United States)

    2017-09-04

    Advanced Malignant Solid Neoplasm; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Metastatic Malignant Solid Neoplasm; Progesterone Receptor Negative; PTEN Gene Mutation; Triple-Negative Breast Carcinoma; Unresectable Solid Neoplasm

  1. Suur fondijuhtide ülevaade

    Index Scriptorium Estoniae

    2006-01-01

    Küsimustele vastavad Toomas Reisenbuk, Valdur Jaht, Mehis Raud, Siim Valner, Vahur Madisson, Meelis Angerma, Alo Kullamaa, Endriko Võrklaev, Arne Randmaa, Andrei Zaborski, Robert Kitt, Fabio Filipozzi, Martin Hendre, Piotr Chorzewski, Artjom Saia, Aari Stalde ja Märten Kress

  2. Ghanas Kongo külas. Viiekesi ja vabatahtlikult / Meeli Parijõgi

    Index Scriptorium Estoniae

    Parijõgi, Meeli

    2013-01-01

    Reisist Põhja-Ghanas asuvasse Kongo külla koos Johanna Helinaga arengukoostöö ja maailmahariduse organisatsioonist Mondo, füüsikaõpetaja Mart Kuurme ja dokfilmide tegija Vahur Laiapeaga. Inglise keele õpetaja Anu Joon töötab seal vabatahtlikuna juba septembrist

  3. Tallinna ülikool võitis tudengijalgpalli / Margus Martin

    Index Scriptorium Estoniae

    Martin, Margus

    2007-01-01

    Rakvere spordihallis peetud Eesti üliõpilaste saalijalgpalli meistrivõistlustel võitis meistrikulla ja koos sellega õiguse esindada Eestit saalijalgpalli Euroopa meistrivõistlustel Sloveenias Koperis. Tallinna Ülikooli meeskond koosseisus Vahur Kiis, Lauri Mihkelson, Paul Kask, Viljar Jürna, Henri Paavo, Lennart Tuulmets ja Reijo Kuusik

  4. Euro esimene kümme / Sirje Rank

    Index Scriptorium Estoniae

    Rank, Sirje, 1966-

    2008-01-01

    Ilmunud ka: Delovõje Vedomosti 7. mai lk. 32. Euroopa ühisraha euro asutamine ja areng. Arvamust avaldavad Siim Kallas ja Vahur Kraft. Kommenteerib Raivo Vare: Eesti võib euro saada 2015-2017. Vt. samas: Luukamber uusliikmetele on praegu karmim; Taust; Diagramm: Euro tervis on kümne aastaga tugevamaks muutunud

  5. Ararati mäe otsast näeb Petseri kloostrit / Tiit tuumalu

    Index Scriptorium Estoniae

    Tuumalu, Tiit, 1971-

    2011-01-01

    Riho Västriku film "Teekond Araratile", mis võtab luubi alla baltisaksa maadeuurija Friedrich Parrot, kes tõusis 1829. aastal Ararati tippu ja Vahur Laiapea dokumentaalfilmist "Kloostriga seotud", mis viib vaataja Petseri kloostrisse ja portreteerib Püha Varvara nimelise kiriku preestrit isa Jevgenit, nunn Olgat ja Gennadit

  6. Kirjanikud annavad välja lauluplaadi

    Index Scriptorium Estoniae

    2007-01-01

    20. aprillil esitletakse Tallinna klubis Juuksur heliplaati "Laulvad kirjanikud", esitlus Tartus 5. mail ja Võrus 6. mail. Esitajad: Lauri Sommer, Jüri Kaldmaa, Aapo Ilves, Jan Rahman, Merca, Jaan Pehk, Aleksander Müller, Jürgen Rooste, Vahur Afanasjev. Vt. ka Keskus, 2007, apr., lk. 6 ; Eesti Päevaleht, 2007, 20. apr., lk.15

  7. Vestlusring : Tööturul valitseb segadus / interv. Tõnis Tõnisson

    Index Scriptorium Estoniae

    2005-01-01

    Tööst ja töötusest Raplamaal vestlevad Raplamaa Arendus- ja Ettevõtluskeskuse juhataja Janek Kadarik, projektijuht Rando Lai, Raplamaa Noorte Teabekeskuse juht Marje Reimund, Raplamaa Tööhõiveameti direktor Vahur Soikmets, Rapla Ettevõtjate Ühenduse juhatuse esimees Raivo Erm ja Nädalise reklaamisosakonna juhataja Kaja Ohaka

  8. Riigi saladuste tippkaitsja jäi vahele info tellijate lohakuse tõttu / Rasmus Kagge

    Index Scriptorium Estoniae

    Kagge, Rasmus, 1977-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 24. sept. 2008, lk. 3. Kunagine politseijuht ja riigiametnik Herman Simm annab tunnistusi kahtlustatuna riigi salajase info edastamises. Vt. samas: Herman Simmile ja Heete Simmile kuuluv või kuulunud kinnisvara; Suud lukus; Vahur Koorits. Edutult lõppenud astelpajuäri; Dagne Hanschmidt. Õpetas koolilapsi kodumaad kaitsma

  9. Kak estonski oboroten litovskuju korovu ukral / Jevgenia Garanzha

    Index Scriptorium Estoniae

    Garanža, Jevgenija, 1979-

    2004-01-01

    Leedu teleprogrammide ja -filmide festivalil "Amber arch" ("Merevaigust arkaad") võitis peapreemia Priit Valkna dokumentaalfilm "Hunt", mille tootis Allfilm ETV "Eesti lugude" dokumentaalsarja. Osales ka Vahur Laiapea telesari setudest "Veere pääl". Ulatuslik ülevaade festivalist

  10. Parim Puitehitis 2005 on lasteaed

    Index Scriptorium Estoniae

    2006-01-01

    Eesti Metsatööstuse Liidu korraldatud konkursil 2005. aasta parima puitehitise tiitli pälvinud lasteaed Naba Pirital. Arhitektid Lauri Saar ja Vahur Sova. Sisearhitekt Mari Tosmin. Ehitaja: KMG Ehitus. Kommenteerivad arhitektid, sisearhitekt, firma KMG Ehitus juht Tiit Nurklik, projektijuht Deivy Paavo. 5 värv. ill

  11. Lasteaed Naba / Maris Kerge

    Index Scriptorium Estoniae

    Kerge, Maris

    2005-01-01

    Konkursil "Eesti parim puitehitis 2005" parima puitehitise tiitli pälvinud lasteaed Naba Pirital. Arhitektid Lauri Saar ja Vahur Sova. Sisearhitekt Mari Tosmin. Insener Tõnu Peipman. Ehitus: KMG Ehitus. Ill.: 2 värv. välis- ja 8 sisevaadet

  12. Riiklikud teenetemärgid narvakatele / Sergei Stepanov

    Index Scriptorium Estoniae

    Stepanov, Sergei

    2005-01-01

    Ilmunud ka: Narvskaja Gazeta 5. veebr., lk. 2. President Arnold Rüütel autasustab narvakatest ettevõtjaid Miroslaw Pienkowskit, Aleksandr Brokki, Narva Pensionäride Liidu esinaist Helga Mihelsoni, maavanemat Ago Sildet, kapten Vahur Murulaidi, Ida piirivalvepiirkonna ülemat Roland Peetsi ja Ida-Virumaa ühiskonnategelast Aleksandr Dusmani

  13. Riiklikud teenetemärgid narvakatele / Sergei Stepanov

    Index Scriptorium Estoniae

    Stepanov, Sergei

    2005-01-01

    Ilmunud ka Narvskaja Gazeta (2005/Feb/5) lk. 2. President Arnold Rüütel autasustab narvakatest ettevõtjaid Miroslaw Pienkowskit, Aleksandr Brokki, Narva Pensionäride Liidu esinaist Helga Mihelsoni, maavanemat Ago Sildet, kapten Vahur Murulaidi, Ida piirivalvepiirkonna ülemat Roland Peetsi ja Ida-Virumaa ühiskonnategelast Aleksandr Dusmani

  14. Mida tulevikuga peale hakata? / Arko Olesk

    Index Scriptorium Estoniae

    Olesk, Arko, 1981-

    2014-01-01

    Arvustus: Kaku, Michio. Tulevikufüüsika : kuidas teadus aastal 2100 kujundab inimsaatust ja meie igapäevast elu / tlk. Arko Olesk. Tallinn : Pilgrim, 2013 ; Stevenson, Mark. Optimisti teekond tulevikku : üks uudishimulik sell tahab teada: mis saab edasi? / tlk. Vahur Lokk. Tallinn : Äripäev, 2013

  15. Advokaadi väitel pole Niguliste kirikut kunagi võõrandatud / Hille Tänavsuu

    Index Scriptorium Estoniae

    Tänavsuu, Hille, 1941-2014

    2008-01-01

    Advokaadibüroo Eiche & Partnerid väidab, et Tallinna Niguliste kirik pole kunagi kuulunud EELK Konsistooriumile, seda pole õigusvastaselt võõrandatud ja seega puudub alus ka selle tagastamiseks või kompenseerimiseks. Arvamus toetub arhiivimaterjalidele. Kirikus asub Niguliste muuseum. Kommenteerivad Vahur Glaase, Alar Eiche. Lisatud: Toomkirik kuulub riigile

  16. Nimetage mõned suuremad nõmedused, mida üks ülemus teha saab? / Kairi Ütsmüts, Allan Rosenberg, Katriin Jüriska ... [jt.

    Index Scriptorium Estoniae

    2010-01-01

    Küsimusele vastavad Swedbank Eesti infotehnoloogia projektijuht Kairi Ütsmüts, Aspiro Eesti müügijuht Allan Rosenberg, Uuskasutuskeskuse tegevjuht Katriin Jüriska, Tele2 toote- ja turundusjuht Reilika Ilp, GrabCAD'i omanik ja insener Indrek Narusk ning turismifirma Estfly omanik Vahur Mäe

  17. IMF toetab Eesti maksureformi / Andris Feldmanis, Kertu Ruus

    Index Scriptorium Estoniae

    Feldmanis, Andris, 1982-

    2004-01-01

    Rahvusvahelise Valuutafondi (IMF) Eesti missiooni juht Richard Haas tutvustab äsjailmunud IMF-i raportis esitatud hinnangut Eesti majanduse hetkeseisu kohta ja võimalikke järgneva 15 aasta makroohtusid, sh jooksevkonto puudujääki ja laenamise kiiret kasvu. Rahandusminister Taavi Veskimägi ja Eesti Panga presidendi Vahur Krafti kommentaarid. Diagramm: Eesti laenukoormuse kasv kiireim

  18. Euro on teel / Ivar Jung

    Index Scriptorium Estoniae

    Jung, Ivar

    2005-01-01

    Reet Varblase kureeritud näitus "Oma raha" Tallinna Kunstihoone galeriis 12. XI-4. XII. Gints Gabransi videotest, Jaan Jaanisoo masin-installatsioonist, Siim-Tanel Annuse tööst. 2. XII galeriis toimunud kunstnike, kultuurihuviliste ja rahamaailma esindajate (Eesti Panga asepresident Rein Minka, endine president Vahur Kraft, rahandusministri nõuniku kt Veiko Valkiainen) kohtumisest

  19. Häda mõist(mat)use pärast / Allar Veelma

    Index Scriptorium Estoniae

    Veelma, Allar

    2007-01-01

    Vastukaja artiklile: Koorits, Vahur. Üha enam noori keerab matemaatikale selja // Postimees (2007) 9. märts. 2007. aastal on matemaatika riigieksami valinute arv eelmise aastaga võrreldes kahanenud mitmesaja võrra. Milliseid tagajärgi uuendatava õppekava matemaatika ainekava kinnitamine endaga kaasa toob

  20. Kodumaine ja nooruslik / Piret Veigel, Irene Roos

    Index Scriptorium Estoniae

    Veigel, Piret, 1961-

    2003-01-01

    Arhitekt Vahur Sova projekteeritud ökomaja eeskujul kujundatud elutuba. Värvivalik on inspireeritud looduse sügistalvistest toonidest ja naturaalsetest materjalidest. Stilistid Piret Veigel ja Irene Roos. Vineerkapi on kujundanud Tarmo Luisk, laua Jan J. Graps, sirmi Igor Volkov

  1. Kustas ja Villem sajandi algul / Toomas Haug

    Index Scriptorium Estoniae

    Haug, Toomas, 1956-

    1997-01-01

    1904. a. ajakirjas "Linda" ilmunud Gustav Suitsu (pseud. Kustas Vahur) luuletustest "Mis kell on juba?" ja "Tulevik" ning Friedebert Tuglase (pseud. Villem Tuglas) proosapalast "Öö". Ilmunud ka kogumikus: Haug, Toomas. Troojamäe tõotus. Tallinn : Eesti Keele Sihtasutus, 2004, lk. 24-40

  2. Ettevaatust! Sünnib Eesti esimene päris telenovela / Mart Niineste

    Index Scriptorium Estoniae

    Niineste, Mart, 1983-

    2008-01-01

    Produtsent Kristian Taska filmib Jüri tehnopargis Kalev Spordis näitamiseks Venezuela seebiseriaali Eesti oludele mugandust "Kalevi naised" (lavastaja Ingomar Vihman, osades Maria Avdjuško, Toomas Zupping, Jan Uuspõld, Britta Vahur, Ken Saan jt). Filmivõtetelt

  3. "Kalevi naised" - komöödia, kus nalja ei tehta / Verni Leivak

    Index Scriptorium Estoniae

    Leivak, Verni, 1966-

    2008-01-01

    Produtsent Kristian Taska filmib Jüri tehnopargis Kalev Spordis näitamiseks Venezuela seebiseriaali Eesti oludele mugandust "Kalevi naised" (lavastaja Ingomar Vihman, telerežissöör Hermes Brambat, osades Maria Avdjuško, Andrus Vaarik, Jan Uuspõld, Britta Vahur, Ken Saan jt)

  4. Peripheries of (be)longing in contemporary Estonian literature / Brita Melts

    Index Scriptorium Estoniae

    Melts, Brita, 1984-

    2016-01-01

    Ääremaad tänapäeva eesti kirjanduses: Andrus Kasemaa "Poeedirahu" (2008), Vahur Afanasjevi "Tünsamäe tigu" (2015), Ott Kiluski "Veidrikud ja võpatused" (2012), Lauri Sommeri "Räestu raamat" (2012), Tõnu Õnnepalu "Paradiis" (2009), Lauri Pilteri "Vilekoor ja teisi jutte" (2014), Kristiina Ehini "Kaitseala" (2005) ja Kaja Kannu "Eratee" (2013)

  5. On igatahes kindel, et kui teatrikooli lõpetad, siis antakse sulle võimalus / Brigitta Davidjants

    Index Scriptorium Estoniae

    Davidjants, Brigitta, 1983-

    2006-01-01

    Kohtumiselt Eesti Muusika- ja Teatriakadeemia lavakunstikooli XXII lennu lõpetajatega - Britta Vahur, Veiko Tubin, Mari-Liis Lill, Risto Kübar, Mihkel Kabel, Markus Luik, Tõnn Lamp, Laura Peterson, Lauri Lagle, Ragne Pekarev, Inga Salurand, Sergo Vares, Martin Kõiv, Ursula Rataseppa, Nero Urke. Arvamust lõpetajate kohta avaldavad ka kursuse juhendaja Priit Pedajas ja õppejõud Anu Lamp

  6. Vastutada lustides ja vastupidi / interv. Eva-Liisa Linder

    Index Scriptorium Estoniae

    2006-01-01

    Lavakunstikooli XXII lend räägib kooliajast, õpetajatest ja õppetööst. Kõnelevad Mihkel Kabel, Martin Kõiv, Risto Kübar, Lauri Lagle, Tõnn Lamp, Mari-Liis Lill, Markus Luik, Ragne Pekarev, Laura Peterson, Ursula Ratasepp, Inga Salurand, Veiko Tubin, Nero Urke, Britta Vahur ja Sergo Vares

  7. Nukk peidab Grigori hinge sügavaid saladusi / Andres Laasik

    Index Scriptorium Estoniae

    Laasik, Andres, 1960-2016

    2010-01-01

    Dokumentaalfilmist "Saime kokku Solenzaras" (Ikoon, 2010). Stsenarist ja lavastaja Vahur Laiapea. Film on 73-aastasest Grigorist, kes pärast naise surma meisterdab elusuuruse nuku, kellega jätkab tantsimas käimist, mida ta seni naisega oli teinud

  8. Tipparhitektuur tagasi kinnisvaraturul / Ene Läkk

    Index Scriptorium Estoniae

    Läkk, Ene, 1957-

    2008-01-01

    Müüki on pandud Ralf Tamme projekteeritud kuubikmaja Veskimöldres, Vahur Sova funkmaja Pirital, Kalle Rõõmuse eramu Merirahu elamurajoonis, Ene Priimetsa paarismaja Nõmmel, Mart Liho projekteritud maja Nõmmel. Ralf Tamme ja Tõnu Toomparki kommentaarid. Fotod elamutest

  9. Noorte lühinäidendid jahmatasid publikut / Maria Uuetoa

    Index Scriptorium Estoniae

    Uuetoa, Maria

    2007-01-01

    Eesti Nuku- ja Noorsooteater tõi lavale kolmest lühinäidendist koosneva etenduse "Põlev pööning". Näidendivõistluselt "Pööning" valitud kolm näidendit on Kristiina Jalasto "Kui mind ei oleks, oleks maailm teine" (lav. Andres Dvinjaninov), Priit Põldma "Koerad" (lav. Vahur Keller) ja Maili Lehtpuu "Koristajad" (lav. Reeda Toots)

  10. Kiirabisse jääb vähemalt neli arstibrigaadi

    Index Scriptorium Estoniae

    2005-01-01

    Tallinna Sotsiaal- ja Tervishoiuameti juhataja Vahur Keldrima ja riigi Tervishoiuameti peadirektor Üllar Kaljumäe kirjutasid alla Tallinna Kiirabi tegevuse korraldavale lepingule, mille kohaselt jätkab kiirabi koosseisus tänavu tööd 14 kiirabibrigaadi, neist vähemalt neli on arstibrigaadid

  11. The Estonian Tax System is Under Attack / Craig Rawlings, Daria Sivovol, Kersti Harkmann

    Index Scriptorium Estoniae

    Rawlings, Craig

    2006-01-01

    Ameerika, Briti ja Rootsi Kaubanduskojad Eestis ning Prantsuse-Eesti Äriklubi korraldasid seminari, kus Eesti maksusüsteemi tuleviku üle arutasid 15 põhiesinejat ning üle saja osavõtja. Väljavõte sessioonist, kus vastajateks olid Meelis Atonen, Eiki Nestor, Tarmo Kriis ja Vahur Kraft. Lisa: Esinejate tutvustus

  12. Veikko Täär : mees võib olla naise ori / Kaire Raave

    Index Scriptorium Estoniae

    Raave, Kaire

    2007-01-01

    Jaan Toominga lavastus "Venuse armumängud" austria kirjaniku Leopold von Sacher-Masochi romaani "Venus karusnahas" järgi. Osades Veikko Täär, Britta Vahur. Näitleja Veikko Täär endast ja oma rollist. Lisaks tutvustus "Venuse armumängud"

  13. Lavale jõuab näitemäng armastuse orjast

    Index Scriptorium Estoniae

    2007-01-01

    Komöödiateatril tuleb lavale Jaan Toominga lavastatud "Venuse armumäng" austria kirjaniku Leopold von Sacher-Masochi romaani "Venus karusnahas" järgi. Osades Veikko Täär, Britta Vahur ja kulturist Imre Vähi

  14. Younger Estonian Prose / Peeter Helme

    Index Scriptorium Estoniae

    Helme, Peeter, 1978-

    2008-01-01

    Iga kahe aasta tagant korraldatavast romaanivõistlusest ning uutest ja noortest autoritest, pikemalt Indrek Harglast, Lew R. Bergist, Jaan Apsist, Joonas Sildrest, Diana Leesalust, Marion Andrast, Tiina Laanemist, Olle Laulist, Chaneldiorist, Vahur Afanasjevist, Mehis Heinsaarest, Mart Kangurist, Ivar Ravist, Jaak Rannast

  15. Kitsemõisast Cantervilla lossiks / Helju Koger

    Index Scriptorium Estoniae

    Koger, Helju, 1943-

    2004-01-01

    Põlvamaal asuvast Pikajärve mõisast. 1910. a. lasid Conrad ja Elmar von Müller ehitada uue juugendlik-historitsistliku härrastemaja. 1948.-1990. a. oli häärberis hooldekodu. Praegune omanik Relvo Värton ja tema abikaasa Saima Värton taastavad mõisa Värtonite suguvõsa ja sõprade abiga. Sisekujundamisel on nõustanud kunstiõpetajad Maie Värton, Maris Tigane jt. 3 välis- ja 10 sisevaadet

  16. Decoupling of the PI3K Pathway via Mutation Necessitates Combinatorial Treatment in HER2+ Breast Cancer.

    Directory of Open Access Journals (Sweden)

    James E Korkola

    Full Text Available We report here on experimental and theoretical efforts to determine how best to combine drugs that inhibit HER2 and AKT in HER2(+ breast cancers. We accomplished this by measuring cellular and molecular responses to lapatinib and the AKT inhibitors (AKTi GSK690693 and GSK2141795 in a panel of 22 HER2(+ breast cancer cell lines carrying wild type or mutant PIK3CA. We observed that combinations of lapatinib plus AKTi were synergistic in HER2(+/PIK3CA(mut cell lines but not in HER2(+/PIK3CA(wt cell lines. We measured changes in phospho-protein levels in 15 cell lines after treatment with lapatinib, AKTi or lapatinib + AKTi to shed light on the underlying signaling dynamics. This revealed that p-S6RP levels were less well attenuated by lapatinib in HER2(+/PIK3CA(mut cells compared to HER2(+/PIK3CAwt cells and that lapatinib + AKTi reduced p-S6RP levels to those achieved in HER2(+/PIK3CA(wt cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CA(mut cells following lapatinib + AKTi treatment. Responses of HER2(+ SKBR3 cells transfected with lentiviruses carrying control or PIK3CA(mut sequences were similar to those observed in HER2(+/PIK3CA(mut cell lines but not in HER2(+/PIK3CA(wt cell lines. We used a nonlinear ordinary differential equation model to support the idea that PIK3CA mutations act as downstream activators of AKT that blunt lapatinib inhibition of downstream AKT signaling and that the effects of PIK3CA mutations can be countered by combining lapatinib with an AKTi. This combination does not confer substantial benefit beyond lapatinib in HER2+/PIK3CA(wt cells.

  17. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

    DEFF Research Database (Denmark)

    Jönsson, Mats; Ekstrand, Anna Isinger; Jönsson, Mats

    2010-01-01

    , and PTEN in colorectal cancers linked to hereditary nonpolyposis colorectal cancer (HNPCC). Sequencing was used to identify mutations in PIK3CA, a real-time PCR-based method to identify KRAS mutations, and immunohistochemical staining was used to evaluate the expression of PIK3CA, phosphorylated AKT......The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...

  18. Design of peptidase-resistant peptide inhibitors of myosin light chain kinase.

    Science.gov (United States)

    Khapchaev, Asker Y; Kazakova, Olga A; Samsonov, Mikhail V; Sidorova, Maria V; Bushuev, Valery N; Vilitkevich, Elena L; Az'muko, Andrey A; Molokoedov, Alexander S; Bespalova, Zhanna D; Shirinsky, Vladimir P

    2016-11-01

    Myosin light chain kinase (MLCK) is a key regulator of various forms of cell motility including smooth muscle contraction, cell migration, cytokinesis, receptor capping, secretion, etc. Inhibition of MLCK activity in endothelial and epithelial monolayers using cell-permeant peptide Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys (PIK, Peptide Inhibitor of Kinase) allows protecting the barrier capacity, suggesting a potential medical use of PIK. However, low stability of L-PIK in a biological milieu prompts for development of more stable L-PIK analogues for use as experimental tools in basic and drug-oriented biomedical research. Previously, we designed PIK1, H-(N(α) Me)Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH2 , that was 2.5-fold more resistant to peptidases in human plasma in vitro than L-PIK and equal to it as MLCK inhibitor. In order to further enhance proteolytic stability of PIK inhibitor, we designed the set of six site-protected peptides based on L-PIK and PIK1 degradation patterns in human plasma as revealed by (1) H-NMR analysis. Implemented modifications increased half-live of the PIK-related peptides in plasma about 10-fold, and these compounds retained 25-100% of L-PIK inhibitory activity toward MLCK in vitro. Based on stability and functional activity ranking, PIK2, H-(N(α) Me)Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-D-Arg-Lys-NH2 , was identified as the most stable and effective L-PIK analogue. PIK2 was able to decrease myosin light chain phosphorylation in endothelial cells stimulated with thrombin, and this effect correlated with the inhibition by PIK2 of thrombin-induced endothelial hyperpermeability in vitro. Therefore, PIK2 could be used as novel alternative to other cell-permeant inhibitors of MLCK in cell culture-based and in vivo studies where MLCK catalytic activity inhibition is required. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  19. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides.

    Science.gov (United States)

    Almutairi, Mashal M; Park, Sung Ryeol; Rose, Simon; Hansen, Douglas A; Vázquez-Laslop, Nora; Douthwaite, Stephen; Sherman, David H; Mankin, Alexander S

    2015-10-20

    Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism.

  20. Eesti proosa 2007 - kultuuri ja tsivilisatsiooni vahel / Peeter Helme

    Index Scriptorium Estoniae

    Helme, Peeter, 1978-

    2010-01-01

    2007. a. ilmunud proosaraamatutest: Tiina Laanemi "Väikesed vanamehed", Ene Mihkelsoni "Katkuhaud", Toomas Vindi "Mäluauguga naine", Vahur Afanasjevi "Kaadrid otsustavad", Armin Kõomäe "Nägu, mis jäi üle" (ilmus 2006. a.), Jaan Kaplinski "Seesama jõgi", Tõnu Õnnepalu "Flandria päevik", Maimu Bergi "Unustatud inimesed", Mehis Heinsaare "Rändaja õnn", Mihkel Muti "Siseemigrant", Aarne Biini "Linna valitsemine", Ivar Silla "Tantsiv linn" ja Epp Annuse "Sina, Matilda"

  1. Näitus, mis vaatab kaadri taha / Anneli Sihvart

    Index Scriptorium Estoniae

    Sihvart, Anneli, 1964-

    2010-01-01

    Eesti Ajaloomuuseumis Maarjamäe lossis 27. märtsini avatud fotonäitusel "Püha. Sügis" on väljas fotograafide Andres Haabu, Gabriela Liivamägi, Kaarel Nurga ja Vahur Puigi pildid Veiko Õunpuu filmide "Sügisball" ja "Püha Tõnu kiusamine" võtetelt. Näituse kuraator Anari Koppel, kujundaja Hanna Tiidus

  2. Ideed, mis muudavad maailma

    Index Scriptorium Estoniae

    2012-01-01

    Noorte ettevõtluskonkursi Ajujaht finalistidest: Richard Murutar (Dolphin), Andrus Purde (Achoo), Kalev Külaase, Ülane Vilumets, Rait Kapp (Kohalik Giid), Mart Raus, Vahur Mäe (Grillcube), Dmitri Kuznetsov, Anna Agronova, Julia Abolina, Anatoly Loginov (Healthiest.mobi), Karin Juhe, Karin Aruots (Korsid), Raino Sinisalu, Märt Pikkani, Arkadi Tammik, Varje Papp (Raybike), Egle Loit, Kair Käsper (Pille toidukott)

  3. Kogukonnateatrist Eestis 2008. aasta näitel / Hedi-Liis Toome

    Index Scriptorium Estoniae

    Toome, Hedi-Liis

    2009-01-01

    Kogukonnateatri mõistest ja olemusest. Näiteid neljast lavastusest - Pärimusteatri Loomine "Pärija" (lav. Raivo Trass), MTÜ Tuulekella koostööprojekt Raasiku valla ja rahvamajaga "Ernesaks ja Oamats" (lav. Vahur Keller), Põltsamaa teatri Ellunäod lavastus "Rasputin" (lav. Ain Saviauk) ning rahvusvahelisel teatrifestivalil Baltoscandal 2008 esietendunud projekt "50 Lovely Ways to Die" (lav. Kaja Kann, Juha Valkeapää)

  4. Kodu aedlinnavaikuses / Kati Tshernovitski

    Index Scriptorium Estoniae

    Tshernovitski, Kati

    2004-01-01

    Vahur Sova projekteeritud L-kujuline looduslähedane suurte klaaspindade ja puitvoodriga eramu Kuressaare aedlinnas. Ehitas EBC Ehitus. I korrus on avatud planeeringuga. Disainer Kai Laanmets on oma kodu ise kujundanud ja kavandanud köögimööbli, mille tegi valmis Kalla Mööbel. Elutoas ja kodubüroos on siinivalgustid. I korruse plaan, 2 välis- ja 11 sisevaadet

  5. [Määramised

    Index Scriptorium Estoniae

    2006-01-01

    Ametisse määramised: Kaitseliidu ülem major Raivo Lumiste; Maaväe staabi ülem kolonelleitnant Indrek Sirel; Kaitsejõudude peastaabi personaliosakonna ülem kolonelleitnant Vahur Väljamäe; 1. jalaväebrigaadi ülem kolonelleitnant Artur Tiganik; Scoutspataljoni ülem major Aivar Kokka; Kaitseväe peakaplan major Taavi Laanepere. Haridus, sõjaline kvalifikatsioon, teenistuskäik, auastmed, autasud

  6. Tartule olulised arhitektid kiidavad oma maju ja hindavad teiste omi / Nils Niitra

    Index Scriptorium Estoniae

    Niitra, Nils, 1975-

    2005-01-01

    Arhitektide Vahur Sova (Kaubanduskeskus Zeppelin), Kalle Rõõmuse (Emajõe ärikeskuse I ja II etapp, Tartu vangla, Hansapanga Barclay kontor, Biomeedium), Raivo Puusepa (Tartu Kaubamaja, Uus autoregistrikeskus Sepa tn., Peugeot' automüügikeskus Ringteel), Andres Lunge (GMP-keskus Küüni tn., Treffneri gümnaasiumi rekonstrueerimine, Vanemuise kontserdimaja rekonstrueerimine) ja Uku Põllumaa (Kapitali maja Ülikooli tn., Tehnoloogiainstituut Nooruse tn.) looming Tartus

  7. Kolm sõjafilmi kolme aastaga / Küllo Arjakas

    Index Scriptorium Estoniae

    Arjakas, Küllo, 1959-

    2007-01-01

    Kolmest ajaloolisest sõjafilmist - "Surnupealuu sõdurid" (toimetajad Vahur Lauri ja Epp Ehand : režissöör Anne-Mari Neider : Eesti Televisioon, 2004), "Haukka grupp" (stsenaristid Kiur Aarma, Tiit Pruuli : režissöör Rene Vilbre : Ruut Pictures 2005,) "Sinimäed" (stsenaristid Kiur Aarma, Mart Laar, Eerik-Niiles Kross, Raimo Jõerand : režissöör Raimo Jõerand : Ruut Pictures 2006)

  8. Kätlin Ölluk, Steve Heinlo : kaasaegselt luksuslik

    Index Scriptorium Estoniae

    2006-01-01

    Kätlin Öllukist (sünd. 1977), tema olulisemad tööd. Steve Heinlost (sünd. 1970). Arhitekt Vahur Sova projekteeritud eramu sisekujundus. Sisearhitekt K. Ölluk, kaasautor S. Heinlo. Köögis ja elutoas on Jura Marmorist põrand. Kogu maja mööbel on valmistatud eritellimusel. Ill.: 2 plaani, 12 värv. vaadet, sisearhitektide portreefotod

  9. Short outlines of books by Estonian authors / Brita Melts, Rutt Hinrikus and Janika Kronberg

    Index Scriptorium Estoniae

    Melts, Brita

    2015-01-01

    Arvustus: Afanasjev, Vahur. Tünsamäe tigu. Tartu Tartu NAK, 2015 ; Vadi, Urmas. Kuidas me kõik reas niimoodi läheme. Tallinn : Tuum, 2014 ; Traat, Mats. Kolm Solveigi. Tartu : Ilmamaa, 2015 ; Saat, Mari. Matused ja laulupeod. Tartu : Petrone Print, 2015 ; Kivisilla, Veronika. Cantus firmus. Tallinn : Näo Kirik, 2015 ; Kolk, Jüri. Suur võidujooks. Tallinn : Tuum, 2015 ; Mudlum. Tõsine inimene. Tallinn : ZA/UM, 2014

  10. Systemic epidermal nevus with involvement of the oral mucosa due to FGFR3 mutation

    DEFF Research Database (Denmark)

    Bygum, Anette; Fagerberg, Christina R; Clemmensen, Ole J

    2011-01-01

    Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated.......Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated....

  11. Approaching Resistance to Targeted Inhibition of PI3K in Breast Cancer

    Science.gov (United States)

    2011-10-01

    ig . 1 Sc h em a ti c vi ew of...preselection PIK3CA alleles did not show any mutational prevalence . SOLiD se- quencing is based on parallel sequencing of short DNA frag- ments that...the ectopic virally encoded PIK3CA and the antibiotic marker puromycin. Notably, we could not detect even nominal RNA levels of the ectopic

  12. BEAMing Up Personalized Medicine: Mutation Detection In Blood

    OpenAIRE

    Richardson, Andrea L.; Iglehart, J. Dirk

    2012-01-01

    BEAMing is a feasible, accurate and sensitive method for detection of PIK3CA mutations in circulating tumor DNA in blood. Mutation status of PIK3CA may change between primary tumor and recurrence. The results suggest a new approach for non-invasive determination of current mutation status in patients with metastatic disease.

  13. An In Vitro Comparison of Pantographic Techniques

    Science.gov (United States)

    2001-05-01

    The primary use of pantography is to program an articulator so the articulator movements will more closely harmonize with the patient’s mandibular ...Water Pik), electronic-stylus (Pantronic, Teledyne Water Pik), and optoelectronic (Condylocomp, Dentron) pantograph performed protrusive condylar path...progressive mandibular lateral translation, and immediate mandibular lateral translation determinations. The experimental design restricted the

  14. "Kohtume Eestis!" algtaseme keelefunktsioonidest lähtudes / Elle Sõrmus

    Index Scriptorium Estoniae

    Sõrmus, Elle

    2002-01-01

    Rets. rmt.: Sander, Klarika. Kohtume Eestis! : eestin kielen alkeisoppikirja = Estonian for beginners. Helsinki : Finn Lectura, 1999. 202 lk. + 1 helikassett. Õpik on mõeldud täiskasvanud õppijale, kes alustab eesti keele õppimist algtasemel

  15. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides

    DEFF Research Database (Denmark)

    Almutairi, Mashal M; Park, Sung Ryeol; Rose, Simon

    2015-01-01

    activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken......Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces...... venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S r...

