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Sample records for beljaeva vahur pik

  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. 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.

  4. 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

  5. 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

  6. Vahur-Paul Põldma - tõlkis raamatu, lavastas etenduse, ise mängib ja üksi / Vahur-Paul Põldma ; interv. Triin Tael

    Index Scriptorium Estoniae

    Põldma, Vahur-Paul

    2008-01-01

    Alessandro Baricco teos "Novecento", mida Vahur-Paul Põldma mängib Uue Vana Teatri nime all ühemeheetendusena. Lisaks tutvustus "Kes on Alessandro Baricco?" ja "Vahur-Pauli salaminevik : töö lasteaiakasvatajana"

  7. Eesti Panga presidendi Vahur Krafti kõne Tammsaare pargis / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2004-01-01

    Ilmunud ka: Kroon & Economy, 2004, nr. 2, lk. 48-53. Autor põhjendab euro kasutuselevõtu vajalikkust ning kuulutab välja Eesti euromüntide rahvusliku külje kujunduskonkursi. Vahur Krafti kõne 18. juunil 2004 Eesti Panga poolt korraldatud kõnekoosolekul Tammsaare pargis

  8. 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

  9. Ökomaja / Vahur Sova ; interv. Erik Konze

    Index Scriptorium Estoniae

    Sova, Vahur

    2003-01-01

    Eesti Metsatööstuse Liidu korraldatud konkursile "Eesti parim puitehitis 1997-2002" pääsenud, 2002. a. valminud, arhitekt Vahur Sova projekteeritud eramust Leppneemes. Puidu kui ehitusmaterjali eelistest. 4 välisvaadet

  10. Eesti kodanik on ka Euroopa Liidu kodanik / Vahur Kukk

    Index Scriptorium Estoniae

    Kukk, Vahur, 1955-

    2009-01-01

    Europe Directi Jõgevamaa infokeskuse juhataja Vahur Kuke sõnul on 2010. a. üheks prioriteetseks töösuunaks EL-i puudutava teabe viimine Peipsi-äärsesse piirkonda. Kodanikupäeva puhul kutsuti Mustvee kooliõpilastega kohtuma Ukraina Vabariigi suursaadik Eestis hr. Pavlo Kiriakov

  11. 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

  12. PIK3CA in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Gieri eCathomas

    2014-03-01

    Full Text Available PIK3CA, the catalytic subunit of PI3K, is mutated in many different tumours, including colorectal cancer. Mutations of PIK3CA have been reported in 10 – 20% of colorectal cancer, about 80% of mutations found in two hot spots in exon 9 and exon 20. In RAS wild-type colorectal cancers, PIK3CA mutations have been associated with a worse clinical outcome and with a negative prediction of a response to targeted therapy by anti-EGFR monoclonal antibodies. However, these findings have not been confirmed in all studies and subsequent more detailed analysis has revealed that these effects may be restricted to mutations in Exon 20. Finally, mutations in PIK3CA may be the long sought biomarker for successful adjuvant therapy with aspirin in patients with colorectal cancer. Therefore, PIK3CA mutations appear to be a promising predictive biomarker; however, further data are needed to conclusively define the impact of somatic mutations in the PIK3CA gene for the management of patients with colorectal cancer.

  13. 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

  14. Isospin odd {pi}K scattering length

    Energy Technology Data Exchange (ETDEWEB)

    Schweizer, J. [Institut fuer Theoretische Physik, University of Vienna, A-1090 Vienna (Austria)]. E-mail: julia.schweizer@univie.ac.at

    2005-10-13

    We make use of the chiral two-loop representation of the {pi}K scattering amplitude [J. Bijnens, P. Dhonte, P. Talavera, JHEP 0405 (2004) 036] to investigate the isospin odd scattering length at next-to-next-to-leading order in the SU(3) expansion. This scattering length is protected against contributions of m{sub s} in the chiral expansion, in the sense that the corrections to the current algebra result are of order M{sub {pi}}{sup 2}. In view of the planned lifetime measurement on {pi}K atoms at CERN it is important to understand the size of these corrections.

  15. RNAi knockdown of PIK3CA preferentially inhibits invasion of mutant PIK3CA cells

    Institute of Scientific and Technical Information of China (English)

    Xin-Ke Zhou; Sheng-Song Tang; Gao Yi; Min Hou; Jin-Hui Chen; Bo Yang; Ji-Fang Liu; Zhi-Min He

    2011-01-01

    AIM: To explore the effects of siRNA silencing of PIK3CA on proliferation, migration and invasion of gastric cancer cells and to investigate the underlying mechanisms.METHODS: The mutation of PIK3CA in exons 9 and 20 of gastric cancer cell lines HGC-27, SGC-7901, BGC-823, MGC-803 and MKN-45 was screened by poly-merase chain reaction (PCR) followed by sequencing. BGC-823 cells harboring no mutations in either of the exons, and HGC-27 cells containing PIK3CA mutations were employed in the current study. siRNA targeting PIK3CA was chemically synthesized and was transfect-ed into these two cell lines in vitro. mRNA and protein expression of PIK3CA were detected by real-time PCR and Western blotting, respectively. We also measured phosphorylation of a serine/threonine protein kinase (Akt) using Western blotting. The proliferation, migra-tion and invasion of these cells were examined sepa-rately by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-razolium bromide (MTT), wound healing and Transwell chambers assay.RESULTS: The siRNA directed against PIK3CA effec-tively led to inhibition of both endogenous mRNA and protein expression of PIK3CA, and thus significantly down-regulated phosphorylation of Akt (P < 0.05). Furthermore, simultaneous silencing of PIK3CA result-ed in an obvious reduction in tumor cell proliferation activity, migration and invasion potential (P < 0.01). Intriguing, mutant HGC-27 cells exhibited stronger invasion ability than that shown by wild-type BGC-823 cells. Knockdown of PIK3CA in mutant HGC-27 cells contributed to a reduction in cell invasion to a greater extent than in non-mutant BGC-823 cells.CONCLUSION: siRNA mediated targeting of PIK3CA may specifically knockdown the expression of PIK3CA in gastric cancer cells, providing a potential implication for therapy of gastric cancer.

  16. Karin Hango ja Vahur Murutar: kõigepealt kuulame tippjuhi ära, siis vaatame, kas koostööst saab asja! / Karin Hango, Vahur Murutar

    Index Scriptorium Estoniae

    Hango, Karin, 1958-

    2010-01-01

    Konsultatsioonifirma SELF II juhid Karin Hango ja Vahur Murutar vastavad küsimustele, mis puudutavad ettevõtte asutamist, konkurentsivõimet, SELFI töötajate hea taseme tagamist, töö ja eraelu ühitamist ning majanduskriisi mõju ettevõttele

  17. Trypanosoma cruzi: Genome characterization of phosphatidylinositol kinase gene family (PIK and PIK-related) and identification of a novel PIK gene.

    Science.gov (United States)

    Oliveira, Priscila; Lima, Fabio Mitsuo; Cruz, Mario Costa; Ferreira, Renata Carmona; Sanchez-Flores, Alejandro; Cordero, Esteban Maurício; Cortez, Danielle Rodrigues; Ferreira, Éden Ramalho; Briones, Marcelo Ribeiro da Silva; Mortara, Renato Arruda; da Silveira, José Franco; Bahia, Diana

    2014-07-01

    Chagas disease is caused by the protozoan Trypanosoma cruzi which affects 10 million people worldwide. Very few kinases have been characterized in this parasite, including the phosphatidylinositol kinases (PIKs) that are at the heart of one of the major pathways of intracellular signal transduction. Recently, we have classified the PIK family in T. cruzi using five different models based on the presence of PIK conserved domains. In this study, we have mapped PIK genes to the chromosomes of two different T. cruzi lineages (G and CL Brener) and determined the cellular localization of two PIK members. The kinases have crucial roles in metabolism and are assumed to be conserved throughout evolution. For this reason, they should display a conserved localization within the same eukaryotic species. In spite of this, there is an extensive polymorphism regarding PIK localization at both genomic and cellular levels, among different T. cruzi isolates and between T. cruzi and Trypanosomabrucei, respectively. We showed in this study that the cellular localization of two PIK-related proteins (TOR1 and 2) in the T. cruzi lineage is distinct from that previously observed in T. brucei. In addition, we identified a new PIK gene with peculiar feature, that is, it codes for a FYVE domain at N-terminal position. FYVE-PIK genes are phylogenetically distant from the groups containing exclusively the FYVE or PIK domain. The FYVE-PIK architecture is only present in trypanosomatids and in virus such as Acanthamoeba mimivirus, suggesting a horizontal acquisition. Our Bayesian phylogenetic inference supports this hypothesis. The exact functions of this FYVE-PIK gene are unknown, but the presence of FYVE domain suggests a role in membranous compartments, such as endosome. Taken together, the data presented here strengthen the possibility that trypanosomatids are characterized by extensive genomic plasticity that may be considered in designing drugs and vaccines for prevention of Chagas disease.

  18. 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

  19. 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

  20. Mis on muutunud noorte huvis huvitegevuse vastu? / Toomas-Vahur Lihtmaa, Peep Tobreluts, Annely Köster ... [jt.

    Index Scriptorium Estoniae

    2012-01-01

    Küsimusele vastasid Tallinna kunstikooli direktor Toomas-Vahur Lihtmaa, Viljandi huvikooli loodusringi juhendaja Peep Tobreluts, Sally stuudio juhataja Annely Köster, Abja tehnikaringi juhendaja Tarmo Raba, Kullo huvikeskuse automodellismi huviringi juhendaja Mait Murumäe

  1. 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)

  2. 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

    tissue samples of breast carcinoma and normal breast tissue were obtained from 175 breast cancer patients at the time of primary surgery, of these 105 patients were lymph node positive. Expression of PIK3CA and PTEN mRNA was quantified with Quantitative Real Time PCR. Somatic mutations in exon 9 and exon......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...... suppressor, phosphatase and tensin homolog (PTEN), in breast carcinoma tissue and normal breast tissue. Furthermore, we examine whether expression of PIK3CA and PTEN mRNA and occurrence of PIK3CA mutations are associated with lymph node metastases in patients with primary breast cancer. METHODS: Paired...

  3. 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

  4. 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

  5. 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

  6. Mutations in PIK3CA are infrequent in neuroblastoma

    Directory of Open Access Journals (Sweden)

    Mazanek Pavel

    2006-07-01

    Full Text Available Abstract Background Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. Methods Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain "hot spots" where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. Results We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%. Neither mutation (R524M and E982D has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively. Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model

  7. p55PIK Transcriptionally Activated by MZF1 Promotes Colorectal Cancer Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Yu Deng

    2013-01-01

    Full Text Available p55PIK, regulatory subunit of class IA phosphatidylinositol 3-kinase (PI3K, plays a crucial role in cell cycle progression by interaction with tumor repressor retinoblastoma (Rb protein. A recent study showed that Rb protein can localize to the mitochondria in proliferative cells. Aberrant p55PIK expression may contribute to mitochondrial dysfunction in cancer progression. To reveal the mechanisms of p55PIK transcriptional regulation, the p55PIK promoter characteristics were analyzed. The data show that myeloid zinc finger 1, MZF1, is necessary for p55PIK gene transcription activation. ChIP (Chromatin immuno-precipitation assay shows that MZF1 binds to the cis-element “TGGGGA” in p55PIK promoter. In MZF1 overexpressed cells, the promoter activity, expression of p55PIK, and cell proliferation rate were observed to be significantly enhanced. Whereas in MZF1-silenced cells, the promoter activity and expression of p55PIK and cell proliferation level was statistically decreased. In CRC tissues, MZF1 and p55PIK mRNA expression were increased (P=0.046, P=0.047, resp.. A strong positive correlation (Rs=0.94 between MZF1 and p55PIK mRNA expression was observed. Taken together, we concluded that p55PIK is transcriptionally activated by MZF1, resulting in increased proliferation of colorectal cancer cells.

  8. piK Scattering in Three Flavour ChPT

    Science.gov (United States)

    Bijnens, Johan; Dhonte, Pierre; Talavera, Pere

    2004-05-01

    We present the scattering lengths for the piK processes in the three flavour Chiral Perturbation Theory (ChPT) framework at next-to-next-to-leading order (NNLO). The calculation has been performed analytically but we only include analytical results for the dependence on the low-energy constants (LECs) at NNLO due to the size of the expressions. These results, together with resonance estimates of the NNLO LECs are used to obtain constraints on the Zweig rule suppressed LECs at NLO, L4r and L6r. Contrary to expectations from NLO order calculations we find them to be compatible with zero. We do a preliminary study of combining the results from pipi scattering, piK scattering and the scalar form-factors and find only a marginal compatibility with all experimental/dispersive input data.

  9. 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.

  10. 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...

  11. The prevalence of PIK3CA mutations in gastric and colon cancer

    NARCIS (Netherlands)

    Velho, S; Oliveira, C; Ferreira, A; Ferreira, AC; Suriano, G; Schwartz, S; Duval, A; Carneiro, F; Machado, JC; Hamelin, R; Seruca, R

    2005-01-01

    A wide variety of tumours show PIK3CA mutations leading to increased phosphatidylinositol-3 kinase (PI3K) activity. We have determined the frequency of PIK3CA mutations in exons 9 and 20 that has previously been reported as mutational hotspot regions in distinct tumour models. One hundred and fifty

  12. 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.

  13. Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin.

    Science.gov (United States)

    Turturro, Sanja B; Najor, Matthew S; Ruby, Carl E; Cobleigh, Melody A; Abukhdeir, Abde M

    2016-02-01

    A review of the literature finds that women diagnosed with breast cancer, who were on an aspirin regimen, experienced a decreased risk of distant metastases and death. Several recent studies have reported an improvement in overall survival in colorectal cancer patients who harbored mutations in the oncogene PIK3CA and received a daily aspirin regimen. Breast cancer patients on a daily aspirin regimen experienced decreased risk of distant metastases and death. PIK3CA is the most frequently mutated oncogene in breast cancer, occurring in up to 45 % of all breast cancers. In order to determine if mutations in PIK3CA sensitized breast cancers to aspirin treatment, we employed the use of isogenic cellular clones of the non-tumorigenic, breast epithelial cell line MCF-10A that harbored mutations in either PIK3CA or KRAS or both. We report that mutations in both PIK3CA and KRAS are required for the greatest aspirin sensitivity in breast cancer, and that the GSK3β protein was hyperphosphorylated in aspirin-treated double knockin cells, but not in other clones/treatments. A more modest effect was observed with single mutant PIK3CA, but not KRAS alone. These observations were further confirmed in a panel of breast cancer cell lines. Our findings provide the first evidence that mutations in PIK3CA sensitize breast cancer cells to aspirin.