  16. The Chinese Armed Forces in the 21st Century

    Science.gov (United States)

    1999-12-01

    Intelligence, Chinese Exercise Strait 961: 8-25 March 1996, Office of Naval Intelligence: Washington, DC, May 1996. 5. Vivien Pik- Kwan Chan, "Beijing...1998, p. 19. 71. See Alistair Iain Johnston, Cultural Realism: Strategic Culture and Grand Strategy in Chinese History, Princeton: Princeton...Vivien Pik- kwan Chan, "Arms Sales To Taipei ’Assault On Sovereignty’," South China Morning Post, August 29,1998. 319 CHAPTER 8 CONCLUDING COMMENT: THE

  17. Eesti proosa 2007 - kultuuri ja tsivilisatsiooni vahel / Peeter Helme

    Index Scriptorium Estoniae

    Helme, Peeter, 1978-

    2008-01-01

    Ülevaade 2007. aasta eesti proosast. Käsitletakse järgimisi autoreid ja nende teoseid: Ene Mihkelson "Katkuhaud", Jaan Kaplinski "Seesama jõgi", Toomas Vint "Mäluauguga naine", Mehis Heinsaar "Rändaja õnn", Maimu Berg "Unustatud inimesed", Mihkel Mutt "Siseemigrant", Vahur Afanasjev "Kaadrid otsustavad", Epp Annus "Sina, Matilda", Ivar Sild "Tantsiv linn", Tiina Laanem "Väikesed vanamehed", Olle Lauli "Niguliste õpilased", Aarne Biin "Linna valitsemine", Jaan Aps ja Joonas Sildre "Hinglõõm". Ka Armin Kõomäe loomingust. Artikli aluseks on Eesti Kirjanduse Seltsi 2007. a. eesti kirjanduse ülevaatekoosolekul peetud ettekanne

  18. Eesti parim puitehitis 2005 / Veljo Kaasik

    Index Scriptorium Estoniae

    Kaasik, Veljo

    2005-01-01

    Žürii esimees konkursist ja premeeritud töödest. 2005. a. parim puitehitis - lasteaed Naba Pirital (arhitektid Vahur Sova, Lauri Saar). Aramärgitud objektid - AS Palmako tootmishoone Kavastus (insener Paul Sõrmus), kortermaja Tabasalus Lucca külas (arhitekt Oliver Alver). Liimpuidu eripreemia - autode varjualune Õie t. Nõmmel (arhitekt Indrek Allmann). Vineeri eripreemia - Kuressaare Linnavalitsuse hoone fassaadiuuendus (arhitektid Toomas Paavae, Terje Truumaa). Voodrilaua eripreemia - Estonian Golf and Country Club Jõelähtmes (arhitekt Andres Siim)

  19. Milline/millised viimastel aastatel eesti keeles ilmunud ilukirjandusteos(ed) on pälvinud liiga vähe tähelepanu või jäänud ebaõiglaselt tähelepanuta? Miks võiks antud teos(t)ele rohkem tähelepanu juhtida? : [küsitlus] / Doris Kareva, Berk

    Index Scriptorium Estoniae

    2010-01-01

    Nimetatakse konkreetseid teoseid, näiteks Berk Vaher kirjutab Andi Meistri romaanist "Valgus olematust aknast" (2009), Mihkel Mutt Marcin Świetlicki kriminaalromaanist "Kaksteist" (tlk. Hendrik Lindepuu, 2009), Aare Pilv, Eliina Kortsu luulekogust "Lööklaused murravad metsi" (2006), Jaak Tomberg Vahur Afanasjevi luulekogust "Katedraal Emajões" (2006), Birk Rohelend Siim Nurkliku näidendist "Kas ma olen nüüd elus" (2010), Igor Kotjuh Toomas Raudami proosapalast "Mees, kes kirjutas merd" (2006). Enim muretsetakse tõlkekirjanduse, eriti luule retseptsiooni puudumise pärast

  20. Vikergallup : eesti kirjandus 2001 : [vastused Vikerkaare küsitlusele

    Index Scriptorium Estoniae

    2002-01-01

    Aut.: Vahur Afanasjev, Veiko Belials, Piret Jaaks, Jan Kaus, Janek Kraavi, Priit Kruus, Leo Luks, Ilona Martson, Hedda Maurer, Anneli Mihkelev, Jürgen Rooste, Aarne Ruben, Mihkel Samarüütel, François Serpent, Ivar Sild, Karl Martin Sinijärv, Lauri Sommer, Jaak Urmet, Berk Vaher. 2001. a. parima uudisraamatu tiitlit jagasid Mehis Heinsaare "Härra Pauli kroonikad", Jan Kausi "Maailm ja mõni" ning Ene Mihkelsoni "Ahasveeruse uni"; parimaks esikraamatuks valiti Mehis Heinsaare "Vanameeste näppaja"

  1. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092.

    Science.gov (United States)

    Yu, Yi; Savage, Ronald E; Eathiraj, Sudharshan; Meade, Justin; Wick, Michael J; Hall, Terence; Abbadessa, Giovanni; Schwartz, Brian

    2015-01-01

    As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating the membrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other tumor models with an activated AKT pathway, both compounds exhibited strong anti-tumor activity. Combination studies conducted in in vivo breast tumor models demonstrated that ARQ 092 enhanced tumor inhibition of a common chemotherapeutic agent (paclitaxel). In a large panel of diverse cancer cell lines, ARQ 092 and ARQ 751 inhibited proliferation across multiple tumor types but were most potent in leukemia, breast, endometrial, and colorectal cancer cell lines. Moreover, inhibition by ARQ 092 and ARQ 751 was more prevalent in cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17K mutations can potentially be used as predictive biomarkers for patient selection in clinical studies.

  2. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092.

    Directory of Open Access Journals (Sweden)

    Yi Yu

    Full Text Available As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating the membrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other tumor models with an activated AKT pathway, both compounds exhibited strong anti-tumor activity. Combination studies conducted in in vivo breast tumor models demonstrated that ARQ 092 enhanced tumor inhibition of a common chemotherapeutic agent (paclitaxel. In a large panel of diverse cancer cell lines, ARQ 092 and ARQ 751 inhibited proliferation across multiple tumor types but were most potent in leukemia, breast, endometrial, and colorectal cancer cell lines. Moreover, inhibition by ARQ 092 and ARQ 751 was more prevalent in cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17K mutations can potentially be used as predictive biomarkers for patient selection in clinical studies.

  3. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-specific Inhibitor, with Letrozole in ER+/HER2-Negative Metastatic Breast Cancer

    Science.gov (United States)

    Mayer, Ingrid A.; Abramson, Vandana G.; Formisano, Luigi; Balko, Justin M.; Estrada, Mónica V.; Sanders, Melinda E.; Juric, Dejan; Solit, David; Berger, Michael F.; Won, Helen H.; Li, Yisheng; Cantley, Lewis C.; Winer, Eric; Arteaga, Carlos L.

    2016-01-01

    Purpose Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic anti-tumor activity with endocrine therapy against ER+/PIK3CA mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole’s safety, tolerability and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. Patients and Methods Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and Next Generation Sequencing. Results Alpelisib’s maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA mutated and 20% in PIK3CA wild-type tumors; 95% CI [17%; 56%]), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro. Conclusion The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status although clinical benefit was seen in a higher proportion of patients with PIK3CA mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing. PMID:27126994

  4. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.

    Science.gov (United States)

    Mayer, Ingrid A; Abramson, Vandana G; Formisano, Luigi; Balko, Justin M; Estrada, Mónica V; Sanders, Melinda E; Juric, Dejan; Solit, David; Berger, Michael F; Won, Helen H; Li, Yisheng; Cantley, Lewis C; Winer, Eric; Arteaga, Carlos L

    2017-01-01

    Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER(+) breast cancer refractory to endocrine therapy. Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing. Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER(+)/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER(+) breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR. ©2016 American Association for Cancer Research.

  5. The effect of the disruption of a gene encoding a PI4 kinase on the developmental defect exhibited by Dictyostelium rasC(-) cells.

    Science.gov (United States)

    Khosla, Meenal; Spiegelman, George B; Weeks, Gerald

    2005-08-15

    The disruption of the gene encoding the Dictyostelium Ras subfamily protein, RasC results in a strain that fails to aggregate with defects in both cAMP signal relay and chemotaxis. Restriction enzyme mediated integration disruption of a second gene in the rasC(-) strain resulted in cells that were capable of forming multicellular structures in plaques on bacterial lawns. The disrupted gene, designated pikD(1), encodes a member of the phosphatidyl-inositol-4-kinase beta subfamily. Although the rasC(-)/pikD(1) cells were capable of progressing through early development, when starved on a plastic surface under submerged conditions, they did not form aggregation streams or exhibit pulsatile motion. The rasC(-)/pikD(1) cells were extremely efficient in their ability to chemotax to cAMP in a spatial gradient, although the reduced phosphorylation of PKB in response to cAMP observed in rasC(-) cells, was unchanged. In addition, the activation of adenylyl cyclase, which was greatly reduced in the rasC(-) cells, was only minimally increased in the rasC(-)/pikD(1) strain. Thus, although the rasC(-)/pikD(-) cells were capable of associating to form multicellular structures, normal cell signaling was clearly not restored. The disruption of the pikD gene in a wild type background resulted in a strain that was delayed in aggregation and formed large aggregation streams, when starved on a plastic surface under submerged conditions. This strain also exhibited a slight defect in terminal development. In conclusion, disruption of the pikD gene in a rasC(-) strain resulted in cells that were capable of forming multicellular structures, but which did so in the absence of normal signaling and aggregation stream formation.

  6. Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations.

    Directory of Open Access Journals (Sweden)

    William J Tapper

    Full Text Available Two megalencephaly (MEG syndromes, megalencephaly-capillary malformation (MCAP and megalencephaly-polymicrogyriapolydactyly-hydrocephalus (MPPH, have recently been defined on the basis of physical and neuroimaging features. Subsequently, exome sequencing of ten MEG cases identified de-novo postzygotic mutations in PIK3CA which cause MCAP and de-novo mutations in AKT and PIK3R2 which cause MPPH. Here we present findings from exome sequencing three unrelated megalencephaly patients which identified a causal PIK3CA mutation in two cases and a causal PIK3R2 mutation in the third case. However, our patient with the PIK3R2 mutation which is considered to cause MPPH has a marked bifrontal band heterotopia which is a feature of MCAP. Furthermore, one of our patients with a PIK3CA mutation lacks syndactyly/polydactyly which is a characteristic of MCAP. These findings suggest that the overlap between MCAP and MPPH may be greater than the available studies suggest. In addition, the PIK3CA mutation in one of our patients could not be detected using standard exome analysis because the mutation was observed at a low frequency consistent with somatic mosaicism. We have therefore investigated several alternative methods of exome analysis and demonstrate that alteration of the initial allele frequency spectrum (AFS, used as a prior for variant calling in samtools, had the greatest power to detect variants with low mutant allele frequencies in our 3 MEG exomes and in simulated data. We therefore recommend non-default settings of the AFS in combination with stringent quality control when searching for causal mutation(s that could have low levels of mutant reads due to post-zygotic mutation.

  7. Aspirin suppresses growth in PI3K-mutant breast cancer by activating AMPK and inhibiting mTORC1 signaling

    Science.gov (United States)

    Henry, Whitney S.; Laszewski, Tyler; Tsang, Tiffany; Beca, Francisco; Beck, Andrew H.; McAllister, Sandra S.; Toker, Alex

    2016-01-01

    Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiological studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA. Here we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-κB). We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mammalian target of rapamycin complex 1 (mTORC1) inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, while combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports evaluation of aspirin and PI3K pathway inhibitors as combination therapy for targeting breast cancer. PMID:27940576

  8. Evidence for $\\pi K$ -atoms with DIRAC-II

    CERN Document Server

    Allkofer, Yves

    2008-01-01

    DIRAC-II is a fixed-target experiment at the CERN Proton Synchroton (PS) which has been designed to search for piK atoms, a bound state of a pi±K± pair, and measure their lifetime. These atoms are observed through an excess of low energetic piK pairs over the background, detected in the two spectrometer arms. This excess comes from the ionization of piK atoms in the target and can be related to their mean life. The piK S-wave scattering length combination |a1/2 - a3/2| (for isospin 1/2 and 3/2) can be related to the latter. The aim of the upgraded DIRAC-II experiment is a measurement of the scattering length combination |a1/2 - a3/2| with a precision of 5%. piK atoms have not been observed so far. The original DIRAC experiment was designed to measure the scattering lengths of pipi atoms. So far, close to 15 000 atoms have been detected, leading to a precision on |a0 - a2| which is better than 10%. In chiral perturbation theories (ChPT) the pipi scattering lengths have been calculated with 2% precision a...

  9. Immunohistochemical analysis of PDK1 expression in breast cancer.

    Science.gov (United States)

    Arsenic, Ruza

    2014-04-16

    3-phosphoinositide-dependent protein kinase-1 (PDK1) functions downstream of phosphoinositide 3-kinase (PIK3) and activates members of the AGC family of protein kinases that are known to play crucial roles in physiological processes associated with cell metabolism, growth, proliferation and survival. Changes in the expression and activity of PDK1 and several AGC kinases have been linked to human disease, including cancer. We used immunohistochemical analysis to determine PDK1 expression in 241 tumors from patients with breast cancer in which we had previously analyzed PIK3CA mutation status. Moderate or high expression of PDK1 was observed in 213 of the 241 cases (88%). There was no correlation between PIK3CA mutation status and PDK1 overexpression. Our findings indicate that PDK1 is independently activated in breast cancer and not only as part of the PIK3CA pathway, suggesting that PDK1 plays a specific and distinct role from the canonical PIK3/Akt pathway and promotes oncogenesis independently of AKT. Our data implicate PDK-1 and downstream components of the PDK-1 signaling pathway as promising therapeutic targets for the treatment of breast cancer.

  10. Molecular Scree ning of Blast Resistance Genes in Rice Germplasms Resistant to Magnaporthe oryzae

    Directory of Open Access Journals (Sweden)

    Liang Yan

    2017-01-01

    Full Text Available Molecular screening of major rice blast resistance genes was determined with molecular markers, which showed close-set linkage to 11 major rice blast resistance genes (Pi-d2, Pi-z, Piz-t, Pi-9, Pi-36, Pi-37, Pi5, Pi-b, Pik-p, Pik-h and Pi-ta2, in a collection of 32 accessions resistant to Magnaporthe oryzae. Out of the 32 accessions, the Pi-d2 and Pi-z appeared to be omnipresent and gave positive express. As the second dominant, Pi-b and Piz-t gene frequencies were 96.9% and 87.5%. And Pik-h and Pik-p gene frequencies were 43.8% and 28.1%, respectively. The molecular marker linkage to Pi-ta2 produced positive bands in eleven accessions, while the molecular marker linkage to Pi-36 and Pi-37 in only three and four accessions, respectively. The natural field evaluation analysis showed that 30 of the 32 accessions were resistant, one was moderately resistant and one was susceptible. Infection types were negatively correlated with the genotype scores of Pi-9, Pi5, Pi-b, Pi-ta2 and Pik-p, although the correlation coefficients were very little. These results are useful in identification and incorporation of functional resistance genes from these germplasms into elite cultivars through marker-assisted selection for improved blast resistance in China and worldwide.

  11. Caracterización de alteraciones moleculares en tumores de endometrio

    OpenAIRE

    Núñez Lozano, Mercedes

    2011-01-01

    [ES]Los genes comúnmente mutados en carcinoma endometrial (EC) son PTEN, PIK3CA, KRAS, BRAF, ß-catenina, p53, p16 y E-Cadherina; todos ellos pertenecientes a señalización intracelular relacionada con crecimiento, diferenciación, apoptosis, etc. Hemos identificado mutaciones en PTEN en el 57,1% de los casos, 19% en PIK3CA, 14,3% en KRAS, 19% en CTNNB1, 23,8% en p53, 4,8% en CDH1 y 2,4% en p16. Hemos analizado la naturaleza de ciertas mutaciones en PTEN, PIK3CA y p53 para comprobar la per...

  12. Bringing Climate Into the Classroom: Inside a Teaching Retreat Around Naomi Klein’s This Changes Everything

    Directory of Open Access Journals (Sweden)

    Bill Bigelow

    2015-06-01

    Full Text Available Jill Howdyshell lives and teaches 5th grade in Togiak, a small Yu’pik fishing village in southwestern Alaska. In Togiak, harvesting berries is a practice that goes back countless generations. The berries are the key ingredient in akutaq, called eskimo ice cream. In her classes, Howdyshell’s students write identity poems with lines proclaiming “I am from akutaq,” and describing cherished excursions with parents and grandparents. In 2014, residents discovered that there would be no berries that year: the tundra had not frozen for a sufficient length of time for the berries to regenerate. With a dramatic rise in temperatures, Yu’pik people can no longer rely on digging deep into the permafrost to store food in makeshift freezers. And most distressing: as a result of rising seas, during the next few years, Yu’pik people will be forced to relocate large parts of their community.

  13. miR-203 inhibits cell proliferation and promotes cisplatin induced cell death in tongue squamous cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Jiong; Lin, Yao [Guangdong Provincial Key Laboratory of Stomatology, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, 510055 (China); Fan, Li [Department of Pharmaceutical Analysis, School of Pharmacy, The Fourth Military Medical University, Xi' an, Shaanxi, 710032 (China); Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, 510055 (China); Kuang, Wei [Department of Stomatology, Guangzhou General Hospital of Guangzhou Military Command, 111 Liuhua Road, Guangzhou, 510010 (China); Zheng, Liwei [State Key Laboratory of Oral Diseases, Sichuan University, Wuhou District, Chengdu, 610041 (China); Wu, Jiahua [Guangdong Provincial Key Laboratory of Stomatology, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, 510055 (China); Shang, Peng [Patient-specific Orthopedic Technology Research Center in GuangDong Research Centre for Neural Engineering, 1068 Xueyuan Boulevard, University Town of Shenzhen, Xili, Nanshan, Shenzhen, 518055 (China); Wang, Qiaofeng [Department of Pharmaceutical Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi' an, Shanxi, 710032 (China); Tan, Jiali, E-mail: jasminenov@163.com [Guangdong Provincial Key Laboratory of Stomatology, Department of Orthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, 510055 (China)

    2016-04-29

    Oral squamous cell carcinoma (OSCC) is one of the most common types of the head and neck cancer. Chemo resistance of OSCC has been identified as a substantial therapeutic hurdle. In this study, we analyzed the role of miR-203 in the OSCC and its effects on cisplatin-induced cell death in an OSCC cell line, Tca8113. There was a significant decrease of miR-203 expression in OSCC samples, compared with the adjacent normal, non-cancerous tissue. After 3 days cisplatin treatment, the survived Tca8113 cells had a lower expression of miR-203 than that in the untreated control group. In contrast, PIK3CA showed an inverse expression in cancer and cisplatin survived Tca8113 cells. Transfection of Tca8113 cells with miR-203 mimics greatly reduced PIK3CA expression and Akt activation. Furthermore, miR-203 repressed PIK3CA expression through targeting the 3′UTR. Restoration of miR-203 not only suppressed cell proliferation, but also sensitized cells to cisplatin induced cell apoptosis. This effect was absent in cells that were simultaneously treated with PIK3CA RNAi. In summary, these findings suggest miR-203 plays an important role in cisplatin resistance in OSCC, and furthermore delivery of miR-203 analogs may serve as an adjuvant therapy for OSCC. - Highlights: • Much lower miR-203 expression in cisplatin resistant Tca8113 cells is discovered. • Delivery of miR-203 can sensitize the Tca8113 cells to cisplatin induced cell death. • MiR-203 can downregulate PIK3CA through the 3′UTR. • The effects of miR-203 on cisplatin sensitivity is mainly through PIK3CA pathway.

  14. A comprehensive analysis of transcript signatures of the phosphatidylinositol-3 kinase/protein kinase B signal-transduction pathway in prostate cancer.

    Science.gov (United States)

    Hellwinkel, Olaf J C; Rogmann, Jan-Peer; Asong, Legrehndem E; Luebke, Andreas M; Eichelberg, Christian; Ahyai, Sascha; Isbarn, Hendrik; Graefen, Markus; Huland, Hartwig; Schlomm, Thorsten

    2008-06-01

    To assess the gene activities of various important members of the phosphatidylinositol 3 kinase (PIK3)/protein kinase B (PKB/Akt) pathway (involved in the promotion and regulation of cellular metabolism, proliferation and apoptosis) for alterations in prostate carcinoma. Using quantitative real-time reverse-transcription polymerase chain reaction, we analysed the transcript levels of 12 genes involved in the PIK3/PKB pathway in microdissected tumour tissues from 20 patients with varying stages of prostate cancer, assessing differences from adjacent normal tissues and from a pool of prostate tissues from healthy controls. In cancer samples with a high Gleason grade, the PIK3/PKB pathway was principally affected by marked decreases in expression over almost all the investigated stages of the pathway. These changes were in effectors of the pathway, especially PIK3 p85 alpha (PIK3R1) and integrin-linked kinase, and the pathway target fork-head box protein (FOXO)-1A, while the transcript quantities of regulators, e.g. phosphatase/tensin homologue (PTEN), were decreased in a smaller proportion of the patients. Transcript amounts of FOXO-1A and FOXO-3A were significantly higher in normal tumour-adjacent tissues than in the healthy controls. Down-regulation of the PIK3/PKB pathway by repression of involved effector and regulator genes at all stages of the molecular pathway could represent a marker for the formation of highly de-differentiated prostate cancers from low-grade tumour foci. Also, parts of the pathway are deviant in normal tumour-adjacent tissue; this might represent a reaction to neighbouring tumours or be a sign of pre-cancerous biological alterations.

  15. Assessment of applicability index for better management of municipal solid waste: a case study of Dhanbad, India.

    Science.gov (United States)

    Yadav, Pooja; Samadder, S R

    2017-06-01

    Selection of suitable municipal solid waste management (MSWM) options is one of the major challenges in urban areas of the developing countries. Success of MSWM requires accurate data of generation rate, composition and physico-chemical characteristics of solid wastes. Improper handling of solid waste can have significant environmental and aesthetical impacts. The present study proposes a new method (applicability index - Pik values) for identifying the most appropriate disposal option with the help of applicability values of Composting-CP, Incineration-IP and Landfill-LP for individual components of MSW based on the results of the physico-chemical analysis of the collected representative solid waste samples from the study area, Dhanbad, India. The mean values of moisture content, carbon, hydrogen, oxygen, nitrogen, sulfur, volatile organic carbon, fixed carbon, ash content, density and calorific values (CV) of individual components were used as input values in this process. Based on the proposed applicability index (Pik), the highest Pik values were obtained for incineration (IP) for plastics, polythene, paper, coconut shell, wood, cardboard, textile, thermocol (polystyrene), rubber, sugarcane bagasse, cow dung and leather wastes (IP > CP > LP) due to high CV of these solid waste components; the highest Pik values were obtained for composting (CP) of kitchen waste (CP > IP > LP); and the highest Pik values for inert wastes were obtained for landfill option (LP > IP > CP). The highest Pik value for a particular waste for a specific treatment option signifies that the waste is suitable for treatment/disposal using that option.

  16. A mutant crp allele that differentially activates the operons of the fuc regulon in Escherichia coli.

    Science.gov (United States)

    Zhu, Y; Lin, E C

    1988-05-01

    L-Fucose is used by Escherichia coli through an inducible pathway mediated by a fucP-encoded permease, a fucI-encoded isomerase, a fucK-encoded kinase, and a fucA-encoded aldolase. The adolase catalyzes the formation of dihydroxyacetone phosphate and L-lactaldehyde. Anaerobically, lactaldehyde is converted by a fucO-encoded oxidoreductase to L-1,2-propanediol, which is excreted. The fuc genes belong to a regulon comprising four linked operons: fucO, fucA, fucPIK, and fucR. The positive regulator encoded by fucR responds to fuculose 1-phosphate as the effector. Mutants serially selected for aerobic growth on propanediol became constitutive in fucO and fucA [fucO(Con) fucA(Con)], but noninducible in fucPIK [fucPIK(Non)]. An external suppressor mutation that restored growth on fucose caused constitutive expression of fucPIK. Results from this study indicate that this suppressor mutation occurred in crp, which encodes the cyclic AMP-binding (or receptor) protein. When the suppressor allele (crp-201) was transduced into wild-type strains, the recipient became fucose negative and fucose sensitive (with glycerol as the carbon and energy source) because of impaired expression of fucA. The fucPIK operon became hyperinducible. The growth rate on maltose was significantly reduced, but growth on L-rhamnose, D-galactose, L-arabinose, glycerol, or glycerol 3-phosphate was close to normal. Lysogenization of fuc+ crp-201 cells by a lambda bacteriophage bearing crp+ restored normal growth ability on fucose. In contrast, lysogenization of [fucO(Con)fucA(Con)fucPIK(Non)crp-201] cells by the same phage retarded their growth on fucose.

  17. A Clinical Single-Blind Trial

    OpenAIRE

    Kossack, Christoph K.-H.

    2010-01-01

    Material and method: The (A) manual interX short brush-head toothbrush (elmex), the (B) Sonic Speed SR-100E sonic toothbrush (Water Pik), the (C) Sonic Speed toothbrush in conjunction with the electric interdental cleaning device Flosser FL-110 (Water Pik) and (D) the Sonic Speed toothbrush in conjunction with multi-floss three-phase dental floss (elmex) were tested in the present clinical single-blind four-way crossover study over a period of six months for their e...

  18. LHCb: Observation of CP violation in $B^{\\pm} \\to DK^{\\pm}$ decays at LHCb

    CERN Multimedia

    Gandini, Paolo

    2012-01-01

    An analysis of $B^+ \\to DK^+$ and $B^+ \\to D\\pi^+$ decays is presented where the D meson is reconstructed in the two-body final states: $K^+\\pi-, K^+K^-, \\pi^+\\pi^-$ and $\\pi^+K^-$. Using 1.0 fb$^{-1}$ of LHCb data, measurements of several observables are made including the first observation of the suppressed mode $B^+ \\to DK^+, D \\to \\pi^+K^-$. CP violation in $B^+ \\to DK^+$ decays is observed with 5.8 $\\sigma$ significance.

  19. 2005. aasta parim puitehitis on lasteaed / Mait Eelrand

    Index Scriptorium Estoniae

    Eelrand, Mait

    2005-01-01

    Eesti Metsatööstuse Liidu korraldatud arhitektuurikonkursist "Eesti parim puitehitis 2005", mille võitis lasteaed Naba Pirital (arhitektid Vahur Sova, Lauri Saar, insener Tõnu Peipman). Äramärgitud tööd: AS Palmako tootmishoone Tartumaal Kavastus (insener Paul Sõrmus, arhitekt Ott Ojamaa), kortermajad Tabasalus (arhitekt Oliver Alver, insener Eino Hint); liimpuidu eriauhind: autode varjualune Nõmmel (arhitekt Indrek Allmann, insener Indrek Einola); vineeri kasutamise eriauhind: Kuressaare linnavalitsuse hoone fassaad (arhitekt Toomas Paaver, Terje Truumaa); höövelpuidu eriauhind: Estonian Golf and Country Club Jõelähtmel (arhitekt Andres Siim, insenerid Villu Leppik, Ragnar Pabort, Alar Just). Kommenteerijad: K. Vasarik, M. Riistop. 10 värv. ill

  20. Kuressaarest kaks laureaaditiitlit / Riina Mägi

    Index Scriptorium Estoniae

    Mägi, Riina, 1957-

    2008-01-01

    Maakondlikust etlejate konkursist. Žüriisse kuulusid Maret Oomer, Asta Leiten ja Kalle Piiskoppel. 5.-7. klasside arvestuses I koht: Marleen Petersell. Äramärkimist leidsid: Kristian Käresk, Maarja-Liis Mölder ja Anita Tuula. 7.-9. klasside arvestuses I koht: Oliver Taul. Esile tõsteti: Rauno Reinas, Riko Osila, Linda Maisväli ja Piia Puuraid. 10.-12. klasside arvestuses I koht: Karl Sakrits. Ära märgiti: Elin Küti, Virgo Ernits, Maria Orb. Kommenteerisid Asta Leiten, Liann Saage-Vahur. Ka Kuressaares toimunud vabariiklikust etlejate konkursist, kommentaare jagasid Merle Rekaya, Rita Ilves. Zhürisse kuulusid Aare Toikka, Tiina Rebane, Hans Kaldoja, Kristiina Omer ja Keete Viira. Peapreemia nooremas vanuseastmes Markkus Pulgale, keskmises vanuseastmes Anna Talvile ja vanemas vanuseastmes Doris Täkkerile.

  1. Short outlines of books by Estonian authors / Janika Kronberg, Rutt Hinrikus

    Index Scriptorium Estoniae

    Kronberg, Janika, 1963-

    2008-01-01

    Arvustus: Afanasjev, Vahur. Kosmos. Tallinn : Jutulind, 2008 ; Hvostov, Andrei. Võõrad lood. Tallinn : Tänapäev, 2008 ; Lauli, Olle. Niguliste õpilased. Tallinn : Verb, 2007 ; Rooste, Jürgen. Tavaline eesti idioot. Pärnu : Ji, 2008 ; Talvet, Jüri. Silmad peksavad une seinu. Tartu : Ilmamaa, 2008 ; Beekman, Aimée. Proovielu. Tallinn : Varrak, 2008 ; Kivi, Aita. Lähedal. Tallinn : Ajakirjade Kirjastus, 2008 ; Beekman, Vladimir. Alles see oli. Tallinn : Tänapäev, 2008 ; Viiding, Elo. Püha Maama. Tallinn : Tuum, 2008 ; Nõu, Helga. Peaaegu geenius ehk Schrödingeri kassi otsimas. Tallinn : Atlex, 2008 ; Unt, Lii. Parim näitleja linnas. Varanasi päevaraamat. Tallinn : Eesti Ekspressi Kirjastus, 2007 ; Sild, Ivar. Tantsiv linn. Tallinn : Tuum, 2007

  2. Neivelt : olen vaba mees / Indrek Neivelt ; interv. Inno Tähismaa

    Index Scriptorium Estoniae

    Neivelt, Indrek, 1967-

    2005-01-01

    Hansapanga kauaaegne juht Indrek Neivelt põhjendab oma ametist lahkumist kui ühe etapi läbisaamist oma karjääris. Lisa: Hansapanga areng Neivelti juhtimisel. Vt. samas: Indrek Neivelt põhjendas eile oma ametist lahkumist uue ajastu algusega Hansapangas; Erkki Raasuke: teisi lahkujaid praegu pole; Peeter Raidla. Hansapank oli Neivelti esimene tõsine töökoht; Kadi Heinsalu. Hansapanga töötajaid tabas uudis Indrek Neivelti lahkumisest ootamatult; Lauri Matsulevitsh. Jüri Mõis: Indrek polnud hea käsutäitja; Annika Matson. Hansapanga väikeaktsionärid veetsid koosoleku mornis meeleolus; Swedbank otsustas Hansapanga dividendid salve jätta. Kommenteerivad: Andrus Ansip, Vahur Kraft, Edgar Savisaar, Meelis Milder, Kuldar Leis, Mihkel Oviir, Valdo Kalm, Joakim Helenius, Mati Jostov, Rein Kilk, Cardo Remmel, Urmas Sõõrumaa, Oliver Kruuda

  3. to view fulltext PDF

    Indian Academy of Sciences (India)

    Acharyya, Suman, International Centre for Theoretical. Sciences (ICTS), India. Agarwal, Ankit, University of Potsdam, Potsdam, Germany,. PIK, GFZ. Allmin Pradhap Singh, Susaiyah, Indian Institute of. Technology, Madras, India. Anand, Sajini, Tata Institute of Fundamental Research. (TIFR), India. Apte, Amid, Tata Institute of ...

  4. Some Interesting Mathematical Gems

    Indian Academy of Sciences (India)

    Pentagonal numbers; Pik's formula; power triangle; formulae to generate prime numbers; Kaprekar's conjecture; Rogers-Ramanujan identity; hypersphere and hypercube. Author Affiliations. V G Tikekar1. c/o Thakar New Mahadwar Road Near Padmaraje School Kolhapur 416006, India. Resonance – Journal of Science ...

  5. Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities?

    Science.gov (United States)

    2014-10-01

    appreciation of cancer health disparity research. Shadowing included didactic lectures to the students. Year 2 goals: i. Submit manuscript by the end of...discipline -- Understanding prostate cancer biology and disparities. Taken together, our in vitro and in vivo findings with the CA PIK3CD-long and AA

  6. The Effects of Melatonin on Menstrual Characteristics, Prolactin and Premenstrual Syndrome-Like Symptoms During a Simulated Eastward Deployment

    Science.gov (United States)

    1998-06-01

    Connecticut and Melanie Clayton, Pik Rivera, Santiago Arroyo, Rhonda Strickland, Nancy Gamer , Regina Bay-Wright, Keith Bleser, Mary Brock...Colmenero, M.D., Terrados, N., Fernandez, B. and Marin, B. 1993. Melatonin and gonadotropin hormones in pubertal sports girls . Rev.Esp.Fisiol. 49:17

  7. Sequence Classification: 894817 [

    Lifescience Database Archive (English)

    Full Text Available Non-TMB TMH Non-TMB Non-TMB Non-TMB Non-TMB >gi|6322526|ref|NP_012600.1| PIK-related protein kinase and rapa...mycin target; subunit of TORC1, a complex that controls growth in response to nutri

  8. RESEARCH NOTE Clinical Utility of a 377 gene custom NGS ...

    Indian Academy of Sciences (India)

    2016-11-11

    Nov 11, 2016 ... encephalopathies, (3) malformation disorders, (4) epilepsy in X-linked intellectual disability, (5) storage diseases and organelle dysfunction (6) syndromic disorders with epilepsy, .... N-glycanase 1. Congenital disorder of deglycosylation. PIK3R2. AD. Phosphatidylinositol 3-kinase, regulatory subunit 2.

  9. ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration

    Czech Academy of Sciences Publication Activity Database

    Jaiswal, H.; Benada, Jan; Müllers, E.; Akopyan, K.; Burdová, Kamila; Koolmeister, T.; Helleday, T.; Medema, R.H.; Macůrek, Libor; Lindqvist, A.

    2017-01-01

    Roč. 36, č. 14 (2017), s. 2161-2176 ISSN 0261-4189 R&D Projects: GA ČR GA13-18392S Institutional support: RVO:68378050 Keywords : ATM * ATR * checkpoint recovery * G2 * Pik1 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 9.792, year: 2016

  10. Räpinas esietendub näitemäng [13. juulil 2002

    Index Scriptorium Estoniae

    2002-01-01

    "Ööpik Võhandu kaldalt", Jaan Vahtra mälestuste ja novelli "Vanajumal ja vanapagan", Herman Julius Schmalzi elukäigu ja loomingu jt materjalide põhjal kirjutanud Aapo Ilves. Mängivad Räpina rahvanäitlejad (lav. Raivo Adlas)

  11. Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

    DEFF Research Database (Denmark)

    Quaye, L; Song, H; Ramus, S J

    2009-01-01

    oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence...

  12. influence of calcium and magnesium based fertilizers on fungal

    African Journals Online (AJOL)

    PUBLICATIONS1

    Magnesium that activates many dehy- drogenases and phosphate transfer enzymes. (Öpik and Rolfe, 2005) may stimulate the ef- fects of calcium and/or ABA on fruit yield since ABA regulates fruit maturation, seed stor- age reserve accumulation and induces protein synthesis in seeds (Davies, 2007; Taiz and. Zeiger, 2006).

  13. 7 CFR 1435.504 - Timing of distribution of CCC-owned sugar.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Timing of distribution of CCC-owned sugar. 1435.504... CORPORATION, DEPARTMENT OF AGRICULTURE LOANS, PURCHASES, AND OTHER OPERATIONS SUGAR PROGRAM Processor Sugar Payment-In-Kind (PIK) Program § 1435.504 Timing of distribution of CCC-owned sugar. Distribution of sugar...

  14. A systematic review of targeted agents for non-small cell lung cancer

    DEFF Research Database (Denmark)

    Vestergaard, Hannah H; Christensen, Marcus R; Lassen, Ulrik N

    2017-01-01

    regarding the use of TA for Rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), ROS proto-oncogene 1 (ROS1) rearrangement, Receptor tyrosine-protein kinase erbB-2 (ERBB2), Phosphatidylinositol 3-kinase (PIK3CA)/v-akt murine thymoma viral oncogene homolog; protein kinase B(AKT)/Phosphatase and tensin...

  15. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

    DEFF Research Database (Denmark)

    Ekstrand, Anna Isinger; Jönsson, Mats; Lindblom, Annika

    2010-01-01

    The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...... and 75% and were strongly associated (P = 0.005). Reduced/lost PTEN expression was found in 63% of the tumors. Though HNPCC-associated colorectal cancers show simple genetic profiles with few chromosomal alterations, we demonstrate frequent and repeated targeting of the PI3K/AKT/mTOR pathway, which...

  16. Ablation of phosphoinositide-3-kinase class II alpha suppresses hepatoma cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Stanley K.L. [Singapore Immunology Network A-STAR (Singapore); Neo, Soek-Ying, E-mail: neo_soek_ying@sics.a-star.edu.sg [Singapore Immunology Network A-STAR (Singapore); Yap, Yann-Wan [Singapore Immunology Network A-STAR (Singapore); Karuturi, R. Krishna Murthy; Loh, Evelyn S.L. [Genome Institute of Singapore A-STAR (Singapore); Liau, Kui-Hin [Department of General Surgery, Tan Tock Seng Hospital (Singapore); Ren, Ee-Chee, E-mail: ren_ee_chee@immunol.a-star.edu.sg [Singapore Immunology Network A-STAR (Singapore); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (Singapore)

    2009-09-18

    Cancer such as hepatocellular carcinoma (HCC) is characterized by complex perturbations in multiple signaling pathways, including the phosphoinositide-3-kinase (PI3K/AKT) pathways. Herein we investigated the role of PI3K catalytic isoforms, particularly class II isoforms in HCC proliferation. Among the siRNAs tested against the eight known catalytic PI3K isoforms, specific ablation of class II PI3K alpha (PIK3C2{alpha}) was the most effective in impairing cell growth and this was accompanied by concomitant decrease in PIK3C2{alpha} mRNA and protein levels. Colony formation ability of cells deficient for PIK3C2{alpha} was markedly reduced and growth arrest was associated with increased caspase 3 levels. A small but significant difference in gene dosage and expression levels was detected between tumor and non-tumor tissues in a cohort of 19 HCC patients. Taken together, these data suggest for the first time that in addition to class I PI3Ks in cancer, class II PIK3C2{alpha} can modulate HCC cell growth.

  17. PI3Kγ drives priming and survival of autoreactive CD4(+ T cells during experimental autoimmune encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Iain Comerford

    Full Text Available The class IB phosphoinositide 3-kinase gamma enzyme complex (PI3Kγ functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg(-/- mice and a selective PI3Kγ inhibitor, we show that PI3Kγ promotes development of experimental autoimmune encephalomyelitis (EAE. In pik3cg(-/- mice, EAE is markedly suppressed and fewer leukocytes including CD4(+ and CD8(+ T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4(+ T cell priming in secondary lymphoid organs is reduced in pik3cg(-/- mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110γ. Together, this results in suppressed autoreactive T cell responses in pik3cg(-/- mice, with more CD4(+ T cells undergoing apoptosis and fewer cytokine-producing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kγ inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kγ may be useful therapeutics for MS.

  18. Tartu Ülikooli kümme geeniust / Alo Lõhmus

    Index Scriptorium Estoniae

    Lõhmus, Alo

    2007-01-01

    Valik Tartu Ülikoolis 375 aasta jooksul kõige rohkem maailmateadust mõjutanud teadlasi: Friedrich Georg Wilhelm Stuve, Martin Heinrich Rathke, Karl Ernst von Baer, Karl Wilhelm von Kupffer, Juri Lotman, Ludvig Puusepp Nikolai Pirogov, Ernst Öpik, Ivan Kondakov, Karl Bücher, Karl Friedrich Burdach ja Gustav Teichmüller

  19. The Genome of the Chicken DT40 Bursal Lymphoma Cell Line

    DEFF Research Database (Denmark)

    Molnar, Janos; Poti, Adam; Pipek, Orsolya

    2014-01-01

    inactivating the PIK3R1 and ATRX genes likely contributed to the oncogenic transformation. In addition to a known avian leukosis virus integration in the MYC gene, we detected further integration sites that are likely to de-regulate gene expression. The new findings support the hypothesis that DT40...

  20. Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer.

    Science.gov (United States)

    Guarneri, Valentina; Dieci, Maria Vittoria; Frassoldati, Antonio; Maiorana, Antonino; Ficarra, Guido; Bettelli, Stefania; Tagliafico, Enrico; Bicciato, Silvio; Generali, Daniele Giulio; Cagossi, Katia; Bisagni, Giancarlo; Sarti, Samanta; Musolino, Antonino; Ellis, Catherine; Crescenzo, Rocco; Conte, PierFranco

    2015-09-01

    The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. A biomarker program was prospectively planned to identify potential predictors of sensitivity to different treatments and to evaluate treatment effect on tumor biomarkers. Overall, 121 breast cancer patients positive for human epidermal growth factor 2 (HER2) were randomly assigned to neoadjuvant chemotherapy plus trastuzumab, lapatinib, or both trastuzumab and lapatinib. Pre- and post-treatment samples were centrally evaluated for HER2, p95-HER2, phosphorylated AKT (pAKT), phosphatase and tensin homolog, Ki67, apoptosis, and PIK3CA mutations. Fresh-frozen tissue samples were collected for genomic analyses. A mutation in PIK3CA exon 20 or 9 was documented in 20% of cases. Overall, the pCR rates were similar in PIK3CA wild-type and PIK3CA-mutated patients (33.3% vs. 22.7%; p = .323). For patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild-type tumors (48.4% vs. 12.5%; p = .06). Ki67, pAKT, and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. The integrated analysis of gene expression and copy number data demonstrated that a 50-gene signature specifically predicted the lapatinib-induced pCR. PIK3CA mutations seem to identify patients who are less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of phosphoinositide 3-kinase pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib. HER2 is currently the only validated marker to select breast cancer patients for anti-HER2 treatment; however, it is becoming evident that HER2-positive breast cancer is a heterogeneous disease. In addition, more

  1. Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers.

    Directory of Open Access Journals (Sweden)

    Martin Kächele

    Full Text Available Phosphoinositide 3-kinase γ (PI3Kγ is a G-protein-coupled receptor-activated lipid kinase mainly expressed in leukocytes and cells of the cardiovascular system. PI3Kγ plays an important signaling role in inflammatory processes. Since subclinical inflammation is a hallmark of atherosclerosis, obesity-related insulin resistance, and pancreatic β-cell failure, we asked whether common genetic variation in the PI3Kγ gene (PIK3CG contributes to body fat content/distribution, serum adipokine/cytokine concentrations, alterations in plasma lipid profiles, insulin sensitivity, insulin release, and glucose homeostasis.Using a tagging single nucleotide polymorphism (SNP approach, we analyzed genotype-phenotype associations in 2,068 German subjects genotyped for 10 PIK3CG SNPs and characterized by oral glucose tolerance tests. In subgroups, data from hyperinsulinaemic-euglycaemic clamps, magnetic resonance spectroscopy of the liver, whole-body magnetic resonance imaging, and intravenous glucose tolerance tests were available, and peripheral blood mononuclear cells (PBMCs were used for gene expression analysis.After appropriate adjustment, none of the PIK3CG tagging SNPs was significantly associated with body fat content/distribution, adipokine/cytokine concentrations, insulin sensitivity, insulin secretion, or blood glucose concentrations (p>0.0127, all; Bonferroni-corrected α-level: 0.0051. However, six non-linked SNPs displayed at least nominal associations with plasma HDL-cholesterol concentrations, two of them (rs4288294 and rs116697954 reaching the level of study-wide significance (p = 0.0003 and p = 0.0004, respectively. More precisely, rs4288294 and rs116697954 influenced HDL2-, but not HDL3-, cholesterol. With respect to the SNPs' in vivo functionality, rs4288294 was significantly associated with PIK3CG mRNA expression in PBMCs.We could demonstrate that common genetic variation in the PIK3CG locus, possibly via altered PIK3CG gene expression

  2. Improving Counselling Skills about Reproductive Health among Students by Using Peer Counselor Training

    Directory of Open Access Journals (Sweden)

    Ririn Harini

    2016-09-01

    Full Text Available Introduction: Nowadays, the goal of MDGs to improve maternal health is one of the priorities of many countries. Indonesian Government, by the National Family Planning Board (BKKBN, has followed up by monitoring and evaluating programs which is realized by providing technical guidance resilience in young people through Generation Planning program and developing Information and Consultation Center for Students Reproductive Health (PIK-KRM. In order to improve the role of peer counselors, a training should be done to increase their knowledge, attitudes, and skills. The objective of this research was to determine the effects of training on peer counselor’s knowledge, attitudes, and skills at PIK-KRM. Methods: The study was used quasy experiment pre-test and post-test nonequivalent control group design. Population were the committee of PIK-KRM at Faculty of Health, University of Muhammadiyah Malang, 80 students were included. Independent variable was training, while dependent variables were peer counselor’s knowledge, attitude, and skills. Data were collected by using questionnaire and observation form. Data were then analyzed by using paired t–test, independent sample t-test, simple linear regression. Results: The results of linear regression had showed that training have significant effect on peer counselor’s knowledge (p=0.000; R square=0.254, attitude (p=0.000; R square=0.432, and skills (p=0.000; R square=0.191. Discussion: Training can improve peer counselor’s knowledge, attitude, and skills at PIK-KRM board in giving information and counseling about reproductive health (sexuality, HIV/AIDS, and drugs. Nurses should provide continous training regularly, so their ability can be more better. Keywords: training, peer counselors, knowledge, attitudes, skills, PIK-KRM board, students reproductive health

  3. The role of phosphoinositide 3-kinases in neutrophil migration in 3D collagen gels.

    Directory of Open Access Journals (Sweden)

    Kayleigh J S Martin

    Full Text Available The entry of neutrophils into tissue has been well characterised; however the fate of these cells once inside the tissue microenvironment is not fully understood. A variety of signal transduction pathways including those involving class I PI3 Kinases have been suggested to be involved in neutrophil migration. This study aims to determine the involvement of PI3 Kinases in chemokinetic and chemotactic neutrophil migration in response to CXCL8 and GM-CSF in a three-dimensional collagen gel, as a model of tissue. Using a three-dimensional collagen assay chemokinetic and chemotactic migration induced by CXCL8 was inhibited with the pan PI3 Kinase inhibitor wortmannin. Analysis of the specific Class I PI3 Kinase catalytic isoforms alpha, delta and gamma using the inhibitors PIK-75, PIK-294 and AS-605240 respectively indicated differential roles in CXCL8-induced neutrophil migration. PIK-294 inhibited both chemokinetic and chemotactic CXCL8-induced migration. AS-605240 markedly reduced CXCL8 induced chemokinetic migration but had no effect on CXCL8 induced chemotactic migration. In contrast PIK-75 inhibited chemotactic migration but not chemokinetic migration. At optimal concentrations of GM-CSF the inhibitors had no effect on the percentage of neutrophil migration in comparison to the control however at suboptimal concentrations wortmannin, AS-605240 and PIK-294 inhibited chemokinesis. This study suggests that PI3 Kinase is necessary for CXCL8 induced migration in a 3D tissue environment but that chemokinetic and chemotactic migration may be controlled by different isoforms with gamma shown to be important in chemokinesis and alpha important in chemotaxis. Neutrophil migration in response to suboptimal concentrations of GM-CSF is dependent on PI3 Kinase, particularly the gamma and delta catalytic isoforms.

  4. Nanotechnology-based inhalation treatments for lung cancer: state of the art

    Directory of Open Access Journals (Sweden)

    Ahmad J

    2015-11-01

    Full Text Available Javed Ahmad,1,* Sohail Akhter,2,3,* Md Rizwanullah,1 Saima Amin,1 Mahfoozur Rahman,4 Mohammad Zaki Ahmad,5 Moshahid Alam Rizvi,6 Mohammad A Kamal,7 Farhan Jalees Ahmad1,21Department of Pharmaceutics, 2Nanomedicine Research Lab, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India; 3Centre de Biophysique Moléculaire(CBM-CNRS UPR4301, University of Orléans, Orléans Cedex 2, France; 4Department of Pharmaceutics, Abhilashi College of Pharmacy, Mandi, HP, India; 5Department of Pharmaceutics, College of Pharmacy, Najran University, Saudi Arabia; 6Department of Biosciences, Jamia Millia Islamia, New Delhi, India; 7Metabolomics and Enzymology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia*These authors contributed equally to this workAbstract: Considering the challenges associated with conventional chemotherapy, targeted and local delivery of chemotherapeutics via nanoparticle (NP carriers to the lungs is an emerging area of interest. Recent studies and growing clinical application in cancer nanotechnology showed the huge potential of NPs as drug carriers in cancer therapy, including in lung carcinoma for diagnosis, imaging, and theranostics. Researchers have confirmed that nanotechnology-based inhalation chemotherapy is viable and more effective than conventional chemotherapy, with lesser side effects. Recently, many nanocarriers have been investigated, including liposomes, polymeric micelles, polymeric NPs, solid lipid NPs, and inorganic NPs for inhalation treatments of lung cancer. Yet, the toxicity of such nanomaterials to the lungs tissues and further distribution to other organs due to systemic absorption on inhalation delivery is a debatable concern. Here, prospect of NPs-based local lung cancer targeting through inhalation route as well as its associated challenges are discussed.Keywords: nanoparticles, lung cancer, inhalational chemotherapy, drug targeting, nanotoxicity

  5. Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation.

    Science.gov (United States)

    Jorge, Susan E; Schulman, Sol; Freed, Jason A; VanderLaan, Paul A; Rangachari, Deepa; Kobayashi, Susumu S; Huberman, Mark S; Costa, Daniel B

    2015-12-01

    Genomic aberrations involving ALK, ROS1 and MET can be driver oncogenes in lung adenocarcinomas. Identification of tyrosine kinase inhibitors (TKIs) with activity against these tumors and of preclinical systems to model response are warranted. We analyzed cases with lung adenocarcinomas for representative genomic aberrations, evaluated the response to the multitargeted MET/ALK/ROS1 crizotinib TKI in cases with MET aberrations and profiled lung cancer cell lines with the aforementioned genomic changes. Lung cancer cell lines with ALK rearrangement, ROS1 rearrangement or MET amplification had expected in vitro responses to crizotinib and the ALK/ROS1 TKI ceritinib. However, a commercially-available cell line with MET exon 14 skipping mutation and co-occurring PIK3CA-p.Glu545Lys mutation did not respond to crizotinib; suggesting the latter abrogated response. 10% of MET exon 14 skipping mutation co-occurred with PIK3CA mutation in the TCGA cohort. Putative crizotinib-responsive somatic mutations (ALK rearrangements, ROS1 rearrangements, high level MET amplification or MET exon 14 skipping mutations) were present in 10% of lung adenocarcinomas analyzed at our service and in 9.5% of the TCGA lung adenocarcinoma database. One patient each whose advanced tumors harbored high level MET amplification with wild-type PIK3CA or MET exon 14 skipping mutation with PIK3CA-p.Glu542Lys had significant responses to crizotinib; suggesting that PIK3CA co-mutation did not affect clinical response. Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to MET TKIs in human lung adenocarcinomas but co-occurrence of PIK3CA mutation needs to be better evaluated as a modifier of response to TKI therapy. MET TKIs should not be omitted from MET exon 14 skipping mutated tumors until further preclinical and clinical data can confirm or refute mechanisms of primary or

  6. Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas

    Science.gov (United States)

    2017-09-01

    chose to make new medulloblastoma models with oncogenic PIK3CA (PIK3CAH1047R). However, this change caused major delay in our progress since we have not...these tumors. 15. SUBJECT TERMS cancer stem cells, medulloblastoma, targeted therapy, therapy resistance , pediatric cancer, brain tumor, Notch1...Keywords……………………………………………………………. 4 3. Accomplishments………..………………………………………….. 4 4. Impact…………………………...…………………………………… 8 5. Changes /Problems

  7. Identification of Epigenetic Changes in Prostate Cancer using Induced Pluripotent Stem Cells

    Science.gov (United States)

    2013-04-01

    02 CCNE1,CDK4 HMGB1 Signaling 7.33E-01 5.05E-02 FOS,RHOQ,RHOC,PIK3C3,MAPK10 Growth Hormone Signaling 7.31E-01 5.26E-02 FOS,PIK3C3,SOCS5,PRKCB...in Lymphocytes 6.39E-01 5.26E-02 FOS,MAP3K7,MAPK10 Cholecystokinin/ Gastrin - mediated Signaling 6.36E-01 4.72E-02 FOS,RHOQ,RHOC,MAPK10,PRKCB NRF2...CASP7,XIAP Corticotropin Releasing Hormone Signaling 5.34E-01 3.68E-02 SHH,CALM1 (includes others),FOS,GUCY1A3,PRKCB Synaptic Long Term Depression

  8. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides

    DEFF Research Database (Denmark)

    Almutairi, Mashal M; Park, Sung Ryeol; Rose, Simon

    2015-01-01

    activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken...... together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism.......Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces...

  9. Energy fluxes and spectra for turbulent and laminar flows

    KAUST Repository

    Verma, Mahendra K.

    2017-05-14

    Two well-known turbulence models to describe the inertial and dissipative ranges simultaneously are by Pao~[Phys. Fluids {\\\\bf 8}, 1063 (1965)] and Pope~[{\\\\em Turbulent Flows.} Cambridge University Press, 2000]. In this paper, we compute energy spectrum $E(k)$ and energy flux $\\\\Pi(k)$ using spectral simulations on grids up to $4096^3$, and show consistency between the numerical results and predictions by the aforementioned models. We also construct a model for laminar flows that predicts $E(k)$ and $\\\\Pi(k)$ to be of the form $\\\\exp(-k)$, and verify the model predictions using numerical simulations. The shell-to-shell energy transfers for the turbulent flows are {\\\\em forward and local} for both inertial and dissipative range, but those for the laminar flows are {\\\\em forward and nonlocal}.

  10. Lessons in Effector and NLR Biology of Plant-Microbe Systems.

    Science.gov (United States)

    Białas, Aleksandra; Zess, Erin K; De la Concepcion, Juan Carlos; Franceschetti, Marina; Pennington, Helen G; Yoshida, Kentaro; Upson, Jessica L; Chanclud, Emilie; Wu, Chih-Hang; Langner, Thorsten; Maqbool, Abbas; Varden, Freya A; Derevnina, Lida; Belhaj, Khaoula; Fujisaki, Koki; Saitoh, Hiromasa; Terauchi, Ryohei; Banfield, Mark J; Kamoun, Sophien

    2017-11-16

    A diversity of plant-associated organisms secrete effectors-proteins and metabolites that modulate plant physiology to favor host infection and colonization. However, effectors can also activate plant immune receptors, notably nucleotide-binding domain and leucine-rich repeat region (NLR)-containing proteins, enabling plants to fight off invading organisms. This interplay between effectors, their host targets, and the matching immune receptors is shaped by intricate molecular mechanisms and exceptionally dynamic coevolution. In this article, we focus on three effectors, AVR-Pik, AVR-Pia, and AVR-Pii, from the rice blast fungus Magnaporthe oryzae (syn. Pyricularia oryzae), and their corresponding rice NLR immune receptors, Pik, Pia, and Pii, to highlight general concepts of plant-microbe interactions. We draw 12 lessons in effector and NLR biology that have emerged from studying these three little effectors and are broadly applicable to other plant-microbe systems.

  11. High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Kristensen, Louise; Kielsgaard Kristensen, Thomas; Abildgaard, Niels

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the Western world. Autophagy is a highly conserved process in eukaryotic cells. In CLL autophagy is involved in mediating the effect of chemotherapy but the role of autophagy in CLL pathogenesis remains unknown....... In the present study, we used real-time RT-PCR to analyze expression of the PIK3C3, PIK3R4, and BECN1 genes. These genes encode the components of the PI3K core complex, which is central to initiation of autophagy. A consecutive series of 149 well-characterized CLL cases from Region of Southern Denmark were...... included in the study. All three genes were observed to be independent markers of prognosis in CLL with high expression being associated with more aggressive disease. With this clear association with outcome in CLL, these genes thereby represent promising candidates for future functional studies...

  12. Structural Basis for Binding Specificity between Subclasses of Modular Polyketide Synthase Docking Domains

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Tonia J.; Geders, Todd W.; Bartley, III, Frank E.; Reynolds, Kevin A.; Smith, Janet L.; Sherman, David H.; (Michigan); (Portland SU)

    2009-04-02

    Bacterial type I polyketide synthases (PKSs) assemble structurally diverse natural products of significant clinical value from simple metabolic building blocks. The synthesis of these compounds occurs in a processive fashion along a large multiprotein complex. Transfer of the acyl intermediate across interpolypeptide junctions is mediated, at least in large part, by N- and C-terminal docking domains. We report here a comprehensive analysis of the binding affinity and selectivity for the complete set of discrete docking domain pairs in the pikromycin and erythromycin PKS systems. Despite disconnection from their parent module, each cognate pair of docking domains retained exquisite binding selectivity. Further insights were obtained by X-ray crystallographic analysis of the PikAIII/PikAIV docking domain interface. This new information revealed a series of key interacting residues that enabled development of a structural model for the recently proposed H2-T2 class of polypeptides involved in PKS intermodular molecular recognition.

  13. Conformal Stereotactic Radiosurgery With Multileaf Collimation.

    Science.gov (United States)

    1992-01-01

    INVESTIGATIONAL DOSIMETRY The current dose model used in the University of Flori- da stereotactic radiosurgery planning system is the TMR/ OAR model...Systems U.K. (1991) Pik87 B. Pike, E.B. Podgorsak, T.M. Peters, C. Pla, " Dose distributions in dynamic stereotactic radiosurgery ," Med. Phys. 14:780...34Optimization of dose distribution for the system of linear accelerator based stereotactic radiosurgery ," Ph.D. Dissertation, University of Florida (1990

  14. Regulation of amyloid precursor protein processing by the Beclin 1 complex.

    Directory of Open Access Journals (Sweden)

    Philipp A Jaeger

    2010-06-01

    Full Text Available Autophagy is an intracellular degradation pathway that functions in protein and organelle turnover in response to starvation and cellular stress. Autophagy is initiated by the formation of a complex containing Beclin 1 (BECN1 and its binding partner Phosphoinositide-3-kinase, class 3 (PIK3C3. Recently, BECN1 deficiency was shown to enhance the pathology of a mouse model of Alzheimer Disease (AD. However, the mechanism by which BECN1 or autophagy mediate these effects are unknown. Here, we report that the levels of Amyloid precursor protein (APP and its metabolites can be reduced through autophagy activation, indicating that they are a substrate for autophagy. Furthermore, we find that knockdown of Becn1 in cell culture increases the levels of APP and its metabolites. Accumulation of APP and APP C-terminal fragments (APP-CTF are accompanied by impaired autophagosomal clearance. Pharmacological inhibition of autophagosomal-lysosomal degradation causes a comparable accumulation of APP and APP-metabolites in autophagosomes. Becn1 reduction in cell culture leads to lower levels of its binding partner Pik3c3 and increased presence of Microtubule-associated protein 1, light chain 3 (LC3. Overexpression of Becn1, on the other hand, reduces cellular APP levels. In line with these observations, we detected less BECN1 and PIK3C3 but more LC3 protein in brains of AD patients. We conclude that BECN1 regulates APP processing and turnover. BECN1 is involved in autophagy initiation and autophagosome clearance. Accordingly, BECN1 deficiency disrupts cellular autophagy and autophagosomal-lysosomal degradation and alters APP metabolism. Together, our findings suggest that autophagy and the BECN1-PIK3C3 complex regulate APP processing and play an important role in AD pathology.

  15. Composite Biomarkers For Non-invasive Screening, Diagnosis And Prognosis Of Colorectal Cancer

    KAUST Repository

    Mansour, Hicham

    2014-09-11

    The present invention concerns particular biomarkers for diagnosing and/or prognosticating colorectal cancer, in particular in a non-invasive manner. The methods and compositions concern analysis of methylation patterns of one or more genes from a set of 29 genes identified as described herein. In certain embodiments, the gene set includes at least P15.INK4b, SST, GAS7, CNRIP1, and PIK3CG.

  16. Late onset epidermal nevus with hypertrichosis and facial hemihypertrophy

    Directory of Open Access Journals (Sweden)

    M Saritha

    2014-01-01

    Full Text Available Epidermal nevus syndromes are rare conditions, characterized by different types of keratinocytic or organoid epidermal nevi in association with ocular, neurological, and skeletal manifestations. We present a case of late onset epidermal nevus with hypertrichosis and hemihypertrophy of face. Genetic analysis did not reveal presence of FGFR3 or PIK3CA mutations. The patient has features that cannot be categorized into the present well-known syndromes.

  17. Chromosomal imbalances are uncommon in chagasic megaesophagus

    Directory of Open Access Journals (Sweden)

    Silva Ana E

    2010-02-01

    Full Text Available Abstract Background Chagas' disease is a human tropical parasitic illness and a subset of the chronic patients develop megaesophagus or megacolon. The esophagus dilation is known as chagasic megaesophagus (CM and one of the severe late consequences of CM is the increased risk for esophageal carcinoma (ESCC. Based on the association between CM and ESCC, we investigated whether genes frequently showing unbalanced copy numbers in ESCC were altered in CM by fluorescence in situ (FISH technology. Methods A total of 50 formalin-fixed, paraffin-embedded esophageal mucosa specimens (40 from Chagas megaesophagus-CM, and 10 normal esophageal mucosa-NM were analyzed. DNA FISH probes were tested for FHIT, TP63, PIK3CA, EGFR, FGFR1, MYC, CDKN2A, YES1 and NCOA3 genes, and centromeric sequences from chromosomes 3, 7 and 9. Results No differences between superficial and basal layers of the epithelial mucosa were found, except for loss of copy number of EGFR in the esophageal basal layer of CM group. Mean copy number of CDKN2A and CEP9 and frequency of nuclei with loss of PIK3CA were significantly different in the CM group compared with normal mucosa and marginal levels of deletions in TP63, FHIT, PIK3CA, EGFR, CDKN2A, YES and gains at PIK3CA, TP63, FGFR1, MYC, CDNK2A and NCOA3 were detected in few CM cases, mainly with dilation grades III and IV. All changes occurred at very low levels. Conclusions Genomic imbalances common in esophageal carcinomas are not present in chagasic megaesophagus suggesting that these features will not be effective markers for risk assessment of ESCC in patients with chagasic megaesophagus.

  18. PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients.

    Science.gov (United States)

    Westin, Shannon N; Ju, Zhenlin; Broaddus, Russell R; Krakstad, Camilla; Li, Jane; Pal, Navdeep; Lu, Karen H; Coleman, Robert L; Hennessy, Bryan T; Klempner, Samuel J; Werner, Henrica M J; Salvesen, Helga B; Cantley, Lewis C; Mills, Gordon B; Myers, Andrea P

    2015-10-01

    Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse-phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P obese (body mass index ≥ 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non-obese population while decreased expression of β-CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity-related cancers and impact ongoing clinical trials with PI3K pathway inhibitors. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  19. Frequent genetic abnormalities of the PI3K/AKT pathway in primary ovarian cancer predict patient outcome

    Science.gov (United States)

    Huang, Jia; Zhang, Lin; Greshock, Joel; Colligon, Theresa A.; Wang, Yan; Ward, Renee; Katsaros, Dionyssios; Lassus, Heini; Butzow, Ralf; Godwin, Andrew K.; Testa, Joseph R.; Nathanson, Katherine L.; Gimotty, Phyllis A.; Coukos, George; Weber, Barbara L.; Degenhardt, Yan

    2011-01-01

    Identification and characterization of underlying genetic aberrations could facilitate diagnosis and treatment of ovarian cancer. Copy number analysis using array Comparative Genomic Hybridization (aCGH) on 93 primary ovarian tumors identified PI3K/AKT pathway as the most frequently altered cancer related pathway. Furthermore, survival analyses to correlate gene copy number and mutation data with patient outcome showed that copy number gains of PIK3CA, PIK3CB and PIK3R4 in these tumors were associated with decreased survival. To confirm these findings at the protein level, immunohistochemistry (IHC) for PIK3CA product p110α and p-Akt was performed on tissue microarrays from 522 independent serous ovarian cancers. Overexpression of either of these two proteins was found to be associated with decreased survival. Multivariant analysis from these samples further showed that overexpression of p-AKT and /or p110α is an independent prognostic factor for these tumors. siRNAs targeting altered PI3K/AKT pathway genes inhibited proliferation and induced apoptosis in ovarian cancer cell lines. In addition, the effect of the siRNAs in different cell lines seemed to correlate with the particular genetic alterations that the cell line carries. These results strongly support the utilization of PI3K pathway inhibitors in ovarian cancer. They also suggest identifying the specific component in the PI3K pathway that is genetically altered has the potential to help select the most effective therapy. Both mutation as well as copy number changes can be used as predictive markers for this purpose. PMID:21563232

  20. Systematic functional characterization of resistance to PI3K inhibition in breast cancer

    OpenAIRE

    Le, Xiuning; Antony, Rajee; Razavi, Pedram; Treacy, Daniel J.; Luo, Flora; Ghandi, Mahmoud; Castel, Pau; Scaltriti, Maurizio; Baselga, Jose; Garraway, Levi A.

    2016-01-01

    PIK3CA (which encodes the phosphoinositide-3 kinase (PI3K) alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, PIM kinases conferred resistance by ...

  1. Molecular Subgroup Analysis of Clinical Outcomes in a Phase 3 Study of Gemcitabine and Oxaliplatin with or without Erlotinib in Advanced Biliary Tract Cancer

    Directory of Open Access Journals (Sweden)

    Seung Tae Kim

    2015-02-01

    Full Text Available BACKGROUND: We previously reported that the addition of erlotinib to gemcitabine and oxaliplatin (GEMOX resulted in greater antitumor activity and might be a treatment option for patients with biliary tract cancers (BTCs. Molecular subgroup analysis of treatment outcomes in patients who had specimens available for analysis was undertaken. METHODS: Epidermal growth factor receptor (EGFR, KRAS, and PIK3CA mutations were evaluated using peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp reactions. Survival and response rates (RRs were analyzed according to the mutational status. Sixty-four patients (48.1% were available for mutational analysis in the chemotherapy alone group and 61 (45.1% in the chemotherapy plus erlotinib group. RESULTS: 1.6% (2/116 harbored an EGFR mutation (2 patients; exon 20, 9.6% (12/121 harbored a KRAS mutation (12 patients; exon 2, and 9.6% (12/118 harbored a PIK3CA mutation (10 patients, exon 9 and 2 patients, exon 20. The addition of erlotinib to GEMOX in patients with KRAS wild-type disease (n = 109 resulted in significant improvements in overall response compared with GEMOX alone (30.2% vs 12.5%, P = .024. In 95 patients with both wild-type KRAS and PIK3CA, there was evidence of a benefit associated with the addition of erlotinib to GEMOX with respect to RR as compared with GEMOX alone (P = .04. CONCLUSION: This study demonstrates that KRAS mutational status might be considered a predictive biomarker for the response to erlotinib in BTCs. Additionally, the mutation status of PIK3CA may be a determinant for adding erlotinib to chemotherapy in KRAS wild-type BTCs.

  2. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer.

    Science.gov (United States)

    Yaeger, Rona; Cowell, Elizabeth; Chou, Joanne F; Gewirtz, Alexandra N; Borsu, Laetitia; Vakiani, Efsevia; Solit, David B; Rosen, Neal; Capanu, Marinela; Ladanyi, Marc; Kemeny, Nancy

    2015-04-15

    RAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain. We performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis. Among the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P brain metastasis and on multivariate analysis was an independent predictor of involvement of these sites (HR, 1.5, 1.6, and 3.7, respectively). PIK3CA mutations occurred in 10% of the 786 cases genotyped, did not predict for worse survival, and did not exhibit a site-specific pattern of metastatic spread. The metastatic potential of CRC varies with the presence of RAS mutation. RAS mutation is associated with worse OS and increased incidence of lung, bone, and brain metastasis. An understanding of this site-specific pattern of spread may help to inform physicians' assessment of symptoms in patients with mCRC. © 2014 American Cancer Society.

  3. Politseiharidus - koolid koos või lahus? / Andres Anvelt

    Index Scriptorium Estoniae

    Anvelt, Andres, 1969-

    2004-01-01

    Sisekaitseakadeemia politseikolledži ja Politseikooli ühendamise põhjustest ja eesmärkidest. Liitmise tulemusena tekib Eestisse ühtne politseikoolitussüsteem, mis võimaldab ühtlustada õppekavad, -metoodika ja -kvaliteedi ning kasutada efektiivsemalt ressursse. Kommenteerivad Toivo Maimets, Raivo Õpik, Peeter Järvelaid, Jaanus Rahumägi ja Jüri Merits

  4. Cell of Origin: Exploring an Alternative Contributor to Ovarian Cancer

    Science.gov (United States)

    2015-12-01

    KRAS, or PIK3CA were successfully constructed. 9. The viral constructs were initially validated in a human endometrial cancer cell line and mouse...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Our studies to date have determined that human oogonial stem cells, while far less stable...tumorigenicity of these cells with the ultimate goal of comparing the DNA signature of the oogonial stem cell-derived tumors to that of primary human ovarian

  5. Kolmepoolne koostöölepe Tehnikaülikooli, OÜ TTÜ Sport ja SEB Ühispanga vahel

    Index Scriptorium Estoniae

    2006-01-01

    Tallinna Tehnikaülikool rektor Peep Sürje, Osaühing TTÜ Sport juhatuse esimees Andres Öpik ja AS SEB Eesti Ühispank juhatuse esimees Mart Altvee allkirjastasid kolmepoolse koostöölepingu, milles nähakse ette ühistegevused TTÜ üliõpilastele õppekavadega seotud äriplaanikonkursi korraldamisel, üliõpilaste sporditegevuse edasiarendamisel ning üliõpilastele osutatud pangateenuste parandamisel

  6. Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer.

    Science.gov (United States)

    Hanker, Ariella B; Estrada, Mónica Valeria; Bianchini, Giampaolo; Moore, Preston D; Zhao, Junfei; Cheng, Feixiong; Koch, James P; Gianni, Luca; Tyson, Darren R; Sánchez, Violeta; Rexer, Brent N; Sanders, Melinda E; Zhao, Zhongming; Stricker, Thomas P; Arteaga, Carlos L

    2017-06-15

    PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280-92. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. An alteration of the gut-liver axis drives pulmonary inflammation after intoxication and burn injury in mice.

    Science.gov (United States)

    Chen, Michael M; Zahs, Anita; Brown, Mary M; Ramirez, Luis; Turner, Jerrold R; Choudhry, Mashkoor A; Kovacs, Elizabeth J

    2014-10-01

    Approximately half of all adult burn patients are intoxicated at the time of their injury and have worse clinical outcomes than those without prior alcohol exposure. This study tested the hypothesis that intoxication alters the gut-liver axis, leading to increased pulmonary inflammation mediated by burn-induced IL-6 in the liver. C57BL/6 mice were given 1.2 g/kg ethanol 30 min prior to a 15% total body surface area burn. To restore gut barrier function, the specific myosin light chain kinase inhibitor membrane-permeant inhibitor of kinase (PIK), which we have demonstrated to reduce bacterial translocation from the gut, was administered 30 min after injury. Limiting bacterial translocation with PIK attenuated hepatic damage as measured by a 47% reduction in serum alanine aminotransferase (P intoxicated and burn-injured mice without PIK. This mitigation of hepatic damage was associated with a 49% decline in pulmonary neutrophil infiltration (P intoxication and burn injury. Overall, these data suggest that the gut-liver axis is deranged when intoxication precedes burn injury and that limiting bacterial translocation in this setting attenuates hepatic damage and pulmonary inflammation. Copyright © 2014 the American Physiological Society.

  8. Gene Expression Correlation for Cancer Diagnosis: A Pilot Study

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    Binbing Ling

    2014-01-01

    Full Text Available Poor prognosis for late-stage, high-grade, and recurrent cancers has been motivating cancer researchers to search for more efficient biomarkers to identify the onset of cancer. Recent advances in constructing and dynamically analyzing biomolecular networks for different types of cancer have provided a promising novel strategy to detect tumorigenesis and metastasis. The observation of different biomolecular networks associated with normal and cancerous states led us to hypothesize that correlations for gene expressions could serve as valid indicators of early cancer development. In this pilot study, we tested our hypothesis by examining whether the mRNA expressions of three randomly selected cancer-related genes PIK3C3, PIM3, and PTEN were correlated during cancer progression and the correlation coefficients could be used for cancer diagnosis. Strong correlations (0.68≤r≤1.0 were observed between PIK3C3 and PIM3 in breast cancer, between PIK3C3 and PTEN in breast and ovary cancers, and between PIM3 and PTEN in breast, kidney, liver, and thyroid cancers during disease progression, implicating that the correlations for cancer network gene expressions could serve as a supplement to current clinical biomarkers, such as cancer antigens, for early cancer diagnosis.

  9. Role of p38 MAPK in enhanced human cancer cells killing by the combination of aspirin and ABT-737

    Science.gov (United States)

    Zhang, Chong; Shi, Jing; Mao, Shi-ying; Xu, Ya-si; Zhang, Dan; Feng, Lin-yi; Zhang, Bo; Yan, You-you; Wang, Si-cong; Pan, Jian-ping; Yang, You-ping; Lin, Neng-ming

    2015-01-01

    Regular use of aspirin after diagnosis is associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. In this study, we showed that clinically achievable concentrations of aspirin and ABT-737 in combination could induce a synergistic growth arrest in several human PIK3CA wild-type cancer cells. In addition, our results also demonstrated that long-term combination treatment with aspirin and ABT-737 could synergistically induce apoptosis both in A549 and H1299 cells. In the meanwhile, short-term aspirin plus ABT-737 combination treatment induced a greater autophagic response than did either drug alone and the combination-induced autophagy switched from a cytoprotective signal to a death-promoting signal. Furthermore, we showed that p38 acted as a switch between two different types of cell death (autophagy and apoptosis) induced by aspirin plus ABT-737. Moreover, the increased anti-cancer efficacy of aspirin combined with ABT-737 was further validated in a human lung cancer A549 xenograft model. We hope that this synergy may contribute to failure of aspirin cancer therapy and ultimately lead to efficacious regimens for cancer therapy. PMID:25388762

  10. Coordinated Expression of Phosphoinositide Metabolic Genes during Development and Aging of Human Dorsolateral Prefrontal Cortex.

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    Stanley I Rapoport

    Full Text Available Phosphoinositides, lipid-signaling molecules, participate in diverse brain processes within a wide metabolic cascade.Gene transcriptional networks coordinately regulate the phosphoinositide cascade during human brain Development and Aging.We used the public BrainCloud database for human dorsolateral prefrontal cortex to examine age-related expression levels of 49 phosphoinositide metabolic genes during Development (0 to 20+ years and Aging (21+ years.We identified three groups of partially overlapping genes in each of the two intervals, with similar intergroup correlations despite marked phenotypic differences between Aging and Development. In each interval, ITPKB, PLCD1, PIK3R3, ISYNA1, IMPA2, INPPL1, PI4KB, and AKT1 are in Group 1, PIK3CB, PTEN, PIK3CA, and IMPA1 in Group 2, and SACM1L, PI3KR4, INPP5A, SYNJ1, and PLCB1 in Group 3. Ten of the genes change expression nonlinearly during Development, suggesting involvement in rapidly changing neuronal, glial and myelination events. Correlated transcription for some gene pairs likely is facilitated by colocalization on the same chromosome band.Stable coordinated gene transcriptional networks regulate brain phosphoinositide metabolic pathways during human Development and Aging.