  14. PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers.

    Directory of Open Access Journals (Sweden)

    Filip Janku

    Full Text Available BACKGROUND: Oncogenic mutations of PIK3CA, RAS (KRAS, NRAS, and BRAF have been identified in various malignancies, and activate the PI3K/AKT/mTOR and RAS/RAF/MEK pathways, respectively. Both pathways are critical drivers of tumorigenesis. METHODS: Tumor tissues from 504 patients with diverse cancers referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center starting in October 2008 were analyzed for PIK3CA, RAS (KRAS, NRAS, and BRAF mutations using polymerase chain reaction-based DNA sequencing. RESULTS: PIK3CA mutations were found in 54 (11% of 504 patients tested; KRAS in 69 (19% of 367; NRAS in 19 (8% of 225; and BRAF in 31 (9% of 361 patients. PIK3CA mutations were most frequent in squamous cervical (5/14, 36%, uterine (7/28, 25%, breast (6/29, 21%, and colorectal cancers (18/105, 17%; KRAS in pancreatic (5/9, 56%, colorectal (49/97, 51%, and uterine cancers (3/20, 15%; NRAS in melanoma (12/40, 30%, and uterine cancer (2/11, 18%; BRAF in melanoma (23/52, 44%, and colorectal cancer (5/88, 6%. Regardless of histology, KRAS mutations were found in 38% of patients with PIK3CA mutations compared to 16% of patients with wild-type (wtPIK3CA (p = 0.001. In total, RAS (KRAS, NRAS or BRAF mutations were found in 47% of patients with PIK3CA mutations vs. 24% of patients wtPIK3CA (p = 0.001. PIK3CA mutations were found in 28% of patients with KRAS mutations compared to 10% with wtKRAS (p = 0.001 and in 20% of patients with RAS (KRAS, NRAS or BRAF mutations compared to 8% with wtRAS (KRAS, NRAS or wtBRAF (p = 0.001. CONCLUSIONS: PIK3CA, RAS (KRAS, NRAS, and BRAF mutations are frequent in diverse tumors. In a wide variety of tumors, PIK3CA mutations coexist with RAS (KRAS, NRAS and BRAF mutations.

  15. Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women.

    Science.gov (United States)

    Chung, Tony K H; Cheung, Tak Hong; Yim, So Fan; Yu, Mei Yun; Chiu, Rossa W K; Lo, Keith W K; Lee, Ida P C; Wong, Raymond R Y; Lau, Kitty K M; Wang, Vivian W; Worley, Michael J; Elias, Kevin M; Fiascone, Stephen J; Smith, David I; Berkowitz, Ross S; Wong, Yick Fu

    2017-08-01

    Cervical cancer is the fourth most common female cancer worldwide. The prognosis for women with advanced-stage or recurrent cervical cancer remains poor and response to treatment is variable. Standardized management protocols leave little room for individualization. We report on a novel blood-based liquid biopsy for specific PIK3CA mutations as a clinically useful biomarker in patients with invasive cervical cancer. One hundred seventeen Hong Kong Chinese women with primary invasive cervical cancer and their pre-treatment plasma samples were investigated. Two PIK3CA mutations, p.E542K and p.E545K were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. This liquid biopsy of PIK3CA in cervical cancer was correlated to clinico-pathological features to verify the potential of PIK3CA as a clinically useful molecular biomarker for predicting disease prognosis and monitoring for progression. PIK3CA mutations, either p.E542K or p.E545K, were detected in plasma cfDNA from 22.2% of the patients. PIK3CA mutation status was significantly correlated to median tumor size (p<0.01). PIK3CA mutations detected in the plasma were significantly associated with decreased disease-free survival and overall survival (p<0.05). As a liquid molecular biopsy, analysis of circulating PIK3CA mutations shows promise as a way to refine risk stratification of individual patients with cervical cancer, and provides a platform for further research to offer individualized therapy with the purpose of improving outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. KRAS, BRAF and PIK3CA status in squamous cell anal carcinoma (SCAC.

    Directory of Open Access Journals (Sweden)

    Andrea Casadei Gardini

    Full Text Available Anti-EGFR therapy appears to be a potential treatment option for squamous cell anal carcinoma (SCAC. KRAS mutation is a rare event in SCAC, indicating the absence of the principal mechanism of resistance to this type of therapy. However, no information is available from the literature regarding the status of BRAF or PIK3CA in this cancer type. We analysed KRAS, BRAF and PIK3CA status in SCAC patients in relation to the clinical-pathological characteristics of patients and to the presence of the human papilloma virus (HPV. One hundred and three patients were treated with the Nigro scheme for anal cancer from March 2001 to August 2012. Fifty patients were considered for the study as there was insufficient paraffin-embedded tumour tissue to perform molecular analysis the remaining 53. DNA was extracted from paraffin-embedded sections. KRAS, BRAF and PIK3CA gene status and HPV genotype were evaluated by pyrosequencing. KRAS and BRAF genes were wild-type in all cases. Conversely, PIK3CA gene was found to be mutated in 11 (22% cases. In particular, 8 mutations occurred in exon 9 and 3 in exon 20 of the PIK3CA gene. These findings suggest that SCAC could potentially respond to an anti-EGFR drug. PIK3CA mutation may be involved in the process of carcinogenesis in some cases of SCAC.

  17. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice.

    Science.gov (United States)

    Kinross, Kathryn M; Montgomery, Karen G; Kleinschmidt, Margarete; Waring, Paul; Ivetac, Ivan; Tikoo, Anjali; Saad, Mirette; Hare, Lauren; Roh, Vincent; Mantamadiotis, Theo; Sheppard, Karen E; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L; Christensen, James G; Cullinane, Carleen; Hicks, Rodney J; Pearson, Richard B; Johnstone, Ricky W; McArthur, Grant A; Phillips, Wayne A

    2012-02-01

    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.

  18. 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.

  19. 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.

  20. 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.

  1. Mutational analyses of the BRAF, KRAS, and PIK3CA genes in oral squamous cell carcinoma

    Science.gov (United States)

    Bruckman, Karl C.; Schönleben, Frank; Qiu, Wanglong; Woo, Victoria L.; Su, Gloria H.

    2010-01-01

    OBJECTIVES The development of oral squamous cell carcinoma (OSCC) is a complex, multistep process. To date, numerous oncogenes and tumor-suppressor genes have been implicated in oral carcinogenesis. Of particular interest in this regard are genes involved in cell cycling and apoptosis, such BRAF, KRAS, and PIK3CA genes. STUDY DESIGN Mutations of BRAF, KRAS, and PIK3CA were evaluated by direct genomic sequencing of exons 1 of KRAS, 11 and 15 of BRAF, and 9 and 20 of PIK3CA in OSCC specimens. RESULTS Both BRAF and KRAS mutations were detected with a mutation frequency of 2% (1/42). PIK3CA mutations were detected at 3% (1/35). CONCLUSIONS This is the first report implicating BRAF mutation in OSCC. Our study supports that mutations in the BRAF, KRAS, and PIK3CA genes make at least a minor contribution to OSCC tumorigenesis, and pathway-specific therapies targeting these two pathways should be considered for OSCC in a subset of patients with these mutations. PMID:20813562

  2. 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

  3. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models

    Science.gov (United States)

    Sabha, Nesrin; Volpatti, Jonathan R.; Gonorazky, Hernan; Davidson, Ann E.; Li, Xingli; Eltayeb, Nadine M.; Dall’Armi, Claudia; Di Paolo, Gilbert; Brooks, Susan V.; Buj-Bello, Ana; Feldman, Eva L.; Dowling, James J.

    2016-01-01

    Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets. PMID:27548528

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

    OpenAIRE

    2015-01-01

    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 Xanthomona...

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

    Directory of Open Access Journals (Sweden)

    Shun Liang

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  6. 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.

  7. Development of PIK-75 nanosuspension formulation with enhanced delivery efficiency and cytotoxicity for targeted anti-cancer therapy.

    Science.gov (United States)

    Talekar, Meghna; Ganta, Srinivas; Amiji, Mansoor; Jamieson, Stephen; Kendall, Jackie; Denny, William A; Garg, Sanjay

    2013-06-25

    PIK-75 is a phosphatidylinositol 3-kinase (PI3K) inhibitor that shows selectivity toward p110-α over the other PI3K class Ia isoforms p110-β and p110-δ, but it lacks solubility, stability and other kinase selectivity. The purpose of this study was to develop folate-targeted PIK-75 nanosuspension for tumor targeted delivery and to improve therapeutic efficacy in human ovarian cancer model. High pressure homogenization was used to prepare the non-targeted and targeted PIK-75 nanosuspensions which were characterized for size, zeta potential, entrapment efficiency, morphology, saturation solubility and dissolution velocity. In vitro analysis of drug uptake, cell viability and cell survival was conducted in SKOV-3 cells. Drug pharmacokinetics and pAkt expression were determined in SKOV-3 tumor bearing mice. PIK-75 nanosuspensions showed an improvement in dissolution velocity and an 11-fold increase in saturation solubility over pre-milled PIK-75. In vitro studies in SKOV-3 cells indicated a 2-fold improvement in drug uptake and 0.4-fold decrease in IC50 value of PIK-75 following treatment with targeted nanosuspension compared to non-targeted nanosuspension. The improvement in cytotoxicity was attributed to an increase in caspase 3/7 and hROS activity. In vivo studies indicated a 5-10-fold increased PIK-75 accumulation in the tumor with both the nanosuspension formulations compared to PIK-75 suspension. The targeted nanosuspension showed an enhanced downregulation of pAkt compared to non-targeted formulation system. These results illustrate the opportunity to formulate PIK-75 as a targeted nanosuspension to enhance uptake and cytotoxicity of the drug in tumor.

  8. 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....

  9. 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.

  10. Molecular spectrum of KRAS, BRAF, and PIK3CA gene mutation: determination of frequency, distribution pattern in Indian colorectal carcinoma.

    Science.gov (United States)

    Bisht, Swati; Ahmad, Firoz; Sawaimoon, Satyakam; Bhatia, Simi; Das, Bibhu Ranjan

    2014-09-01

    Molecular evaluation of KRAS, BRAF, and PIK3CA mutation has become an important part in colorectal carcinoma evaluation, and their alterations may determine the therapeutic response to anti-EGFR therapy. The current study demonstrates the evaluation of KRAS, BRAF, and PIK3CA mutation using direct sequencing in 204 samples. The frequency of KRAS, BRAF, and PIK3CA mutations was 23.5, 9.8, and 5.9 %, respectively. Five different substitution mutations at KRAS codon 12 (G12S, G12D, G12A, G12V, and G12C) and one substitution type at codon 13 (G13D) were observed. KRAS mutations were significantly higher in patients who were >50 years, and were associated with moderate/poorly differentiated tumors and adenocarcinomas. All mutations in BRAF gene were of V600E type, which were frequent in patients who were ≤ 50 years. Unlike KRAS mutations, BRAF mutations were more frequent in well-differentiated tumors and right-sided tumors. PIK3CA-E545K was the most recurrent mutation while other mutations detected were T544I, Q546R, H1047R, G1049S, and D1056N. No significant association of PIK3CA mutation with age, tumor differentiation, location, and other parameters was noted. No concomitant mutation of KRAS and BRAF mutations was observed, while, interestingly, five cases showed concurrent mutation of KRAS and PIK3CA mutations. In conclusion, to our knowledge, this is the first study to evaluate the PIK3CA mutation in Indian CRC patients. The frequency of KRAS, BRAF, and PIK3CA was similar to worldwide reports. Furthermore, identification of molecular markers has unique strengths, and can provide insights into the pathogenic process and help optimize personalized prevention and therapy.

  11. 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.

  12. GA binding protein augments autophagy via transcriptional activation of BECN1-PIK3C3 complex genes.

    Science.gov (United States)

    Zhu, Wan; Swaminathan, Gayathri; Plowey, Edward D

    2014-09-01

    Macroautophagy is a vesicular catabolic trafficking pathway that is thought to protect cells from diverse stressors and to promote longevity. Recent studies have revealed that transcription factors play important roles in the regulation of autophagy. In this study, we have identified GA binding protein (GABP) as a transcriptional regulator of the combinatorial expression of BECN1-PIK3C3 complex genes involved in autophagosome initiation. We performed bioinformatics analyses that demonstrated highly conserved putative GABP sites in genes that encode BECN1/Beclin 1, several BECN1 interacting proteins, and downstream autophagy proteins including the ATG12-ATG5-ATG16L1 complex. We demonstrate that GABP binds to the promoter regions of BECN1-PIK3C3 complex genes and activates their transcriptional activities. Knockdown of GABP reduced BECN1-PIK3C3 complex transcripts, BECN1-PIK3C3 complex protein levels and autophagy in cultured cells. Conversely, overexpression of GABP increased autophagy. Nutrient starvation increased GABP-dependent transcriptional activity of BECN1-PIK3C3 complex gene promoters and increased the recruitment of GABP to the BECN1 promoter. Our data reveal a novel function of GABP in the regulation of autophagy via transcriptional activation of the BECN1-PIK3C3 complex.

  13. Semiclassical Distorted Wave Model Analysis of the $(\\pi^-,K^+)$ $\\Sigma$ Formation Inclusive Spectrum

    CERN Document Server

    Kohno, M; Kawai, M; Ogata, K; Watanabe, Y

    2006-01-01

    $(\\pi^-,K^+)$ hyperon production inclusive spectra with $p_\\pi =1.2$ GeV/c measured at KEK on $^{12}$C and $^{28}$Si are analyzed by the semiclassical distorted wave model. Single-particle wave functions of the target nucleus are treated using Wigner transformation. This method is able to account for the energy and angular dependences of the elementary process in nuclear medium without introducing the factorization approximation frequently employed. Calculations of the $(\\pi^+,K^+)$ $\\Lambda$ formation process, for which there is no free parameter since the $\\Lambda$ s.p. potential is known, demonstrate that the present model is useful to describe inclusive spectra. It is shown that in order to account for the experimental data of the $\\Sigma^-$ formation spectra a repulsive $\\Sigma$-nucleus potential is necessary whose magnitude is not so strong as around 100 MeV previously suggested.