  11. Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.

    Science.gov (United States)

    Le, Xiuning; Antony, Rajee; Razavi, Pedram; Treacy, Daniel J; Luo, Flora; Ghandi, Mahmoud; Castel, Pau; Scaltriti, Maurizio; Baselga, Jose; Garraway, Levi A

    2016-10-01

    PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers. PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. Cancer Discov; 6(10); 1134-47. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069. ©2016 American Association for Cancer Research.

  12. Structure, design and statistical programme library of the meteorological database of Potsdam-Institut fuer Klimaforschung; Struktur, Aufbau und statistische Programmbibliothek der meteorologischen Datenbank am Potsdam-Institut fuer Klimaforschung

    Energy Technology Data Exchange (ETDEWEB)

    Oesterle, H.; Glauer, J. [Potsdam-Institut fuer Klimafolgenforschung (PIK), Potsdam (Germany); Denhard, M. [Frankfurt Univ. (Germany). Inst. fuer Meteorologie und Geophysik

    1999-01-01

    The relational database management system (ORACLE) using different client interfaces (browser, SQL, precompiler) is the most important basis for data organization and storage. The creation of a data bank system at PIK includes: Acquisition of meteorological data series for the projects executed at PIK; development of a database structure on the basis of daily values; control, analysis and classification of data into given storage formats; development and application of statistical software. There are currently 20 different types of data sets with daily, monthly and annual data which are functionally interconnected and updated. All data sets are continuously updated. (orig.) [Deutsch] Wesentliche Grundlage der Datenorganisation und -speicherung bildet das relationale Datenbanksystem ORACLE mit den dazugehoerigen Werkzeugen (Browser, SQL- und Precompiler). Die Entwicklung des Datenbanksystems am PIK umfasst folgende Etappen: - Erwerb von meteorologischen Datensaetzen fuer die am Institut laufenden Forschungsvorhaben; - Entwicklung einer Speicherstruktur auf der Basis von Tageswerten; - Kontrolle, Analyse und Einordnung der Daten in die vorgegebenen Speicherformate; - Entwicklung der zur Datennutzung notwendigen statistischen Programmbibliothek. Zur Zeit gibt es 20 verschiedene Typen von Datensaetzen. Sie enthalten taegliche, monatliche und jaehrliche Daten und sind funktional miteinander verbunden. Alle Datensaetze werden kontinuierlich erweitert. (orig.)

  13. Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors.

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    Joaquim Bellmunt

    Full Text Available An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS in patients with advanced urothelial carcinoma (UC treated with platinum-based chemotherapy.DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE invasive high-grade UC samples and were screened for mutations, copy number variation (CNV and gene expression analysis. Clinical data were available from 85 cases. Mutations were analyzed by mass-spectrometry based on genotyping platform (Oncomap 3 and genomic imbalances were detected by comparative genomic hybridization (CGH analysis. Regions with threshold of log2 ratio ≥0.4, or ≤0.6 were defined as either having copy number gain or loss and significantly recurrent CNV across the set of samples were determined using a GISTIC analysis. Expression analysis on selected relevant UC genes was conducted using Nanostring. To define the co-occurrence pattern of mutations and CNV, we grouped genomic events into 5 core signal transduction pathways: 1 TP53 pathway, 2 RTK/RAS/RAF pathway, 3 PI3K/AKT/mTOR pathway, 4 WNT/CTNNB1, 5 RB1 pathway. Cox regression was used to assess pathways abnormalities with survival outcomes.35 samples (41% harbored mutations on at least one gene: TP53 (16%, PIK3CA (9%, FGFR3 (2%, HRAS/KRAS (5%, and CTNNB1 (1%. 66% of patients had some sort of CNV. PIK3CA/AKT/mTOR pathway alteration (mutations+CNV had the greatest impact on OS (p=0.055. At a gene level, overexpression of CTNNB1 (p=0.0008 and PIK3CA (p=0.02 were associated with shorter OS. Mutational status on PIK3CA was not associated with survival. Among other individually found genomic alterations, TP53 mutations (p=0.07, mTOR gain (p=0.07 and PTEN overexpression (p=0.08 have a marginally significant negative impact on OS.Our study suggests that targeted therapies focusing on the PIK3CA/AKT/mTOR pathway genomic alterations can generate the greatest impact in the overall patient

  14. Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia

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    Md Shaki Mostaid

    2017-11-01

    Full Text Available Investigation of peripheral gene expression patterns of transcripts within the NRG–ErbB signaling pathway, other than neuregulin-1 (NRG1, among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS is limited. The present study built on our previous work demonstrating elevated levels of NRG1 EGFα, EGFβ, and type I(Ig2 containing transcripts in TRS by investigating 11 NRG–ErbB signaling pathway mRNA transcripts (NRG2, ErbB1, ErbB2, ErbB3, ErbB4, PIK3CD, PIK3R3, AKT1, mTOR, P70S6K, eIF4EBP1 in whole blood of TRS patients (N = 71 and healthy controls (N = 57. We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs from 15 healthy individuals. Five transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1 were significantly elevated in TRS patients compared to healthy controls but only expression of P70S6K (Pcorrected = 0.018, a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini–Hochberg method. Investigation of clinical factors revealed that ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our in vitro PBMC clozapine exposure experiment. Taken together with previously published NRG1 results, our findings suggest an overall upregulation of transcripts within the NRG–ErbB signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the NRG–ErbB signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.

  15. BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.

    Science.gov (United States)

    Chen, Jing; Guo, Fang; Shi, Xin; Zhang, Lihua; Zhang, Aifeng; Jin, Hui; He, Youji

    2014-11-03

    Mutations in KRAS, BRAF and PIK3CA are the most common somatic alterations found in the colorectal cancer (CRC) patients from Western countries; but their prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of these genes in Chinese CRC patients and to investigate their impact on prognosis. The sequences of exon 2 of KRAS, exon 15 of BRAF and exons 9 and 20 of PIK3CA were evaluated by PCR and direct sequencing using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues from primary CRC tumors of 214 patients (colon/rectum: 126/88). KRAS, BRAF and PIK3CA mutations were identified in 44.9% (96/214), 4.2% (9/214) and 12.3% (26/212) CRCs, respectively. The most frequent mutations in KRAS, BRAF and PIK3CA were G12D, V600E and H1047R, respectively. All BRAF and 80.8% PIK3CA mutations were from colon cancer patients. BRAF V600E was associated with advanced TNM (P mutations (N = 25) had significantly worse OS (P = 0.016; multivariate HR = 2.7, P = 0.011), whereas KRAS codon 12-mutated cases were not significantly associated with survival. Among the three most common KRAS mutations, G13D (N = 23) showed significant association with poor OS (P = 0.024; multivariate HR = 2.6, P = 0.016) compared with KRAS wt/BRAF wt patients. Our findings indicate that PI3K/RAS-RAF signaling pathway genes are frequently mutated in Chinese CRC patients, but have different characteristics than found in Western patients. BRAF V600E is an independent prognostic factor for Chinese patients. Our finding that KRAS codon 13 mutations (in particular G13D) are associated with inferior survival in BRAF wild-type CRCs in Chinese patients was not reported thus far. Our data emphasizes the importance of prospective evaluation of molecular features in CRC patients, because a single mutation type may represent a distinct biologic effect and clinical implication.

  16. Plume-Lithosphere Interaction in the Ethiopian CFB Province: Breaking up Gondwana

    Science.gov (United States)

    Plummer, C. L.; Furman, T.

    2006-12-01

    The Ethiopia-Yemen continental flood basalt (CFB) province formed 30 Ma and today covers some 600,000 sq. km with an approximate total volume of 350,000 sq. km of basalt and associated rhyolite. The majority of lavas were extruded over about 1 my (Baker et al. 1996; Pik et al. 1998) and have not been subject to tectonism, making this area ideal for study of processes associated with continental break-up, mantle plume impacts and CFB magmatism. The Ethiopian province is the youngest of the Mesozoic CFB occurrences associated with break-up of Gondwana, following the Karoo and Ferrar (180-175 Ma), Parana-Etendeka (134- 132 Ma) and Deccan (67-65 Ma) events. In Ethiopia, as with other Gondwana CFB provinces, basalts have been separated into high titanium (HT) and low titanium (LT) series (Pik et al. 1998). Stratigraphic studies indicate HT and LT units erupted contemporaneously so temporal control cannot explain the chemical variations; Pik et al (1998) drew a NE-SW trending line separating the region into HT and LT sub-provinces. Detailed investigation of new study sites along the SW margin of the flood basalt province (Tesfaye 2006) found interlayered LT and HT units indicating more complex spatial controls. Our investigation of Ethiopian CFBs evaluates source and process heterogeneities that could produce voluminous mafic magmatism in these two distinctive series. To first order the mildly alkalic HT lavas have higher incompatible trace element abundances than the tholeiitic LT basalts (Pik et al. 1998, 1999; Keiffer et al. 2004), suggesting derivation of the former by lower degrees of partial melting at greater pressures (Furman et al. 2006). Sr-Nd-Pb isotopic signatures of the LT and HT series largely overlap with one another and with the modern Afar plume; in detail the highest Ti-lavas (HT2 of Pik et al. 1998) are isotopically and geochemically distinct from LT and HT1 basalts, which form a broad continuum in all representations of data. HT2 basalts have mantle

  17. Job satisfaction among nurses working in the private and public sectors: a qualitative study in tertiary care hospitals in Pakistan

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    Hamid S

    2014-01-01

    Full Text Available Saima Hamid,1 Asmat Ullah Malik,2 Irum Kamran,3 Musarat Ramzan41Health Services Academy, Islamabad, Pakistan; 2Integrated Health Services, Islamabad, Pakistan; 3GIZ, Islamabad, Pakistan; 4Wah Medical College, Wah Cantt, University of Health Sciences, Wah, PakistanBackground: Many low and middle income countries lack the human resources needed to deliver essential health interventions. A health care system with a limited number of nurses cannot function effectively. Although the recommended nurse to doctor ratio is 4:1, the ratio in Pakistan is reversed, with 2.7 doctors to one nurse.Methods: A qualitative study using narrative analysis was undertaken in public and private tertiary care hospitals in Pakistan to examine and compare job satisfaction among nurses and understand the factors affecting their work climate. Interactive interviews were conducted with nurses working with inpatients and outpatients.Results: All of the respondents had joined the profession by choice and were supported by their families in their decision to pursue their career, but now indicated that they were dissatisfied with their jobs. Three types of narratives were identified, namely, “Working in the spirit of serving humanity”, “Working against all odds”, and “Working in a functional system and facing pressures of increased accountability”. Nurses working in a public sector hospital are represented in the first two narrative types, whereas the third represents those working in a private sector hospital. The first narrative represents nurses who were new in the profession and despite hard working conditions were performing their duties. The second narrative represents nurses working in the public sector with limited resources, and the third narrative is a representation of nurses who were working hard and stressed out despite a well functioning system.Conclusion: The study shows that the presence of a well trained health workforce is vital, and that certain

  18. Specific gene expression signatures induced by the multiple oncogenic alterations that occur within the PTEN/PI3K/AKT pathway in lung cancer.

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    Carmela De Marco

    Full Text Available Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B expressing active mutant AKT1 (AKT1-E17K, active mutant PIK3CA (PIK3CA-E545K or that are silenced for PTEN. We found that, altogether, aberrant PI3K/AKT signalling in lung epithelial cells regulated the expression of 1,960/20,436 genes (9%, though only 30 differentially expressed genes (DEGs (15 up-regulated, 12 down-regulated and 3 discordant out of 20,436 that were common among BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells (0.1%. Conversely, DEGs specific for mutant AKT1 were 133 (85 up-regulated; 48 down-regulated, DEGs specific for mutant PIK3CA were 502 (280 up-regulated; 222 down-regulated and DEGs specific for PTEN loss were 1549 (799 up-regulated, 750 down-regulated. The results obtained from array analysis were confirmed by quantitative RT-PCR on selected up- and down-regulated genes (n = 10. Treatment of BEAS-C cells and the corresponding derivatives with pharmacological inhibitors of AKT (MK2206 or PI3K (LY294002 further validated the significance of our findings. Moreover, mRNA expression of selected DEGs (SGK1, IGFBP3, PEG10, GDF15, PTGES, S100P, respectively correlated with the activation status of the PI3K/AKT pathway assessed by S473 phosphorylation in NSCLC cell lines (n = 6. Finally, we made use of Ingenuity Pathway Analysis (IPA to investigate the relevant Bio

  19. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

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    Martha C Castaño-Betancourt

    2016-10-01

    Full Text Available Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW, a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8 SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851, PIK3R1 (rs10471753, SLBP/FGFR3 (rs2236995, and TREH/DDX6 (rs496547, while the other two (DOT1L and SUPT3H/RUNX2 were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

  20. Phase Ib Study of Safety and Pharmacokinetics of the PI3K Inhibitor SAR245408 with the HER3-Neutralizing Human Antibody SAR256212 in Patients with Solid Tumors.

    Science.gov (United States)

    Abramson, Vandana G; Supko, Jeffrey G; Ballinger, Tarah; Cleary, James M; Hilton, John F; Tolaney, Sara M; Chau, Nicole G; Cho, Daniel C; Pearlberg, Joseph; Lager, Joanne; Shapiro, Geoffrey I; Arteaga, Carlos L

    2017-07-15

    Purpose: This phase Ib study was designed to determine the MTD, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) mAb SAR256212 in combination with the oral PI3K inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors.Experimental Design: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3 + 3 dose-escalation design until occurrence of disease progression or dose-limiting toxicity. Objective response rate, pharmacokinetics, pharmacodynamics, and PIK3CA mutational status were also evaluated.Results: Twenty-seven patients were enrolled. Thirteen of 20 patients tested (65%) had a hotspot-activating mutation in PIK3CA in their tumor. The MTD was determined to be SAR256212 at 40 mg/kg loading dose followed by 20 mg/kg weekly, plus SAR245408 200 mg daily. Dose-limiting toxicities included rash and hypotension; the most frequent treatment-related side effect was diarrhea (66.7%). Twenty-three patients were evaluable for efficacy, of which 12 patients (52.2%) had stable disease and 11 patients (47.8%) had progression of disease as best response. In this study with a limited sample size, there was no difference in best response between patients with PI3KCA-mutant versus PIK3CA wild-type tumors (P = 0.07). The concurrent administration of SAR245408 and SAR256212 did not appear to have an effect on the pharmacokinetics of either drug.Conclusions: The combination of SAR256212 and SAR245408 resulted in stable disease as the best response. Side effects seen in combination were similar to the profiles of each individual drug. Patient outcome was the same regardless of tumor PI3KCA mutation status. Clin Cancer Res; 23(14); 3520-8. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

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    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  2. Use of molecular markers in identification and characterization of resistance to rice blast in India.

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    Manoj Kumar Yadav

    Full Text Available Rice blast disease caused by Magnaporthe oryzae is one of the most destructive disease causing huge losses to rice yield in different parts of the world. Therefore, an attempt has been made to find out the resistance by screening and studying the genetic diversity of eighty released rice varieties by National Rice Research Institute, Cuttack (NRVs using molecular markers linked to twelve major blast resistance (R genes viz Pib, Piz, Piz-t, Pik, Pik-p, Pikm Pik-h, Pita/Pita-2, Pi2, Pi9, Pi1 and Pi5. Out of which, nineteen varieties (23.75% showed resistance, twenty one were moderately resistant (26.25% while remaining forty varieties (50% showed susceptible in uniform blast nursery. Rice varieties possessing blast resistance genes varied from four to twelve and the frequencies of the resistance genes ranged from 0 to 100%. The cluster analysis grouped the eighty NRVs into two major clusters at 63% level of genetic similarity coefficient. The PIC value for seventeen markers varied from 0 to 0.37 at an average of 0.20. Out of seventeen markers, only five markers, 195R-1, Pi9-i, Pita3, YL155/YL87 and 40N23r corresponded to three broad spectrum R genes viz. Pi9, Pita/Pita2 and Pi5 were found to be significantly associated with the blast disease with explaining phenotypic variance from 3.5% to 7.7%. The population structure analysis and PCoA divided the entire 80 NRVs into two sub-groups. The outcome of this study would help to formulate strategies for improving rice blast resistance through genetic studies, plant-pathogen interaction, identification of novel R genes, development of new resistant varieties through marker-assisted breeding for improving rice blast resistance in India and worldwide.

  3. Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

    Science.gov (United States)

    Bis, Joshua C; White, Charles C; Franceschini, Nora; Brody, Jennifer; Zhang, Xiaoling; Muzny, Donna; Santibanez, Jireh; Gibbs, Richard; Liu, Xiaoming; Lin, Honghuang; Boerwinkle, Eric; Psaty, Bruce M; North, Kari E; Cupples, L Adrienne; O'Donnell, Christopher J

    2014-06-01

    Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG). We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples. © 2014 American Heart Association, Inc.

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

    Science.gov (United States)

    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; Vander Heiden, Matthew G; Batchelor, Tracy T; Iafrate, A John; Cahill, Daniel P; Chi, Andrew S

    2014-06-01

    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. 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. 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 = 0.0007). 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 whereas 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 = 0.0011). 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. Clin Cancer Res; 20(11); 2898-909. ©2014 AACR. ©2014 American Association for Cancer Research.

  5. PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma.

    Science.gov (United States)

    Deguchi, Yasunori; Okabe, Hiroshi; Oshima, Nobu; Hisamori, Shigeo; Minamiguchi, Sachiko; Muto, Manabu; Sakai, Yoshiharu

    2017-05-01

    Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as "gastroesophageal adenocarcinoma"; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy. PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G1 cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5). PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.

  6. Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers.

    Science.gov (United States)

    Keum, NaNa; Yuan, Chen; Nishihara, Reiko; Zoltick, Emilie; Hamada, Tsuyoshi; Martinez Fernandez, Alejandro; Zhang, Xuehong; Hanyuda, Akiko; Liu, Li; Kosumi, Keisuke; Nowak, Jonathan A; Jhun, Iny; Soong, T Rinda; Morikawa, Teppei; Tabung, Fred K; Qian, Zhi Rong; Fuchs, Charles S; Meyerhardt, Jeffrey A; Chan, Andrew T; Ng, Kimmie; Ogino, Shuji; Giovannucci, Edward L; Wu, Kana

    2017-06-15

    Accumulating evidence suggests that post-diagnostic insulin levels may influence colorectal cancer (CRC) survival. Yet, no previous study has examined CRC survival in relation to a post-diagnostic diet rich in foods that increase post-prandial insulin levels. We hypothesized that glycemic and insulin scores (index or load; derived from food frequency questionnaire data) may be associated with survival from specific CRC subtypes sensitive to the insulin signaling pathway. We prospectively followed 1,160 CRC patients from the Nurses' Health Study (1980-2012) and Health Professionals Follow-Up Study (1986-2012), resulting in 266 CRC deaths in 10,235 person-years. CRC subtypes were defined by seven tumor biomarkers (KRAS, BRAF, PIK3CA mutations, and IRS1, IRS2, FASN and CTNNB1 expression) implicated in the insulin signaling pathway. For overall CRC and each subtype, hazard ratio (HR) and 95% confidence interval (95% CI) for an increase of one standard deviation in each of glycemic and insulin scores were estimated using time-dependent Cox proportional hazards model. We found that insulin scores, but not glycemic scores, were positively associated with CRC mortality (HR = 1.19, 95% CI = 1.02-1.38 for index; HR = 1.23, 95% CI = 1.04-1.47 for load). The significant positive associations appeared more pronounced among PIK3CA wild-type cases and FASN-negative cases, with HR ranging from 1.36 to 1.60 across insulin scores. However, we did not observe statistically significant interactions of insulin scores with PIK3CA, FASN, or any other tumor marker (p interaction > 0.12). While additional studies are needed for definitive evidence, a high-insulinogenic diet after CRC diagnosis may contribute to worse CRC survival. © 2017 UICC.

  7. Prediction for response duration to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutated never smoker lung adenocarcinoma.

    Science.gov (United States)

    Kim, Hye Ryun; Cho, Byoung Chul; Shim, Hyo Sup; Lim, Sun Min; Kim, Se Kyu; Chang, Joon; Kim, Dae Joon; Kim, Joo Hang

    2014-03-01

    Among non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations, ∼ 20-30% exhibit de novo resistance to EGFR-tyrosine kinase inhibitor (TKI). The aim of this study was to examine whether mutations in the EGFR-downstream genes may be associated with de novo resistance to EGFR-TKIs in EGFR mutation-positive patients. Sixty-eight never-smoker adenocarcinoma patients with an activating EGFR mutation were included in the mutational analysis and 55 patients treated with EGFR-TKIs were analyzed for the treatment outcomes to EGFR-TKIs. We concurrently analyzed mutations in PIK3CA, PTEN, AKT and STK11, which are all EGFR-downstream genes. Mutations in PIK3CA, PTEN, AKT, and STK11 were analyzed by polymerase chain reaction-based sequencing. PIK3CA mutations were detected in 4.4% (3/68) of patients, PTEN mutations in 16.1% (11/68), AKT mutations in 5.9% (4/68), and STK11 mutations in 13.2% (9/68). One patient with an activating exon 21 L858R mutation concomitantly had an exon 20 T790M mutation in EGFR. The proportion of patients who had mutations in EGFR-downstream genes was 32.4% (22/68). When we analyzed the treatment outcome of 55 patients treated with EGFR-TKI, the presence of mutations in EGFR-downstream genes correlated with a poor overall response rate to EGFR-TKIs (63.6 vs.14.5% in patients with mutation in EGFR-downstream gene, Padenocarcinoma patients with activating EGFR mutations. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  8. PI3K-C2α knockdown decreases autophagy and maturation of endocytic vesicles.

    Directory of Open Access Journals (Sweden)

    Nathan M Merrill

    Full Text Available Phosphoinositide 3-kinase (PI3K family members are involved in diverse cellular fates including cell growth, proliferation, and survival. While many molecular details are known about the Class I and III PI3Ks, less is known about the Class II PI3Ks. To explore the function of all eight PI3K isoforms in autophagy, we knock down each gene individually and measure autophagy. We find a significant decrease in autophagy following siRNA-mediated PIK3C2A (encoding the Class 2 PI3K, PI3K-C2α knockdown. This defective autophagy is rescued by exogenous PI3K-C2α, but not kinase-dead PI3K-C2α. Using confocal microscopy, we probe for markers of endocytosis and autophagy, revealing that PI3K-C2α colocalizes with markers of endocytosis. Though endocytic uptake is intact, as demonstrated by transferrin labeling, PIK3C2A knockdown results in vesicle accumulation at the recycling endosome. We isolate distinct membrane sources and observe that PI3K-C2α interacts with markers of endocytosis and autophagy, notably ATG9. Knockdown of either PIK3C2A or ATG9A/B, but not PI3KC3, results in an accumulation of transferrin-positive clathrin coated vesicles and RAB11-positive vesicles at the recycling endosome. Taken together, these results support a role for PI3K-C2α in the proper maturation of endosomes, and suggest that PI3K-C2α may be a critical node connecting the endocytic and autophagic pathways.

  9. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

    Science.gov (United States)

    Metrustry, Sarah; Liu, Youfang; den Hollander, Wouter; Kraus, Virginia B.; Yau, Michelle S.; Mitchell, Braxton D.; Muir, Kenneth; Hofman, Albert; Doherty, Michael; Doherty, Sally; Zhang, Weiya; Kraaij, Robert; Rivadeneira, Fernando; Barrett-Connor, Elizabeth; Maciewicz, Rose A.; Arden, Nigel; Nelissen, Rob G. H. H.; Kloppenburg, Margreet; Jordan, Joanne M.; Nevitt, Michael C.; Slagboom, Eline P.; Hart, Deborah J.; Lafeber, Floris; Styrkarsdottir, Unnur; Zeggini, Eleftheria; Evangelou, Evangelos; Spector, Tim D.; Uitterlinden, Andre G.; Lane, Nancy E.; Meulenbelt, Ingrid; Valdes, Ana M.; van Meurs, Joyce B. J.

    2016-01-01

    Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies. PMID:27701424

  10. Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Erica L Bradshaw-Pierce

    Full Text Available PURPOSE: The PI3K/AKT/mTOR pathway is frequently dysregulated in cancers and inhibition of mTOR has demonstrated the ability to modulate pro-survival pathways. As such, we sought to determine the ability of the mTOR inhibitor everolimus to potentiate the antitumor effects of irinotecan in colorectal cancer (CRC. EXPERIMENTAL DESIGN: The combinatorial effects of everolimus and irinotecan were evaluated in vitro and in vivo in CRC cell lines harboring commonly found mutations in PIK3CA, KRAS and/or BRAF. Pharmacokinetically-directed dosing protocols of everolimus and irinotecan were established and used to assess the in vivo antitumor effects of the agents. At the end of treatment, 3-6 tumors per treatment arm were harvested for biomarker analysis by NMR metabolomics. RESULTS: Everolimus and irinotecan/SN38 demonstrated synergistic anti-proliferative effects in multiple CRC cell lines in vitro. Combination effects of everolimus and irinotecan were determined in CRC xenograft models using clinically-relevant dosing protocols. Everolimus demonstrated significant tumor growth inhibition alone and when combined with irinotecan in HT29 and HCT116 tumor xenografts. Metabolomic analysis showed that HT29 tumors were more metabolically responsive than HCT116 tumors. Everolimus caused a decrease in glycolysis in both tumor types whilst irinotecan treatment resulted in a profound accumulation of lipids in HT29 tumors indicating a cytotoxic effect. CONCLUSIONS: Quantitative analysis of tumor growth and metabolomic data showed that the combination of everolimus and irinotecan was more beneficial in the BRAF/PIK3CA mutant HT29 tumor xenografts, which had an additive effect, than the KRAS/PIK3CA mutant HCT116 tumor xenografts, which had a less than additive effect.

  11. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  12. Risk factors for brain metastases in patients with metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Christensen, Troels Dreier; Palshof, Jesper Andreas; Larsen, Finn Ole

    2017-01-01

    Background: Brain metastases (BM) from colorectal cancer (CRC) are rare, but the incidence is suspected to rise as treatment of metastatic (m) CRC improves. The aim of this study was to identify possible biological and clinical characteristics at initial presentation of mCRC that could predict...... patients had previously progression on 5-FU, irinotecan and oxaliplatin containing regimens and received CetIri treatment independent of RAS mutations status. We subsequently performed KRAS, NRAS, BRAF, PIK3CA, PTEN, ERBB2 and EGFR sequencing of DNA extracted from primary tumor tissue. Results: Totally...

  13. Potsdam Institute for Climate Impact Research. Biennial report 1996 and 1997; Potsdam-Institut fuer Klimafolgenforschung. Zweijahresbericht 1996 und 1997

    Energy Technology Data Exchange (ETDEWEB)

    Andre, G.; Bruch, S. vom [comps.

    1998-12-31

    The Potsdam Institute for Climate Impact Research was founded in 1992, the year that the Rio Conference was expected to grind out the blue-print for global sustainable development. The Institute`s general philosophy and methodology have been described before (e.g., in the introduction to the first biennal report 1994/95). Here, it is emphasized that the heterogeneity of the scientific tasks to be solved by PIK (ranging from empirical time series analysis to paradigms for ecosphere management) and the complexity of the environmental systems to be investigated call for a specific research strategy, which generally compromises between high-precision analysis and educated guesswork. (orig./KWE)

  14. Erosion in America

    Energy Technology Data Exchange (ETDEWEB)

    1984-03-23

    The US loses about five billion tons of soil a year from erosion, and scientists estimate that from 20 to 50% of world cropland suffers from excessive erosion. The effect of erosion is a loss in both land and water productivity. When combined with the problems of overpopulation, overgrazing, and deforestation, the environmental impacts are very serious. There are some signs that countries are beginning to adopt conservation tilling techniques, but even cooperative government programs in the US such as the 1983 Payment-in-Kind (PIK) program have had only partial success because of expanded production on marginal farmlands. 20 reference 5 figures.

  15. Synergistic Interactions with PI3K Inhibition that Induce Apoptosis. | Office of Cancer Genomics

    Science.gov (United States)

    Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition.

  16. Yritysilmeen uudistaminen Tiilikaisen Kenkä & Musiikki yritykselle

    OpenAIRE

    Saarikoski, Juhani

    2010-01-01

    Opinnäytetyöni käsittelee yritysilmeen uudistusta Tiilikaisten Kenkä & Musiikki -yritykselle. Uudistus koskee koko yrityksen ilmettä. Uudistamisen takana oli yrityksen jo yli satavuotinen historia Kannuksessa. Vakioasiakkaana minulla oli hyvä mahdollisuus käyttää tuntemustani niin asiakkaana kuin tuttavana suunnitellessani heidän uutta yritysilmettään ja graafista ohjeistoa. Opinnäytetyöni pääpaino kohdistuu uudistuksen läpikäymiseen, miten olemme päätyneet tiettyihin ratkaisuihin ja mit...

  17. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes

    OpenAIRE

    Rostislavleva, Ksenia; Soler, Nicolas; Ohashi, Yohei; Zhang, Lufei; Pardon, Els; Burke, John E.; Masson, Glenn?R.; Johnson, Chris; Steyaert, Jan; Ktistakis, Nicholas T.; Williams, Roger L.

    2015-01-01

    Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis and autophagy. We present the 4.4 Å crystal structure of the 385 kDa endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1) and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm where the Vps15 kinase domain engages the Vps34 activation loop to regulate its acti...

  18. SEARCH FOR CP VIOLATION IN B --> PI H DECAYS AND B --> RHO H DECAYS WITH BABAR EXPERIMENT

    Energy Technology Data Exchange (ETDEWEB)

    Yeche, C

    2003-12-02

    The authors present BABAR experiment studies to observe CP violation in the two-body decays ({pi}K and {pi}{pi}) and the quasi two-body decays ({rho}K and {rho}{pi}) of B mesons. The results are obtained from data samples of about 89(123) million {Upsilon}(4S) {yields} B{bar B} decays collected between 1999 and 2002(2003) with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC.

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

    DEFF Research Database (Denmark)

    McGranahan, Nicholas; Favero, Francesco; de Bruin, Elza C.

    2015-01-01

    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...

  20. Vapaus tehdä mitä huvittaa? : Omarahoitteisen elokuvanteon sisällölliset haasteet ja hyödyt

    OpenAIRE

    Mäkelä, Tanja

    2015-01-01

    Tässä tutkimuksessa käydään läpi, kuinka omarahoitteisuus elokuvanteossa vaikuttaa niin tekoprosessiin kuin myös itse valmiiseen elokuvaan. Aihetta käsitellään lähinnä kolmen omarahoitteisen elokuvatuotannon ja niiden tekijöiden kautta. Yhden tuotannossa tekijä on itse ollut mukana. Työssä läpikäytäviä aihealueita ovat esimerkiksi improvisaation käyttäminen, tuotantoon vaikuttavat muuttuvat tekijät, mahdollisten sponsoreiden ja tuotesijoittelun käyttäminen ja se, millä tavoin ulkopuolisen...

  1. Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models

    Directory of Open Access Journals (Sweden)

    Wu Xianhua

    2012-08-01

    Full Text Available Abstract Background Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models. Methods PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC tissues into immunodeficient (SCID/nude mice. HER-2 gene copy number (GCN and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group. Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation. Results None of the PDECX models (or their corresponding patient’s ESCC tissues harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+ in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+. A second HER-2 positive (IHC 2+ model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model. Conclusions

  2. The effects of common genetic variants in oncogenes on ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, L.; Gayther, S.A.; Ramus, S.J.

    2008-01-01

    of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer. EXPERIMENTAL DESIGN: We evaluated the association between 34 tagging single nucleotide polymorphisms and survival...... subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007). CONCLUSION: Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer Udgivelsesdato...

  3. Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis

    DEFF Research Database (Denmark)

    Vestergaard, Anna Lindeløv; Thorup, Katrine; Knudsen, Ulla Breth

    2011-01-01

    using methylation-specific melting curve analysis (MS-MCA), and 9 genes (BRAF, HRAS, NRAS, CTNNB1, CDK4, FGFR3, PIK3CA, TP53 and PTEN) were analyzed for mutations using denaturing gradient gel electrophoresis (DGGE) and direct sequencing. An oncogenic mutation in KRAS (c. 34G>T; p.G12C) was detected...... in a single lesion. No gene alterations were found in the remaining samples. Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis. However, other proto-oncogenes and tumor suppressor genes should be tested for alterations in order...

  4. Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

    Science.gov (United States)

    Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

  5. Naisten takkiosaston kehitystarpeiden kartoitustutkimus tavarataloympäristössä : case: Yritys X

    OpenAIRE

    Pessa, Hertta

    2015-01-01

    Tämän opinnäytetyön lähtökohtana on selvittää merkittävän Suomessa toimivan tavaratalotoimijan kehitystarpeita naisten takkiosastolla. Työn tavoitteena on selvittää, mitkä ovat ne osa-alueet ja määritellyt kehitystarpeet, joilla osaston toimintaa voidaan kehittää ja parantaa, jotta osasto pystyy kokonaisuudessaan palvelemaan asiakastaan paremmin. Yritys X on läpikäynyt valtavat rakenteelliset ja strategiset muutokset vuoden 2014 aikana, mitkä ovat vaikuttaneet suuresti yrityksen arvolupau...

  6. U. S. Naval Forces, Vietnam Monthly Historical Supplement for March 1968

    Science.gov (United States)

    1968-08-29

    34 UNCAOSSIRE1 04’ 0116 1000 107 los boop LAO ~~QA ?mUhW tC 4%*, CUIU NAMIJ THAILAND QAGN CHI nA C Sz SOUT VIETNAM1 To St PIK"ww AN WSM JJNC LSS" T...to average one or more services of some type a day. Weddings, funerals , baptisms, =wrial services, devotional services, and instructional classes on...Number Attendance - - Memorial service 31 2,832 Baptism 14 0 Weddings 3 0 Funerals 8 0 Bible c3•1’,es 156 635 Sunday School 14 124 Choir rehearsal 20 120

  7. Computed tomography assessment of early response to neoadjuvant therapy in colon cancer

    DEFF Research Database (Denmark)

    Dam, Claus; Lund-Rasmussen, Vera; Pløen, John

    2015-01-01

    INTRODUCTION: Using multidetector computed tomography, we aimed to assess the early response of neoadjuvant drug therapy for locally advanced colon cancer. METHODS: Computed tomography with IV contrast was acquired from 67 patients before and after up to three cycles of preoperative treatment. All...... patients had histologically confirmed colon cancer, a T4 or T3 tumour with extramural invasion ≥ 5 mm and no distant metastases or peritoneal nodules. The patients were treated with oxaliplatin and capecitabine. In addition, those with no mutations in the KRAS, BRAF and PIK3CA genes were also treated...

  8. Global characterization of signalling networks associated with tamoxifen resistance in breast cancer

    DEFF Research Database (Denmark)

    Browne, Brigid C.; Hochgräfe, Falko; Wu, Jianmin

    2013-01-01

    was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell–cell and cell matrix‐initiated signalling. Consistent with known roles for Ras/MAPK and PI3‐kinase signalling in tamoxifen resistance, tyrosine‐phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in Tam......R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam...

  9. 212ʻ Fahrenheiti : eesti luule 2006 / Piret Bristol

    Index Scriptorium Estoniae

    Bristol, Piret, 1968-

    2008-01-01

    Järgmistest 2006. a. ilmunud luulekogudest: Ryytle, Indrek. Inglid rokijaamas. Puhja : I. Rüütle ; Runnel, Hando. Viru veri ei värise. Tartu : Ilmamaa ; Vabat, Martin. Mina olengi kirjandusklassik. Tartu : Eesti Kirjanduse Selts ; Korts, Eliina. Lööklaused murravad metsi. Tartu : Eesti Kirjanduse Selts ; Koff, Indrek. Vana laul. Luige : Verb ; Teede, Andra. Takso Tallinna taevas. Luige : Verb ; Vusser, Kaspar. Vusserduste võnked. Tallinn : P. Kukk ; Elbing, Andrus. Siin Beebilõust, tere! : häired pimelinna tänavalt = Ciao, it's Babyface : trouble from the streets of a blind city. Tallinn : Epifanio ; Hint, Miina. Vabaduse vang, ehk, Põrandaalune kirjandus. Tallinn : MR ; Jüriado, Tiiu. Luule on ime. Habaja : Kentaur ; Ligi, Katre. Naabrivalve. Tartu : Ilmamaa ; Krull, Hasso. Talv. Tallinn : Tuum ; Mets, Mae. Pühapäeval on reede. Tartu : Ilmamaa ; Ploom, Ülar. Porr ja sorry. Tallinn : Tuum ; Hirv, Indrek, Surmapõletaja. Tallinn : Tuum ; Piir, Milvi Martina. Kõrkjavaas. Tartu : Fantaasia ; Soomets, Triin. Väljas. Tallinn : Tuum ; Mathura. Kohalolu. Rapla : Allikäärne ; Afanasjev, Vahur. Katedraal Emajões. Tartu ; Brüssel : ID Salong//Sild, Ivar. Spermaga ja puha. Pärnu : Jumalikud Ilmutused ; Meiel, Kaupo. Polügrafisti käsiraamat. Pärnu : Jumalikud Ilmutused ; Kivisildnik, Sven. Vägistatud jäämägi. Pärnu : Jumalikud Ilmutused ; Arder, Ott. Luule sünnib kus sünnib kui sünnib / koost. Leelo Tungal. Tallinn : Tänapäev ; Kompus, Marko. Vallaliste jõgede tõkkejooksja. Tartu : M. Kompus

  10. 2005. aasta arhitektuurivõistlused

    Index Scriptorium Estoniae

    2005-01-01

    Tulemused: Viljandi Metsakalmistu kabel: I - Andres Lember (Male Arhitektid); Tartu Vabaduse sild: I - Stanislav Shulman, Oleg Samohhin (Peterburi, Transmost); Tartu Mõisavahe kvartali hoonestuskava: I .- Ott Kadarik, Villem Tomiste, Mihkel Tüür (Kosmos); Seewaldi ala planeerimine: I - Jüri Martson, Rasmus Reinolt, Ivo-Martin Veelma (Lokomotiiv); Rotermanni kvartali arhitektuurivõistlus: I - Kosmos; aasta betoonehitis 2004: Ülemiste hotell Tallinnas, Martin Aunin; Lasnamäe Jumalaema kirik: I - Oleg Zhemtshugov (AB Z-Projekt), Nikolai Djatko, Jevgeni Kolomenkin; Pärnu vanalinna ja rannapiirkonna tänavakaubanduse inventari ja jäätmejaamade kujundus: I - Peeter Varrak; Kihnu sadamaala planeerimise ja hoonestamise ideevõistlus: I - Siiri Vallner, Kaire Nõmm, Helina Lass, Anna-Liisa Unt (Kavakava); Narva kolledzhi uus hoone: I - Katrin Koov, S. Vallner (Kavakava) ja Indrek Peil (Head Arhitektid); Randvere algkooli hoone: II - Inga Raukas (Arhitektuuriagentuur); Tartu Toomemäe valgustuse ja arhitektuursete väikevormide ideevõistlus: II - K. Koov ja Heidi Urb (Kabvakava) ning Maarja Kask, Ralf Lõoke, Karli Luik (Salto); Metsakalmistu arhitektide kalmeala: I - M. Kask, R. Lõoke; Skoone bastioni ideevõistlus: I - M. Kask, R. Lõoke, K. Luik (Salto); Mahtra talurahvamuuseum: I -Tomomi Hayashi, Hanno Grossschmidt; parim eramu 2004-2005: metallmaja Tabasalus, Muru & Pere; Tallinna loomaaia läänevärav: I - I. Raukas, Monika Löve, Oliver Soomets; parim puitehitis 2005: Naba lasteaed Pirital, arhitektid Vahur Sova, Lauri Saar, sisearhitekt Mari Tosmin; Pae karjääri revitaliseerimine: III - Veronika Valk, Kerli Raamsalu

  11. Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics.

    Science.gov (United States)

    Cohen, Philip R; Tomson, Brett N; Elkin, Sheryl K; Marchlik, Erica; Carter, Jennifer L; Kurzrock, Razelle

    2016-04-26

    Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients.

  12. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

    Science.gov (United States)

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-12

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

  13. Modeling of transports of water and matter in landscape. Proceedings; Modellierung des Wasser- und Stofftransportes in grossen Einzugsgebieten. Beitraege

    Energy Technology Data Exchange (ETDEWEB)

    Bronstert, A.; Krysanova, V.; Schroeder, A.; Becker, A.; Bork, H.R. [eds.

    1998-04-01

    During recent years, the quantitative description of the water fluxes and the coupled transport of physical and chemical matter in the landscape has become steadily more and more important. The reasons for this are an increasing public awareness about the possible impacts of changes of land use, land cover, and of changes in regional and global climatic conditions together with a need for sound, multi-objective management of large river basins. The investigation areas of concern a usually much larger in extent than a typically sized hydrological investigation catchment. The tools primarily used in the quantification of the hydrological fluxes at the large scale are the so-called large-scale hydrological models. These models are comparatively new and still at the stage of development and improvement. The mentioned need for advanced large-scale hydrological models provided the reason for inviting scientists from German-speaking countries with experience in large-scale hydrological and hydro-meteorological models to exchange and discuss their modelling concepts and to identify research needs. The workshop was held at the Potsdam Institute for Climate Impact Research (PIK) on 15 and 16 December 1997, and was jointly organised by PIK, the University of Potsdam and the Centre for Agriculture and Land Use Research (ZALF). The workshop was attended by over 40 scientists, of whom 19 gave a presentation. (orig.)

  14. [Aspirin and colorectal cancer].

    Science.gov (United States)

    Grancher, Adrien; Michel, Pierre; Di Fiore, Frédéric; Sefrioui, David

    2018-02-01

    Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  15. Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Wallin

    Full Text Available The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3 production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.

  16. [Screening of key genes and inflammatory signalling pathway involved in the pathogenesis of HLA-B27-associated acute anterior uveitis by gene expression microarray].

    Science.gov (United States)

    Hu, Xiao-feng; Lu, Hong; Wang, Jing; Zhang, Xiao-sheng; Zhang, Xiao-long; Liu, Xu-hui; Xu, Zhuo-zai; Hu, Jun-min; Lu, Qing-jun

    2013-03-01

    To investigate the genes and signalling pathways located upstream of the inflammatory processes in human leukocyte antigen (HLA)-B27-associated acute anterior uveitis by gene expression microarray. Experimental study. HLA-B27-positive and-negative monocytes isolated from human peripheral blood were stimulated with Vibrio cholera lipopolysaccharide (LPS). Gene expression microarrays were used to identify the differentially expressed genes. Differentially expressed (DE) genes were testified by real-time PCR and analyzed by a series of bioinformatics-based techniques such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes. Gene expression microarray analysis revealed marked differences between HLA-B27-positive acute anterior uveitis (AAU) and HLA-B27-negative healthy control peripheral monocytes in the genes that were upregulated in response to LPS stimulation with 1105 genes and 25 genes respectively. Gene Ontology enrichment and pathway analysis indicated that genes participating in protein transport and folding were essential to the inflammatory process. The LPS receptor-Toll-like receptor (TLR)4 induced TLR signalling pathway and pathway related to Vibrio cholerae infection were located upstream of the network and contribute to the overall response. Among the DE genes, PIK3CA, PIK3CB, AKT3, and MAPK1 might play critical roles in inflammation. Equivalent LPS stimulation induces a different response in HLA-B27-positive peripheral monocytes compared to normal control, suggesting that the TLR pathway is involved in the pathogenesis of HLA-B27-associated AAU.

  17. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility.

    Science.gov (United States)

    Yu, Min; Bardia, Aditya; Aceto, Nicola; Bersani, Francesca; Madden, Marissa W; Donaldson, Maria C; Desai, Rushil; Zhu, Huili; Comaills, Valentine; Zheng, Zongli; Wittner, Ben S; Stojanov, Petar; Brachtel, Elena; Sgroi, Dennis; Kapur, Ravi; Shioda, Toshihiro; Ting, David T; Ramaswamy, Sridhar; Getz, Gad; Iafrate, A John; Benes, Cyril; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A

    2014-07-11

    Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease. Copyright © 2014, American Association for the Advancement of Science.

  18. MDM2 Amplification and PI3KCA Mutation in a Case of Sclerosing Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Ken Kikuchi

    2013-01-01

    Full Text Available A rare sclerosing variant of rhabdomyosarcoma characterized by prominent hyalinization and pseudovascular pattern has recently been described as a subtype biologically distinct from embryonal, alveolar, and pleomorphic forms. We present cytogenetic and molecular findings as well as experimental studies of an unusual case of sclerosing rhabdomyosarcoma. The primary lesion arose within the plantar subcutaneous tissue of the left foot of an otherwise healthy 23-year-old male who eventually developed pulmonary nodules despite systemic chemotherapy. Two genetic abnormalities identified in surgical and/or autopsy samples of the tumor were introduced into 10T1/2 murine fibroblasts to determine whether these genetic changes cooperatively facilitated transformation and growth. Cytogenetic analysis revealed a complex abnormal hyperdiploid clone, and MDM2 gene amplification was confirmed by fluorescence in situ hybridization. Cancer gene mutation screening using a combination of multiplexed PCR and mass spectroscopy revealed a PIK3CA exon 20 H1047R mutation in the primary tumor, lung metastasis, and liver metastasis. However, this mutation was not cooperative with MDM2 overexpression in experimental assays for transformation or growth. Nevertheless, MDM2 and PIK3CA are genes worthy of further investigation in patients with sclerosing rhabdomyosarcoma and might be considered in the enrollment of these patients into clinical trials of targeted therapeutics.

  19. Integrated functional, gene expression and genomic analysis for the identification of cancer targets.

    Directory of Open Access Journals (Sweden)

    Elizabeth Iorns

    Full Text Available The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.

  20. Effects of AFP-activated PI3K/Akt signaling pathway on cell proliferation of liver cancer.

    Science.gov (United States)

    Zheng, Lu; Gong, Wei; Liang, Ping; Huang, XiaoBing; You, Nan; Han, Ke Qiang; Li, Yu Ming; Li, Jing

    2014-05-01

    This study aims to investigate effects of alpha-fetoprotein (AFP)-activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway on hepatocellular carcinoma cell proliferation. Active cirrhosis patients after hepatitis B infection (n = 20) and viral hepatitis patients with hepatocellular carcinoma (HCC) (n = 20) were selected as the subjects of the present study. Another 20 healthy subjects were selected as the control group. The serum AFP expression and liver tissue PI3K and Akt gene mRNA expression were detected. The hepatoma cell model HepG2 which had a stable expression of AFP gene was used. Real-time quantitative PCR and Western blot and other methods were used to analyze the intracellular PI3K and Akt protein levels. Compared with control group and cirrhosis group, the serum AFP levels in HCC group significantly increased, and the tissue PI3K and Akt mRNA expression also significantly increased. HepG2 cells were intervened using AFP, in which the PIK and Akt protein expression significantly increased. After intervention by use of AFP monoclonal antibodies or LY294002 inhibitor, the PIK and Akt protein expression in HepG2 cell was significantly decreased (P AFP can promote the proliferation of hepatoma cells via activation of PI3K/Akt signaling pathway.

  1. No impact of passive smoke on the somatic profile of lung cancers in never-smokers.

    Science.gov (United States)

    Couraud, Sébastien; Debieuvre, Didier; Moreau, Lionel; Dumont, Patrick; Margery, Jacques; Quoix, Elisabeth; Duvert, Bernard; Cellerin, Laurent; Baize, Nathalie; Taviot, Bruno; Coudurier, Marie; Cadranel, Jacques; Missy, Pascale; Morin, Franck; Mornex, Jean-François; Zalcman, Gérard; Souquet, Pierre-Jean

    2015-05-01

    EGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in never-smokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is still debate surrounding whether never-smokers exposed to passive smoke exhibit a "smoker-like" somatic profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive smoking. No significant difference was observed between mutation frequency and passive smoke exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%; ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We observed a nonsignificant trend for a negative association between EGFR mutation and cumulative duration of passive smoke exposure. No association was found for other biomarkers. There is no clear association between passive smoke exposure and somatic profile in lifelong, never-smoker lung cancer. Copyright ©ERS 2015.

  2. PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer.

    Science.gov (United States)

    Kim, Chan; Lee, Choong-Kun; Chon, Hong Jae; Kim, Joo Hoon; Park, Hyung Soon; Heo, Su Jin; Kim, Hyun Jeong; Kim, Tae Soo; Kwon, Woo Sun; Chung, Hyun Cheol; Rha, Sun Young

    2017-12-26

    Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index (HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.

  3. Whole genomes redefine the mutational landscape of pancreatic cancer

    Science.gov (United States)

    Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K.; Kassahn, Karin S.; Bailey, Peter; Johns, Amber L.; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C. J.; Robertson, Alan J.; Fadlullah, Muhammad Z. H.; Bruxner, Tim J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J.; Fink, J. Lynn; Holmes, Oliver; Kazakoff, Stephen H.; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Lee, Hong C.; Jones, Marc D.; Nagrial, Adnan M.; Humphris, Jeremy; Chantrill, Lorraine A.; Chin, Venessa; Steinmann, Angela M.; Mawson, Amanda; Humphrey, Emily S.; Colvin, Emily K.; Chou, Angela; Scarlett, Christopher J.; Pinho, Andreia V.; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S.; Kench, James G.; Pettitt, Jessica A.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B.; Graham, Janet S.; Niclou, Simone P.; Bjerkvig, Rolf; Grützmann, Robert; Aust, Daniela; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Zamboni, Giuseppe; Tortora, Giampaolo; Tempero, Margaret A.; Gill, Anthony J.; Eshleman, James R.; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A.; Pearson, John V.; Biankin, Andrew V.; Grimmond, Sean M.

    2015-01-01

    Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded. PMID:25719666

  4. PtdIns4P recognition by Vps74/GOLPH3 links PtdIns 4-kinase signaling to retrograde Golgi trafficking

    Energy Technology Data Exchange (ETDEWEB)

    Wood, Christopher S.; Schmitz, Karl R.; Bessman, Nicholas J.; Setty, Thanuja Gangi; Ferguson, Kathryn M.; Burd, Christopher G.; (UPENN-MED)

    2010-02-11

    Targeting and retention of resident integral membrane proteins of the Golgi apparatus underly the function of the Golgi in glycoprotein and glycolipid processing and sorting. In yeast, steady-state Golgi localization of multiple mannosyltransferases requires recognition of their cytosolic domains by the peripheral Golgi membrane protein Vps74, an orthologue of human GOLPH3/GPP34/GMx33/MIDAS (mitochondrial DNA absence sensitive factor). We show that targeting of Vps74 and GOLPH3 to the Golgi apparatus requires ongoing synthesis of phosphatidylinositol (PtdIns) 4-phosphate (PtdIns4P) by the Pik1 PtdIns 4-kinase and that modulation of the levels and cellular location of PtdIns4P leads to mislocalization of these proteins. Vps74 and GOLPH3 bind specifically to PtdIns4P, and a sulfate ion in a crystal structure of GOLPH3 indicates a possible phosphoinositide-binding site that is conserved in Vps74. Alterations in this site abolish phosphoinositide binding in vitro and Vps74 function in vivo. These results implicate Pik1 signaling in retention of Golgi-resident proteins via Vps74 and show that GOLPH3 family proteins are effectors of Golgi PtdIns 4-kinases.

  5. Mutations in genes encoding PI3K-AKT and MAPK signaling define anogenital papillary hidradenoma.

    Science.gov (United States)

    Pfarr, Nicole; Sinn, Hans-Peter; Klauschen, Frederick; Flechtenmacher, Christa; Bockmayr, Michael; Ridinger, Kathrin; von Winterfeld, Moritz; Warth, Arne; Lorenz, Katja; Budczies, Jan; Penzel, Roland; Lennerz, Jochen K; Endris, Volker; Weichert, Wilko; Stenzinger, Albrecht

    2016-02-01

    Papillary hidradenoma (a.k.a. hidradenoma papilliferum) is a benign tumor of the anogenital region that almost exclusively arises in middle-aged Caucasian women. These tumors may recur and rare cases of malignant development have been reported. The genetic basis of papillary hidradenoma is currently unknown. Hence, we employed targeted high-coverage next generation sequencing interrogating 50 cancer-related genes and conventional Sanger sequencing to investigate the mutational landscape in a cohort of 15 cases. Additionally, we analyzed the HPV status of these tumors. Thirteen cases (87%) harbored mutations in cancer-related genes. Recurrent mutations in PIK3CA and AKT1 were present in 10 of the cases (67%). One PIK3CA mutated case had a concomitant STK11 mutation. Three cases harbored mutually exclusive mutations in BRAF, APC and ERBB4. The remaining two cases showed no mutations. None of the cases harbored DNA of human papilloma virus. Our results also provide evidence that--just as BRAF V600E mutations in hyperplastic polyps and benign nevi- a mutated driver gene does not imply malignant behavior per se but may set the basis for malignant transformation. The latter point may explain why rare cases of papillary hidradenoma have been reported to take a malignant course. Lastly, our genetic data may suggest treatment avenues beyond conventional surgery for some of these tumors. © 2015 Wiley Periodicals, Inc.

  6. Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA-sequencing.

    Science.gov (United States)

    Liu, Jixi; Liu, Fang; Li, Xiaoou; Song, Xin; Zhou, Lei; Jie, Jianzheng

    2017-07-01

    Colon adenocarcinoma is the third leading cause of cancer-related deaths across the world, developing novel and non-invasive diagnostic and prognostic biomarkers for the early-stage colon adenocarcinoma at molecular level is essential. In our study, RNA-sequencing was performed to identify the differentially expressed genes and miRNAs (DEmiRNAs) in early-stage colon adenocarcinoma compared to tissues of precancerous lesions, colonic intraepithelial neoplasia. The DEmiRNA-target interaction network was constructed and functional annotation of targets of DEmiRNAs was performed. The Cancer Genome Atlas was used to verify the expression of selected differentially expressed genes. The receiver operating characteristic analyses of selected differentially expressed genes was performed. In total, 865 differentially expressed genes, 26 DEmiRNAs, and 329 DEmiRNA-target pairs were obtained. Based on the early-stage colon adenocarcinoma network, miR-548c-5p, miR-548i, and miR-548am-5p were the top three DEmiRNAs that covered most differentially expressed genes. NTRK2, DTNA, and BTG2 were the top three differentially expressed genes regulated by most DEmiRNAs. Cancer and colorectal cancer pathways were two significantly enriched pathways in early-stage colon adenocarcinoma. The common differentially expressed genes in both the pathways were AXIN2, Smad2, Smad4, PIK3R1, and BCL2. The expression levels of eight differentially expressed genes (NTRK2, DTNA, BTG2, COL11A1, Smad2, Smad4, PIK3R1, and BCL2) in The Cancer Genome Atlas database were compatible with our RNA-sequencing. All these eight differentially expressed genes and AXIN2 had the potential diagnosis value for Colon adenocarcinoma. In conclusion, a total of ten differentially expressed genes (NTRK2, DTNA, BTG2, COLCA1, COL11A1, AXIN2, Smad2, Smad4, PIK3R1, and BCL2) and four DEmiRNAs (miR-548c-5p, miR-548i, mir-424-5p, and miR-548am-5p) may be involved in the pathogenesis of early-stage colon adenocarcinoma which may

  7. Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Alberto Ocana

    Full Text Available BACKGROUND: Aberrations in the phosphatidylinositol 3-kinase (PI3K/mammalian target of rapamycin (mTOR/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear. METHODS: PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry with overall survival (OS in solid tumors. Published data were extracted and computed into odds ratios (OR for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model. RESULTS: Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42-3.16, p<0.001. Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04. There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13. CONCLUSION: Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.

  8. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE).

    Science.gov (United States)

    Loibl, Sibylle; de la Pena, Lorena; Nekljudova, Valentina; Zardavas, Dimitrios; Michiels, Stefan; Denkert, Carsten; Rezai, Mahdi; Bermejo, Begoña; Untch, Michael; Lee, Soo Chin; Turri, Sabine; Urban, Patrick; Kümmel, Sherko; Steger, Guenther; Gombos, Andrea; Lux, Michael; Piccart, Martine J; Von Minckwitz, Gunter; Baselga, José; Loi, Sherene

    2017-11-01

    The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15. Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (Pinteraction = 0.03). Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors. NCT01816594. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. TU-CD-BRB-07: Identification of Associations Between Radiologist-Annotated Imaging Features and Genomic Alterations in Breast Invasive Carcinoma, a TCGA Phenotype Research Group Study

    Energy Technology Data Exchange (ETDEWEB)

    Rao, A; Net, J [University of Miami, Miami, Florida (United States); Brandt, K [Mayo Clinic, Rochester, Minnesota (United States); Huang, E [National Cancer Institute, NIH, Bethesda, MD (United States); Freymann, J; Kirby, J [Leidos Biomedical Research Inc., Frederick, MD (United States); Burnside, E [University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (United States); Morris, E; Sutton, E [Memorial Sloan Kettering Cancer Center, New York, NY (United States); Bonaccio, E [Roswell Park Cancer Institute, Buffalo, NY (United States); Giger, M; Jaffe, C [Univ Chicago, Chicago, IL (United States); Ganott, M; Zuley, M [University of Pittsburgh Medical Center - Magee Womens Hospital, Pittsburgh, Pennsylvania (United States); Le-Petross, H [MD Anderson Cancer Center, Houston, TX (United States); Dogan, B [UT MDACC, Houston, TX (United States); Whitman, G [UTMDACC, Houston, TX (United States)

    2015-06-15

    Purpose: To determine associations between radiologist-annotated MRI features and genomic measurements in breast invasive carcinoma (BRCA) from the Cancer Genome Atlas (TCGA). Methods: 98 TCGA patients with BRCA were assessed by a panel of radiologists (TCGA Breast Phenotype Research Group) based on a variety of mass and non-mass features according to the Breast Imaging Reporting and Data System (BI-RADS). Batch corrected gene expression data was obtained from the TCGA Data Portal. The Kruskal-Wallis test was used to assess correlations between categorical image features and tumor-derived genomic features (such as gene pathway activity, copy number and mutation characteristics). Image-derived features were also correlated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) status. Multiple hypothesis correction was done using Benjamini-Hochberg FDR. Associations at an FDR of 0.1 were selected for interpretation. Results: ER status was associated with rim enhancement and peritumoral edema. PR status was associated with internal enhancement. Several components of the PI3K/Akt pathway were associated with rim enhancement as well as heterogeneity. In addition, several components of cell cycle regulation and cell division were associated with imaging characteristics.TP53 and GATA3 mutations were associated with lesion size. MRI features associated with TP53 mutation status were rim enhancement and peritumoral edema. Rim enhancement was associated with activity of RB1, PIK3R1, MAP3K1, AKT1,PI3K, and PIK3CA. Margin status was associated with HIF1A/ARNT, Ras/ GTP/PI3K, KRAS, and GADD45A. Axillary lymphadenopathy was associated with RB1 and BCL2L1. Peritumoral edema was associated with Aurora A/GADD45A, BCL2L1, CCNE1, and FOXA1. Heterogeneous internal nonmass enhancement was associated with EGFR, PI3K, AKT1, HF/MET, and EGFR/Erbb4/neuregulin 1. Diffuse nonmass enhancement was associated with HGF/MET/MUC20/SHIP

  10. Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

    Science.gov (United States)

    Konda, Kenichi; Konishi, Kazuo; Yamochi, Toshiko; Ito, Yoichi M.; Nozawa, Hisako; Tojo, Masayuki; Shinmura, Kensuke; Kogo, Mari; Katagiri, Atsushi; Kubota, Yutaro; Muramoto, Takashi; Yano, Yuichiro; Kobayashi, Yoshiya; Kihara, Toshihiro; Tagawa, Teppei; Makino, Reiko; Takimoto, Masafumi; Imawari, Michio; Yoshida, Hitoshi

    2014-01-01

    Background Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). Methods We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. Results S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). Conclusion We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal

  11. Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice.

    Science.gov (United States)

    Chamcheu, Jean Christopher; Adhami, Vaqar M; Esnault, Stephane; Sechi, Mario; Siddiqui, Imtiaz A; Satyshur, Kenneth A; Syed, Deeba N; Dodwad, Shah-Jahan M; Chaves-Rodriquez, Maria-Ines; Longley, B Jack; Wood, Gary S; Mukhtar, Hasan

    2017-01-10

    The treatment of psoriasis remains elusive, underscoring the need for identifying novel disease targets and mechanism-based therapeutic approaches. We recently reported that the PI3K/Akt/mTOR pathway that is frequently deregulated in many malignancies is also clinically relevant for psoriasis. We also provided rationale for developing delphinidin (Del), a dietary antioxidant for the management of psoriasis. This study utilized high-throughput biophysical and biochemical approaches and in vitro and in vivo models to identify molecular targets regulated by Del in psoriasis. A kinome-level screen and Kds analyses against a panel of 102 human kinase targets showed that Del binds to three lipid (PIK3CG, PIK3C2B, and PIK3CA) and six serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK2, and AURKB) kinases, five of which belong to the PI3K/Akt/mTOR pathway. Surface plasmon resonance and in silico molecular modeling corroborated Del's direct interactions with three PI3Ks (α/c2β/γ), mTOR, and p70S6K. Del treatment of interleukin-22 or TPA-stimulated normal human epidermal keratinocytes (NHEKs) significantly inhibited proliferation, activation of PI3K/Akt/mTOR components, and secretion of proinflammatory cytokines and chemokines. To establish the in vivo relevance of these findings, an imiquimod (IMQ)-induced Balb/c mouse psoriasis-like skin model was employed. Topical treatment of Del significantly decreased (i) hyperproliferation and epidermal thickness, (ii) skin infiltration by immune cells, (iii) psoriasis-related cytokines/chemokines, (iv) PI3K/Akt/mTOR pathway activation, and (v) increased differentiation when compared with controls. Innovation and Conclusion: Our observation that Del inhibits key kinases involved in psoriasis pathogenesis and alleviates IMQ-induced murine psoriasis-like disease suggests a novel PI3K/AKT/mTOR pathway modulator that could be developed to treat psoriasis. Antioxid. Redox Signal. 26, 49-69.

  12. Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

    Directory of Open Access Journals (Sweden)

    Kenichi Konda

    Full Text Available Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs.We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI] and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers alterations in 158 CRNs including 56 polypoid neoplasms (PNs, 25 granular type laterally spreading tumors (LST-Gs, 48 non-granular type LSTs (LST-NGs, 19 depressed neoplasms (DNs and 10 small flat-elevated neoplasms (S-FNs on the basis of macroscopic appearance.S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs (P<0.001. By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively (P<0.007. We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively (P<0.005. Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05. PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41.We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

  13. Genomic alterations in neuroendocrine cancers of the ovary.

    Science.gov (United States)

    Yaghmour, George; Prouet, Philippe; Wiedower, Eric; Jamy, Omer Hassan; Feldman, Rebecca; Chandler, Jason C; Pandey, Manjari; Martin, Mike G

    2016-08-26

    As we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. Patients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007-2015 were identified. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next-generation sequencing (NGS) as well as Sanger sequencing of selected genes. Forty-six patients with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 patients with SCLC for comparison. Patients with SCCO and SCCO-HT were younger (median 42 years [range 12-75] and 26 years [range 8-40], respectively) than patients with NET-O 62 [range 13-76] or SCLC 66 [range 36-86]. SCCO patients were more likely to be metastatic (70 %) than SCCO-HT (50 %) or NET-O (33 %) patients, but at a similar rate to SCLC patients (65 %). PD1 expression varied across tumor type with SCCO (100 %), SCCO-HT (60 %), NET-O (33 %) vs SCLC (42 %). PDL1 expression also varied with SCCO (50 %), SCCO-HT (20 %), NET-O (33 %) and SCLC (0 %). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 1 patient with SCCO having a BRCA2 mutation and 1 patient with NET-O having a PIK3CA mutation. No other actionable mutations were identified. No recurrent actionable mutations or rearrangements were identified using this platform in SCCO. IHC patterns may help guide the use of chemotherapy in these rare tumors.

  14. Integrated Molecular Characterization of Uterine Carcinosarcoma.

    Science.gov (United States)

    Cherniack, Andrew D; Shen, Hui; Walter, Vonn; Stewart, Chip; Murray, Bradley A; Bowlby, Reanne; Hu, Xin; Ling, Shiyun; Soslow, Robert A; Broaddus, Russell R; Zuna, Rosemary E; Robertson, Gordon; Laird, Peter W; Kucherlapati, Raju; Mills, Gordon B; Weinstein, John N; Zhang, Jiashan; Akbani, Rehan; Levine, Douglas A

    2017-03-13

    We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Strategi Komunikasi Badan Kependudukan dan Keluarga Berencana Nasional (BKKBN

    Directory of Open Access Journals (Sweden)

    Herdiana Ayu Susanti

    2015-01-01

    Full Text Available This study aims to determine communication strategy of Population and Family Planning Agency (BKKBN Special Region of Yogyakarta in disseminating Generation Program Planning (GenRe. The study uses descriptive qualitative method. The result shows that communication strategy undertaken by BKKBN Yogyakarta Province in disseminating the program GenRe is through Student Ambassador Selection genre, GenRe Goes To School and GenRe Goes To Campus, Genre Comedy Competition, Poster Competition genre, and Competition NGE - rap genre. BKKBN also uses mass media as a medium of socialization such as Public Service Announcements on television and radio, internet media by creating a website, blog, facebook, and twitter, as well as the use of billboards appeal board. BKKBN also works with schools and colleges to form the Youth Information and Counseling Center / Student (PIK R/M to get closer to teenagers and college students.

  16. Dynamic modeling of а heating system using geothermal energy and storage tank

    Directory of Open Access Journals (Sweden)

    Milanović Predrag D.

    2012-01-01

    Full Text Available This paper analyzes a greenhouse heating system using geothermal energy and storage tank and the possibility of utilization of insufficient amount of heat from geothermal sources during the periods with low outside air temperatures. Crucial for these analyses is modelling of the necessary yearly energy requirements for greenhouse heating. The results of these analyses enable calculation of an appropriate storage tank capacity so that the energy efficiency of greenhouse heating system with geothermal energy could be significantly improved. [Acknowledgement. This work was supported by Ministry of Science and Technology Development of the Republic of Serbia through the National Energy Efficiency Program (Grant 18234 A. The authors are thankful to the stuff and management of the Company “Farmakom MB PIK 7. juli - Debrc” for their assistance during the realization of this project.

  17. Type II thioesterase gene (ECO-orf27) from Amycolatopsis orientalis influences production of the polyketide antibiotic, ECO-0501 (LW01).

    Science.gov (United States)

    Shen, Yang; Huang, He; Zhu, Li; Luo, Minyu; Chen, Daijie

    2012-11-01

    ECO-orf27 associated with the cluster of ECO-0501 (LW01) from Amycolatopsis orientalis is deduced to encode a type II thioesterase. Disruption of ECO-orf27 reduced LW01 production by 95 %. Complementation of the disrupted mutant with intact ECO-orf27 restored the production of LW01 suggesting that ECO-orf27 is crucial for LW01 biosynthesis. ECO-TE I, the gene encoding type I thioesterase from LW01 polyketide synthases, cannot complement ECO-orf27 deficient mutant distinguishing ECO-orf27 from type I thioesterase gene. Type II thioesterase gene pikAV from Streptomyces venezuelae could complement ECO-orf27 in A. orientalis indicating that the two genes are equivalent in their function. Overexpression of ECO-orf27 resulted in a 20 % increase in LW01 production providing an alternative approach for yield improvement.

  18. Subclonal diversification of primary breast cancer revealed by multiregion sequencing

    Science.gov (United States)

    Yates, Lucy R; Gerstung, Moritz; Knappskog, Stian; Desmedt, Christine; Gundem, Gunes; Loo, Peter Van; Aas, Turid; Alexandrov, Ludmil B; Larsimont, Denis; Davies, Helen; Li, Yilong; Ju, Young Seok; Ramakrishna, Manasa; Haugland, Hans Kristian; Lilleng, Peer Kaare; Nik-Zainal, Serena; McLaren, Stuart; Butler, Adam; Martin, Sancha; Glodzik, Dominic; Menzies, Andrew; Raine, Keiran; Hinton, Jonathan; Jones, David; Mudie, Laura J; Jiang, Bing; Vincent, Delphine; Greene-Colozzi, April; Adnet, Pierre-Yves; Fatima, Aquila; Maetens, Marion; Ignatiadis, Michail; Stratton, Michael R; Sotiriou, Christos; Richardson, Andrea L; Lønning, Per Eystein; Wedge, David C; Campbell, Peter J

    2015-01-01

    Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient’s tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole genome and targeted sequencing to multiple samples from each of 50 patients’ tumors (total 303). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13/50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resisting chemotherapy and acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer. PMID:26099045