  14. PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

    Science.gov (United States)

    Thauvin-Robinet, Christel; Auclair, Martine; Duplomb, Laurence; Caron-Debarle, Martine; Avila, Magali; St-Onge, Judith; Le Merrer, Martine; Le Luyer, Bernard; Héron, Delphine; Mathieu-Dramard, Michèle; Bitoun, Pierre; Petit, Jean-Michel; Odent, Sylvie; Amiel, Jeanne; Picot, Damien; Carmignac, Virginie; Thevenon, Julien; Callier, Patrick; Laville, Martine; Reznik, Yves; Fagour, Cédric; Nunes, Marie-Laure; Capeau, Jacqueline; Lascols, Olivier; Huet, Frédéric; Faivre, Laurence; Vigouroux, Corinne; Rivière, Jean-Baptiste

    2013-01-01

    Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts. PMID:23810378

  15. Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations

    Science.gov (United States)

    Huang-Doran, Isabel; Tomlinson, Patsy; Payne, Felicity; Gast, Alexandra; Sleigh, Alison; Bottomley, William; Harris, Julie; Daly, Allan; Rocha, Nuno; Rudge, Simon; Clark, Jonathan; Kwok, Albert; Romeo, Stefano; McCann, Emma; Müksch, Barbara; Dattani, Mehul; Zucchini, Stefano; Wakelam, Michael; Foukas, Lazaros C.; Savage, David B.; Murphy, Rinki; O’Rahilly, Stephen; Semple, Robert K.

    2016-01-01

    Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. PMID:27766312

  16. 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.

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

    CERN Document Server

    Lychagin, E V; Muzychka, A Yu; Nekhaev, G V; Nesvizhevsky, V V; Onegin, M S; Sharapov, E I; Strelkov, A V

    2015-01-01

    We consider ultracold neutron (UCN) sources based on a new method of UCN production in superfluid helium (4He). The PIK reactor is chosen as a perspective example of the application of this idea, which consists of installing a 4He UCN source in a beam of thermal or cold neutrons and surrounding the source with a moderator-reflector, which plays the role of a source of cold neutrons (CNs) feeding the UCN source. The 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 a 4He source with solid methane (CH4) or/and liquid deuterium (D2) moderator-reflector. We show that such a source with CH4 moderator-reflector at the PIK reactor would provide the UCN density of ~1x10^5 1/cm^3, and the UCN production rate of ~2x10^7 1/s. These values are resp...

  18. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

    Science.gov (United States)

    Roy, Achira; Skibo, Jonathan; Kalume, Franck; Ni, Jing; Rankin, Sherri; Lu, Yiling; Dobyns, William B; Mills, Gordon B; Zhao, Jean J; Baker, Suzanne J; Millen, Kathleen J

    2015-01-01

    Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients. DOI: http://dx.doi.org/10.7554/eLife.12703.001 PMID:26633882

  19. Loss of a 1.6 Mb chromosome in Pyricularia oryzae harboring two alleles of AvrPik leads to acquisition of virulence to rice cultivars containing resistance alleles at the Pik locus.

    Science.gov (United States)

    Kusaba, Motoaki; Mochida, Taiga; Naridomi, Takeshi; Fujita, Yoshikatsu; Chuma, Izumi; Tosa, Yukio

    2014-11-01

    A small and extra chromosome of 1.6 Mb was previously identified in a Pyricularia oryzae strain, 84R-62B. To understand a role of the 1.6 Mb chromosome in the pathogenic changeability of P. oryzae, we performed experiments designed to characterize the 1.6 Mb chromosome in the present study. A gene family encoding secreted protein Pex31s in P. oryzae consists of five homologs, Pex31-A to -E. Among them, Pex31-A and -D are known to be recognized by Pik-m and Pik/Pik-m/Pik-p, respectively. In the present study, we identified Pex31-A and -D in the genome of 84R-62B. Segregation analyses using an F1 population between 84R-62B and another rice blast strain, Y93-245c-2, revealed a strong linkage between the two homologs and the 1.6 Mb chromosome of 84R-62B. A CHEF-Southern analysis revealed an association between the 1.6 Mb chromosome and the homologs, indicating that both homologs are located on the 1.6 Mb chromosome of 84R-62B. The loss of the 1.6 Mb chromosome was observed in subcultures of a F1 progeny, F1-327. These subcultures concomitantly acquired virulence on Pik, Pik-m, and Pik-p. The present study is the first report showing that loss of a small and extra chromosome leads to pathogenic mutation of P. oryzae and may provide a new insight into the mechanisms generating pathogenic variation of this fungus.

  20. 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.

  1. 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

  2. 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.

  3. 结直肠癌KRAS、BRAF及PIK3 CA基因突变的检测及内在关系%Detection of KRAS, BRAF and PIK3CA gene mutation s in colorectal cancer and their intrinsic relationship

    Institute of Scientific and Technical Information of China (English)

    常江; 于跃利; 王颖

    2015-01-01

    Objective:To detect the mutations of KRAS, BRAF and PIK3CA genes in colorectal cancer and to analyze the intrinsic relation-ship between the three genes.Method:41 samples of colorectal cancer were collected in the General Surgery Department of Banyannur Hospital from March 2011 to October 2011, whose DNAs were extracted and amplified by using polymerase chain reaction methods.The mutations of KRAS, BRAF and PIK3CA genes were detected and the intrinsic relationship between them were analyzed .Results:15, 5 and 7 patients were found mutations of KRAS, BRAF and PIK3CA genes respectively with the mutation rates being 36.6 %、12.2 % and 17.1 % respectively.(2) There were 5 patients with KRAS gene mutations, all of which were wild-type; there were 7 patients with PIK3CA mutations, 3 (42.9 %) of whom had wild-type KRAS and 4 (57.1%) of whom had KRAS mutation.There was no co -mutation between BRAF and PIK3CA genes. Conclusions: (1) KRAS gene mutation rate is high, so there is a need for regular inspection.(2) BRAF gene mutation in Some patients with wild-type BRAF gene may be one of the reasons for the occurrence and the development of colorectal cancers.The co-mutation of BRAF gene and PIK3CA gene may contribute to the occurrence and development of colorectal cancers.%目的:检测结直肠癌组织KRAS、BRAF及PIK3CA基因突变情况,并分析其内在关系。方法:收集内蒙古巴彦淖尔市医院普外一科2011年3月至2011年8月结直肠癌手术切除标本41例,提取DNA经PCR扩增后,检测KRAS、BRAF和PIK3CA基因的突变情况,分析结直肠癌组织KRAS、BRAF及PIK3CA基因突变间的内在关系。结果:(1)15例患者的KRAS基因发生突变,突变率36.6%,5例患者的BRAF基因发生突变,突变率12.2%,7例患者的PIK3CA基因发生突变,突变率17.1%。(2)BRAF基因突变者共5例,全部为KRAS野生型的患者;PIK3CA基因突变者共7例,其中3例(42.9%

  4. The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer

    Institute of Scientific and Technical Information of China (English)

    Amaury G.Dumont; Sarah N.Dumont; Jonathan C.Trent

    2012-01-01

    The phosphatidylinositol-3 kinase (PI3K) pathway regulates a number of cellular processes,including cell survival,cell growth,and cell cycle progression.Consequently,this pathway is commonly deregulated in cancer.In particular,mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice.These data underscore the role of this pathway during oncogenesis.Thus,an ongoing,large-scale effort is underway to develop clinically active drugs that target elements of the PI3K pathway.However,conflicting data suggest that gain-of-function PIK3CA mutations may be associated with either a favorable or a poor clinical outcome,compared with the wild-type PIK3CA gene.In the current study,we performed a systematic review of breast cancer clinical studies.Upon evaluation of 2587 breast cancer cases from 12 independent studies,we showed that patients with tumors harboring a PIK3CA mutation have a better clinical outcome than those with a wild-type PIK3CA gene.Importantly,this improved prognosis may pertain only to patients with mutations in the kinase domain of p110α and to postmenopausal women with estrogen receptor-positive breast cancer.We propose three potential explanations for this paradoxical observation.First,PIK3CA mutations may interfere with the metastasis process or may induce senescence,which results in a better outcome for patients with mutated tumors.Secondly,we speculate that PIK3CA mutations may increase early tumor diagnosis by modification of the actin cytoskeleton in tumor cells.Lastly,we propose that PIK3CA mutations may be a favorable predictive factor for response to hormonal therapy,giving a therapeutic advantage to these patients.Ultimately,an improved understanding of the clinical impact of PIK3CA mutations is critical for the development of optimally personalized therapeutics against breast cancer and other solid tumors

  5. Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice

    Science.gov (United States)

    McCurdy, Carrie E.; Schenk, Simon; Holliday, Michael J.; Philp, Andrew; Houck, Julie A.; Patsouris, David; MacLean, Paul S.; Majka, Susan M.; Klemm, Dwight J.; Friedman, Jacob E.

    2012-01-01

    Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance; however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α/p55α/p50α) are highly induced in AT from high-fat diet–fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH2-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT. PMID:22698915

  6. PIK3CAH1047R and Her2 initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling

    Science.gov (United States)

    Cheng, Hailing; Liu, Pixu; Ohlson, Carolynn; Xu, Erbo; Symonds, Lynn; Isabella, Adam; Muller, William J.; Lin, Nancy U.; Krop, Ian E.; Roberts, Thomas M.; Winer, Eric P.; Arteaga, Carlos L.; Zhao, Jean J.

    2015-01-01

    Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2 positive breast cancer with coexisting PIK3CAH1047R. Induction of PIK3CAH1047R expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of PI3K/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of PIK3CAH1047R expression. Strikingly, while these Her2+ PIK3CAH1047R initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic PIK3CAH1047R, a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110a. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2 positive cancers with coexisting PIK3CA-activating mutations. PMID:26640141

  7. 结直肠癌KRAS、BRAF及PIK3CA基因突变状态分析%Detection of KRAS, BRAF and PIK3CA gene mutations in colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    罗妙玲; 徐韫健

    2016-01-01

    目的:检测结直肠癌组织KRAS、BRAF及PIK3CA基因突变状态,分析突变与临床特征的关系。方法收集结直肠癌手术切除或穿刺活检标本177例,提取DNA经探针扩增阻滞突变系统聚合酶链反应扩增后,检测KRAS、BRAF及PIK3CA基因的突变状态,分析结直肠癌组织中3个基因间突变的内在关系,并分析KRAS突变与临床特征的关系。结果 KRAS基因突变率为37.9%,以Gly12Val突变最多,占总突变率的32.8%;BRAF基因突变率为4.0%;PIK3CA突变率为14.1%,以E542K突变最多,占总突变率的36.0%。BRAF基因突变者共7例,全部为KRAS和PIK3CA野生型的患者;PIK3CA基因突变者共25例,其中19例(76.0%)与KRAS存在共同突变。结论结直肠癌患者KRAS基因突变率较高,KRAS基因突变与淋巴结转移和肿瘤进展相关。联合检测KRAS、BRAF及PIK3CA基因对指导临床制定个体化治疗有重要意义。%Objective To detect the mutations of KRAS,BRAF and PIK3CA genes in colorectal cancer and to analyze the relations between the mutation and clinical characteristics. Methods 177 samples of colorectal cancer were collected by surgical excision or biopsy, and DNA was extracted and amplified by using amplification refractory mutation system-polymerase chain reaction. The mutations of KRAS, BRAF and PIK3CA genes were detected and the intrinsic relationships between them were analyzed. The relations between KRAS mutation and clinical characteristics were analyzed. Results The mutation rate of KRAS was 37.9%, mostly Gly12Val mutations; the mutation rate of BRAF was 4.0%; the mutation rate of PIK3CA was 14.1%, mostly E542K mutations. There were 7 patients with BRAF gene mutations, all of which were wild-type of KRAS and PIK3CA; there were 25 patients with PIK3CA gene mutations, 19 (76.0%) of them had KRAS mutation. Conclusion The mutation rate of KRAS gene is high, and KRAS mutations are associated with

  8. Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes.

    Directory of Open Access Journals (Sweden)

    Brian F Niemeyer

    Full Text Available Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications.

  9. 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.

  10. Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations.

    Science.gov (United States)

    Foley, Tyler M; Payne, Susan N; Pasch, Cheri A; Yueh, Alex E; Van De Hey, Dana R; Korkos, Demetra P; Clipson, Linda; Maher, Molly E; Matkowskyj, Kristina A; Newton, Michael A; Deming, Dustin A

    2017-02-09

    Therapeutic targeting of the PI3K pathway is an active area of research in multiple cancer types, including breast and endometrial cancers. This pathway is commonly altered in cancer and plays an integral role in numerous vital cellular functions. Mutations in the PIK3CA gene, resulting in a constitutively active form of PI3K, often occur in colorectal cancer, though the population of patients who would benefit from targeting this pathway has yet to be identified. In human colorectal cancers, PIK3CA mutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). Here, treatment strategies are investigated that target the PI3K pathway in colon cancers with mutations in APC and PIK3CA Colorectal cancer spheroids with Apc and Pik3ca mutations were generated and characterized confirming that these cultures represent the tumors from which they were derived. Pan and alpha isomer-specific PI3K inhibitors did not induce a significant treatment response, whereas the dual PI3K/mTOR inhibitors BEZ235 and LY3023414 induced a dramatic treatment response through decreased cellular proliferation and increased differentiation. The significant treatment responses were confirmed in mice with Apc and Pik3ca-mutant colon cancers as measured using endoscopy with a reduction in median lumen occlusion of 53% with BEZ235 and a 24% reduction with LY3023414 compared with an increase of 53% in controls (P APC and PIK3CA-mutant colorectal cancers. Thus, further clinical studies of dual PI3K/mTOR inhibitors are warranted in colorectal cancers with these mutations. Mol Cancer Res; 15(3); 1-11. ©2016 AACR.