  19. Measurement of branching fractions of charmless four-body $\\Lambda_b^0$ and $\\Xi_b^0$ decays arXiv

    CERN Document Server

    Aaij, Roel; Adinolfi, Marco; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Alfonso Albero, Alejandro; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Andreassi, Guido; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Archilli, Flavio; d'Argent, Philippe; Arnau Romeu, Joan; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Atzeni, Michele; Auriemma, Giulio; Baalouch, Marouen; Babuschkin, Igor; Bachmann, Sebastian; Back, John; Badalov, Alexey; Baesso, Clarissa; Baker, Sophie; Balagura, Vladislav; Baldini, Wander; Baranov, Alexander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Baryshnikov, Fedor; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Beiter, Andrew; Bel, Lennaert; Beliy, Nikita; Bellee, Violaine; Belloli, Nicoletta; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Beranek, Sarah; Berezhnoy, Alexander; Bernet, Roland; Berninghoff, Daniel; Bertholet, Emilie; Bertolin, Alessandro; Betancourt, Christopher; Betti, Federico; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bezshyiko, Iaroslava; Bifani, Simone; Billoir, Pierre; Birnkraut, Alex; Bizzeti, Andrea; Bjørn, Mikkel; Blake, Thomas; Blanc, Frederic; Blusk, Steven; Bocci, Valerio; Boettcher, Thomas; Bondar, Alexander; Bondar, Nikolay; Bordyuzhin, Igor; Borghi, Silvia; Borisyak, Maxim; Borsato, Martino; Bossu, Francesco; Boubdir, Meriem; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Braun, Svende; Britton, Thomas; Brodzicka, Jolanta; Brundu, Davide; Buchanan, Emma; Burr, Christopher; Bursche, Albert; Buytaert, Jan; Byczynski, Wiktor; Cadeddu, Sandro; Cai, Hao; Calabrese, Roberto; Calladine, Ryan; Calvi, Marta; Calvo Gomez, Miriam; Camboni, Alessandro; Campana, Pierluigi; Campora Perez, Daniel Hugo; Capriotti, Lorenzo; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carniti, Paolo; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Cattaneo, Marco; Cavallero, Giovanni; Cenci, Riccardo; Chamont, David; Charles, Matthew; Charpentier, Philippe; Chatzikonstantinidis, Georgios; Chefdeville, Maximilien; Chen, Shanzhen; Cheung, Shu Faye; Chitic, Stefan-Gabriel; Chobanova, Veronika; Chrzaszcz, Marcin; Chubykin, Alexsei; Ciambrone, Paolo; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Cogan, Julien; Cogneras, Eric; Cogoni, Violetta; Cojocariu, Lucian; Collins, Paula; Colombo, Tommaso; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombs, George; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Costa Sobral, Cayo Mar; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Crocombe, Andrew; Cruz Torres, Melissa Maria; Currie, Robert; D'Ambrosio, Carmelo; Da Cunha Marinho, Franciole; Dall'Occo, Elena; Dalseno, Jeremy; Davis, Adam; De Aguiar Francisco, Oscar; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Serio, Marilisa; De Simone, Patrizia; Dean, Cameron Thomas; Decamp, Daniel; Del Buono, Luigi; Dembinski, Hans Peter; Demmer, Moritz; Dendek, Adam; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Dey, Biplab; Di Canto, Angelo; Di Nezza, Pasquale; Dijkstra, Hans; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Douglas, Lauren; Dovbnya, Anatoliy; Dreimanis, Karlis; Dufour, Laurent; Dujany, Giulio; Durante, Paolo; Dzhelyadin, Rustem; Dziewiecki, Michal; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Ebert, Marcus; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Farley, Nathanael; Farry, Stephen; Fazzini, Davide; Federici, Luca; Ferguson, Dianne; Fernandez, Gerard; Fernandez Declara, Placido; Fernandez Prieto, Antonio; Ferrari, Fabio; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fini, Rosa Anna; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fleuret, Frederic; Fohl, Klaus; Fontana, Marianna; Fontanelli, Flavio; Forshaw, Dean Charles; Forty, Roger; Franco Lima, Vinicius; Frank, Markus; Frei, Christoph; Fu, Jinlin; Funk, Wolfgang; Furfaro, Emiliano; Färber, Christian; Gabriel, Emmy; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; Garcia Martin, Luis Miguel; García Pardiñas, Julián; Garra Tico, Jordi; Garrido, Lluis; Garsed, Philip John; Gascon, David; Gaspar, Clara; Gavardi, Laura; Gazzoni, Giulio; Gerick, David; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianì, Sebastiana; Gibson, Valerie; Girard, Olivier Göran; Giubega, Lavinia-Helena; Gizdov, Konstantin; Gligorov, Vladimir; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gorelov, Igor Vladimirovich; Gotti, Claudio; Govorkova, Ekaterina; Grabowski, Jascha Peter; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graverini, Elena; Graziani, Giacomo; Grecu, Alexandru; Greim, Roman; Griffith, Peter; Grillo, Lucia; Gruber, Lukas; Gruberg Cazon, Barak Raimond; Grünberg, Oliver; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Göbel, Carla; Hadavizadeh, Thomas; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hamilton, Brian; Han, Xiaoxue; Hancock, Thomas Henry; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Hasse, Christoph; Hatch, Mark; He, Jibo; Hecker, Malte; Heinicke, Kevin; Heister, Arno; Hennessy, Karol; Henrard, Pierre; Henry, Louis; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hombach, Christoph; Hopchev, Plamen Hristov; Hu, Wenhua; Huard, Zachary; Hulsbergen, Wouter; Humair, Thibaud; Hushchyn, Mikhail; Hutchcroft, David; Ibis, Philipp; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jalocha, Pawel; Jans, Eddy; Jawahery, Abolhassan; Jiang, Feng; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kandybei, Sergii; Karacson, Matthias; Kariuki, James Mwangi; Karodia, Sarah; Kazeev, Nikita; Kecke, Matthieu; Keizer, Floris; Kelsey, Matthew; Kenzie, Matthew; Ketel, Tjeerd; Khairullin, Egor; Khanji, Basem; Khurewathanakul, Chitsanu; Kirn, Thomas; Klaver, Suzanne; Klimaszewski, Konrad; Klimkovich, Tatsiana; Koliiev, Serhii; Kolpin, Michael; Kopecna, Renata; Koppenburg, Patrick; Kosmyntseva, Alena; Kotriakhova, Sofia; Kozeiha, Mohamad; Kravchuk, Leonid; Kreps, Michal; Kress, Felix Johannes; Krokovny, Pavel; Kruse, Florian; Krzemien, Wojciech; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kuonen, Axel Kevin; Kvaratskheliya, Tengiz; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lanfranchi, Gaia; Langenbruch, Christoph; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; Leflat, Alexander; Lefrançois, Jacques; Lefèvre, Regis; Lemaitre, Florian; Lemos Cid, Edgar; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Pei-Rong; Li, Tenglin; Li, Yiming; Li, Zhuoming; Likhomanenko, Tatiana; Lindner, Rolf; Lionetto, Federica; Lisovskyi, Vitalii; Liu, Xuesong; Loh, David; Loi, Angelo; Longstaff, Iain; Lopes, Jose; Lucchesi, Donatella; Lucio Martinez, Miriam; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Lusiani, Alberto; Lyu, Xiao-Rui; Machefert, Frederic; Maciuc, Florin; Macko, Vladimir; Mackowiak, Patrick; Maddrell-Mander, Samuel; Maev, Oleg; Maguire, Kevin; Maisuzenko, Dmitrii; Majewski, Maciej Witold; Malde, Sneha; Malecki, Bartosz; Malinin, Alexander; Maltsev, Timofei; Manca, Giulia; Mancinelli, Giampiero; Marangotto, Daniele; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marinangeli, Matthieu; Marino, Pietro; Marks, Jörg; Martellotti, Giuseppe; Martin, Morgan; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Massacrier, Laure Marie; Massafferri, André; Matev, Rosen; Mathad, Abhijit; Mathe, Zoltan; Matteuzzi, Clara; Mauri, Andrea; Maurice, Emilie; Maurin, Brice; Mazurov, Alexander; McCann, Michael; McNab, Andrew; McNulty, Ronan; Mead, James Vincent; Meadows, Brian; Meaux, Cedric; Meier, Frank; Meinert, Nis; Melnychuk, Dmytro; Merk, Marcel; Merli, Andrea; Michielin, Emanuele; Milanes, Diego Alejandro; Millard, Edward James; Minard, Marie-Noelle; Minzoni, Luca; Mitzel, Dominik Stefan; Mogini, Andrea; Molina Rodriguez, Josue; Mombacher, Titus; Monroy, Igancio Alberto; Monteil, Stephane; Morandin, Mauro; Morello, Michael Joseph; Morgunova, Olga; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Mulder, Mick; Müller, Dominik; Müller, Janine; Müller, Katharina; Müller, Vanessa; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nandi, Anita; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Thi Dung; Nguyen-Mau, Chung; Nieswand, Simon; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Nogay, Alla; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Ogilvy, Stephen; Oldeman, Rudolf; Onderwater, Gerco; Ossowska, Anna; Otalora Goicochea, Juan Martin; Owen, Patrick; Oyanguren, Maria Aranzazu; Pais, Preema Rennee; Palano, Antimo; Palutan, Matteo; Papanestis, Antonios; Pappagallo, Marco; Pappalardo, Luciano; Parker, William; Parkes, Christopher; Passaleva, Giovanni; Pastore, Alessandra; Patel, Mitesh; Patrignani, Claudia; Pearce, Alex; Pellegrino, Antonio; Penso, Gianni; Pepe Altarelli, Monica; Perazzini, Stefano; Perret, Pascal; Pescatore, Luca; Petridis, Konstantinos; Petrolini, Alessandro; Petrov, Aleksandr; Petruzzo, Marco; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pikies, Malgorzata; Pinci, Davide; Pistone, Alessandro; Piucci, Alessio; Placinta, Vlad-Mihai; Playfer, Stephen; Plo Casasus, Maximo; Polci, Francesco; Poli Lener, Marco; Poluektov, Anton; Polyakov, Ivan; Polycarpo, Erica; Pomery, Gabriela Johanna; Ponce, Sebastien; Popov, Alexander; Popov, Dmitry; Poslavskii, Stanislav; Potterat, Cédric; Price, Eugenia; Prisciandaro, Jessica; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Pullen, Hannah Louise; Punzi, Giovanni; Qian, Wenbin; Quagliani, Renato; Quintana, Boris; Rachwal, Bartlomiej; Rademacker, Jonas; Rama, Matteo; Ramos Pernas, Miguel; Rangel, Murilo; Raniuk, Iurii; Ratnikov, Fedor; Raven, Gerhard; Ravonel Salzgeber, Melody; Reboud, Meril; Redi, Federico; Reichert, Stefanie; dos Reis, Alberto; Remon Alepuz, Clara; Renaudin, Victor; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vicente; Robbe, Patrick; Robert, Arnaud; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Lopez, Jairo Alexis; Rogozhnikov, Alexey; Roiser, Stefan; Rollings, Alexandra Paige; Romanovskiy, Vladimir; Romero Vidal, Antonio; Ronayne, John William; Rotondo, Marcello; Rudolph, Matthew Scott; Ruf, Thomas; Ruiz Valls, Pablo; Ruiz Vidal, Joan; Saborido Silva, Juan Jose; Sadykhov, Elnur; Sagidova, Naylya; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santimaria, Marco; Santovetti, Emanuele; Sarpis, Gediminas; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrina, Darya; Schael, Stefan; Schellenberg, Margarete; Schiller, Manuel; Schindler, Heinrich; Schmelling, Michael; Schmelzer, Timon; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schreiner, HF; Schubiger, Maxime; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Sepulveda, Eduardo Enrique; Sergi, Antonino; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Siddi, Benedetto Gianluca; Silva Coutinho, Rafael; Silva de Oliveira, Luiz Gustavo; Simi, Gabriele; Simone, Saverio; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Eluned; Smith, Iwan Thomas; Smith, Jackson; Smith, Mark; Soares Lavra, Lais; Sokoloff, Michael; Soler, Paul; Souza De Paula, Bruno; Spaan, Bernhard; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Stefko, Pavol; Stefkova, Slavomira; Steinkamp, Olaf; Stemmle, Simon; Stenyakin, Oleg; Stepanova, Margarita; Stevens, Holger; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Stramaglia, Maria Elena; Straticiuc, Mihai; Straumann, Ulrich; Sun, Jiayin; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Syropoulos, Vasileios; Szumlak, Tomasz; Szymanski, Maciej Pawel; T'Jampens, Stephane; Tayduganov, Andrey; Tekampe, Tobias; Tellarini, Giulia; Teubert, Frederic; Thomas, Eric; van Tilburg, Jeroen; Tilley, Matthew James; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Toriello, Francis; Tourinho Jadallah Aoude, Rafael; Tournefier, Edwige; Traill, Murdo; Tran, Minh Tâm; Tresch, Marco; Trisovic, Ana; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tully, Alison; Tuning, Niels; Ukleja, Artur; Usachov, Andrii; Ustyuzhanin, Andrey; Uwer, Ulrich; Vacca, Claudia; Vagner, Alexander; Vagnoni, Vincenzo; Valassi, Andrea; Valat, Sebastien; Valenti, Giovanni; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vecchi, Stefania; van Veghel, Maarten; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Venkateswaran, Aravindhan; Verlage, Tobias Anton; Vernet, Maxime; Vesterinen, Mika; Viana Barbosa, Joao Vitor; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Viemann, Harald; Vilasis-Cardona, Xavier; Vitti, Marcela; Volkov, Vladimir; Vollhardt, Achim; Voneki, Balazs; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; de Vries, Jacco; Vázquez Sierra, Carlos; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wang, Jianchun; Ward, David; Wark, Heather Mckenzie; Watson, Nigel; Websdale, David; Weiden, Andreas; Weisser, Constantin; Whitehead, Mark; Wicht, Jean; Wilkinson, Guy; Wilkinson, Michael; Williams, Mark Richard James; Williams, Matthew; Williams, Mike; Williams, Timothy; Wilson, Fergus; Wimberley, Jack; Winn, Michael Andreas; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wraight, Kenneth; Wyllie, Kenneth; Xie, Yuehong; Xu, Menglin; Xu, Zhirui; Yang, Zhenwei; Yang, Zishuo; Yao, Yuezhe; Yin, Hang; Yu, Jiesheng; Yuan, Xuhao; Yushchenko, Oleg; Zarebski, Kristian Alexander; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Yanxi; Zhelezov, Alexey; Zheng, Yangheng; Zhu, Xianglei; Zhukov, Valery; Zonneveld, Jennifer Brigitta; Zucchelli, Stefano

    A search for charmless four-body decays of $\\Lambda_{b}^{0}$ and $\\Xi_{b}^{0}$ baryons with a proton and three charged mesons (either kaons or pions) in the final state is performed. The data sample used was recorded in 2011 and 2012 with the LHCb experiment and corresponds to an integrated luminosity of 3 fb$^{-1}$. Six decay modes are observed, among which $\\Lambda_{b}^{0} \\to pK^{-}\\pi^{+}\\pi^{-}$, $\\Lambda_{b}^{0} \\to pK^{-}K^{+}K^{-}$, $\\Xi_{b}^{0} \\to pK^{-}\\pi^{+}\\pi^{-}$ and $\\Xi_{b}^{0} \\to pK^{-} \\pi^{+}K^{-}$ are established for the first time. Their branching fractions (including the ratio of hadronisation fractions in the case of the $\\Xi_{b}^{0}$ baryon) are determined relative to the $\\Lambda_{b}^{0} \\to \\Lambda_{c}^{+}\\pi^{-}$ decay.

  20. Time-dependent CP violation in $B^0_{(s)} \\to h^+h^-$ decays

    CERN Multimedia

    Fazzini, Davide

    2018-01-01

    The direct and mixing-induced CP-violating asymmetries in $B^0 \\to \\pi^+ \\pi^-$ and $B_s \\to K^+ K^-$ decays have been measured using a sample of pp collisions collected by the LHCb experiment during the Run1 of the LHC and corresponding to an integrated luminosity of 3.0 fb$^{-1}$.The time-integrated CP asymmetries in $B^0 \\to K^+ \\pi^-$ and $B_s \\to \\pi^+ K^-$ decays have also been measured, using the same data sample.The measurements of the CP-violating asymmetries of the $B^0 \\to \\pi^+ \\pi^-$, $B_s \\to K^+\\pi^-$ and $B_s \\to \\pi^+K^-$ decays are the most precise from a single experiment. The measurements of the CP-violating asymmetries of the Bs->KK decays are compatible with the previous results from LHCb.

  1. Targeted Sequencing of an Epidemiologically Low Risk patient defines Fibroblast Growth Factor Family Aberrations as a putative driver of Head and Neck Squamous Cell Carcinoma

    Science.gov (United States)

    Tillman, Brittny N.; Yanik, Megan; Birkeland, Andrew C.; Liu, Chia-Jen; Hovelson, Daniel H.; Cani, Andi K.; Palanisamy, Nallasivam; Carskadon, Shannon; Carey, Thomas E.; Bradford, Carol R.; Tomlins, Scott A.; McHugh, Jonathan B.; Spector, Matthew E.; Brenner, J. Chad

    2016-01-01

    Background Targeted sequencing of epidemiologically low risk (ELR) HNSCC patients could help identify novel drivers or lost suppressors leading to precision medicine protocols and improved survival rates. Methods An ELR-HNSCC patient was selected for targeted sequencing. We then assessed next generation sequencing cohorts from the Oncomine Powertool Database, which contains pan-cancer data from The Cancer Genome Atlas(TCGA). Results Targeted sequencing revealed FGFR1 amplifications as a putative driver of the patient’s tumor. HNSCC patients from TCGA data demonstrated FGF family mutations, rearrangements or amplifications in over 35% of HNSCC cases, with a statistically significant higher frequency in African American populations. FGF alterations were unique from activating PIK3CA mutations. Conclusion Together, this data suggests that FGF signaling may be critical for a subset of HNSCC patients independent of other known pathways and provides rationale for leveraging ELR-HNSCC patients to define molecular subsets of high risk HNSCC. PMID:26849095

  2. Study of the decay $B^{\\pm} \\to DK^{*\\pm}$ with two-body $D$ decays

    CERN Document Server

    The LHCb Collaboration

    2016-01-01

    Results on measurement of $CP$-sensitive observables in the decay $B^{\\pm} \\to DK^{*\\pm}$, where $D$ denotes a superposition of $D^0$ and $\\overline{D}{^0}$ are presented. Decays of the $D$ meson to $D \\to K^-\\pi^+, K^-K^+, \\pi^-\\pi^+, \\pi^-K^+$ are used, and the $K^{*\\pm}$ is considered in the $K_S^0\\pi^{\\pm}$ final state. This analysis uses a dataset consisting of 3 fb$^{-1}$ of 7 TeV and 8 TeV data and 1 fb$^{-1}$ of 13 TeV data in proton-proton collisions collected by the LHCb experiment. The $CP$-sensitive observables have sensitivity to the CKM angle $\\gamma$.

  3. Mõned erilised hetked EPIKoja võrgustiku tegemistest aastal 2016

    Index Scriptorium Estoniae

    2016-01-01

    Fotosid Eesti Puuetega Inimeste Koja liikmesorganisatsioonide üritustest 2016. aastal: Eesti Reumaliidu 17. käimispäev Tartus, puuetega noortele tervisepäev Pannjärve terviserajal, Eesti Autismiühingu korraldatud rahvusvahelisest autismipäevast Tallinna Tondi Põhikoolis, Eesti Tsöliaakia Seltsi suvelaager Tartumaal 8.-10. juulil, Vahtra Tantsud Tähtedega 2016 finaal, Tartu PIK-i projektis “Ajaga kaasa” osalejad Stenbocki maja, Eesti Pimedate Liit andis valge kepi päeva tänuseminaril üle tunnustused “Aasta tegu 2016”, Eesti Psoriaasiliit tähistas 26. märtsil oma 25. aastapäeva konverentsiga Tallinnas

  4. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

    Directory of Open Access Journals (Sweden)

    Grace R. Anderson

    2017-07-01

    Full Text Available Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

  5. Organisaatiouudistus henkilöstön näkökulmasta

    OpenAIRE

    Tammisto, Santeri

    2016-01-01

    Tämän opinnäytetyön tavoitteena oli tutkia yritys X:ssä keväällä 2015 toteutettua organisaatiouudistusta henkilöstön näkökulmasta. Tapahtuneet muutokset asiakaskäyttäytymisessä edellyttivät korvausprosessin tehostamista sekä sähköisen asioinnin kehittämistä. Muutosen tavoitteena oli sisäisen yhteistyön, asiakaspalvelun sekä kustannustehokkuuden kehittäminen. Opinnäytetyö selvittää, miten muutoksen läpikäynyt henkilöstö koki muutosten läpiviennin sekä millä tavalla sen olisi voinut hoitaa pare...

  6. B decays and models for CP violation.

    Energy Technology Data Exchange (ETDEWEB)

    He, Xiao Gang [Melbourne Univ., Parkville, VIC (Australia). School of Physics]|[Oregon Univ., Eugene, OR (United States)

    1995-12-01

    The decay modes B to {pi} {pi},{upsilon}K{sub S}{sup ,} K{sup -}D, {pi}K and {eta}K are promising channels to study the unitarity triangle of the CP violating Cabibbo-Kobayashi-Maskawa (CKM) matrix. The consequences of these measurements in the Weinberg model are discussed. It is shown that measurements of CP violation in B decay can be used to distinguish Standard Model from Weinberg model and that the following different mechanisms for CP violation can be distinguished: (1) CP is violated in the CKM sector only; (2) CP is violated spontaneously in the Higgs sector only; and (3) CP is violated in both the CKM and Higgs sectors. 27 refs., 4 figs.

  7. The frequency and damping of ion acoustic waves in collisional and collisionless two-species plasma

    Energy Technology Data Exchange (ETDEWEB)

    Berger, R L; Valeo, E J

    2004-07-15

    The dispersion properties of ion acoustic waves (IAW) are sensitive to the strength of ion-ion collisions in multi-species plasma in which the different species usually have differing charge-to-mass ratios. The modification of the frequency and damping of the fast and slow acoustic modes in a plasma composed of light (low Z) and heavy (high Z) ions is considered. In the fluid limit where the light ion scattering mean free path, {lambda}{sub th} is smaller than the acoustic wavelength, {lambda} = 2{pi}/k, the interspecies friction and heat flow carried by the light ions scattering from the heavy ions causes the damping. In the collisionless limit, k{lambda}{sub lh} >> 1, Landau damping by the light ions provides the dissipation. In the intermediate regime when k{lambda}{sub lh} {approx} 1, the damping is at least as large as the sum of the collisional and Landau damping.

  8. The Frequency and Damping of Ion Acoustic Waves in Collisional and Collisionless Two-species Plasma

    Energy Technology Data Exchange (ETDEWEB)

    R.L. Berger; E.J. Valeo

    2004-08-18

    The dispersion properties of ion acoustic waves (IAW) are sensitive to the strength of ion-ion collisions in multi-species plasma in which the different species usually have differing charge-to-mass ratios. The modification of the frequency and damping of the fast and slow acoustic modes in a plasma composed of light (low Z) and heavy (high Z) ions is considered. In the fluid limit where the light ion scattering mean free path, {lambda}{sub th} is smaller than the acoustic wavelength, {lambda} = 2{pi}/k, the interspecies friction and heat flow carried by the light ions scattering from the heavy ions causes the damping. In the collisionless limit, k{lambda}{sub th} >> 1, Landau damping by the light ions provides the dissipation. In the intermediate regime when k{lambda}{sub th} {approx} 1, the damping is at least as large as the sum of the collisional and Landau damping.

  9. Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events

    DEFF Research Database (Denmark)

    Serizawa, Reza R; Ralfkiaer, Ulrik; Steven, Kenneth

    2011-01-01

    .0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve......The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically...... screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We...

  10. Indication for a K/sup. pi. / = 0/sup -/ octupole band in /sup 150/Nd from electron scattering

    Energy Technology Data Exchange (ETDEWEB)

    Creswell, C.; Hirsch, A.; Bertozzi, W.; Heisenberg, J.; Kowalski, S.; Sargent, C.P.; Turchinetz, W.; Dieperink, A.

    1978-11-01

    Recent electron scattering results on the 0.850 MeV level of /sup 150/Nd, when analyzed in terms of the interacting boson model, are inconsistent with the interpretation of this level as a pure J/sup ..pi../(K) = 2/sup +/(0) state. Very recent (n,n'..gamma..) work has shown this level to be a 1/sup -/, 2/sup +/ doublet. Assuming this level to be the band head of a ''K/sup ..pi../ = 0/sup -/'' octupole band, a simple model is used to predict electron scattering form factors for the 0.850 MeV state and a 3/sup -/ octupole level observed at 0.931 MeV. Comparison is made between these predicted form factors and recent electron scattering data.

  11. New targetable oncogenes in non-small-cell lung cancer.

    Science.gov (United States)

    Oxnard, Geoffrey R; Binder, Adam; Jänne, Pasi A

    2013-03-10

    The identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non-small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non-small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development.

  12. Comparison of the molecular profile of brain metastases from colorectal cancer and corresponding primary tumors.

    Science.gov (United States)

    Aprile, Giuseppe; Casagrande, Mariaelena; De Maglio, Giovanna; Fontanella, Caterina; Rihawi, Karim; Bonotto, Marta; Pisa, Federica E; Tuniz, Francesco; Pizzolitto, Stefano; Fasola, Gianpiero

    2017-01-01

    Little is known about molecular biology of brain metastasis (BM) from colorectal cancer and its concordance with matched primary tumors. We identified 56 consecutive colorectal cancer patients who underwent neurosurgical resection of BM. Tumor samples were tested for KRAS, NRAS, BRAF and PIK3CA. The molecular profile of the brain lesion was compared with the corresponding primary tumor. The molecular profile concordance rate was 95.1%. Median survival after neurosurgery was 5.5 months (95% CI: 4.7-6.3); median overall survival was 24.0 months (95% CI: 15.6-32.4). In this cohort, we report a high frequency of KRAS mutations and a very high concordance rate between the molecular status of BM and that of matched primary tumors.

  13. Metastatic Extramammary Paget’s Disease of Scrotum Responds Completely to Single Agent Trastuzumab in a Hemodialysis Patient: Case Report, Molecular Profiling and Brief Review of the Literature

    Directory of Open Access Journals (Sweden)

    Peter Barth

    2015-01-01

    metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%–40% in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options.

  14. LHCb: Direct CP-asymmetries in $B^0\\to K\\pi$ and $B_s^0 \\to \\pi K$ decays at LHCb

    CERN Document Server

    Zangoli, Maria

    2012-01-01

    The LHCb experiment is designed to perform flavour physics measurements at the Large Hadron Collider. Using a data sample corresponding to an integrated luminosity of 0.35 fb$^{-1}$ collected by LHCb in 2011, we report measurements of the direct CP asymmetries in the $B^0 \\to K^+\\pi^-$ and $B_s^0 \\to \\pi^+K^-$ decays. The results obtained represent the first evidence of CP violation in the decays of $B_s^0$ mesons to $K\\pi$ pairs with a significance of 3.3$\\sigma$. Furthermore, we report the first observation of CP violation in $B^0$ decays at a hadron collider with a significance exceeding 6$\\sigma$.

  15. SOX4 expression in bladder carcinoma

    DEFF Research Database (Denmark)

    Aaboe, Mads; Birkenkamp-Demtroder, Karin; Wiuf, Carsten

    2006-01-01

    strongly impaired cell viability and promoted apoptosis. To characterize downstream target genes and SOX4-induced pathways, we used a time-course global expression study of the overexpressed SOX4. Analysis of the microarray data showed 130 novel SOX4-related genes, some involved in signal transduction (MAP......2K5), angiogenesis (NRP2), and cell cycle arrest (PIK3R3) and others with unknown functions (CGI-62). Among the genes regulated by SOX4, 25 contained at least one SOX4-binding motif in the promoter sequence, suggesting a direct binding of SOX4. The gene set identified in vitro was analyzed...... in the clinical bladder material and a small subset of the genes showed a high correlation to SOX4 expression. The present data suggest a role of SOX4 in the bladder cancer disease....

  16. CT assessment of early response to neoadjuvant therapy in colon cancer

    DEFF Research Database (Denmark)

    Rafaelsen, Søren Rafael; Dam, Claus; Lund-Rasmussen, Vera

    Objectives: Using multidetector computed tomography, we aimed to assess the early response of neoadjuvant drug therapy for locally advanced colon cancer. Methods: Computed tomography with IV contrast was acquired from 67 patients before and after up to three cycles of preoperative treatment. All...... patients had histologically confirmed colon cancer, a T4 or T3 tumour with extramural invasion ≥ 5 mm and no distant metastases or peritoneal nodules. The patients were treated with oxaliplatin and capecitabine. In addition, those with no mutations in the KRAS, BRAF and PIK3CA genes were also treated...... nodes following neoadjuvant treatment of locally advanced colon cancer. NEC may induce not only tumour down-sizing, but may bring about a significant prolongation of disease-free survival and eventually improve overall survival. The shown early response to NEC leads to hope for improvement...

  17. Screening for circulating RAS/RAF mutations by multiplex digital PCR

    DEFF Research Database (Denmark)

    Andersen, Rikke Fredslund; Jakobsen, Anders

    2016-01-01

    by technical challenges primarily due to the low levels of ctDNA in patients with localized disease and in patients responding to therapy. The approach presented here is a multiplex digital PCR method of screening for 31 mutations in the KRAS, NRAS, BRAF, and PIK3CA genes in the plasma. The upper level...... of the limit of blank, which defines the specificity of the multiplexes, was 0.006%-0.06%. Mutations found by multiplex analyses were identified and quantified by duplex analyses. The method was tested on samples from cholangiocarcinoma patients with known tumor mutational status. Mutations found in the tumor...... were also found in plasma samples in all cases with analyses for all other mutations being negative. There was a perfect agreement as to wild type status in tumor and plasma. The method combines a high sensitivity with the ability to analyze for several mutations at a time and could be a step towards...

  18. Measurement of $CP$ violation parameters in $B^0 \\to D K^{*0}$ decays

    CERN Document Server

    Aaij, Roel; Adinolfi, Marco; Affolder, Anthony; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Anderson, Jonathan; Andreassen, Rolf; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Aquines Gutierrez, Osvaldo; Archilli, Flavio; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Bachmann, Sebastian; Back, John; Badalov, Alexey; Balagura, Vladislav; Baldini, Wander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Belogurov, Sergey; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Benton, Jack; Berezhnoy, Alexander; Bernet, Roland; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bien, Alexander; Bifani, Simone; Bird, Thomas; Bizzeti, Andrea; Bjørnstad, Pål Marius; Blake, Thomas; Blanc, Frédéric; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Borghi, Silvia; Borgia, Alessandra; Borsato, Martino; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Brambach, Tobias; van den Brand, Johannes; Bressieux, Joël; Brett, David; Britsch, Markward; Britton, Thomas; Brodzicka, Jolanta; Brook, Nicholas; Brown, Henry; Bursche, Albert; Busetto, Giovanni; Buytaert, Jan; Cadeddu, Sandro; Calabrese, Roberto; Calvi, Marta; Calvo Gomez, Miriam; Campana, Pierluigi; Campora Perez, Daniel; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cauet, Christophe; Cenci, Riccardo; Charles, Matthew; Charpentier, Philippe; Chen, Shanzhen; Cheung, Shu-Faye; Chiapolini, Nicola; Chrzaszcz, Marcin; Ciba, Krzystof; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Collins, Paula; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombes, Matthew; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Counts, Ian; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Cruz Torres, Melissa Maria; Cunliffe, Samuel; Currie, Robert; D'Ambrosio, Carmelo; Dalseno, Jeremy; David, Pascal; David, Pieter; Davis, Adam; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Silva, Weeraddana; De Simone, Patrizia; Decamp, Daniel; Deckenhoff, Mirko; Del Buono, Luigi; Déléage, Nicolas; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Di Canto, Angelo; Dijkstra, Hans; Donleavy, Stephanie; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Dossett, David; Dovbnya, Anatoliy; Dreimanis, Karlis; Dujany, Giulio; Dupertuis, Frederic; Durante, Paolo; Dzhelyadin, Rustem; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; El Rifai, Ibrahim; Elsasser, Christian; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Färber, Christian; Farinelli, Chiara; Farley, Nathanael; Farry, Stephen; Fay, Robert; Ferguson, Dianne; Fernandez Albor, Victor; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fontana, Marianna; Fontanelli, Flavio; Forty, Roger; Francisco, Oscar; Frank, Markus; Frei, Christoph; Frosini, Maddalena; Fu, Jinlin; Furfaro, Emiliano; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; García Pardiñas, Julián; Garofoli, Justin; Garra Tico, Jordi; Garrido, Lluis; Gaspar, Clara; Gauld, Rhorry; Gavardi, Laura; Gavrilov, Gennadii; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianelle, Alessio; Giani', Sebastiana; Gibson, Valerie; Giubega, Lavinia-Helena; Gligorov, Vladimir; Göbel, Carla; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gordon, Hamish; Gotti, Claudio; Grabalosa Gándara, Marc; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graziani, Giacomo; Grecu, Alexandru; Greening, Edward; Gregson, Sam; Griffith, Peter; Grillo, Lucia; Grünberg, Oliver; Gui, Bin; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hall, Samuel; Hamilton, Brian; Hampson, Thomas; Han, Xiaoxue; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; He, Jibo; Head, Timothy; Heijne, Veerle; Hennessy, Karol; Henrard, Pierre; Henry, Louis; Hernando Morata, Jose Angel; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hoballah, Mostafa; Hombach, Christoph; Hulsbergen, Wouter; Hunt, Philip; Hussain, Nazim; Hutchcroft, David; Hynds, Daniel; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jaeger, Andreas; Jalocha, Pawel; Jans, Eddy; Jaton, Pierre; Jawahery, Abolhassan; Jing, Fanfan; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kaballo, Michael; Kandybei, Sergii; Kanso, Walaa; Karacson, Matthias; Karbach, Moritz; Karodia, Sarah; Kelsey, Matthew; Kenyon, Ian; Ketel, Tjeerd; Khanji, Basem; Khurewathanakul, Chitsanu; Klaver, Suzanne; Klimaszewski, Konrad; Kochebina, Olga; Kolpin, Michael; Komarov, Ilya; Koopman, Rose; Koppenburg, Patrick; Korolev, Mikhail; Kozlinskiy, Alexandr; Kravchuk, Leonid; Kreplin, Katharina; Kreps, Michal; Krocker, Georg; Krokovny, Pavel; Kruse, Florian; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kurek, Krzysztof; Kvaratskheliya, Tengiz; La Thi, Viet Nga; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lambert, Dean; Lambert, Robert W; Lanfranchi, Gaia; Langenbruch, Christoph; Langhans, Benedikt; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; van Leerdam, Jeroen; Lees, Jean-Pierre; Lefèvre, Regis; Leflat, Alexander; Lefrançois, Jacques; Leo, Sabato; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Yiming; Likhomanenko, Tatiana; Liles, Myfanwy; Lindner, Rolf; Linn, Christian; Lionetto, Federica; Liu, Bo; Liu, Guoming; Lohn, Stefan; Longstaff, Iain; Lopes, Jose; Lopez-March, Neus; Lowdon, Peter; Lu, Haiting; Lucchesi, Donatella; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Machefert, Frederic; Machikhiliyan, Irina V; Maciuc, Florin; Maev, Oleg; Malde, Sneha; Manca, Giulia; Mancinelli, Giampiero; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marino, Pietro; Märki, Raphael; Marks, Jörg; Martellotti, Giuseppe; Martens, Aurelien; Martín Sánchez, Alexandra; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massafferri, André; Matev, Rosen; Mathe, Zoltan; Matteuzzi, Clara; Mazurov, Alexander; McCann, Michael; McCarthy, James; McNab, Andrew; McNulty, Ronan; McSkelly, Ben; Meadows, Brian; Meier, Frank; Meissner, Marco; Merk, Marcel; Milanes, Diego Alejandro; Minard, Marie-Noelle; Moggi, Niccolò; Molina Rodriguez, Josue; Monteil, Stephane; Morandin, Mauro; Morawski, Piotr; Mordà, Alessandro; Morello, Michael Joseph; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Müller, Katharina; Mussini, Manuel; Muster, Bastien; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Anh Duc; Nguyen, Thi-Dung; Nguyen-Mau, Chung; Nicol, Michelle; Niess, Valentin; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Novoselov, Alexey; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Oggero, Serena; Ogilvy, Stephen; Okhrimenko, Oleksandr; Oldeman, Rudolf; Onderwater, Gerco; Orlandea, Marius; Otalora Goicochea, Juan Martin; Owen, Patrick; Oyanguren, Maria Arantza; Pal, Bilas Kanti; Palano, Antimo; Palombo, Fernando; Palutan, Matteo; Panman, Jacob; Papanestis, Antonios; Pappagallo, Marco; Parkes, Christopher; Parkinson, Christopher John; Passaleva, Giovanni; Patel, Girish; Patel, Mitesh; Patrignani, Claudia; Pazos Alvarez, Antonio; Pearce, Alex; Pellegrino, Antonio; Pepe Altarelli, Monica; Perazzini, Stefano; Perez Trigo, Eliseo; Perret, Pascal; Perrin-Terrin, Mathieu; Pescatore, Luca; Pesen, Erhan; Petridis, Konstantin; Petrolini, Alessandro; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pilař, Tomas; Pinci, Davide; Pistone, Alessandro; Playfer, Stephen; Plo Casasus, Maximo; Polci, Francesco; Poluektov, Anton; Polycarpo, Erica; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Potterat, Cédric; Price, Eugenia; Prisciandaro, Jessica; Pritchard, Adrian; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Wenbin; Rachwal, Bartolomiej; Rademacker, Jonas; Rakotomiaramanana, Barinjaka; Rama, Matteo; Rangel, Murilo; Raniuk, Iurii; Rauschmayr, Nathalie; Raven, Gerhard; Reichert, Stefanie; Reid, Matthew; dos Reis, Alberto; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vincente; Roa Romero, Diego; Robbe, Patrick; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Perez, Pablo; Roiser, Stefan; Romanovsky, Vladimir; Romero Vidal, Antonio; Rotondo, Marcello; Rouvinet, Julien; Ruf, Thomas; Ruffini, Fabrizio; Ruiz, Hugo; Ruiz Valls, Pablo; Saborido Silva, Juan Jose; Sagidova, Naylya; Sail, Paul; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santovetti, Emanuele; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrie, Mauro; Savrina, Darya; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Seco, Marcos; Semennikov, Alexander; Sepp, Indrek; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Shires, Alexander; Silva Coutinho, Rafael; Simi, Gabriele; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Anthony; Smith, Edmund; Smith, Eluned; Smith, Jackson; Smith, Mark; Snoek, Hella; Sokoloff, Michael; Soler, Paul; Soomro, Fatima; Souza, Daniel; Souza De Paula, Bruno; Spaan, Bernhard; Sparkes, Ailsa; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Steinkamp, Olaf; Stenyakin, Oleg; Stevenson, Scott; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Straticiuc, Mihai; Straumann, Ulrich; Stroili, Roberto; Subbiah, Vijay Kartik; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Swientek, Stefan; Syropoulos, Vasileios; Szczekowski, Marek; Szczypka, Paul; Szilard, Daniela; Szumlak, Tomasz; T'Jampens, Stephane; Teklishyn, Maksym; Tellarini, Giulia; Teubert, Frederic; Thomas, Christopher; Thomas, Eric; van Tilburg, Jeroen; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Torr, Nicholas; Tournefier, Edwige; Tourneur, Stephane; Tran, Minh Tâm; Tresch, Marco; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tuning, Niels; Ubeda Garcia, Mario; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vagnoni, Vincenzo; Valenti, Giovanni; Vallier, Alexis; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vázquez Sierra, Carlos; Vecchi, Stefania; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Vesterinen, Mika; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Vilasis-Cardona, Xavier; Vollhardt, Achim; Volyanskyy, Dmytro; Voong, David; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; Voss, Helge; de Vries, Jacco; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wandernoth, Sebastian; Wang, Jianchun; Ward, David; Watson, Nigel; Websdale, David; Whitehead, Mark; Wicht, Jean; Wiedner, Dirk; Wilkinson, Guy; Williams, Matthew; Williams, Mike; Wilson, Fergus; Wimberley, Jack; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wright, Simon; Wu, Suzhi; Wyllie, Kenneth; Xie, Yuehong; Xing, Zhou; Xu, Zhirui; Yang, Zhenwei; Yuan, Xuhao; Yushchenko, Oleg; Zangoli, Maria; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Wen Chao; Zhang, Yanxi; Zhelezov, Alexey; Zhokhov, Anatoly; Zhong, Liang; Zvyagin, Alexander

    2014-01-01

    An analysis of $B^0 \\to D K^{*0}$ decays is presented, where $D$ represents an admixture of $D^0$ and $\\overline{D}^0$ mesons reconstructed in four separate final states: $K^-\\pi^+$, $\\pi^-K^+$, $K^+ K^-$ and $\\pi^+\\pi^-$. The data sample corresponds to 3.0 fb$^-1$ of proton-proton collision, collected by the LHCb experiment. Measurements of several observables are performed, including $CP$ asymmetries. The most precise determination is presented of $r_B(DK^{*0})$, the magnitude of the ratio of the amplitudes of the decay $B^0 \\to D K^+ \\pi^-$ with a $b \\to u$ or a $b \\to c$ transition, in a $K \\pi$ mass region of $\\pm 50$ MeV/$c^2$ around the $K^*(892)$ mass and for an absolute value of the cosine of the $K^{*0}$ helicity angle larger than 0.4.