  11. KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer.

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    Chen Mao

    Full Text Available BACKGROUND: To investigate the frequency and relationship of the KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer (CRC. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA was extracted from the formalin-fixed paraffin-embedded (FFPE tissues of 69 patients with histologically confirmed CRC. Automated sequencing analysis was conducted to detect mutations in the KRAS (codons 12, 13, and 14, BRAF (codon 600 and PIK3CA (codons 542, 545 and 1047. PTEN protein expression was evaluated by immunohistochemistry on 3 mm FFPE tissue sections. Statistical analysis was carried out using SPSS 16.0 software. The frequency of KRAS, BRAF and PIK3CA mutations and loss of PTEN expression was 43.9% (25/57, 25.4% (15/59, 8.2% (5/61 and 47.8% (33/69, respectively. The most frequent mutation in KRAS, BRAF and PIK3CA was V14G (26.7% of all mutations, V600E (40.0% of all mutations and V600L (40.0% of all mutations, and H1047L (80.0% of all mutations, respectively. Six KRAS mutant patients (24.0% harbored BRAF mutations. BRAF and PIK3CA mutations were mutually exclusive. No significant correlation was observed between the four biomarkers and patients' characteristics. CONCLUSIONS/SIGNIFICANCE: BRAF mutation rate is much higher in this study than in other studies, and overlap a lot with KRAS mutations. Besides, the specific types of KRAS and PIK3CA mutations in Chinese patients could be quite different from that of patients in other countries. Further studies are warranted to examine their impact on prognosis and response to targeted treatment.

  12. PIK3CA mutations define favorable prognostic biomarkers in operable breast cancer: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Liu YR

    2014-04-01

    Full Text Available Yi-Rong Liu,* Yi-Zhou Jiang,* Wen-Jia Zuo, Ke-Da Yu, Zhi-Ming ShaoDepartment of Breast Surgery, Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China, *These authors contributed equally to this publication Background: Mutations of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA are among the most common genetic aberrations in human breast cancer. At present, controversy exists concerning the prognostic value of the mutations. Methods: We performed a systematic review and meta-analysis to clarify the association between PIK3CA mutations and survival outcomes. A comprehensive, computerized literature search of PubMed, Web of Science databases, the Chinese Biomedical Literature Database, and Wangfang Data until August 27, 2013 was carried out. Eligible studies were included according to specific inclusion criteria. Pooled hazard ratio was estimated by using the fixed effects model or random effects model according to heterogeneity between studies. Results: Eight eligible studies were included in the analysis, all of which were retrospective cohort studies. The overall meta-analysis demonstrated that the PIK3CA mutations were associated with better clinical outcomes (hazard ratio 0.72; 95% confidence interval: 0.57–0.91; P=0.006. None of the single studies materially altered the original results and no evidence of publication bias was found. Further subgroup analysis of mutations in exons 9 and 20 did not show statistical significance. Conclusion: PIK3CA mutations in operable primary breast cancer indicate a good prognosis. Further studies should be conducted to investigate the effect of PIK3CA mutations on clinical outcomes in different histologic types, different molecular subtypes of breast cancer, and different exons of PIK3CA. Keywords: early breast cancer, p110g catalytic subunit of phosphatidylinositol 3-kinase, somatic mutations, prognosis

  13. Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations.

    Directory of Open Access Journals (Sweden)

    Giovanni Brandi

    Full Text Available The employment of anti-epidermal growth factor receptor (EGFR antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC. However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation, while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted.

  14. 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; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-08-27

    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(+)), PIK3CA(H1047R)-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, PIK3CA(H1047R) 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.

  15. 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.

  16. 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

  17. Pik3r1 Is Required for Glucocorticoid-Induced Perilipin 1 Phosphorylation in Lipid Droplet for Adipocyte Lipolysis.

    Science.gov (United States)

    Kuo, Taiyi; Chen, Tzu-Chieh; Lee, Rebecca A; Nguyen, Nguyen Huynh Thao; Broughton, Augusta E; Zhang, Danyun; Wang, Jen-Chywan

    2017-06-01

    Glucocorticoids promote lipolysis in white adipose tissue (WAT) to adapt to energy demands under stress, whereas superfluous lipolysis causes metabolic disorders, including dyslipidemia and hepatic steatosis. Glucocorticoid-induced lipolysis requires the phosphorylation of cytosolic hormone-sensitive lipase (HSL) and perilipin 1 (Plin1) in the lipid droplet by protein kinase A (PKA). We previously identified Pik3r1 (also called p85α) as a glucocorticoid receptor target gene. Here, we found that glucocorticoids increased HSL phosphorylation, but not Plin1 phosphorylation, in adipose tissue-specific Pik3r1-null (AKO) mice. Furthermore, in lipid droplets, the phosphorylation of HSL and Plin1 and the levels of catalytic and regulatory subunits of PKA were increased by glucocorticoids in wild-type mice. However, these effects were attenuated in AKO mice. In agreement with reduced WAT lipolysis, glucocorticoid- initiated hepatic steatosis and hypertriglyceridemia were improved in AKO mice. Our data demonstrated a novel role of Pik3r1 that was independent of the regulatory function of phosphoinositide 3-kinase in mediating the metabolic action of glucocorticoids. Thus, the inhibition of Pik3r1 in adipocytes could alleviate lipid disorders caused by excess glucocorticoid exposure. © 2017 by the American Diabetes Association.

  18. Characteristics and prevalence of KRAS, BRAF, and PIK3CA mutations in colorectal cancer by high-resolution melting analysis in Taiwanese population.

    Science.gov (United States)

    Hsieh, Li-Ling; Er, Tze-Kiong; Chen, Chih-Chieh; Hsieh, Jan-Sing; Chang, Jan-Gowth; Liu, Ta-Chih

    2012-10-09

    The identification of KRAS, BRAF, and PIK3CA mutations before the administration of anti-epidermal growth factor receptor therapy of colorectal cancer has become important. The aim of the present study was to investigate the occurrence of KRAS, BRAF, and PIK3CA mutations in the Taiwanese population with colorectal cancer. This study was undertaken to identify BRAF and PIK3CA mutations in patients with colorectal cancer by high-resolution melting (HRM) analysis. HRM analysis is a new gene scan tool that quickly performs the PCR and identifies sequence alterations without requiring post-PCR treatment. In the present study, DNAs were extracted from 182 cases of formalin-fixed, paraffin-embedded (FFPE) colorectal cancer samples for clinical KRAS mutational analysis by direct sequencing. All the samples were also tested for mutations within BRAF V600E and PIK3CA (exons 9 and 20) by HRM analysis. The results were confirmed by direct sequencing. The frequency of BRAF and PIK3CA mutations is 1.1%, and 7.1%, respectively. Intriguingly, we found that nine patients (4.9%) with the KRAS mutation were coexistent with the PIK3CA mutation. Four patients (2.2%) without the KRAS mutation were existent with the PIK3CA mutation. Two patients (1.1%) without the KRAS mutation were existent with the BRAF mutation. In the current study, we suppose that HRM analysis is rapid, feasible, and powerful diagnostic tool for the detection of BRAF and PIK3CA mutations in a clinical setting. Additionally, our results indicated the prevalence of KRAS, BRAF, and PIK3CA mutational status in the Taiwanese population. Copyright © 2012 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    Serebrov, A. P.; Fomin, A. K.; Kharitonov, A. G.; Lyamkin, V. A.; Prudnikov, D. V.; Ivanov, S. A.; Erykalov, A. N.; Onegin, M. S.; Gridnev, K. A.

    2016-01-01

    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 103-104 cm-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.

  20. 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.

  1. Physiological Levels of Pik3caH1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERα-Positive Tumors

    Science.gov (United States)

    Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G.; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A.

    2012-01-01

    PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3caH1047R, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin−; CD29lo; CD24+; CD61+) cell population. The Pik3caH1047R expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3caH1047R in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3caH1047R mutation in mammary tumorigenesis both in vivo and in vitro. PMID:22666336

  2. Physiological levels of Pik3ca(H1047R) mutation in the mouse mammary gland results in ductal hyperplasia and formation of ERα-positive tumors.

    Science.gov (United States)

    Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A

    2012-01-01

    PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3ca(H1047R), into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin(-); CD29(lo); CD24(+); CD61(+)) cell population. The Pik3ca(H1047R) expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3ca(H1047R) in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3ca(H1047R) mutation in mammary tumorigenesis both in vivo and in vitro.

  3. A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia.

    Science.gov (United States)

    Al Tassan, Nada; Khalil, Dania; Shinwari, Jameela; Al Sharif, Latifa; Bavi, Prashant; Abduljaleel, Zainularifeen; Abu Dhaim, Nada; Magrashi, Amna; Bobis, Steve; Ahmed, Hala; Alahmed, Samaher; Bohlega, Saeed

    2012-02-01

    Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.

  4. PIK3CA mutations define favorable prognostic biomarkers in operable breast cancer: a systematic review and meta-analysis

    OpenAIRE

    Liu YR; Jiang YZ; Zuo WJ; Yu KD; Shao ZM

    2014-01-01

    Yi-Rong Liu,* Yi-Zhou Jiang,* Wen-Jia Zuo, Ke-Da Yu, Zhi-Ming ShaoDepartment of Breast Surgery, Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China, *These authors contributed equally to this publication Background: Mutations of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) are among the most common genetic aberrations in human breast cancer. At present, controversy exists concerning...

  5. GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3.

    Science.gov (United States)

    Zhang, Dongdong; Zhang, Weimin; Li, Dan; Fu, Ming; Chen, Runsheng; Zhan, Qimin

    2015-01-01

    GADD45A is a TP53-regulated and DNA damage-inducible tumor suppressor protein, which regulates cell cycle arrest, apoptosis, and DNA repair, and inhibits tumor growth and angiogenesis. However, the function of GADD45A in autophagy remains unknown. In this report, we demonstrate that GADD45A plays an important role in regulating the process of autophagy. GADD45A is able to decrease LC3-II expression and numbers of autophagosomes in mouse tissues and different cancer cell lines. Using bafilomycin A1 treatment, we have observed that GADD45A regulates autophagosome initiation. Likely, GADD45A inhibition of autophagy is through its influence on the interaction between BECN1 and PIK3C3. Immunoprecipitation and GST affinity isolation assays exhibit that GADD45A directly interacts with BECN1, and in turn dissociates the BECN1-PIK3C3 complex. Furthermore, we have mapped the 71 to 81 amino acids of the GADD45A protein that are necessary for the GADD45A interaction with BECN1. Knockdown of BECN1 can abolish autophagy alterations induced by GADD45A. Taken together, these findings provide the novel evidence that GADD45A inhibits autophagy via impairing the BECN1-PIK3C3 complex formation.

  6. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.

    Science.gov (United States)

    Young, Christian D; Pfefferle, Adam D; Owens, Philip; Kuba, María G; Rexer, Brent N; Balko, Justin M; Sánchez, Violeta; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-07-01

    Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations.

  7. KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors.

    Directory of Open Access Journals (Sweden)

    Ignacio Garrido-Laguna

    Full Text Available PURPOSE: To evaluate clinicopathologic and molecular features of patients with metastatic colorectal cancer (mCRC and their outcomes in early-phase trials using pathway-targeting agents. PATIENTS AND METHODS: We analyzed characteristics of 238 patients with mCRC referred to the phase 1 trials unit at MD Anderson Cancer Center. KRAS, PIK3CA and BRAF status were tested using PCR-based DNA sequencing. RESULTS: Fifty-one percent of patients harbored KRAS mutations; 15% had PIK3CA mutations. In the multivariate regression model for clinical characteristics KRAS mutations were associated with an increased incidence of lung and bone metastases and decreased incidence of adrenal metastases; PIK3CA mutations were marginally correlated with mucinous tumors (p = 0.05. In the univariate analysis, KRAS and PIK3CA mutations were strongly associated. Advanced Duke's stage (p<0.0001 and KRAS mutations (p = 0.01 were the only significant independent predictors of poor survival (Cox proportional hazards model. Patients with PIK3CA mutations had a trend toward shorter progression-free survival when treated with anti-EGFR therapies (p = 0.07. Eighteen of 78 assessable patients (23% treated with PI3K/Akt/mTOR axis inhibitors achieved stable disease [SD] ≥6 months or complete response/partial response (CR/PR, only one of whom were in the subgroup (N = 15 with PIK3CA mutations, perhaps because 10 of these 15 patients (67% had coexisting KRAS mutations. No SD ≥6 months/CR/PR was observed in the 10 patients treated with mitogen-activating protein kinase (MAPK pathway targeting drugs. CONCLUSIONS: KRAS and PIK3CA mutations frequently coexist in patients with colorectal cancer, and are associated with clinical characteristics and outcome. Overcoming resistance may require targeting both pathways.

  8. Expression of P21ras and PIK3CA in human tissues of hepatocellular carcinoma and hepatic cirrhosis%P21ras、PIK3CA在肝癌与肝硬化中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    郑鹏飞; 李玉民; 李汛; 刘士源; 张全保; 何雯婷; 刘涛

    2010-01-01

    Objective To investigate the expression of P21ras and PIK3CA proteins in hepatitis B virus-related hepatocellular carcinoma(HBV-HCC), post-hepatitis B hepatic cirrhosis (HBV-hepatic cirrhosis)and normal hepatic tissues specimen, and their correlation between HBV-HCC and HBV-hepatic cirrhosis tissues.Methods Using immunohistochemistry, the expression of P21ras and PIK3CA proteins in 34 cases of HBV-HCC, 37 cases of HBV-hepatic cirrhosis and 30 cases of normal liver tissues specimen were detected and compared. Results The mean gray scales of P21ras protein in HBV-HCC, HBV-hepatic cirrhosis and normal hepatic tissue specimen were 138.86 ± 2.9, 145. 34 ± 2.06 and 152.07 ± 1.17 (P < 0. 0l), respectively, and were related to the progression of hepatopathy (P <0.01). The mean gray scales of PIK3CA protein in HBV-HCC, HBV-hepatic cirrhosis and normal hepatic tissue specimen were 138.20 ± 3. 14, 149.49 ±0. 78 and 154.71 ± 1.29 (P < 0.01), respectively, and were related to the progression of hepatopathy (P < 0. 01).There were apparent correlation between P21ras and PIK3CA in HBV-HCC and HBV-hepatic cirrhosis respectively (r =0. 64, P <0. 05; r =0. 42, P <0. 05). Conclusion The overexpression of P21ras and PIK3CA in HCC and hepatic cirrhosis tissue suggests that they participate in the tumorigenesis and development of hepatocellular carcinoma and hepatic cirrhosis, and there may be a signal transduction pathway of P21ras-PI3K in HBV-HCC and HBV-hepatic cirrhosis.%目的 研究P21ras和PIK3CA蛋白在乙肝病毒相关性肝细胞肝癌、乙型病毒性肝炎后肝硬化及正常肝组织标本中的表达差异、相关性及意义.方法 收集乙肝病毒相关性肝细胞肝癌组织标本34例、乙型病毒性肝炎后肝硬化37例、正常肝组织标本30例,用免疫组化检测P21ras和PIK3CA蛋白表达水平,并进行比较和相关性分析.结果 P21 ras在乙肝病毒相关性肝细胞肝癌、乙型病毒性肝炎后肝硬化及正常肝组

  9. Meta-analysis on the association of PIK3CA expression with the effects of Kras wild-type mCRC patients treated with anti-EGFR MoAbs%PIK3CA表达水平与抗EGFR单抗治疗KRAS野生型转移性结直肠癌疗效的META分析

    Institute of Scientific and Technical Information of China (English)

    张岱; 裴毅

    2014-01-01

    目的:探讨PIK3CA表达水平与抗EGFR单抗治疗KRAS野生型转移性结直肠癌的疗效关系。方法:通过PubMed、EMBASE、中国知网和万方数据库检索,采用Meta分析的方法,评价PIK3CA表达水平与抗EGFR抗体治疗mCRC患者疗效的关系。结果:共纳入8项研究,在抗EGFR单抗治疗KRAS野生型转移性结直肠癌患者中PIK3CA突变有较短的无进展生存期、总生存期以及较低的肿瘤反应率。结论: PIK3CA是抗EGFR单抗治疗KRAS野生型转移性结直肠癌疗效的预测因子。%Aims This article explore the relationship between the expression of PIK3CA and the efficacy of KRAS wild-type mCRC patients treated with anti-EGFR MoAbs. Methods We performed a systematic literature search in PubMed, EMBASE, CNKI and Wan Fang Digital Journals retrieval, a meta-analysis was used to analyze the relationship between the expression of PIK3CA and anti-EGFR MoAbs effects of KRAS wild-type mCRC patients.Results In the KRAS wild-type metastatic colorectal cancer patients with anti-EGFR MoAbs , PIK3CA mutation was associated shorter PFS, shorter OS and lower ORR.Conclusions The expression level of PIK3CA is a predictive factor for the effects of KRAS wild-type metastatic colorectal cancer patients with anti-EGFR MoAbs.

  10. Functional Analysis of PsPik1 Encoding Type III Phosphatidylinositol 4-kinase in Puccinia striiformis f. sp. tritici%小麦条锈菌III型磷脂酰肌醇4-羟基激酶基因(PsPik1)的功能分析

    Institute of Scientific and Technical Information of China (English)

    何付新; 张阳; 秦娟; 马微; 康振生; 郭军

    2015-01-01

    Objective]The objective of this study is to clone a gene PsPik1 encoding type III PtdIns 4-kinase from Puccinia striiformis f. sp. tritici (Pst) and characterize its function during Pst growth and development. [Method]The full-length cDNA of PsPik1 was obtained using RT-PCR. Bioinformatic methods were used to analyze molecular properties of PsPik1. Quantitative real-time PCR (qRT-PCR) was applied to examine the expression profiles of PsPik1 at twelve different development stages. The transcript level of PsPik1 was calculated by the 2-△△CT method with the EF1 gene of Pst as endogenous reference for normalization. BSMV-HIGS was employed to analyze the function of PsPik1 by knocking down its expression. Selected PsPik1 gene fragment was amplified by PCR from Pst cDNA using primers with restriction enzymes Not I and Pac I sites. Amplicon was ligated into the BSMVγvector generating BSMV:γ:PsPik1-as. The native BSMV:γ:0-as and BSMV:γ:TaPDS-as were used as negative and positive control, respectively. After inoculation with BSMV at the two-leaf stage, wheat seedlings were maintained in a growth chamber and examined for symptoms at regular intervals. After 10-day post virus inoculation, the fourth leaves of inoculated wheat seedlings in the PsPik1 silencing group were inoculated with urediospores of Pst race CYR32. The fourth leaves were collected at 24, 48 and 120 hours post inoculation (hpi) for histological observation and detection of silencing efficiency. Stained leaf segments were examined with an Olympus BX-51 microscope for the numbers of hyphal branches and haustorial mother cells and lengths of infection hyphae at 48 hpi and for colony size at 120 hpi. The incidence of stripe rust was observed and recorded with camera at 12 days post inoculation (dpi).[Result] Based on the bioinformatic analysis and RT-PCR, the full-length cDNA of PsPik1 was cloned. The open reading frame (ORF) of PsPik1 was 4 485 bp in length, encoding 1 494 amino acids containing lipid

  11. Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice

    OpenAIRE

    McCurdy, Carrie E.; Schenk, Simon; Holliday, Michael J.; Philp, Andrew; Houck, Julie A.; Patsouris, David; MacLean, Paul S.; Majka, Susan M.; Klemm, Dwight J.; Friedman, Jacob E. (Jed)

    2012-01-01

    Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance; however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α/p55α/p50α...

  12. 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.

  13. Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology.

    Science.gov (United States)

    Ogino, S; Lochhead, P; Giovannucci, E; Meyerhardt, J A; Fuchs, C S; Chan, A T

    2014-06-05

    Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the 'Provocative Questions' in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the 'colorectal continuum' paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as 'epidemiology of molecular heterogeneity of disease'. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine

  14. Discovery of Colorectal Cancer PIK3CA Mutation as Potential Predictive Biomarker: Power and Promise of Molecular Pathological Epidemiology

    Science.gov (United States)

    Ogino, Shuji; Lochhead, Paul; Giovannucci, Edward; Meyerhardt, Jeffrey A; Fuchs, Charles S; Chan, Andrew T

    2013-01-01

    Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anti-cancer effect of aspirin represents one of the “Provocative Questions” in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent “Molecular Pathological Epidemiology” (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K enzyme plays a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the “colorectal continuum” paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as “epidemiology of molecular heterogeneity of disease”. Because exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Hence, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, etc. MPE research opportunities are currently limited by paucity of tumor molecular data in existing large-scale population-based studies. However, genomic, epigenomic, and molecular pathology testing (e.g., analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) is becoming routine clinical practice. In order for integrative molecular

  15. Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance.

    Science.gov (United States)

    Oikonomou, Eftychia; Koc, Michal; Sourkova, Vladimira; Andera, Ladislav; Pintzas, Alexander

    2011-01-01

    Documented sensitivity of melanoma cells to PLX4720, a selective BRAFV600E inhibitor, is based on the presence of mutant BRAF(V600E) alone, while wt-BRAF or mutated KRAS result in cell proliferation. In colon cancer appearance of oncogenic alterations is complex , since BRAF, like KRAS mutations, tend to co-exist with those in PIK3CA and mutated PI3K has been shown to interfere with the successful application of MEK inhibitors. When PLX4720 was used to treat colon tumours, results were not encouraging and herein we attempt to understand the cause of this recorded resistance and discover rational therapeutic combinations to resensitize oncogene driven tumours to apoptosis. Treatment of two genetically different BRAF(V600E) mutant colon cancer cell lines with PLX4720 conferred complete resistance to cell death. Even though p-MAPK/ ERK kinase (MEK) suppression was achieved, TRAIL, an apoptosis inducing agent, was used synergistically in order to achieve cell death by apoptosis in RKO(BRAFV600E/PIK3CAH1047) cells. In contrast, for the same level of apoptosis in HT29(BRAFV600E/PIK3CAP449T) cells, TRAIL was combined with 17-AAG, an Hsp90 inhibitor. For cells where PLX4720 was completely ineffective, 17-AAG was alternatively used to target mutant BRAF(V600E). TRAIL dependence on the constitutive activation of BRAF(V600E) is emphasised through the overexpression of BRAF(V600E) in the permissive genetic background of colon adenocarcinoma Caco-2 cells. Pharmacological suppression of the PI3K pathway further enhances the synergistic effect between TRAIL and PLX4720 in RKO cells, indicating the presence of PIK3CA(MT) as the inhibitory factor. Another rational combination includes 17-AAG synergism with TRAIL in a BRAF(V600E) mutant dependent manner to commit cells to apoptosis, through DR5 and the amplification of the apoptotic pathway. We have successfully utilised combinations of two chemically unrelated BRAF(V600E) inhibitors in combination with TRAIL in a BRAF(V600E

  16. Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance.

    Directory of Open Access Journals (Sweden)

    Eftychia Oikonomou

    Full Text Available Documented sensitivity of melanoma cells to PLX4720, a selective BRAFV600E inhibitor, is based on the presence of mutant BRAF(V600E alone, while wt-BRAF or mutated KRAS result in cell proliferation. In colon cancer appearance of oncogenic alterations is complex , since BRAF, like KRAS mutations, tend to co-exist with those in PIK3CA and mutated PI3K has been shown to interfere with the successful application of MEK inhibitors. When PLX4720 was used to treat colon tumours, results were not encouraging and herein we attempt to understand the cause of this recorded resistance and discover rational therapeutic combinations to resensitize oncogene driven tumours to apoptosis. Treatment of two genetically different BRAF(V600E mutant colon cancer cell lines with PLX4720 conferred complete resistance to cell death. Even though p-MAPK/ ERK kinase (MEK suppression was achieved, TRAIL, an apoptosis inducing agent, was used synergistically in order to achieve cell death by apoptosis in RKO(BRAFV600E/PIK3CAH1047 cells. In contrast, for the same level of apoptosis in HT29(BRAFV600E/PIK3CAP449T cells, TRAIL was combined with 17-AAG, an Hsp90 inhibitor. For cells where PLX4720 was completely ineffective, 17-AAG was alternatively used to target mutant BRAF(V600E. TRAIL dependence on the constitutive activation of BRAF(V600E is emphasised through the overexpression of BRAF(V600E in the permissive genetic background of colon adenocarcinoma Caco-2 cells. Pharmacological suppression of the PI3K pathway further enhances the synergistic effect between TRAIL and PLX4720 in RKO cells, indicating the presence of PIK3CA(MT as the inhibitory factor. Another rational combination includes 17-AAG synergism with TRAIL in a BRAF(V600E mutant dependent manner to commit cells to apoptosis, through DR5 and the amplification of the apoptotic pathway. We have successfully utilised combinations of two chemically unrelated BRAF(V600E inhibitors in combination with TRAIL in a BRAF(V600

  17. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.

    Science.gov (United States)

    Kotoula, Vassiliki; Karavasilis, Vasilios; Zagouri, Flora; Kouvatseas, George; Giannoulatou, Eleni; Gogas, Helen; Lakis, Sotiris; Pentheroudakis, George; Bobos, Mattheos; Papadopoulou, Kyriaki; Tsolaki, Eleftheria; Pectasides, Dimitrios; Lazaridis, Georgios; Koutras, Angelos; Aravantinos, Gerasimos; Christodoulou, Christos; Papakostas, Pavlos; Markopoulos, Christos; Zografos, George; Papandreou, Christos; Fountzilas, George

    2016-07-01

    The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

  18. 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.

  19. Genetic and bioinformatic analyses of the expression and function of PI3K regulatory subunit PIK3R3 in an Asian patient gastric cancer library

    Directory of Open Access Journals (Sweden)

    Zhou Jin

    2012-08-01

    Full Text Available Abstract Background While there is strong evidence for phosphatidylinositol 3-kinase (PI3K involvement in cancer development, there is limited information about the role of PI3K regulatory subunits. PIK3R3, the gene that encodes the PI3K regulatory subunit p55γ, is over-expressed in glioblastoma and ovarian cancers, but its expression in gastric cancer (GC is not known. We thus used genetic and bioinformatic approaches to examine PIK3R3 expression and function in GC, the second leading cause of cancer mortality world-wide and highly prevalent among Asians. Methods Primary GC and matched non-neoplastic mucosa tissue specimens from a unique Asian patient gastric cancer library were comprehensively profiled with platforms that measured genome-wide mRNA expression, DNA copy number variation, and DNA methylation status. Function of PIK3R3 was predicted by IPA pathway analysis of co-regulated genes with PIK3R3, and further investigated by siRNA knockdown studies. Cell proliferation was estimated by crystal violet dye elution and BrdU incorporation assay. Cell cycle distribution was analysed by FACS. Results PIK3R3 was significantly up-regulated in GC specimens (n = 126, p  Conclusion Using a combination of genetic, bioinformatic, and molecular biological approaches, we showed that PIK3R3 was up-regulated in GC and promoted cell cycle progression and proliferation; and thus may be a potential new therapeutic target for GC.

  20. 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.