  19. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

    Science.gov (United States)

    Cristofanilli, Massimo; Turner, Nicholas C; Bondarenko, Igor; Ro, Jungsil; Im, Seock-Ah; Masuda, Norikazu; Colleoni, Marco; DeMichele, Angela; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Zhang, Ke; Theall, Kathy Puyana; Jiang, Yuqiu; Bartlett, Cynthia Huang; Koehler, Maria; Slamon, Dennis

    2016-04-01

    In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Between Oct 7, 2013, and Aug 26, 2014, 521 patients were

  20. ASHIPH counters for the KEDR detector

    CERN Document Server

    Barnyakov, A Y; Bobrovnikov, V S; Buzykaev, A R; Danilyuk, A F; Guber, F F; Kolachev, G M; Kononov, S A; Krasnov, V A; Kravchenko, E A; Kurepin, A B; Minakov, G D; Onuchin, A P; Savinov, G A; Tayursky, V A

    2002-01-01

    The status of the ASHIPH (Aerogel, wavelength SHIfter, and PHotomultipliers) system of the KEDR detector is described. The measurement of the quality of the particle identification with the ASHIPH counters was performed. The pi/K separation is 4.5 sigma for the momentum 1.2 GeV/c and 4.7 sigma for the momentum 0.86 GeV/c. Timing properties of the ASHIPH counter are measured. The time resolution for pions is 2 ns, and the BBQ decay time is 15 ns. The advantages and disadvantages of Cherenkov counters filled with aerogel crumb are discussed. The process of the mass counter production for the KEDR detector is described.

  1. Investigation of the effects of elevated atmospheric CO{sub 2} on a whet crop of the Free-Air Carbondioxide Enrichment (FACE) Experiment, Maricopa, USA. Final report; Untersuchung der Auswirkungen erhoehter atmosphaerischer CO{sub 2}-Konzentrationen auf Weizenbestaende des Free-Air Carbondioxid Enrichment (FACE)-Experimentes Maricopa (USA). Abschlussbericht

    Energy Technology Data Exchange (ETDEWEB)

    Kartschall, T.; Grossman, S.; Michaelis, P.; Wechsung, F. [Potsdam-Institut fuer Klimafolgenforschung e.V., Potsdam (Germany). Abt. Globaler Wandel und Natuerliche Systeme; Graefe, J.; Waloszczyk, K. [Professor-Hellriegel-Institut e.V., Bernburg (Germany); Wechsung, G. [US Water-Conservation Lab., Phoenix, AZ (United States); Blum, E.; Blum, M.

    1998-02-01

    A version of the demeter model was developed which describes both the quantitative and qualitative effects of elevated atmospheric CO{sub 2} on a wheat crop under conditions of limited water and/or nitrogen supply. In the model`s photosynthesis and energy balance modules, first versions of components were developed which it should be possible to apply in further ecosystem models (starting with the cereals models of the demeter family). Experimental data from the Maricopa FACE wheat experiments 1992-1996, in which scientists from PIK were involved, were used for the development and testing of the model. Model solutions obtained were applied for the first time of central European climatic and site conditions as part of a regional yield study for the Federal State of Brandenburg. (orig.)

  2. Driver gene mutations of non-small-cell lung cancer are rare in primary carcinoids of the lung: NGS study by ion Torrent.

    Science.gov (United States)

    Armengol, Gemma; Sarhadi, Virinder Kaur; Rönty, Mikko; Tikkanen, Milja; Knuuttila, Aija; Knuutila, Sakari

    2015-04-01

    Lung carcinoids are rare neuroendocrine tumors of the lung. Very little is known about the genetic background of these tumors. We applied Ion Torrent Ampliseq next-generation technology to study hotspot mutations of 22 lung cancer-related genes from typical and atypical lung carcinoid tumors. DNA isolated from 25 formalin-fixed, paraffin-embedded carcinoid tumors were amplified to prepare barcoded libraries covering 507 mutations included in 90 amplicons. The libraries were pooled, purified, enriched, and sequenced on ion personal genome machine. The sequences were aligned and checked for known and novel variations using Torrent Suite Software v.4.0.2. One out of 25 patients had mutations in the targeted regions sequenced. This patient had mutations in BRAF, SMAD4, PIK3CA, and KRAS. All these mutations were confirmed as somatic and are previously known mutations. In summary, mutations in genes commonly mutated in non-small-cell lung cancer are not common in lung carcinoids.

  3. Intact initiation of autophagy and mitochondrial fission by acute exercise in skeletal muscle of patientswith type 2 diabetes

    DEFF Research Database (Denmark)

    Kruse Sørensen, Rikke; Pedersen, Andreas James Thestrup; Kristensen, Jonas Møller

    2017-01-01

    AIMS: Type 2 diabetes (T2D) is characterized by insulin resistance, mitochondrial dysregulation, and, in some studies, exercise resistance in skeletal muscle. Regulation of autophagy and mitochondrial dynamics during exercise and recovery is important for skeletal muscle homeostasis......, and these responses may be altered in T2D. MATERIALS AND METHODS: We examined the effect of acute exercise on markers of autophagy and mitochondrial fusion and fission in skeletal muscle biopsies from patients with T2D (n=13) and weight-matched controls (n=14) before, immediately after and 3h after an acute bout...... of exercise. RESULTS: While mRNA levels of most markers of autophagy ( PIK3C, MAP1LC3B, SQSTM1, BNIP3, BNIP3L ) and mitochondrial dynamics ( OPA1, FIS1 ) remained unchanged, some either increased during and after exercise (GABARAPL1 ), decreased in the recovery period ( BECN1, ATG7, DNM1L ), or both ( MFN2...

  4. The dark side of the moon: the PI3K/PTEN/AKT pathway in colorectal carcinoma.

    Science.gov (United States)

    Silvestris, Nicola; Tommasi, Stefania; Petriella, Daniela; Santini, Daniele; Fistola, Ettore; Russo, Antonio; Numico, Gianmauro; Tonini, Giuseppe; Maiello, Evaristo; Colucci, Giuseppe

    2009-01-01

    Wild-type KRAS status is required but not sufficient to confer sensitivity to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in colorectal cancer patients. As a consequence, one of the major challenges is to identify, in non-mutant KRAS patients, other markers that can predict lack of response to this therapy. Small series have investigated the clinical effect of PIK3CA mutations on resistance to anti-EGFR mAbs and discrepant results have been observed. Furthermore, PTEN loss in metastases may be predictive of resistance to anti-EGFR mAbs, even if PTEN determination is far from an immediate clinical application. The introduction of modulators of the PI3K/AKT/mTOR pathway as potential targeted anticancer drugs is encouraging, but this attractive therapy option is still at an early stage of development. Copyright 2010 S. Karger AG, Basel.

  5. Landscape mapping of functional proteins in insulin signal transduction and insulin resistance: a network-based protein-protein interaction analysis.

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    Chiranjib Chakraborty

    Full Text Available The type 2 diabetes has increased rapidly in recent years throughout the world. The insulin signal transduction mechanism gets disrupted sometimes and it's known as insulin-resistance. It is one of the primary causes associated with type-2 diabetes. The signaling mechanisms involved several proteins that include 7 major functional proteins such as INS, INSR, IRS1, IRS2, PIK3CA, Akt2, and GLUT4. Using these 7 principal proteins, multiple sequences alignment has been created. The scores between sequences also have been developed. We have constructed a phylogenetic tree and modified it with node and distance. Besides, we have generated sequence logos and ultimately developed the protein-protein interaction network. The small insulin signal transduction protein arrangement shows complex network between the functional proteins.

  6. Progression inference for somatic mutations in cancer

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    Leif E. Peterson

    2017-04-01

    Full Text Available Computational methods were employed to determine progression inference of genomic alterations in commonly occurring cancers. Using cross-sectional TCGA data, we computed evolutionary trajectories involving selectivity relationships among pairs of gene-specific genomic alterations such as somatic mutations, deletions, amplifications, downregulation, and upregulation among the top 20 driver genes associated with each cancer. Results indicate that the majority of hierarchies involved TP53, PIK3CA, ERBB2, APC, KRAS, EGFR, IDH1, VHL, etc. Research into the order and accumulation of genomic alterations among cancer driver genes will ever-increase as the costs of nextgen sequencing subside, and personalized/precision medicine incorporates whole-genome scans into the diagnosis and treatment of cancer.

  7. Parameterization for subgrid-scale motion of ice-shelf calving fronts

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    T. Albrecht

    2011-01-01

    Full Text Available A parameterization for the motion of ice-shelf fronts on a Cartesian grid in finite-difference land-ice models is presented. The scheme prevents artificial thinning of the ice shelf at its edge, which occurs due to the finite resolution of the model. The intuitive numerical implementation diminishes numerical dispersion at the ice front and enables the application of physical boundary conditions to improve the calculation of stress and velocity fields throughout the ice-sheet-shelf system. Numerical properties of this subgrid modification are assessed in the Potsdam Parallel Ice Sheet Model (PISM-PIK for different geometries in one and two horizontal dimensions and are verified against an analytical solution in a flow-line setup.

  8. Silencing TAK1 alters gene expression signatures in bladder cancer cells.

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    Chen, Jimin; Zhang, Nan; Wen, Jiaming; Zhang, Zhewei

    2017-05-01

    The aim of the present study was to identify the differentially expressed genes (DEGs) that are induced by the silencing of transforming growth factor-β-activated kinase 1 (TAK1) in bladder cancer cells and to analyze the potential biological effects. Dataset GSE52452 from mutant fibroblast growth factor receptor 3 (FGFR3) bladder cancer cells transfected with control siRNA or TAK1-specific siRNA was downloaded from Gene Expression Omnibus. The DEGs between the two groups were identified using Limma package following data pre-processing by Affy in Bioconductor. Enrichment analysis of DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, followed by functional annotation using TRANSFAC, TSGene and TAG databases. Integrated networks were constructed by Cytoscape and sub-networks were extracted employing BioNet, followed by enrichment analysis of DEGs in the sub-network. A total of 43 downregulated and 21 upregulated genes were obtained. The downregulated genes were enriched in five pathways, including NOD-like receptor signaling pathway and functions related to cellular response. The upregulated genes were associated with cellular developmental processes. Transcription factor EGR1 and 9 tumor-associated genes were screened from the DEGs. Among the DEGs, 10 hub nodes may represent important roles in the complex metabolic network, including EGFR, CYP3A5, MAP3K7, GSTA1, PTHLH, ALDH1A1, KCND2, EGR1, ARRB1 and ITPR1. Additionally, EGFR was correlated with ERBB2, GRB2 and PIK3R1, and these were enriched in ErbB signaling pathway and various cancer-associated pathways. Silencing TAK1 may decrease cellular response to chemical stimulus via downregulating CYP3A5, MAP3K7, GSTA1, ALDH1A1, ARRB1 and ITPR1; increase cancer cell development via upregulating EGFR, EGR1 and PTHLH; and regulate cancer metastasis through EGFR, ERBB2, GRB2 and PIK3R1.

  9. A global historical data set of tropical cyclone exposure (TCE-DAT)

    Science.gov (United States)

    Geiger, Tobias; Frieler, Katja; Bresch, David N.

    2018-01-01

    Tropical cyclones pose a major risk to societies worldwide, with about 22 million directly affected people and damages of USD 29 billion on average per year over the last 20 years. While data on observed cyclones tracks (location of the center) and wind speeds are publicly available, these data sets do not contain information about the spatial extent of the storm and people or assets exposed. Here, we apply a simplified wind field model to estimate the areas exposed to wind speeds above 34, 64, and 96 knots (kn). Based on available spatially explicit data on population densities and gross domestic product (GDP) we estimate (1) the number of people and (2) the sum of assets exposed to wind speeds above these thresholds accounting for temporal changes in historical distribution of population and assets (TCE-hist) and assuming fixed 2015 patterns (TCE-2015). The associated spatially explicit and aggregated country-event-level exposure data (TCE-DAT) cover the period 1950 to 2015 and are freely available at https://doi.org/10.5880/pik.2017.011" target="_blank">https://doi.org/10.5880/pik.2017.011 (Geiger at al., 2017c). It is considered key information to (1) assess the contribution of climatological versus socioeconomic drivers of changes in exposure to tropical cyclones, (2) estimate changes in vulnerability from the difference in exposure and reported damages and calibrate associated damage functions, and (3) build improved exposure-based predictors to estimate higher-level societal impacts such as long-term effects on GDP, employment, or migration. We validate the adequateness of our methodology by comparing our exposure estimate to estimated exposure obtained from reported wind fields available since 1988 for the United States. We expect that the free availability of the underlying model and TCE-DAT will make research on tropical cyclone risks more accessible to non-experts and stakeholders.

  10. Intertumor heterogeneity of non-small-cell lung carcinomas revealed by multiplexed mutation profiling and integrative genomics.

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    Tan, Daniel S W; Camilleri-Broët, Sophie; Tan, Eng Huat; Alifano, Marco; Lim, Wan-Teck; Bobbio, Antonio; Zhang, Shenli; Ng, Quan-Sing; Ang, Mei-Kim; Iyer, N Gopalakrishna; Takano, Angela; Lim, Kiat Hon; Régnard, Jean-François; Tan, Patrick; Broët, Philippe

    2014-09-01

    Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, with a burden of genomic alterations exceeding most other tumors. The goal of our study was to evaluate the frequencies of co-occurring mutations and copy-number aberrations (CNAs) within the same tumor and to evaluate their potential clinical impact. Mass-spectrometry based mutation profiling using a customized lung cancer panel evaluating 214 mutations across 26 key NSCLC genes was performed on 230 nonsquamous NSCLC and integrated with genome-wide CNAs and clinical variables. Among the 138 cases having at least one mutation, one-third (41, 29.7%) showed two or more mutations, either in the same gene (double mutation) or in different genes (co-mutations). In epidermal growth factor receptor (EGFR) mutant cancers, there was a double mutation in 18% and co-mutations in the following genes: TP53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were detected between EGFR mutation and 1p, 7p copy gains (harboring the EGFR gene) as well as 13q copy loss. KRAS mutation was significantly related with 1q gain and 3q loss. For Stage I, tumors harboring at least one mutation or PIK3CA mutation were significantly correlated with poor prognosis (p-value = 0.02). When combining CNAs and mutational status, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis (p-value = 0.03). Our study highlights the clinical relevance of studying tumor complexity by integrative genomic analysis and the need for developing assays that broadly screen for both "actionable" mutations and copy-number alterations to improve precision of stratified treatment approaches. © 2014 UICC.

  11. Identification of Top-ranked Proteins within a Directional Protein Interaction Network using the PageRank Algorithm: Applications in Humans and Plants.

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    Li, Xiu-Qing; Xing, Tim; Du, Donglei

    2016-01-01

    Somatic mutation of signal transduction genes or key nodes of the cellular protein network can cause severe diseases in humans but can sometimes genetically improve plants, likely because growth is determinate in animals but indeterminate in plants. This article reviews protein networks; human protein ranking; the mitogen-activated protein kinase (MAPK) and insulin (phospho- inositide 3kinase [PI3K]/phosphatase and tensin homolog [PTEN]/protein kinase B [AKT]) signaling pathways; human diseases caused by somatic mutations to the PI3K/PTEN/ AKT pathway; use of the MAPK pathway in plant molecular breeding; and protein domain evolution. Casitas B-lineage lymphoma (CBL), PTEN, MAPK1 and PIK3CA are among PIK3CA the top-ranked proteins in directional rankings. Eight proteins (ACVR1, CDC42, RAC1, RAF1, RHOA, TGFBR1, TRAF2, and TRAF6) are ranked in the top 50 key players in both signal emission and signal reception and in interaction with many other proteins. Top-ranked proteins likely have major impacts on the network function. Such proteins are targets for drug discovery, because their mutations are implicated in various cancers and overgrowth syndromes. Appropriately managing food intake may help reduce the growth of tumors or malformation of tissues. The role of the protein kinase C/ fatty acid synthase pathway in fat deposition in PTEN/PI3K patients should be investigated. Both the MAPK and insulin signaling pathways exist in plants, and MAPK pathway engineering can improve plant tolerance to biotic and abiotic stresses such as salinity.

  12. Currently recognized genes for schizophrenia: High-resolution chromosome ideogram representation.

    Science.gov (United States)

    Butler, Merlin G; McGuire, Austen B; Masoud, Humaira; Manzardo, Ann M

    2016-03-01

    A large body of genetic data from schizophrenia-related research has identified an assortment of genes and disturbed pathways supporting involvement of complex genetic components for schizophrenia spectrum and other psychotic disorders. Advances in genetic technology and expanding studies with searchable genomic databases have led to multiple published reports, allowing us to compile a master list of known, clinically relevant, or susceptibility genes contributing to schizophrenia. We searched key words related to schizophrenia and genetics from peer-reviewed medical literature sources, authoritative public access psychiatric websites and genomic databases dedicated to gene discovery and characterization of schizophrenia. Our list of 560 genes were arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms. Genome wide pathway analysis using GeneAnalytics was carried out on the resulting list of genes to assess the underlying genetic architecture for schizophrenia. Recognized genes of clinical relevance, susceptibility or causation impact a broad range of biological pathways and mechanisms including ion channels (e.g., CACNA1B, CACNA1C, CACNA1H), metabolism (e.g., CYP1A2, CYP2C19, CYP2D6), multiple targets of neurotransmitter pathways impacting dopamine, GABA, glutamate, and serotonin function, brain development (e.g., NRG1, RELN), signaling peptides (e.g., PIK3CA, PIK4CA) and immune function (e.g., HLA-DRB1, HLA-DQA1) and interleukins (e.g., IL1A, IL10, IL6). This summary will enable clinical and laboratory geneticists, genetic counselors, and other clinicians to access convenient pictorial images of the distribution and location of contributing genes to inform diagnosis and gene-based treatment as well as provide risk estimates for genetic counseling of families with affected relatives. © 2015 Wiley Periodicals, Inc.

  13. Morphology and Syntax in Holes and Scratches: The Latest Stage of Kugyol Research

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    Yong LEE

    2011-04-01

    Full Text Available The first part of this article reviews the differences between the Chinese, Korean and Japanese languages, and explains the importance of Buddhist texts in the history of these languages, especially in the development of written languages in Korea and Japan. The kugyol tradition (a convention for adding Korean grammatical markers at appropriate places to aid the reading of originally Chinese texts is then explained with concrete examples in three parts: eumdok kugyol (transliteration kugyol, seokdok kugyol (translation kugyol, and jeomto seokdok-kugyol (traslation kugyol with point marks. The latest developments in kugyol research were seen in the 21st century, after the discovery of Yugasijiron in the year 2000, including the detailed point maps. Some questions concerning the jeomto seokdok-kugyol are still open.----- Prvi del članka obravnava razlike med kitajskim, korejskim in japonskim jezikom ter poudarja pomembnost budističnih besedil v zgodovini omenjenih jezikov, zlasti pri oblikovanju pisnih jezikov v Koreji in na Japonskem.  V glavnem delu razlaga tradicijo kugyol (konvencijo, po kateri se dodajajo slovnični znaki na ustreznih mestih kot pomoč pri branju prvotno kitajskih besedil z dejanskimi primeri v treh delih:  eumdok kugyol (transliteracijski kugyol, seokdok kugyol (prevajalski kugyol in jeomto seokdok-kugyol (prevajalski kugyol z dodajanjem pik. Najnovejše v raziskavi kugyol tradicije je bilo narejeno v tem stoletju, po odkritju Yugasijiron v letu 2000, npr. Podrobna porazdelitev pik idr.  Nekatera vprašanja v zvezi z  jeomto seokdok-kugyol ostajajo odprta.  

  14. Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.

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    Douglas G Ward

    Full Text Available Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA.DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+ and 91 bladder cancer patients post-TURBT (89 cancer-free.Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage, FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity.This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.

  15. Oncogene mutational profile in nasopharyngeal carcinoma

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    Zhang ZC

    2014-03-01

    Full Text Available Zi-Chen Zhang,1,* Sha Fu,1,* Fang Wang,1 Hai-Yun Wang,1 Yi-Xin Zeng,2 Jian-Yong Shao11Department of Molecular Diagnostics, 2Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China *These authors contributed equally to this work Abstract: Nasopharyngeal carcinoma (NPC is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher's exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1% NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%, five NRAS mutations (4.1%, four KIT mutations (3.3%, two PDGFRA mutations (1.6%, two ABL mutations (1.6%, and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%. Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019. No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis. Keywords: NPC, oncogene, mutation

  16. AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake.

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    Ramachandran Rashmi

    Full Text Available PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability.Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233* were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206 with or without the glucose analogue 2-deoxyglucose (2-DG. Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG. Cell migration was assessed by scratch assay.Activating PIK3CA (E545K, E542K and inactivating PTEN (R233* mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56% and MK-2206 (30 µM-49% treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.

  17. Plaque and gingivitis reduction in patients undergoing orthodontic treatment with fixed appliances-comparison of toothbrushes and interdental cleaning aids. A 6-month clinical single-blind trial.

    Science.gov (United States)

    Kossack, Christoph; Jost-Brinkmann, Paul-Georg

    2005-01-01

    Comparison of the efficacy of different oral cleaning devices to improve dental hygiene in patients with multibracket appliances. In a single-blind four-way crossover clinical trial, the following toothbrushes and cleaning aids were tested over 6 months to determine their efficacy in removing plaque and preventing gingivitis: the (A) manual interX short brush-head toothbrush (elmex), the (B) Sonic Speed SR-100E sonic toothbrush (Water Pik), the (C) Sonic Speed toothbrush in conjunction with the electric interdental cleaning device Flosser FL-110 (Water Pik), and (D) the Sonic Speed sonic toothbrush in conjunction with multi-floss 3-phase dental floss (elmex). Forty patients were randomly split up into four groups. Each group brushed their teeth for 4 weeks using cleaning aids/combinations A, B, C or D in different orders. The trial organization was controlled by a computer system that also assisted in recording the modified Quigley Hein Index (mQHI) and Papillary Bleeding Index (PBI) every two weeks using voice control. Initial improvement was observed with all cleaning aids/combinations, but after 4 weeks of application, conditions deteriorated again--except one. After 4 weeks of application, only cleaning involving the combined use of the sonic toothbrush and the Flosser FL-110 (C) was found to be significantly more effective than cleaning with the manual toothbrush (A), and that was mainly attributed to the flosser. In patients with good oral hygiene (mQHI(initial) or = 1.5)-by using an interdental cleaning aid. In the long run, the Flosser FL-110 is more effective than multi-floss 3-phase dental floss.

  18. Comprehensive Mutation Analysis in Colorectal Flat Adenomas

    Science.gov (United States)

    Voorham, Quirinus J. M.; Carvalho, Beatriz; Spiertz, Angela J.; Claes, Bart; Mongera, Sandra; van Grieken, Nicole C. T.; Grabsch, Heike; Kliment, Martin; Rembacken, Bjorn; van de Wiel, Mark A.; Quirke, Philip; Mulder, Chris J. J.; Lambrechts, Diether; van Engeland, Manon; Meijer, Gerrit A.

    2012-01-01

    Background Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. Methods A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in “hot spot” regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (β-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. Results APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. Conclusion The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway. PMID:22848674

  19. Activation of the PI3K/AKT pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models.

    Science.gov (United States)

    Qian, Chao-Nan; Furge, Kyle A; Knol, Jared; Huang, Dan; Chen, Jindong; Dykema, Karl J; Kort, Eric J; Massie, Aaron; Khoo, Sok Kean; Vanden Beldt, Kristin; Resau, James H; Anema, John; Kahnoski, Richard J; Morreau, Hans; Camparo, Philippe; Comperat, Eva; Sibony, Mathilde; Denoux, Yves; Molinie, Vincent; Vieillefond, Annick; Eng, Charis; Williams, Bart O; Teh, Bin Tean

    2009-11-01

    Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents.

  20. In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor.

    Science.gov (United States)

    Yu, Yi; Hall, Terence; Eathiraj, Sudharshan; Wick, Michael J; Schwartz, Brian; Abbadessa, Giovanni

    2017-06-01

    The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic. The highest percentage of synergism was found on endometrial and ovarian cancer cell lines. Mutational analysis revealed that PIK3CA/PIK3R1 mutations and aberrant activation of FGFR2 predicted synergism, whereas Ras mutations showed a reverse correlation. Pathway analysis revealed that a combination of ARQ 092 and ARQ 087 enhanced the inhibition of both the AKT and FGFR pathways in cell lines in which synergistic effects were found (AN3CA and IGROV-1). Cell cycle arrest and apoptotic response occurred only in AN3CA cell, and was not seen in IGROV-1 cells. Furthermore, enhanced antitumor activity was observed in mouse models with endometrial cancer cell line and patient-derived tumors when ARQ 092 and ARQ 087 were combined. These results from in-vitro and in-vivo studies provide a strong rationale in treating endometrial and other cancers with the activated PI3K/AKT and FGFR pathways.

  1. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  2. Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models.

    Science.gov (United States)

    Troiani, Teresa; Napolitano, Stefania; Martini, Giulia; Martinelli, Erika; Cardone, Claudia; Normanno, Nicola; Vitagliano, Donata; Morgillo, Floriana; Fenizia, Francesca; Lambiase, Matilde; Formisano, Luigi; Bianco, Roberto; Ciardiello, Davide; Ciardiello, Fortunato

    2015-09-15

    The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and/or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab. ©2015 American Association for Cancer Research.

  3. A food-based approach that targets interleukin-6, a key regulator of chronic intestinal inflammation and colon carcinogenesis.

    Science.gov (United States)

    Sido, Abigail; Radhakrishnan, Sridhar; Kim, Sung Woo; Eriksson, Elisabeth; Shen, Frank; Li, Qunhua; Bhat, Vadiraja; Reddivari, Lavanya; Vanamala, Jairam K P

    2017-05-01

    Studies have shown a causal link between high-calorie diet (HCD) and colon cancer. However, molecular mechanisms are not fully elucidated. To understand etiology of HCD-induced colon carcinogenesis, we screened 10 pathways linked to elevated colonic cell proliferation and chronic inflammation in an HCD-consuming human-relevant pig model. We observed elevated colonic mucosal interleukin-6 (IL-6) expression in HCD-consuming pigs compared to standard diet controls (SD, P=.04), and IL-6 strongly correlated with Ki-67 proliferative index and zone, early biomarkers of colon cancer risk (r=0.604 and 0.743 and P=.017 and .002, respectively). Liquid chromatography-tandem mass spectrometry-based proteomic analysis and Ingenuity Pathway Analysis showed that HCD consumption altered IL-6 signaling pathway proteins (PI3KR4, IL-1α, Mapk10, Akt3, PIK3CG, PIK3R5, Map2k2). Furthermore, these proteins also correlated with Ki-67 proliferative index/zone. Anti-IL-6 therapeutics are available for treating colon cancer; however, they are expensive and induce negative side effects. Thus, whole foods could be a better way to combat low-grade chronic colonic inflammation and colon cancer. Whole plant foods have been shown to decrease chronic diseases due to the potential of anti-inflammatory dietary compounds acting synergistically. We observed that supplementation of HCD with anthocyanin-containing purple-fleshed potatoes (10% w/w), even after baking, suppressed HCD-induced IL-6 expression (P=.03) and the IL-6-related proteins IL-1α and Map2k1 (P≤.1). Our results highlight the importance of IL-6 signaling in diet-linked induction/prevention of colonic inflammation/cancer and demonstrate the potential of a food-based approach to target IL-6 signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Consistency and reproducibility of next-generation sequencing and other multigene mutational assays: A worldwide ring trial study on quantitative cytological molecular reference specimens.

    Science.gov (United States)

    Malapelle, Umberto; Mayo-de-Las-Casas, Clara; Molina-Vila, Miguel A; Rosell, Rafael; Savic, Spasenija; Bihl, Michel; Bubendorf, Lukas; Salto-Tellez, Manuel; de Biase, Dario; Tallini, Giovanni; Hwang, David H; Sholl, Lynette M; Luthra, Rajyalakshmi; Weynand, Birgit; Vander Borght, Sara; Missiaglia, Edoardo; Bongiovanni, Massimo; Stieber, Daniel; Vielh, Philippe; Schmitt, Fernando; Rappa, Alessandra; Barberis, Massimo; Pepe, Francesco; Pisapia, Pasquale; Serra, Nicola; Vigliar, Elena; Bellevicine, Claudio; Fassan, Matteo; Rugge, Massimo; de Andrea, Carlos E; Lozano, Maria D; Basolo, Fulvio; Fontanini, Gabriella; Nikiforov, Yuri E; Kamel-Reid, Suzanne; da Cunha Santos, Gilda; Nikiforova, Marina N; Roy-Chowdhuri, Sinchita; Troncone, Giancarlo

    2017-08-01

    Molecular testing of cytological lung cancer specimens includes, beyond epidermal growth factor receptor (EGFR), emerging predictive/prognostic genomic biomarkers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA). Next-generation sequencing (NGS) and other multigene mutational assays are suitable for cytological specimens, including smears. However, the current literature reflects single-institution studies rather than multicenter experiences. Quantitative cytological molecular reference slides were produced with cell lines designed to harbor concurrent mutations in the EGFR, KRAS, NRAS, BRAF, and PIK3CA genes at various allelic ratios, including low allele frequencies (AFs; 1%). This interlaboratory ring trial study included 14 institutions across the world that performed multigene mutational assays, from tissue extraction to data analysis, on these reference slides, with each laboratory using its own mutation analysis platform and methodology. All laboratories using NGS (n = 11) successfully detected the study's set of mutations with minimal variations in the means and standard errors of variant fractions at dilution points of 10% (P = .171) and 5% (P = .063) despite the use of different sequencing platforms (Illumina, Ion Torrent/Proton, and Roche). However, when mutations at a low AF of 1% were analyzed, the concordance of the NGS results was low, and this reflected the use of different thresholds for variant calling among the institutions. In contrast, laboratories using matrix-assisted laser desorption/ionization-time of flight (n = 2) showed lower concordance in terms of mutation detection and mutant AF quantification. Quantitative molecular reference slides are a useful tool for monitoring the performance of different multigene mutational

  5. Oncogene mutation profiling reveals poor prognosis associated with FGFR1/3 mutation in liposarcoma.

    Science.gov (United States)

    Li, Chengfang; Shen, Yaoyuan; Ren, Yan; Liu, Wei; Li, Man; Liang, Weihua; Liu, Chunxia; Li, Feng

    2016-09-01

    Liposarcoma (LPS) is one of the most prevalent soft tissue sarcomas. LPS shows a poor response to radiation and chemotherapy. The causes of death in patients with LPS include locally recurrent and metastatic disease. We sought to examine novel gene mutations and pathways in primary and matched recurrent LPSs to identify potential therapeutic targets. We conducted a high-throughput analysis of 238 known mutations in 19 oncogenes using Sequenom MassARRAY technology. Nucleic acids were extracted from 19 primary and recurrent LPS samples, encompassing 9 dedifferentiated LPSs (DDLPS), 9 myxoid/round cell LPSs, and 1 pleomorphic LPS. Mutation screening revealed missense mutations in 21.1% (4/19) of the LPS specimens, including 4 different genes (FGFR1, FGFR3, PIK3CA, and KIT). Based on histologic subtypes, 22.2% DDLPS (2/9) and 22.2% myxoid cell LPS (2/9) contained gene mutations. Specifically, 3 (23.1%) of 13 primary tumors harbored mutations. Furthermore, although gene mutations were identified in 1 (11.1%) of 9 recurrent LPS samples, the difference between the primary and the recurrence was not statistically significant. Analysis of patient survival data indicated that patients harboring FGFR1/3 mutations experienced reduced overall survival (P<.05). Despite the limited number of samples, our findings provide the first evidence of FGFR1/3 mutations in DDLPS, which were associated with poor clinical outcomes. The FGFR pathway may play an important role in the development and progression of DDLPS and warrants further investigation; moreover, PIK3CA mutation is a common event (11.1%) in myxoid cell LPS. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers.

    Science.gov (United States)

    Flågeng, Marianne Hauglid; Larionov, Alexey; Geisler, Jürgen; Knappskog, Stian; Prestvik, Wenche S; Bjørkøy, Geir; Lilleng, Peer Kåre; Dixon, J Michael; Miller, William R; Lønning, Per Eystein; Mellgren, Gunnar

    2017-01-01

    While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Large-scale RNA interference screening in mammalian cells identifies novel regulators of mutant huntingtin aggregation.

    Directory of Open Access Journals (Sweden)

    Tomoyuki Yamanaka

    Full Text Available In polyglutamine (polyQ diseases including Huntington's disease (HD, mutant proteins containing expanded polyQ stretch form aggregates in neurons. Genetic or RNAi screenings in yeast, C. elegans or Drosophila have identified multiple genes modifying polyQ aggregation, a few of which are confirmed effective in mammals. However, the overall molecular mechanism underlying polyQ protein aggregation in mammalian cells still remains obscure. We here perform RNAi screening in mouse neuro2a cells to identify mammalian modifiers for aggregation of mutant huntingtin, a causative protein of HD. By systematic cell transfection and automated cell image analysis, we screen ∼ 12000 shRNA clones and identify 111 shRNAs that either suppress or enhance mutant huntingtin aggregation, without altering its gene expression. Classification of the shRNA-targets suggests that genes with various cellular functions such as gene transcription and protein phosphorylation are involved in modifying the aggregation. Subsequent analysis suggests that, in addition to the aggregation-modifiers sensitive to proteasome inhibition, some of them, such as a transcription factor Tcf20, and kinases Csnk1d and Pik3c2a, are insensitive to it. As for Tcf20, which contains polyQ stretches at N-terminus, its binding to mutant huntingtin aggregates is observed in neuro2a cells and in HD model mouse neurons. Notably, except Pik3c2a, the rest of the modifiers identified here are novel. Thus, our first large-scale RNAi screening in mammalian system identifies previously undescribed genetic players that regulate mutant huntingtin aggregation by several, possibly mammalian-specific mechanisms.

  8. Characterization of a naturally occurring breast cancer subset enriched in EMT and stem cell characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Hennessy, Bryan T.; Gonzalez-Angulo, Ana-Maria; Stemke-Hale, Katherine; Gilcrease, Michael Z.; Krishnamurthy, Savitri; Lee, Ju-Seog; Fridlyand, Jane; Sahin, Aysegul; Agarwal, Roshan; Joy, Corwin; Liu, Wenbin; Stivers, David; Baggerly, Keith; Carey, Mark; Lluch, Ana; Monteagudo, Carlos; He, Xiaping; Weigman, Victor; Fan, Cheng; Palazzo, Juan; Hortobagyi, Gabriel N.; Nolden, Laura K.; Wang, Nicholas J.; Valero, Vicente; Gray, Joe W.; Perou, Charles M.; Mills, Gordon B.

    2009-05-19

    Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a 'tumorigenic' signature defined using CD44{sup +}/CD24{sup -} breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

  9. [Point somatic mutations in bladder cancer: key carcinogenesis events, diagnostic markers and therapeutic targets].

    Science.gov (United States)

    Mikhailenko, D S; Nemtsova, M V

    2016-02-01

    Development of bladder cancer (BC) involves accumulating several genetic alterations in somatic cells: point mutations, extended deletions in the localization of tumor suppressor genes, amplification of oncogenes, aberrant DNA methylation, changes in the expression pattern of regulatory RNAs and numerous structural genes. From all of the above, point mutations have the greatest potential as diagnostic markers, as they frequently occur in carcinogenesis, characterize initiation and further clonal evolution of malignancy and represent a change in DNA detectable by routine molecular genetic methods. If we look at the clinical classification of bladder cancer, 90% of the BC presented by urothelial carcinoma, 80% of patients had superficial and 20% - of muscle-invasive tumors. The differences in morphological classification, staging and prognosis of bladder cancer represent different pathogenic pathways of tumor development. Superficial bladder cancer develops through a stage of hyperplasia involving activation of mutations in the genes FGFR3, PIK3CA, HRAS, ERBB2, TERT and others. It is shown that frequent point mutations FGFR3, PIK3CA and TERT are present in the tumor cells in the urine sediment and can be considered as markers for non-invasive molecular genetic diagnosis of primary BC and for monitoring of disease recurrence. Muscle-invasive bladder cancer develops through the stages of dysplasia and carcinoma in situ, in which mutations initially occur in key suppressor genes (TP53 and RB1) and a number of chromatin remodeling genes. This leads to genomic instability and multiple chromosome aberrations that are subjected to selection in the further clonal evolution of tumors towards predominance of more malignant subclones. This review presents systematized information about the main mutations in BC carcinogenesis, their role in the primary tumor progression, metastasizing and role as a target for diagnosis and targeted therapy.

  10. Detection of multiple mutations in urinary exfoliated cells from male bladder cancer patients at diagnosis and during follow-up.