  1. PI3K expression and PIK3CA mutations are related to colorectal cancer metastases

    Institute of Scientific and Technical Information of China (English)

    Yu-Fen Zhu; Bao-Hua Yu; Da-Li Li; Hong-Lin Ke; Xian-Zhi Guo; Xiu-Ying Xiao

    2012-01-01

    AIM:To assess the significance of phosphatidylinositol 3-kinase (PI3K) in colorectal cancer (CRC) and toxicity of LY294002 in CRC cells with different metastatic abilities.METHODS:Sixty formalin-fixed and paraffin-embedded CRC tumor specimens were investigated.Adjacent normal colonic mucosa specimens from 10 of these cases were selected as controls.PI3K protein was detected by immunohistochemistry and PIK3CA mutations were investigated by gene sequencing analysis.A flowcytometry-based apoptosis detection kit was used to determine PI3K inhibitor-induced apoptosis in CRC cell lines SW480 and SW620.Expression of phosphorylated protein kinase B in CRC cell lines was detected by Western blotting.RESULTS:There was a significant difference in the proportion of primary lesions (30%,18/60) vs metastatic lesions (46.7%,28/60) that were positive for PI3K (P <0.05).Mutations were detected in exon 9 (13.3%) and exon 20 (8.3%).Out of 60 cases,seven mutations were identified:two hotspot mutations,C.1633G>A resulting in E545A,and C.3140A>G resulting in H1047R; two novel missense mutations C.1624G>A and C.3079G>A;and three synonymous mutations (C.1641G>A,C.1581C>T and C.3027T>A).Exposure of SW480 cells to PI3K inhibitor for 48 h resulted in a significant increase of apoptotic cells in a dose-dependent manner [3.2% apoptotic cells in 0 μmol/L,4.3% in 5 μmol/L,6.3% in 10 μ.mol/L (P < 0.05),and 6.7% in 20 μmol/L (P < 0.05)].Moreover,PI3K inhibitor induced a similar significant increase of apoptotic cells in the SW620 cell line for 48 h [3.3% apoptotic cells in 0 μmol/L,13.3%in 5 μmol/L (P < 0.01),19.2% in 10 μmol/L (P < 0.01),and 21.3% in 20 μmol/L (P < 0.01)J.CONCLUSION:High PI3K expression is associated with CRC metastasis.PI3K inhibitor induced apoptosis in CRC cells and displayed strong cytotoxicity for highly metastatic cells.PI3K inhibition may be an effective treatment for CRC.

  2. 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

  3. The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis.

    Science.gov (United States)

    Engels, Charla C; Kiderlen, Mandy; Bastiaannet, Esther; van Eijk, Ronald; Mooyaart, Antien; Smit, Vincent T H B M; de Craen, Anton J M; Kuppen, Peter J K; Kroep, Judith R; van de Velde, Cornelis J H; Liefers, Gerrit Jan

    2016-04-01

    Studies to confirm the effect of acknowledged prognostic markers in older breast cancer patients are scarce. The aim of this study was to evaluate the prognostic value of HER-2 overexpression and PIK3CA mutations in older breast cancer patients. Female breast cancer patients aged 65 years or older, diagnosed between 1997 and 2004 in a geographical region in The Netherlands, with an invasive, non-metastatic tumour and tumour material available, were included in the study. The primary endpoint was relapse-free period and secondary endpoint was relative survival. Determinants were immunochemical HER-2 scores (0/1+, 2+ or 3+) and PIK3CA as a binary measure. Overall, 1698 patients were included, and 103 had a HER-2 score of 3+. HER-2 overexpression was associated with a higher recurrence risk (5 years recurrence risk 34 % vs. 12 %, adjusted p = 0.005), and a worse relative survival (10 years relative survival 48 % vs. 84 % for HER-2 negative; p = 0.004). PIK3CA mutations had no significant prognostic effect. We showed, in older breast cancer patients, that HER-2 overexpression was significantly associated with a worse outcome, but PIK3CA mutations had no prognostic effect. These results imply that older patients with HER-2 overexpressing breast cancer might benefit from additional targeted anti-HER-2 therapy.

  4. De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly.

    Science.gov (United States)

    Kuhlen, Michaela; Hönscheid, Andrea; Loizou, Loizos; Nabhani, Schafiq; Fischer, Ute; Stepensky, Polina; Schaper, Jörg; Klapper, Wolfram; Siepermann, Meinolf; Schuster, Friedhelm; Meisel, Roland; Borkhardt, Arndt

    2016-01-01

    PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) gain-of-function has recently been described in patients with recurrent sinopulmonary infections, chronic CMV-/EBV-infections, lymphoproliferation, and hypogammaglobulinemia. Here we report a 15-year-old boy with treatment refractory CMV lymphadenitis, severe combined immunodeficiency, microcephaly and a severe developmental defect of Th17 cells. To avoid poor outcome, hematopoietic stem cell transplantation (HSCT) was performed. Subsequently, whole exome sequencing revealed a de novo heterozygous G-to-C mutation (chr5: 5:67,589,663: G>C) at the splice donor site of the PIK3R1 gene. Our data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function. T-cell subsets play a critical role in the regulation of immune response against infectious agents and of autoimmunity and thus may be particularly accountable for the clinical phenotype of affected patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. 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.

  6. Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study.

    Science.gov (United States)

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Bp, Manasa; Minhas, Sachin; Shokeen, Yogender; Aggarwal, Shyam

    2017-02-01

    Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.

  7. 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.

  8. Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.

    Directory of Open Access Journals (Sweden)

    Paraskevi Gkeka

    2014-10-01

    Full Text Available 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.

  9. Effectors of epidermal growth factor receptor pathway: the genetic profiling ofKRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine.

    Directory of Open Access Journals (Sweden)

    Yinchen Shen

    Full Text Available Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61, BRAF (exon 11 and exon 15, PIK3CA (exon 9 and exon 20 and NRAS (codons12, 13 and 61. Clinicopathological characteristics associations were analyzed together with overall survival (OS of metastatic colorectal cancer patients (mCRC. We found 35.9% (242/674 tumors harbored a KRAS mutation, 6.96% (47/675 harbored a BRAF mutation, 9.9% (62/625 harbored a PIK3CA mutation and 4.19% (26/621 harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027 while NRAS mutation almost existed in KRAS wild-types (P<0.001. Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively; BRAF (V600E mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively; proximal tumors appeared a higher PIK3CA mutation (P<0.001 and distant metastatic tumors shared a higher NRAS mutation (P = 0.010. However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.

  10. 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 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......, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer....

  11. Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach.

    Science.gov (United States)

    Kumar, D Thirumal; Doss, C George Priya

    2016-01-01

    Oncogenic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are the most frequently reported in association with various forms of cancer. Several studies have reported the significance of hotspot mutations in a catalytic subunit of PIK3CA in association with breast cancer. Mutations are frequently observed in the highly conserved region of the kinase domain (797-1068 amino acids) of PIK3CA are activating or gain-of-function mutations. Mutation in codon 1047 occurs in the C-terminal region of the kinase domain with histidine (H) replaced by arginine (R), lysine (L), and tyrosine (Y). Pathogenicity and protein stability predictors PhD-SNP, Align GVGD, HANSA, iStable, and MUpro classified H1047R as highly deleterious when compared to H1047L and H1047Y. To explore the inhibitory activity of Wortmannin toward PIK3CA, the three-dimensional structure of the mutant protein was determined using homology modeling followed by molecular docking and molecular dynamics analysis. Docking studies were performed for the three mutants and native with Wortmannin to measure the differences in their binding pattern. Comparative docking study revealed that H1047R-Wortmannin complex has a higher number of hydrogen bonds as well as the best binding affinity next to the native protein. Furthermore, 100 ns molecular dynamics simulation was initiated with the docked complexes to understand the various changes induced by the mutation. Though Wortmannin was found to nullify the effect of H1047R over the protein, further studies are required for designing a better compound. As SNPs are major genetic variations observed in disease condition, personalized medicine would provide enhanced drug therapy.

  12. Mutation analysis of KRAS, NRAS, BRAF and PIK3CA genes in 252 cases of colorectal cancer tissues%252例结直肠癌组织中KRAS、NRAS、 BRAF、PIK3CA的基因突变分析

    Institute of Scientific and Technical Information of China (English)

    刘影; 郑细闰; 朱亚珍; 何青莲; 郑广娟

    2016-01-01

    目的 分析结直肠癌(colorectal cancer,CRC)组织中KRAS、NRAS、BRAF和PIK3CA基因的常见突变类型及其与临床病理指标的关系.方法 对252例CRC石蜡包埋组织进行DNA提取,采用Sanger测序法对KRAS、NRAS、BRAF和PIK3CA基因进行检测,分析各个基因的突变率与临床病理特征的关系,并统计各个基因的突变类型.结果 252例CRC中,KRAS、BRAF、NRAS和PIK3CA突变发生率在性别、年龄、肿瘤部位、病理分期和有无淋巴结转移上差异均无统计学意义(P>0.05);检测阳性突变共140例(55.5%),其中KRAS 113例(44.8%),NRAS 1例(0.4%),BRAF 19例(7.5%),PIK3CA 28例(11.1%),包括PIK3 CA与KRAS、NRAS、BRAF基因发生双突变21例(8.3%);KRAS的主要突变类型包括G12A、G12C、G12D、G12R、G12S、G12V、G13D、T20M、A59T、Q61H、Q61L、Q61P;NRAS仅有1例突变为G12D;BRAF的主要突变类型为V600E、D594G、K601E;PIK3CA的主要突变类型包括E542K、E545K、Q546K、Q546P、Q546R、M1043I、H1047R.PIK3CA与KRAS、NRAS、BRAF之间会发生交叉突变,但KRAS、NRAS、BRAF三者之间基本不存在交叉突变.结论 CRC中KRAS阳性突变率居高,PIK3CA次之,BRAF、NRAS突变率最低,且PIK3CA常与KRAS、NRAS、BRAF发生交叉突变.对CRC患者行KRAS、NRAS、BRAF、PIK3CA等多基因检测,可正确指导并选择抗EGFR单抗药,从而实现真正意义上的个体化靶向治疗.

  13. Asymmetric real-time PCR and multiplex melting curve analysis with TaqMan probes for detecting PIK3CA mutations

    Directory of Open Access Journals (Sweden)

    Irina V. Botezatu

    2015-12-01

    Full Text Available The data in this article are related to the research article entitled “Optimization of melting analysis with TaqMan probes for detection of KRAS, NRAS, and BRAF mutations” Botezatu et al. [1]. Somatic mutations in the PIK3CA gene (“hot spots” in exons 9 and 20 are found in many human cancers, and their presence can determine prognosis and a treatment strategy. An effective method of mutation scanning PIK3CA in clinical laboratories is DNA Melting Analysis (DMA (Vorkas et al., 2010; Simi et al., 2008 [2,3]. It was demonstrated recently that the TaqMan probes which have been long used in Real Time PCR may also be utilized in DMA (Huang et al., 2011 [4]. After optimization of this method Botezatu et al. [1], it was used for multiplex scanning PIK3CA hotspot mutations in formalin-fixed paraffin-embedded (FFPE samples from patients with colorectal and lung cancer.

  14. A novel PIK3CD C896T mutation detected in bilateral sudden sensorineural hearing loss using next generation sequencing:An indication of primary immunodeficiency

    Institute of Scientific and Technical Information of China (English)

    Jing Zou; Xiangqiang Duan; Guiliang Zheng; Zhen Zhao; Shiyue Chen; Pu Dai; Hongliang Zheng

    2016-01-01

    Objective:To investigate immune-related genetic background in bilateral sudden sensorineural hearing loss (SSNHL). Case report and methods: The case is a 45-year-old man presenting with a 7-year history of bilateral profound SSNHL. Blood biochemical testing demonstrated increased levels of total cholesterol (5.88 mmol/L). Tests for hepatitis B showed a positive antibody against the hepatitis B core antigen. Complement C3 was below the normal value, and complement C4 and IgG were in the lower range of normal values. CT images showed a normal inner ear and vestibular aqueduct but round window membranous ossification on both sides. A total number of 232 immune-associated genes were sequenced using the next generation sequencing technique. Results: Mutations were detected in 5 genes, including the phosphoinositide 3-kinase catalytic subunit delta (PIK3CD), caspase recruitment domain-containing protein 9 (CARD9), complement factor H-related (CFHR2), immunoglobulin lambda-like polypeptide 1 Protein (IGLL1), and transmembrane channel-like gene family 8 (TMC8). In the PIK3CD gene, a C896T substitute in exon 7 was detected. This mutation causes primary immunodeficiency and is an autosomal dominant disease. Conclusion: The PIK3CD C896T mutation responsible for primary immunodeficiency may contribute to the onset of bilateral SSNHL with subsequent rapid progression.

  15. Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

    Science.gov (United States)

    Döcker, Dennis; Schubach, Max; Menzel, Moritz; Spaich, Christiane; Gabriel, Heinz-Dieter; Zenker, Martin; Bartholdi, Deborah; Biskup, Saskia

    2015-01-01

    Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly—thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations. PMID:24939587

  16. Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP)--pure coincidence?

    Science.gov (United States)

    Döcker, Dennis; Schubach, Max; Menzel, Moritz; Spaich, Christiane; Gabriel, Heinz-Dieter; Zenker, Martin; Bartholdi, Deborah; Biskup, Saskia

    2015-03-01

    Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactyly--thus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A>G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (>100 × coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (>1000 × coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G>A; p.(Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

  17. Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer

    Science.gov (United States)

    Ibarrola-Villava, Maider; Llorca-Cardeñosa, Marta J.; Tarazona, Noelia; Mongort, Cristina; Fleitas, Tania; Perez-Fidalgo, José Alejandro; Roselló, Susana; Navarro, Samuel; Ribas, Gloria; Cervantes, Andrés

    2015-01-01

    Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10−5) and 73.8% (P = 1.00 × 10−3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10−6), miR-19a-3p (P = 1.23 × 10−4), miR-128-3p (P = 3.49 × 10−4), miR-130b-3p (P = 1.00 × 10−3) and miR-34a-5p (P = 4.00 × 10−3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy. PMID:26334097

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Low-energy pi-pi and pi-K scatterings revisited in three-flavour resummed chiral perturbation theory

    CERN Document Server

    Descotes-Genon, S

    2007-01-01

    Chiral symmetry breaking may exhibit significantly different patterns in two chiral limits: N_f=2 massless flavours (m_u=m_d=0, m_s physical) and N_f=3 massless flavours (m_u=m_d=0=m_s=0). Such a difference may arise due to vacuum fluctuations of s-bar{s} pairs related to the violation of the Zweig rule in the scalar sector, and could yield a numerical competition between contributions counted as leading order and next-to-leading in the chiral expansions of observables. We recall and extend Resummed Chiral Perturbation Theory (ReChPT), a framework that we introduced previously to deal with such instabilities: it requires a more careful definition of the relevant observables and their one-loop chiral expansions. We analyse the amplitudes for low-energy pi-pi and pi-K scatterings within ReChPT, which we match in subthreshold regions with dispersive representations obtained from the solutions Roy and Roy-Steiner equations. Using a frequentist approach, we constrain the quark mass ratio as well as the quark conde...

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

    Directory of Open Access Journals (Sweden)

    Xusheng Bai

    Full Text Available 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.