    Science.gov (United States)

    Critelli, Rossana; Fasanelli, Francesca; Oderda, Marco; Polidoro, Silvia; Assumma, Manuela Bianca; Viberti, Clara; Preto, Mirko; Gontero, Paolo; Cucchiarale, Giuseppina; Lurkin, Irene; Zwarthoff, Ellen C; Vineis, Paolo; Sacerdote, Carlotta; Matullo, Giuseppe; Naccarati, Alessio

    2016-10-11

    Most bladder cancer (BC) patients need life-long, invasive and expensive monitoring and treatment, making it a serious burden on the health system. Thus, there is a pressing need for an accurate test to assist diagnosis and surveillance of BC as an alternative to cystoscopy. Mutations in human TERT, FGFR3, PIK3CA, and RAS genes have been proposed as potential molecular markers in bladder tumor. Their concomitant presence in urine samples has not been fully explored.We investigated a panel of mutations in DNA from exfoliated urinary cells of 255 BC patients at diagnosis. Forty-one mutations in TERT, FGFR3, PIK3CA, and RAS were analyzed by SNaPshot assay in relation to clinical outcome. In 81 of these patients under surveillance, the same set of mutations was screened in additional 324 samples prospectively collected.The most common mutations detected in urine at diagnosis were in the TERT promoter. In non-invasive BC, these mutations were related to high risk and grade (pFGFR3 mutations were observed in low-grade BC (p=0.02) and patients with recurrences (p=0.05). Stronger associations were observed for combined TERT and FGFR3 mutations and number of recurrences (OR: 4.54 95% CI: 1.23-16.79, p=0.02). Analyses of the area under the curve for combinations of mutations detected at diagnosis and follow-up showed an accuracy of prediction of recurrence of 0.80 (95% CI: 0.71-0.89).Mutations in urine of BC patients may represent reliable biomarkers. In particular, TERT and FGFR3 mutations have a good accuracy of recurrence prediction.

  11. Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.

    Science.gov (United States)

    Ward, Douglas G; Baxter, Laura; Gordon, Naheema S; Ott, Sascha; Savage, Richard S; Beggs, Andrew D; James, Jonathan D; Lickiss, Jennifer; Green, Shaun; Wallis, Yvonne; Wei, Wenbin; James, Nicholas D; Zeegers, Maurice P; Cheng, K K; Mathews, Glenn M; Patel, Prashant; Griffiths, Michael; Bryan, Richard T

    2016-01-01

    Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA. DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free). Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity). This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.

  12. Surprising roles for phospholipid binding proteins revealed by high throughput genetics.

    Science.gov (United States)

    LeBlanc, Marissa A; McMaster, Christopher R

    2010-08-01

    Saccharomyces cerevisiae remains an ideal organism for studying the cell biological roles of lipids in vivo, as yeast has phospholipid metabolic pathways similar to mammalian cells, is easy and economical to manipulate, and is genetically tractable. The availability of isogenic strains containing specific genetic inactivation of each non-essential gene allowed for the development of a high-throughput method, called synthetic genetic analysis (SGA), to identify and describe precise pathways or functions associated with specific genes. This review describes the use of SGA to aid in elucidating the function of two lipid-binding proteins that regulate vesicular transport, Sec14 and Kes1. Sec14 was first identified as a phosphatidylcholine (PC) - phosphatidylinositol (PI) transfer protein required for viability, with reduced Sec14 function resulting in diminished vesicular transport out of the trans-Golgi. Although Sec14 is required for cell viability, inactivating the KES1 gene that encodes for a member of the oxysterol binding protein family in cells lacking Sec14 function results in restoration of vesicular transport and cell growth. SGA analysis identified a role for Kes1 and Sec14 in regulating the level and function of Golgi PI-4-phosphate (PI-4-P). SGA also determined that Sec14 not only regulates vesicular transport out of the trans-Golgi, but also transport from endosomes to the trans-Golgi. Comparing SGA screens in databases, coupled with genetic and cell biological analyses, further determined that the PI-4-P pool affected by Kes1 is generated by the PI 4-kinase Pik1. An important biological role for Sec14 and Kes1 revealed by SGA is coordinate regulation of the Pik1-generated Golgi PI-4-P pool that in turn is essential for vesicular transport into and out of the trans-Golgi.

  13. The influence of the CHIEF pathway on colorectal cancer-specific mortality.

    Directory of Open Access Journals (Sweden)

    Martha L Slattery

    Full Text Available Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555 and rectal cancer (n = 754 cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035. Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR were associated with colon cancer mortality (PARTP < 0.05; JAK2 (PARTP  = 0.0086, PIK3CA (PARTP = 0.0098, and SMAD3 (PARTP = 0.0059 had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05. SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002. Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1 were significantly associated with rectal cancer (PARTP < 0.05. The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74 and was 10.99 (95% CI 5.30, 22.78 for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies.

  14. Profiling of Oncogenic Driver Events in Lung Adenocarcinoma Revealed MET Mutation as Independent Prognostic Factor.

    Science.gov (United States)

    Yeung, Sai F; Tong, Joanna H M; Law, Peggy P W; Chung, Lau Y; Lung, Raymond W M; Tong, Carol Y K; Chow, Chit; Chan, Anthony W H; Wan, Innes Y P; Mok, Tony S K; To, Ka F

    2015-09-01

    Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never-smoker predominated Chinese lung adenocarcinoma. We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations.

  15. Primary Immunodeficiencies Associated with EBV Disease.

    Science.gov (United States)

    Cohen, Jeffrey I

    2015-01-01

    Epstein-Barr virus (EBV) infects nearly all humans and usually is asymptomatic, or in the case of adolescents and young adults, it can result in infectious mononucleosis. EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells. While mutations in proteins important for B cell function can affect EBV infection of these cells, these mutations do not result in severe EBV infection. Some genetic disorders affecting T and NK cell function result in failure to control EBV infection, but do not result in increased susceptibility to other virus infections. These include mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, CORO1A, and LRBA. Since EBV is the only virus that induces proliferation of B cells, the study of these diseases has helped to identify proteins critical for interactions of T and/or NK cells with B cells. Mutations in three genes associated with hemophagocytic lymphohistocytosis, PRF1, STXBP2, and UNC13D, can also predispose to severe chronic active EBV disease. Severe EBV infection can be associated with immunodeficiencies that also predispose to other viral infections and in some cases other bacterial and fungal infections. These include diseases due to mutations in PIK3CD, PIK3R1, CTPS1, STK4, GATA2, MCM4, FCGR3A, CARD11, ATM, and WAS. In addition, patients with severe combined immunodeficiency, which can be due to mutations in a number of different genes, are at high risk for various infections as well as EBV B cell lymphomas. Identification of proteins important for control of EBV may help to identify new targets for immunosuppressive therapies.

  16. Identification of frequent somatic mutations in inflammatory breast cancer.

    Science.gov (United States)

    Matsuda, Naoko; Lim, Bora; Wang, Ying; Krishnamurthy, Savitri; Woodward, Wendy; Alvarez, Ricardo H; Lucci, Anthony; Valero, Vicente; Reuben, James M; Meric-Bernstam, Funda; Ueno, Naoto T

    2017-06-01

    Inflammatory breast cancer is an aggressive form of breast cancer that shows distinct clinical features from non-inflammatory breast cancer. Genomic understanding of inflammatory breast cancer will shed light on biological targets for this disease. Our objective was to identify targeted hotspot mutations using multiplex genome sequencing in inflammatory breast cancer and compare the findings with those for patients with non-inflammatory breast cancer to further recognize novel targets. We studied 400 patients with metastatic breast cancer who had somatic hotspot mutation testing using a 46- or 50-gene multiplex platform from March 2012 to December 2014. Among this population, 24 patients had inflammatory breast cancer and 376 patients had non-inflammatory breast cancer. We tested a total of 26 samples from 24 patients with inflammatory breast cancer. The average number of mutations per patient was higher in inflammatory breast cancer than in non-inflammatory breast cancer (1.23 vs. 0.65, respectively). Identified somatic mutations in inflammatory breast cancer were TP53 (n = 18, 75%), PIK3CA (n = 10, 41.7%), and ERBB2 (n = 4, 16.7%). TP53 and ERBB2 mutations were significantly more prevalent in inflammatory breast cancer than in non-inflammatory breast cancer (P breast cancer patients. While the inflammatory breast cancer TP53 and PIK3CA mutations mirrored previously reported data for metastatic non-inflammatory breast cancer, this is the first report of higher frequency of ERBB2 mutation in inflammatory breast cancer, especially in the HR+ subtype. Once validated in a larger cohort of inflammatory breast cancer patients, this novel finding could lead to development of treatments for HR+ inflammatory breast cancer.

  17. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

    Science.gov (United States)

    Yu, Helena A; Arcila, Maria E; Rekhtman, Natasha; Sima, Camelia S; Zakowski, Maureen F; Pao, William; Kris, Mark G; Miller, Vincent A; Ladanyi, Marc; Riely, Gregory J

    2013-04-15

    All patients with EGF receptor (EGFR)-mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%-70%] and four had small cell transformation (3%, 95% CI, 0%-6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%-13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%-4%). Overlap among mechanisms of acquired resistance was seen in 4%. This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs.

  18. Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Dawei W. Dong

    2015-12-01

    Full Text Available Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial electron transport component, the cytochrome c oxidase (CcO, leads to increased glycolysis and carcinogenesis. Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca2+ sensitive Calcineurin (Ppp3ca and the expression of PI3-kinase (Pik3r4 and Pik3cb increased by two folds. This Ca2+/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01 between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10−5. Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.

  19. Interleukin 21 Controls mRNA and MicroRNA Expression in CD40-Activated Chronic Lymphocytic Leukemia Cells.

    Directory of Open Access Journals (Sweden)

    Loris De Cecco

    Full Text Available Several factors support CLL cell survival in the microenvironment. Under different experimental conditions, IL21 can either induce apoptosis or promote CLL cell survival. To investigate mechanisms involved in the effects of IL21, we studied the ability of IL21 to modulate gene and miRNA expressions in CD40-activated CLL cells. IL21 was a major regulator of chemokine production in CLL cells and it modulated the expression of genes involved in cell movement, metabolism, survival and apoptosis. In particular, IL21 down-regulated the expression of the chemokine genes CCL4, CCL3, CCL3L1, CCL17, and CCL2, while it up-regulated the Th1-related CXCL9 and CXCL10. In addition, IL21 down-regulated the expression of genes encoding signaling molecules, such as CD40, DDR1 and PIK3CD. IL21 modulated a similar set of genes in CLL and normal B-cells (e.g. chemokine genes, whereas other genes, including MYC, TNF, E2F1, EGR2 and GAS-6, were regulated only in CLL cells. An integrated analysis of the miRNome and gene expression indicated that several miRNAs were under IL21 control and these could, in turn, influence the expression of potential target genes. We focused on hsa-miR-663b predicted to down-regulate several relevant genes. Transfection of hsa-miR-663b or its specific antagonist showed that this miRNA regulated CCL17, DDR1, PIK3CD and CD40 gene expression. Our data indicated that IL21 modulates the expression of genes mediating the crosstalk between CLL cells and their microenvironment and miRNAs may take part in this process.

  20. Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

    Science.gov (United States)

    Kerr, K M; Dafni, U; Schulze, K; Thunnissen, E; Bubendorf, L; Hager, H; Finn, S; Biernat, W; Vliegen, L; Losa, J H; Marchetti, A; Cheney, R; Warth, A; Speel, E-J; Blackhall, F; Monkhorst, K; Jantus Lewintre, E; Tischler, V; Clark, C; Bertran-Alamillo, J; Meldgaard, P; Gately, K; Wrona, A; Vandenberghe, P; Felip, E; De Luca, G; Savic, S; Muley, T; Smit, E F; Dingemans, A-M C; Priest, L; Baas, P; Camps, C; Weder, W; Polydoropoulou, V; Geiger, T R; Kammler, R; Sumiyoshi, T; Molina, M A; Shames, D S; Stahel, R A; Peters, S

    2018-01-01

    Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

  1. AKT hyper-phosphorylation associated with PI3K mutations in lymphatic endothelial cells from a patient with lymphatic malformation.

    Science.gov (United States)

    Boscolo, Elisa; Coma, Silvia; Luks, Valerie L; Greene, Arin K; Klagsbrun, Michael; Warman, Matthew L; Bischoff, Joyce

    2015-04-01

    Lymphatic malformations (LM) are characterized by abnormal formation of lymphatic vessels and tissue overgrowth. The lymphatic vessels present in LM lesions may become blocked and enlarged as lymphatic fluid collects, forming a mass or cyst. Lesions are typically diagnosed during childhood and are often disfiguring and life threatening. Available treatments consist of sclerotherapy, surgical removal and therapies to diminish complications. We isolated lymphatic endothelial cells (LM-LEC) from a surgically removed microcystic LM lesion. LM-LEC and normal human dermal-LEC (HD-LEC) expressed endothelial (CD31, VE-Cadherin) as well as lymphatic endothelial (Podoplanin, PROX1, LYVE1)-specific markers. Targeted gene sequencing analysis in patient-derived LM-LEC revealed the presence of two mutations in class I phosphoinositide 3-kinases (PI3K) genes. One is an inherited, premature stop codon in the PI3K regulatory subunit PIK3R3. The second is a somatic missense mutation in the PI3K catalytic subunit PIK3CA; this mutation has been found in association with overgrowth syndromes and cancer growth. LM-LEC exhibited angiogenic properties: both cellular proliferation and sprouting in collagen were significantly increased compared with HD-LEC. AKT-Thr308 was constitutively hyper-phosphorylated in LM-LEC. Treatment of LM-LEC with PI3-Kinase inhibitors Wortmannin and LY294 decreased cellular proliferation and prevented the phosphorylation of AKT-Thr308 in both HD-LEC and LM-LEC. Treatment with the mTOR inhibitor rapamycin also diminished cellular proliferation, sprouting and AKT phosphorylation, but only in LM-LEC. Our results implicate disrupted PI3K-AKT signaling in LEC isolated from a human lymphatic malformation lesion.

  2. Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer.

    Science.gov (United States)

    Arcaroli, John; Quackenbush, Kevin; Dasari, Arvind; Powell, Rebecca; McManus, Martine; Tan, Aik-Choon; Foster, Nathan R; Picus, Joel; Wright, John; Nallapareddy, Sujatha; Erlichman, Charles; Hidalgo, Manuel; Messersmith, Wells A

    2012-10-01

    Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] "top scoring pairs" polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3' untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible.

  3. Düzce University

    Directory of Open Access Journals (Sweden)

    Ali GURSEL

    2014-12-01

    Full Text Available Titanyum ve Titanyum alaşımları, yüksek mukavemet, düşük ağırlık oranı ve mükemmel korozyon direnci sebebiyle, medikal ve havacılık endüstrisi dahil olmak üzere birçok alanda başarıyla kullanılmaktadır. Bu alanlarda yapılan üretimler için uygulanan kaynak ve iyileştirme işlemleri için birçok teknik mevcuttur. Bu teknikler arasında, lazer kaynağı hassas ve hızlı işlem kabiliyeti sayesinde Titanyum alaşımları için çok önemli avantajlar sağlamaktadır. Darbe ya da atış şekli, enerji, süre, kaynak hızı, pik gücü ve frekans gibi Nd:YAG lazer parametereleri, doğrudan ya da dolaylı olarak kaynak dikiş kalitesini ve morfolojisini etkilemektedir. Bu çalışmada, 1.5 mm kalınlığında Ti6Al4V Titanyum alaşımı levha yüzeyi SigmaLaser®300 Nd:YAG tipi lazer kaynak cihazıyla işlenmiştir. Pik gücü ve frekans değerlerinin kaynak kalitesine, dikiş morfolojisine ve numune yüzeylerine etkisi incelenmiştir. Dikiş kalitesi, morfoloji ve mikro sertlik değerleri bakımından karekterize edilmiştir

  4. Actionable mutations in canine hemangiosarcoma.

    Directory of Open Access Journals (Sweden)

    Guannan Wang

    Full Text Available Angiosarcomas (AS are rare in humans, but they are a deadly subtype of soft tissue sarcoma. Discovery sequencing in AS, especially the visceral form, is hampered by the rarity of cases. Most diagnostic material exists as archival formalin fixed, paraffin embedded tissue which serves as a poor source of high quality DNA for genome-wide sequencing. We approached this problem through comparative genomics. We hypothesized that exome sequencing a histologically similar tumor, hemangiosarcoma (HSA, that occurs in approximately 50,000 dogs per year, may lead to the identification of potential oncogenic drivers and druggable targets that could also occur in angiosarcoma.Splenic hemangiosarcomas are common in dogs, which allowed us to collect a cohort of archived matched tumor and normal tissue samples suitable for whole exome sequencing. Mapping of the reads to the latest canine reference genome (Canfam3 demonstrated that >99% of the targeted exomal regions were covered, with >80% at 20X coverage and >90% at 10X coverage.Sequence analysis of 20 samples identified somatic mutations in PIK3CA, TP53, PTEN, and PLCG1, all of which correspond to well-known tumor drivers in human cancer, in more than half of the cases. In one case, we identified a mutation in PLCG1 identical to a mutation observed previously in this gene in human visceral AS. Activating PIK3CA mutations present novel therapeutic targets, and clinical trials of targeted inhibitors are underway in human cancers. Our results lay a foundation for similar clinical trials in canine HSA, enabling a precision medicine approach to this disease.

  5. Actionable mutations in canine hemangiosarcoma.

    Science.gov (United States)

    Wang, Guannan; Wu, Ming; Maloneyhuss, Martha A; Wojcik, John; Durham, Amy C; Mason, Nicola J; Roth, David B

    2017-01-01

    Angiosarcomas (AS) are rare in humans, but they are a deadly subtype of soft tissue sarcoma. Discovery sequencing in AS, especially the visceral form, is hampered by the rarity of cases. Most diagnostic material exists as archival formalin fixed, paraffin embedded tissue which serves as a poor source of high quality DNA for genome-wide sequencing. We approached this problem through comparative genomics. We hypothesized that exome sequencing a histologically similar tumor, hemangiosarcoma (HSA), that occurs in approximately 50,000 dogs per year, may lead to the identification of potential oncogenic drivers and druggable targets that could also occur in angiosarcoma. Splenic hemangiosarcomas are common in dogs, which allowed us to collect a cohort of archived matched tumor and normal tissue samples suitable for whole exome sequencing. Mapping of the reads to the latest canine reference genome (Canfam3) demonstrated that >99% of the targeted exomal regions were covered, with >80% at 20X coverage and >90% at 10X coverage. Sequence analysis of 20 samples identified somatic mutations in PIK3CA, TP53, PTEN, and PLCG1, all of which correspond to well-known tumor drivers in human cancer, in more than half of the cases. In one case, we identified a mutation in PLCG1 identical to a mutation observed previously in this gene in human visceral AS. Activating PIK3CA mutations present novel therapeutic targets, and clinical trials of targeted inhibitors are underway in human cancers. Our results lay a foundation for similar clinical trials in canine HSA, enabling a precision medicine approach to this disease.

  6. Mastimännid ja muu mets : mitmekülgsuse võlu Eesti proosast aastal 2007 / Sirje Olesk

    Index Scriptorium Estoniae

    Olesk, Sirje, 1954-

    2008-01-01

    Ülevaade 2007. aasta eesti proosast. Käsitletakse järgimisi autoreid ja nende teoseid: Ene Mihkelson "Katkuhaud", Andrus Kivirähk "Mees, kes teadis ussisõnu", Jaan Kaplinski "Seesama jõgi", Tõnu Õnnepalu "Flandria päevik", Toomas Vint "Mäluauguga naine", Indrek Hargla "French ja Koulu Tarbatus", Kalle Käsper "Buridanid IV", Jaan Tooming "Teekond mäe südamesse", Ustav Mikelsaar "Tunnimehed", Henn Mikelsaar "Teema variatsioonidega", Reet Kudu "Pidupäevad võõrsil", Mara Maret Aronovich "Tagasikäiguga edasi", Aimée Beekman "Proovielu", Valentine Nõlvak "Ellujääja : mälestused", Mehis Heinsaar "Rändaja õnn", Maimu Berg "Unustatud inimesed", Mats Traat "Sarviku armastus : valik kultuuriloolisi novelle", Mihkel Mutt "Siseemigrant : novellid Rui taevalike kommentaaridega", Paavo Kivine "Kaks kavaleri", Kärt Hellerma "Ma armastasin David Copperfieldi", Piret Bristol "Paralleelmeri", Imre Siil "Mereröövlite loss", Kalju Saaber "Issanda loomaaed. Viru sektor", Veiko Märka "Lendas üle marmortahvli", Vahur Afanasjev "Kaadrid otsustavad, ehk, Sööbik ja Pisik seiklevad jälle, ehk, Eesti rahva lühike, kuid õnnelik ajalugu, Ehk kirjalik komejant tühjusest", Aarne Ruuben "Lugusid Anveltist ja Kingissepast", Epp Annus "Sina, Matilda", Peeter Helme "Puudutus", Ivar Sild "Tantsiv linn", Tui Hirv "Tähe tänav. Per musica ad astra", Tiina Laanem "Väikesed vanamehed", Angela Hofberg (pseud.) "Päev nagu elu", Marion Andra "Vähemalt...", Olle Lauli "Niguliste õpilased", Aarne Biin "Linna valitsemine", Erik Tohvri "Mürgiliblikas", Riina Kangur "Elisa", Kerttu Rakke "Küpsiseparadiis", Epp Petrone ja Dagmar Reintam "Õun ära süüa?", Elme Väljaste "Päriselu Proletariaadi puiesteel", Ketlin Priilinn "Hõbeingel", Ira Lember "Kohvik pärnade all", Paul Pajos "Krimijutud edasijõudnuile", Andres Anvelt "Punane elavhõbe", Klaara ja Kaarel Kivi "Mõrvasügis", Tiit Sepa "Hommik ühele", Lembit Uustulnd "Ruutuemanda sündroom : rahvusvaheline

  7. Lasteaia ja lõbumaja vahel : eesti proosa 2008 / Vaapo Vaher

    Index Scriptorium Estoniae

    Vaher, Vaapo, 1945-

    2009-01-01

    Ülevaade 2008. aasta eesti proosast. Pikemalt käsitletakse järgmisi autoreid ja nende teoseid: Mihkel Raud "Musta pori näkku", Olev Remsu "Musketäride muundumised", Rein Põder "Juba olnud", Juhan Nurme "Ligimene", Jaan Tangsoo "Méduse'i parv", Esta Aksli "Tare poole tõttaja", Mari Saat "Lasnamäe lunastaja", Peeter Morgen "Sõnum", Mait Raun "Dr. Mööbi seiklused Inglismaal", Andrei Hvostov "Võõrad lood" ja "Projektijuht Posse", Chaneldior "Kontrolli alt väljas", Vahur Afanasjev "Kosmos", Egon Ilisson "Isased", Jaak Leer "Kaks kabanossi ja Maaja", Kärt Hellerma "Sinine missa", Elo Viiding "Püha Maama", Toomas Raudam "Miks ma ei taha olla kirjanik?", Mart Kivastik "Kurb raamat", Jüri Tuulik "Räim, pisike kena kala", Tarmo Teder "12 jõulujuttu", Dagmar Lamp (koostaja) "Tule, ma jutustan sulle loo", Eia Uus "Kahe näoga jumal", Barthol Lo Mejor "Popdada 2007-2008", Anti Saar "Nemad kaks", Ketlin Priilinn "Liiseli võti" ja "Vaim", Aita Kivi "Lähedal", Marje Ernits "Hoia mu kätt", Kati Murutar "Naisena sündinud : kakskümmend aastat hiljem", Tuule Lind "Pööratud tuul", Siiri Laidla "Lihtne lugu, ehk, Senta suvepuhkus", Kätlin Padesaar "Veel üks paradiis", Aimée Beekman "Proovielu", Lehte Hainslau "Kolmkõla, ehk, 3 kõla", Ira Lember "Ööviiulid", Tamur Kusnets "Hundipäikese aeg : metsiku jahi algus", Kaupo Pähkel "Ehatähe rüütel", Arvo Valton "Ülemiste vanake", Tiit Aleksejev "Palveränd", Ants Eret "Afgaanide vang", Mario Merirand "Afganistani päevik", Leo Kunnas "Gort Ashryn", Rein Raud "Vend", Peeter Sauter "Beibi bluu", Marion Andra "Pimend", Kristjan Sander "13 talvist hetke", Helga Nõu "Peaaegu geenius, ehk, Schrödingeri kassi otsimas", Tiit Sepa "Eefa hüüdnimega Siug", Kaarel ja Klaara Kivi "Varandus seinal", Merike Jürjo "Mälestusteta maja", Rein Vahisalu "Viies kabinet", Aarne Biin "Mees otsib naist", Erik Tohvri "Ümberasujad" ja "Sulasest sai peremees", Arnold Laugus "Elav maa", Jüri v. Grauberg "Selguse poole", J

  8. Lasteaia ja lõbumaja vahel : Eesti proosa 2008 / Vaapo Vaher

    Index Scriptorium Estoniae

    Vaher, Vaapo, 1945-

    2012-01-01

    Ülevaade 2008. aasta eesti proosast. Pikemalt käsitletakse järgmisi autoreid ja nende teoseid: Mihkel Raud "Musta pori näkku", Olev Remsu "Musketäride muundumised", Rein Põder "Juba olnud", Juhan Nurme "Ligimene", Jaan Tangsoo "Méduse'i parv", Esta Aksli "Tare poole tõttaja", Mari Saat "Lasnamäe lunastaja", Peeter Morgen "Sõnum", Mait Raun "Dr. Mööbi seiklused Inglismaal", Andrei Hvostov "Võõrad lood" ja "Projektijuht Posse", Chaneldior "Kontrolli alt väljas", Vahur Afanasjev "Kosmos", Egon Ilisson "Isased", Jaak Leer "Kaks kabanossi ja Maaja", Kärt Hellerma "Sinine missa", Elo Viiding "Püha Maama", Toomas Raudam "Miks ma ei taha olla kirjanik?", Mart Kivastik "Kurb raamat", Jüri Tuulik "Räim, pisike kena kala", Tarmo Teder "12 jõulujuttu", Dagmar Lamp (koostaja) "Tule, ma jutustan sulle loo", Eia Uus "Kahe näoga jumal", Barthol Lo Mejor "Popdada 2007-2008", Anti Saar "Nemad kaks", Ketlin Priilinn "Liiseli võti" ja "Vaim", Aita Kivi "Lähedal", Marje Ernits "Hoia mu kätt", Kati Murutar "Naisena sündinud : kakskümmend aastat hiljem", Tuule Lind "Pööratud tuul", Siiri Laidla "Lihtne lugu, ehk, Senta suvepuhkus", Kätlin Padesaar "Veel üks paradiis", Aimée Beekman "Proovielu", Lehte Hainslau "Kolmkõla, ehk, 3 kõla", Ira Lember "Ööviiulid", Tamur Kusnets "Hundipäikese aeg : metsiku jahi algus", Kaupo Pähkel "Ehatähe rüütel", Arvo Valton "Ülemiste vanake", Tiit Aleksejev "Palveränd", Ants Eret "Afgaanide vang", Mario Merirand "Afganistani päevik", Leo Kunnas "Gort Ashryn", Rein Raud "Vend", Peeter Sauter "Beibi bluu", Marion Andra "Pimend", Kristjan Sander "13 talvist hetke", Helga Nõu "Peaaegu geenius, ehk, Schrödingeri kassi otsimas", Tiit Sepa "Eefa hüüdnimega Siug", Kaarel ja Klaara Kivi "Varandus seinal", Merike Jürjo "Mälestusteta maja", Rein Vahisalu "Viies kabinet", Aarne Biin "Mees otsib naist", Erik Tohvri "Ümberasujad" ja "Sulasest sai peremees", Arnold Laugus "Elav maa", Jüri v. Grauberg "Selguse poole", J

  9. The memorable service and monastic humility – the history of Stanisław Konarski’s heart

    Directory of Open Access Journals (Sweden)

    Ryszard Mączyński

    2016-12-01

    Full Text Available The article concentrates on an interesting 130-year-old artefact located in the Krakow church of Piarists – the decoration of the place where Stanisław Konarski’s (1700–1773 heart was buried. Konarski was a monk of the Pious Schools in the 18th century, as well as publisher of a collection of national laws Volumina legum, a bold commentator calling for strengthening royal power and abolishing liberum veto, reformer of the educational system and founder of the renowned, modern Collegium Nobilium. The circumstances of the discovery and relocation of the relic in 1882 from Warsaw to Krakow and the ceremony of its introduction to the monastic Church of the Transfiguration of Jesus on February 13 are also outlined. Three significant research issues are also discussed. The first one is the problem of the authenticity of the artefact, which was discovered more than a hundred years after Konarski’s death in the possession of a Warsaw optician Jakub Pik. It was then that the question started occupying the minds of researchers, including the rector of the Krakow college Adam Słotwiński. The question is made more relevant by the lack of any direct evidence from 1773 about the removal of Stanisław Konarski’s heart from his body after his death. The information gathered so far allow us to assume, with probability bordering on certainty, that it is authentic and the only surviving part of this famous monk’s body. Another question, totally absent from past reflections on the subject, is the reason why the heart was removed. This particular aspect turns our attention at a strikingly popular early-modern Polish tradition – first in royal families, later also among magnates and nobility – of burying hearts separately, usually by entombing them in a church founded by the deceased. It was found that a considerable number of hearts removed from bodies had been inhumed in Piarist churches (Rzeszów, Warsaw or Łowicz. This tradition, however, did

  10. Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.

    Science.gov (United States)

    Steinbach, Erin C; Kobayashi, Taku; Russo, Steven M; Sheikh, Shehzad Z; Gipson, Gregory R; Kennedy, Samantha T; Uno, Jennifer K; Mishima, Yoshiyuki; Borst, Luke B; Liu, Bo; Herfarth, Hans; Ting, Jenny P Y; Sartor, R Balfour; Plevy, Scott E

    2014-04-15

    The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly less IL-10 compared with wild-type mice. p110δ(KD) APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC-T cell interactions in colitis pathogenesis in vivo, Rag1(-/-)/p110δ(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110δ(KD) recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+D4+ T cells compared with Rag1(-/-) recipient mice. Intestinal tissue samples from patients with Crohn's disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non-inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.

  11. Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity.

    Science.gov (United States)

    Liu, Su-Yang; Joseph, Nancy M; Ravindranathan, Ajay; Stohr, Bradley A; Greenland, Nancy Y; Vohra, Poonam; Hosfield, Elizabeth; Yeh, Iwei; Talevich, Eric; Onodera, Courtney; Van Ziffle, Jessica A; Grenert, James P; Bastian, Boris C; Chen, Yunn-Yi; Krings, Gregor

    2016-09-01

    Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior. Few efficacious treatment options exist for progressed or metastatic disease. The molecular features of malignant phyllodes tumors are poorly defined, and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches. We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors, including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation. Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors, including non-heterologous and heterologous components of tumors with heterologous differentiation. Activating hotspot mutations in FGFR1 were identified in 2 tumors. Additional recurrently mutated genes included TERT promoter (6/10), TP53 (4/10), PIK3CA (3/10), MED12 (3/10), SETD2 (2/10) and KMT2D (2/10). Together, genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 (80%) tumors and included mutually exclusive and potentially actionable activating FGFR1, PIK3CA and BRAF V600E mutations, inactivating TSC2 mutation, EGFR amplification and PTEN loss. Seven (70%) malignant phyllodes tumors harbored TERT aberrations (six promoter mutations, one amplification). For comparison, TERT promoter mutations were identified by Sanger sequencing in 33% borderline (n=12) and no (0%, n=8) benign phyllodes tumors (P=0.391 and P=0.013 vs malignant tumors, respectively). Genetic features specific to liposarcoma, including CDK4/MDM2 amplification, were not identified. Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation. Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with

  12. IDENTIFICATION OF A MAJOR QUANTITATIVE TRAIT LOCUS CONFERRING RICE BLAST RESISTANCE USING RECOMBINANT INBRED LINES

    Directory of Open Access Journals (Sweden)

    Sobrizal Sobrizal

    2013-05-01

    Full Text Available Blast disease caused by Pyricularia oryzae is one of the limiting factors for rice production world wide. The use of resistant varieties for managing blast disease is considered as the most eco-friendly approaches. However, their resistances may be broken down within a few years due to the appearance of new virulent blast races in the field. The objective of the present study was to identify the quantitative trait locus (QTL conferring resistance to blast disease using 126 recombinant inbred (RI lines originated from a crossing of a durably resistant upland rice genotype (Laka and a highly susceptible rice accession cultivar (Kencana Bali. The RI population was developed through a single seed descent method from 1997 to 2004. Resistance of the RI lines was evaluated for blast in an endemic area of Sukabumi, West Java, in 2005. Disease intensity of the blast was examined following the standard evaluation system developed by the International Rice Research Institute (IRRI. At the same year the RI lines were analyzed with 134 DNA markers. Results of the study showed that one major QTL was found to be associated with blast resistance, and this QTL was located near RM2136 marker on the long arm of chromosome 11. This QTL explained 87% of the phenotypic variation with 37% additive effect. The map position of this QTL differed from that of a partial resistant gene, Pi34, identified previously on chromosome 11 in the Japanese durably resistant variety, Chubu 32. The QTL, however, was almost at the same position as that of the multiple allele-resistant gene, Pik. Therefore, an allelic test should be conducted to clarify the allelic relationship between QTL identified in this study and the Pik. The RI lines are the permanent segregating population that could be very useful for analysing phenotypic variations of important agronomic traits possibly owned by the RI lines. The major QTL identified in this study could be used as a genetic resource in

  13. Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status.

    Science.gov (United States)

    Hamada, Tsuyoshi; Cao, Yin; Qian, Zhi Rong; Masugi, Yohei; Nowak, Jonathan A; Yang, Juhong; Song, Mingyang; Mima, Kosuke; Kosumi, Keisuke; Liu, Li; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Keum, NaNa; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey A; Giovannucci, Edward L; Giannakis, Marios; Rodig, Scott J; Freeman, Gordon J; Nevo, Daniel; Wang, Molin; Chan, Andrew T; Fuchs, Charles S; Nishihara, Reiko; Ogino, Shuji

    2017-06-01

    Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell-mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway. Patients and Methods Using data from 617 patients with rectal and colon cancer in the Nurses' Health Study and the Health Professionals Follow-Up Study, we examined the association of postdiagnosis aspirin use with patient survival in strata of tumor CD274 expression status measured by immunohistochemistry. We used multivariable Cox proportional hazards regression models to control for potential confounders, including disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, cyclooxygenase-2 (PTGS2), and CDX2 expression, and KRAS, BRAF, and PIK3CA mutations. Results The association of postdiagnosis aspirin use with colorectal cancer-specific survival differed by CD274 expression status ( Pinteraction < .001); compared with aspirin nonusers; multivariable-adjusted hazard ratios for regular aspirin users were 0.16 (95% CI, 0.06 to 0.41) in patients with low CD274 and 1.01 (95% CI, 0.61 to 1.67) in patients with high CD274. This differential association seemed consistent in patients with microsatellite-stable or PIK3CA wild-type disease and in strata of PTGS2 expression, CDX2 expression, tumor-infiltrating lymphocytes, or prediagnosis aspirin use status. Conclusion The association of aspirin use with colorectal cancer survival is stronger in patients with

  14. Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma.

    Science.gov (United States)

    Basturk, Olca; Berger, Michael F; Yamaguchi, Hiroshi; Adsay, Volkan; Askan, Gokce; Bhanot, Umesh K; Zehir, Ahmet; Carneiro, Fatima; Hong, Seung-Mo; Zamboni, Giuseppe; Dikoglu, Esra; Jobanputra, Vaidehi; Wrzeszczynski, Kazimierz O; Balci, Serdar; Allen, Peter; Ikari, Naoki; Takeuchi, Shoko; Akagawa, Hiroyuki; Kanno, Atsushi; Shimosegawa, Tooru; Morikawa, Takanori; Motoi, Fuyuhiko; Unno, Michiaki; Higuchi, Ryota; Yamamoto, Masakazu; Shimizu, Kyoko; Furukawa, Toru; Klimstra, David S

    2017-12-01

    Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2

  15. Avirulence (AVR) Gene-Based Diagnosis Complements Existing Pathogen Surveillance Tools for Effective Deployment of Resistance (R) Genes Against Rice Blast Disease.

    Science.gov (United States)

    Selisana, S M; Yanoria, M J; Quime, B; Chaipanya, C; Lu, G; Opulencia, R; Wang, G-L; Mitchell, T; Correll, J; Talbot, N J; Leung, H; Zhou, B

    2017-06-01

    Avirulence (AVR) genes in Magnaporthe oryzae, the fungal pathogen that causes the devastating rice blast disease, have been documented to be major targets subject to mutations to avoid recognition by resistance (R) genes. In this study, an AVR-gene-based diagnosis tool for determining the virulence spectrum of a rice blast pathogen population was developed and validated. A set of 77 single-spore field isolates was subjected to pathotype analysis using differential lines, each containing a single R gene, and classified into 20 virulent pathotypes, except for 4 isolates that lost pathogenicity. In