  1. 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)

  2. MiR-126 regulates proliferation and invasion in the bladder cancer BLS cell line by targeting the PIK3R2-mediated PI3K/Akt signaling pathway

    Directory of Open Access Journals (Sweden)

    Xiao J

    2016-08-01

    Full Text Available Jun Xiao,1 Huan-Yi Lin,2 Yuan-Yuan Zhu,3 Yu-Ping Zhu,1 Ling-Wu Chen2 1Department of Urology, Anhui Provincial Hospital, Anhui Medical University, Hefei, 2Department of Urology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 3Clinical Laboratory, Anhui Provincial Hospital, Anhui Medical University, Hefei, People’s Republic of China Objective: To assess whether microRNA-126 (miR-126 targets phosphatidylinositol 3-kinase regulatory subunit beta (PIK3R2 and to determine the potential roles of miR-126 in regulating proliferation and invasion via the PIK3R2-mediated phosphatidylinositol 3 kinase (PI3K-protein kinase B (Akt signaling pathway in the human bladder BLS cell line. Materials and methods: A recombinant lentivirus (Lv vector expressing miR-216 (Lv-miR-126 was successfully constructed, and Lv-miR-126 and Lv vector were transfected into the BLS cell line. A direct regulatory relationship between miR-126 and the PIK3R2 gene was demonstrated by luciferase reporter assays. To determine whether PIK3R2 directly participates in the miR-126-induced effects in BLS cells, anti-miR-126 and a PIK3R2 small interfering RNA (siRNA were transfected into the BLS cells. Quantitative real-time polymerase chain reaction was used to measure miR-126 and PIK3R2 expressions. 5-Ethynyl-2'-deoxyuridine and colony formation assays to assess cell proliferation, flow cytometry for cell apoptosis and cell cycle analysis, Transwell assays for cell migration and invasion, and Western blots for PIK3R2, PI3K, phosphorylated PI3K (p-PI3K, Akt, and phosphorylated Akt (p-Akt protein expressions were performed. Results: Lv-miR-126 significantly enhanced the relative expression of miR-126 in the BLS cells after infection (P<0.0001. MiR-126 overexpression inhibited the proliferation, cloning, migration, and invasion of BLS cells, promoted cell apoptosis, and induced S phase arrest (all P<0.05. PIK3R2, p-PI3K, and p-Akt protein expressions were significantly

  3. Kollendavate puulehtede aegu / Vahur Kalmre

    Index Scriptorium Estoniae

    Kalmre, Vahur, 1956-

    2005-01-01

    Muutustest Euroopa ajalehtede kujunduses. The Wall Street Journali ümberkujundusest räägib ajalehekujundaja Mario Garcia. Skandinaavia ajalehtede kujundusemuudatustest Rolf F. Rehe sõnul. Kommenteeritakse Mihkel Muti "Sirbi" kujundusemuudatuste vastast mõtteavaldust

  4. 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

  5. Juhendamine juhtimise asemel / Vahur Murutar

    Index Scriptorium Estoniae

    Murutar, Vahur, 1961-

    2003-01-01

    Rets. rmt.: Patrick J. McKenna, David H. Maister. Esimene võrdsete seas. Fontes, Pärnu Konverentsid 2003. Autor selgitab McKenna ja Maisteri raamatule tuginedes, mida eeldab maailmas üha enam populaarsust koguv juhi roll meeskonna treenerina

  6. FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features.

    Directory of Open Access Journals (Sweden)

    Sara A Byron

    Full Text Available Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI and clinicopathological features including overall survival (OS and disease-free survival (DFS were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466; KRAS (87/464; CTNNB1 (88/454 and PIK3CA (104/464. KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05 and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002. Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06 towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II, FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008 and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025 and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045. In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.

  7. A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.

    Science.gov (United States)

    Joshi, Shaurya; Wei, Jianqin; Bishopric, Nanette H

    2016-02-01

    The let-7 family of microRNAs (miRs) regulates critical cell functions, including survival signaling, differentiation, metabolic control and glucose utilization. These functions may be important during myocardial ischemia. MiR-let-7 expression is under tight temporal and spatial control through multiple redundant mechanisms that may be stage-, isoform- and tissue-specific. To determine the mechanisms and functional consequences of miR-let-7 regulation by hypoxia in the heart. MiR-let-7a, -7c and -7g were downregulated in the adult mouse heart early after coronary occlusion, and in neonatal rat ventricular myocytes subjected to hypoxia. Let-7 repression did not require glucose depletion, and occurred at a post-transcriptional level. Hypoxia also induced the RNA binding protein Lin28, a negative regulator of let-7. Hypoxia ineither induced Lin28 nor repressed miR-let-7 in cardiac fibroblasts. Both changes were abrogated by treatment with the histone deacetylase inhibitor trichostatin A. Restoration of let-7g to hypoxic myocytes and to ischemia-reperfused mouse hearts in vivo via lentiviral transduction potentiated the hypoxia-induced phosphorylation and activation of Akt, and prevented hypoxia-dependent caspase activation and death. Mechanistically, phosphatidyl inositol 3-kinase interacting protein 1 (Pik3ip1), a negative regulator of PI3K, was identified as a novel target of miR-let-7 by a crosslinking technique showing that miR-let-7g specifically targets Pik3ip1 to the cardiac myocyte Argonaute complex RISC. Finally, in non-failing and failing human myocardium, we found specific inverse relationships between Lin28 and miR-let-7g, and between miR-let-7g and PIK3IP1. A conserved hypoxia-responsive Lin28-miR-let-7-Pik3ip1 regulatory axis is specific to cardiac myocytes and promotes apoptosis during myocardial ischemic injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. In situ single cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2+ breast cancer

    Science.gov (United States)

    Janiszewska, Michalina; Liu, Lin; Almendro, Vanessa; Kuang, Yanan; Paweletz, Cloud; Sakr, Rita A.; Weigelt, Britta; Hanker, Ariella B.; Chandarlapaty, Sarat; King, Tari A.; Reis-Filho, Jorge S.; Arteaga, Carlos L.; Park, So Yeon; Michor, Franziska; Polyak, Kornelia

    2015-01-01

    Detection of minor genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (Specific-To-Allele PCR – FISH), a novel method for the combined detection of single nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2/ERBB2 amplification within HER2+ breast cancer during neoadjuvant therapy. We found that the two genetic events are not always present within the same cell. Chemotherapy selects for PIK3CA mutant cells, a minor subpopulation in nearly all treatment-naïve samples, and modulates genetic diversity within tumors. Treatment-associated changes in spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant trastuzumab therapy. Our findings support the use of in situ single-cell based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance. PMID:26301495

  9. 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.

    Science.gov (United States)

    De Roock, Wendy; Claes, Bart; Bernasconi, David; De Schutter, Jef; Biesmans, Bart; Fountzilas, George; Kalogeras, Konstantine T; Kotoula, Vassiliki; Papamichael, Demetris; Laurent-Puig, Pierre; Penault-Llorca, Frédérique; Rougier, Philippe; Vincenzi, Bruno; Santini, Daniele; Tonini, Giuseppe; Cappuzzo, Federico; Frattini, Milo; Molinari, Francesca; Saletti, Piercarlo; De Dosso, Sara; Martini, Miriam; Bardelli, Alberto; Siena, Salvatore; Sartore-Bianchi, Andrea; Tabernero, Josep; Macarulla, Teresa; Di Fiore, Frédéric; Gangloff, Alice Oden; Ciardiello, Fortunato; Pfeiffer, Per; Qvortrup, Camilla; Hansen, Tine Plato; Van Cutsem, Eric; Piessevaux, Hubert; Lambrechts, Diether; Delorenzi, Mauro; Tejpar, Sabine

    2010-08-01

    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-KRAS selection era. 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types

  10. PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer.

    Science.gov (United States)

    Yan, Li-Xu; Liu, Yan-Hui; Xiang, Jian-Wen; Wu, Qi-Nian; Xu, Lei-Bo; Luo, Xin-Lan; Zhu, Xiao-Lan; Liu, Chao; Xu, Fang-Ping; Luo, Dong-Lan; Mei, Ping; Xu, Jie; Zhang, Ke-Ping; Chen, Jie

    2016-02-01

    We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR‑21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS

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

    Directory of Open Access Journals (Sweden)

    Zacharenia Saridaki

    Full Text Available 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, 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. CONCLUSIONS: These results

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA)

    Science.gov (United States)

    Burke, John E.; Perisic, Olga; Masson, Glenn R.; Vadas, Oscar; Williams, Roger L.

    2012-01-01

    The p110α catalytic subunit (PIK3CA) is one of the most frequently mutated genes in cancer. We have examined the activation of the wild-type p110α/p85α and a spectrum of oncogenic mutants using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We find that for the wild-type enzyme, the natural transition from an inactive cytosolic conformation to an activated form on membranes entails four distinct events. Analysis of oncogenic mutations shows that all up-regulate the enzyme by enhancing one or more of these dynamic events. We provide the first insight into the activation mechanism by mutations in the linker between the adapter-binding domain (ABD) and the Ras-binding domain (RBD) (G106V and G118D). These mutations, which are common in endometrial cancers, enhance two of the natural activation events: movement of the ABD and ABD–RBD linker relative to the rest of the catalytic subunit and breaking the C2–iSH2 interface on binding membranes. C2 domain mutants (N345K and C420R) also mimic these events, even in the absence of membranes. A third event is breaking the nSH2–helical domain contact caused by phosphotyrosine-containing peptides binding to the enzyme, which is mimicked by a helical domain mutation (E545K). Interaction of the C lobe of the kinase domain with membranes is the fourth activation event, and is potentiated by kinase domain mutations (e.g., H1047R). All mutations increased lipid binding and basal activity, even mutants distant from the membrane surface. Our results elucidate a unifying mechanism in which diverse PIK3CA mutations stimulate lipid kinase activity by facilitating allosteric motions required for catalysis on membranes. PMID:22949682

  14. 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.

  15. Screening of Putative Proteins That are Interacted with NBS-LRR Protein Pik-h by the Yeast Two-Hybrid System%水稻NBS-LRR类抗稻瘟病蛋白Pik-h的互作蛋白筛选

    Institute of Scientific and Technical Information of China (English)

    王加峰; 刘浩; 王慧; 陈志强

    2016-01-01

    【目的】利用酵母双杂交系统,以组成抗稻瘟病基因Pik-h的2个紧密连锁且功能独立的Pikh-1和Pikh-2蛋白为诱饵,在水稻叶片中筛选与之互作的蛋白,以便深入研究抗病基因Pik-h介导的抗病反应途径。【方法】以含抗稻瘟病基因Pik-h的近等基因系IRBL8为材料,取稻瘟病菌(Magnaporthe oryzae)GD0193接种12和24 h后的水稻叶片,等量混合后提取总RNA,按照酵母双杂交试剂盒(Make Your Own “Mate&Plate” Library System)的要求构建水稻叶片靶标cDNA文库。利用快速重组克隆的方法构建pGBKT7-Pikh1和pGBKT7-Pikh2诱饵载体,并分别将它们转化至酵母菌株Y2H Gold,提取细胞总蛋白后利用Western blot检测Pikh1和Pikh2的表达情况,并对这2个诱饵载体自激活和毒性分析后进行酵母双杂交筛选。提取SD/-Ade/-Leu/-Trp/-His/X-α-Gal筛选平板培养基上呈蓝色的酵母单克隆的质粒,将其分别与对应的诱饵载体共转化酵母菌株Y2H Gold,涂布于筛选平板培养基上进行互作的重复验证,将通过重复验证的质粒测序分析所得的序列比对水稻基因组数据库以确定目的基因,并对这些基因进行gene ontology(GO)注释分析以确定其分子功能、生物过程及细胞组成。【结果】靶标cDNA文库的库容量约为2.2×106,插入片段长度均大于400 bp,表明水稻cDNA文库质量高。诱饵载体pGBKT7-Pikh1和pGBKT7-Pikh2均能在酵母细胞中正确表达出对应的Pikh1及Pikh2蛋白,无自激活活性而且对酵母无毒性作用,符合文库筛选的要求。利用含有诱饵载体的酵母菌株Y2H Gold与靶标文库菌株Y187结合(Mating)的方式筛选,获得13个与Pikh-1相互作用的蛋白、5个与Pikh-2相互作用的蛋白,其中有2个与Pikh-1及Pikh-2同时存在相互作用。这些蛋白包括4个在逆境响应或激素信号转导过程中起到重要作用的(辅)转录因子、3

  16. Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

    Science.gov (United States)

    Chen, Jie-Ying; Cheng, Ya-Nan; Han, Lei; Wei, Feng; Yu, Wen-Wen; Zhang, Xin-Wei; Cao, Shui; Yu, Jin-Pu

    2015-01-01

    Objective A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients. Methods Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated. Results Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs. Conclusion K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment. PMID:26175928

  17. Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs:a systemic review and meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Jie-Ying Chen; Ya-Nan Cheng; Lei Han; Feng Wei; Wen-Wen Yu; Xin-Wei Zhang; Shui Cao; Jin-Pu Yu

    2015-01-01

    Objective:A meta-analysis was performed to augment the insuffcient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical effciency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients. Methods:Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated. Results:Mutation in K-ras signiifcantly predicted poor ORR [OR=0.22;95%conifdence interval (CI), 0.13-0.35], shorter PFS (HR=1.56;95%CI, 1.27-1.92), and shorter OS (HR=1.59;95%CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA signiifcantly predicted shorter OS (HR=1.83;95%CI, 1.05-3.20), showed poor ORR (OR=0.70;95%CI, 0.22-2.18), and shorter PFS (HR=1.79;95%CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs. Conclusion:K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will beneift from EGFR-TKI treatment.

  18. NGS detection for Chinese primary lung cancer patients gene mutation on EGFR, KRAS, BRAF and PIK3CA%NGS技术检测中国原发性肺癌患者的EGFR、KRAS、BRAF和PIK3CA基因突变

    Institute of Scientific and Technical Information of China (English)

    支修益; 胡牧; 王鑫

    2015-01-01

    Objective To evaluate the feasibility of application of next generation sequencing (NGS) technology in clinical molecular diagnosis of lung cancer. Method The NGS platform-Ion Torrent was utilized in this study to examine the mutational status of EGFR, KRAS, BRAF and PIK3CA in 30 cases of lung cancer. The NGS results were compared with qPCR results. Result The technical parameters of NGS method were stable and the NGS results were entirely consistent with qPCR results (100%). Conclusion After further technical validation of more clinical samples, NGS technology is expected to be applied broadly in clinical setting. It is believed to elevate the molecular diagnosis and individualized treatment of lung cancer to a new level.%目的:评估下一代测序(NGS)技术在原发性肺癌临床分子诊断中应用的可行性。方法本研究应用Ion Torrent NGS平台,一次性检测30例肺癌病理样本EGFR、KRAS、BRAF和PIK3CA基因的突变情况,并与实时荧光定量核酸扩增检测(qPCR)技术检测结果进行对比。结果 NGS检测方法技术参数稳定,且与qPCR技术检测结果完全一致(100%)。结论经过更多临床样本的方法验证后, NGS技术有望得到临床推广,并将原发性肺癌分子诊断和个体化诊疗提高到一个新的水平。

  19. 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.

  20. 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.

  1. PTEN/PIK3CA genes are frequently mutated in spontaneous and medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumours of tree shrews.

    Science.gov (United States)

    Xia, Hou-Jun; He, Bao-Li; Wang, Chun-Yan; Zhang, Hai-Lin; Ge, Guang-Zhe; Zhang, Yuan-Xu; Lv, Long-Bao; Jiao, Jian-Lin; Chen, Ceshi

    2014-12-01

    Tree shrew has increasingly become an attractive experimental animal model for human diseases, particularly for breast cancer due to spontaneous breast tumours and their close relationship to primates and by extension to humans. However, neither normal mammary glands nor breast tumours have been well characterised in the Chinese tree shrew (Tupaia belangeri chinensis). In this study, normal mammary glands from four different developmental stages and 18 spontaneous breast tumours were analysed. Haematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) showed that normal mammary gland morphology and structures of tree shrews were quite similar to those found in humans. Spontaneous breast tumours of tree shrews were identified as being intraductal papilloma, papillary carcinoma, and invasive ductal carcinoma with or without lung metastasis. To further analyse breast cancer tumours among tree shrews, 40 3-4 month-old female tree shrews were orally administrated 20 mg 7,12-dimethylbenz(a)anthracene (DMBA) or peanut oil thrice, and then, 15 of these DMBA administrated tree shrews were implanted with medroxyprogesterone acetate (MPA) pellets. DMBA was shown to induce breast tumours (12%) while the addition of MPA increased the tumour incidence (50%). Of these, three induced breast tumours were intraductal papillary carcinomas and one was invasive ductal carcinoma (IDC). The PTEN/PIK3CA (phosphatase and tensin homologue/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), but not TP53 and GATA3, genes are frequently mutated in breast tumours, and the PTEN/PIK3CA gene mutation status correlated with the expression of pAKT in tree shrew breast tumours. These results suggest that tree shrews may be a promising animal model for a subset of human breast cancers with PTEN/PIK3CA gene mutations.

  2. Vesiviljelus : [kalakasvatus ja turustus] / 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. 118-121. Statistikaameti andmeil oli Eestis 2003. a. 30 vesiviljelusega tegelevat ettevõtet. Diagramm. Tabelid

  3. Enim kasvas poolehoid IRLile / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Turu-uuringute AS-is valminud 787 vastajaga küsitlusest selgus, et võrreldes oktoobriga erakondade toetus novembris muutunud ei ole, küll on aga augustiga võrreldes kasvanud valitsusliidu erakondade ja Keskerakonna toetus. Diagramm

  4. 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

  5. Baden-Badenist kostab sokulaulu / Vahur Afanasjev

    Index Scriptorium Estoniae

    Afanasjev, Vahur, 1979-

    2005-01-01

    Arvustus: Vaginov, Konstantin. Sokulaul: [romaan] / vene keelest tõlkinud Rein Saluri. [Tallinn] : Kultuurileht, 2005 ; Tsõpkin, Leonid. Suvi Baden-Badenis / vene keelest tõlkinud Jüri Ojamaa ; Susan Sontagi järelsõna. Tallinn : Tänapäev, 2005

  6. Pole demokraatiat, pole probleemi / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-

    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

  7. 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

  8. Kotkapoja sünd / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-

    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

  9. 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

  10. Hollandi saadik pole kiusamiskaebusi esitanud / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Hollandi suursaadik Hans Glaubitz, kes väidab, et lahkub Eestist tema mustanahalise homoseksuaalse abikaasa tagakiusamise tõttu, ei ole varem Eesti või Hollandi välisministeeriumile sellekohaseid kaebusi esitanud

  11. Lapsed tervitasid keisripaari lauluga / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Jaapani keisri Akihito ja keisrinna Michiko auks Tallinna lauluväljakul toimunud kontserdist. President Toomas Hendrik Ilves andis külaliste auks Kadrioru kunstimuuseumis piduliku lõunasöögi. Vt. samas: Vastastikused kingitused

  12. Jõumees Baricco / Vahur-Paul Põldma

    Index Scriptorium Estoniae

    Põldma, Vahur-Paul

    2008-01-01

    Alessandro Bariccost, kes on esseistis, dramaturg, režissöörist, stsenarist. Tema tööd on enamasti seotud muusika ja muusikutega. Katkendeid tema esseedest Rossini ja Beethoveni muusikast tõlkinud ja redigeerinud M Põldma

  13. 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

    Aaij, R.; Adinolfi, M.; Affolder, A.; Ajaltouni, Z.; Albrecht, J.; Alessio, F.; Alexander, M.; Ali, S.; Alkhazov, G.; Cartelle, P. Alvarez; Alves, A.A.; Amato, S.; Amerio, S.; Amhis, Y.; An, L.; Anderlini, L.; Anderson, J.; Andreassen, R.; Andreotti, M.; Andrews, J.E.; Appleby, R.B.; Gutierrez, O. Aquines; 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.; Bjørnstad, 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.; Brand, J. van den; 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.; Gomez, M. Calvo; Camboni, A.; Campana, P.; Perez, D. Campora; Carbone, A.; Carboni, G.; Cardinale, R.; Cardini, A.; Carranza-Mejia, H.; Carson, L.; Akiba, K. Carvalho; 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.; Vidal, X. Cid; 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.; Torres, M. Cruz; 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.; Déléage, N.; Derkach, D.; Deschamps, O.; Dettori, F.; Di Canto, A.; Dijkstra, H.; Donleavy, S.; Dordei, F.; Dorigo, M.; Suárez, A. Dosil; 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.; Rifai, I. El; Elsasser, Ch.; Esen, S.; Falabella, A.; Färber, C.; Farinelli, C.; Farley, N.; Farry, S.; Fay, RF; Ferguson, D.; Albor, V. Fernandez; Rodrigues, F. Ferreira; 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.; Torreira, A. Gallas; Galli, D.; Gallorini, S.; Gambetta, S.; Gandelman, M.; Gandini, P.; Gao, Y.; Garofoli, J.; Tico, J. Garra; Garrido, L.; Gaspar, C.; Gauld, R.; Gavardi, L.; Geraci, A.; Gersabeck, E.; Gersabeck, M.; Gershon, T.; Ghez, Ph.; Gianelle, A.; Giani', S.; Gibson, V.; Giubega, L.; Gligorov, V.V.; Göbel, C.; Golubkov, D.; Golutvin, A.; Gomes, A.; Gordon, H.; Gotti, C.; Gándara, M. Grabalosa; Diaz, R. Graciani; Cardoso, L. A. Granado; Graugés, E.; Graziani, G.; Grecu, A.; Greening, E.; Gregson, S.; Griffith, P.; Grillo, L.; Grünberg, 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.; Morata, J. A. Hernando; 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.; 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.; Gac, R. Le; van Leerdam, J.; Lees, J. -P.; Lefèvre, R.; Leflat, A.; Lefrançois, 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.; Mapelli, A.; Maratas, J.; Marchand, J.F.; Marconi, U.; Benito, C. Marin; Marino, P.; Märki, R.; Marks, J.; Martellotti, G.; Martens, A.; Sánchez, A. Martín; Martinelli, M.; Santos, D. Martinez; Vidal, F. Martinez; Tostes, D. Martins; 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.; Rodriguez, J. Molina; Monteil, S.; Moran, D.; Morandin, M.; Morawski, P.; Mordà, A.; Morello, M.J.; Moron, J.; Mountain, R.; Muheim, F.; Müller, 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.; Goicochea, J. M. Otalora; 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.; Alvarez, A. Pazos; Pearce, A.; Pellegrino, A.; Altarelli, M. Pepe; Perazzini, S.; Trigo, E. Perez; Perret, P.; Perrin-Terrin, M.; Pescatore, L.; Pesen, E.; Petridis, K.; Petrolini, A.; Olloqui, E. Picatoste; Pietrzyk, B.; Pilař, T.; Pinci, D.; Pistone, A.; Playfer, S.; Casasus, M. Plo; Polci, F.; Poluektov, A.; Polycarpo, E.; Popov, A.; Popov, D.; Popovici, B.; Potterat, C.; Powell, A.; Prisciandaro, J.; Pritchard, A.; Prouve, C.; Pugatch, V.; Navarro, A. Puig; 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.; Reis, A. C. dos; Ricciardi, S.; Richards, A.; Rihl, M.; Rinnert, K.; Molina, V. Rives; Romero, D. A. Roa; Robbe, P.; Rodrigues, A.B.; Rodrigues, E.; Perez, P. Rodriguez; Roiser, S.; Romanovsky, V.; Vidal, A. Romero; Rotondo, M.; Rouvinet, J.; Ruf, T.; Ruffini, F.; Ruiz, H.; Valls, P. Ruiz; Sabatino, G.; Silva, J. J. Saborido; Sagidova, N.; Sail, P.; Saitta, B.; Guimaraes, V. Salustino; Mayordomo, C. Sanchez; Sedes, B. Sanmartin; Santacesaria, R.; Rios, C. Santamarina; 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, J.; Smith, M.; Snoek, H.; Sokoloff, M.D.; Soler, F.J.P.; Soomro, F.; Souza, D.; De Paula, B. Souza; Spaan, B.; Sparkes, A.; 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.; Gomez, R. Vazquez; Regueiro, P. Vazquez; Sierra, C. Vázquez; Vecchi, S.; Velthuis, J.J.; Veltri, M.; Veneziano, G.; Vesterinen, M.; Viaud, B.; Vieira, D.; Diaz, M. Vieites; 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 $\\Delta\\Gamma_{s}$.

  14. Lack of Association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and Carotid Intima-Media Thickness, Carotid Plaques, and Cardiovascular Disease in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Raquel López-Mejías

    2014-01-01

    Full Text Available Introduction. Rheumatoid arthritis (RA is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT and presence/absence of carotid plaques and CV disease in RA. Material and Methods. 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. Results. No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. Conclusion. Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA.

  15. 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.

    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 $\\Delta\\Gamma_{s}$.

  16. Management of Heat and Cold Stress -- Guidance to NATO Medical Personnel (Gestion des contraintes thermiques (chaleur et froid) Conseils aux personnels medicaux de I’OTAN)

    Science.gov (United States)

    2013-12-01

    Brussels BELGIUM Christian.carton@mil.be Prof. Dr. Vahur Ööpik Institute of Exercise Biology and Physiotherapy Estonian Centre of Behavioural and...including prior history of heat stroke , use of medications, alcohol or drugs abuse). Fit, healthy, heat acclimatized, fully hydrated, and well-rested...casualties (heat exhaustion and heat stroke ). For these casualties, preparation should include arrangements for rapid cooling (cool or cold water

  17. Global gene expression profiling of a mouse model of ovarian clear cell carcinoma caused by ARID1A and PIK3CA mutations implicates a role for inflammatory cytokine signaling

    Directory of Open Access Journals (Sweden)

    Ronald L. Chandler

    2015-09-01

    Full Text Available Ovarian clear-cell carcinoma (OCCC is an aggressive form of epithelial ovarian cancer (EOC. OCCC represents 5–25% of all EOC incidences and is the second leading cause of death from ovarian cancer (Glasspool and McNeish, 2013 [1]. A recent publication by Chandler et al. reported the first mouse model of OCCC that resembles human OCCC both genetically and histologically by inducing a localized deletion of ARID1A and the expression of the PIK3CAH1047R substitution mutation (Chandler et al., 2015 [2]. We utilized Affymetrix Mouse Gene 2.1 ST arrays for the global gene expression profiling of mouse primary OCCC tumor samples and animal-matched normal ovaries to identify cancer-dependent gene expression. We describe the approach used to generate the differentially expressed genes from the publicly available data deposited at the Gene Expression Omnibus (GEO database under the accession number GSE57380. These data were used in cross-species comparisons to publically available human OCCC gene expression data and allowed the identification of coordinately regulated genes in both mouse and human OCCC and supportive of a role for inflammatory cytokine signaling in OCCC pathogenesis (Chandler et al., 2015 [2].

  18. Haṭhayogapradīpikā

    DEFF Research Database (Denmark)

    Olesen, Bjarne Wernicke; Einarsen, Silje Lyngar

    (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 askese i almindelighed - såvel i den...

  19. 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).

  20. 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...

  1. 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

  2. Nord Streami toetajad võtavad rivvi / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-

    2007-01-01

    Autor arutleb Vene-Saksa Läänemerre rajatava gaasijuhtme üle ja leiab, et Eesti ei peaks Nord Streamile merepõhja uuringuiks luba andma, sest see seaks meid sõltuvusse Venemaast. Vastukaja Andres Kasekampi artiklile 10. sept. Postimehes

  3. 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

  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. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. Muinsuskaitsjad võtaks Sakala ajutise kaitse alla / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Muinsuskaitse nõukogu juures tegutseva arhitektuurimälestiste ekspertnõukogu ettepanekust võtta Tallinna kesklinnas asuv Sakala keskus ajutise kaitse alla. Hoone interjööri säilitamisest, kommenteerivad Kalev Uustalu, Raivo Palmaru

  11. Merkel kinnitab toetust Gruusiale / Vahur Koorits, Liisi Poll

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 27. aug. 2008, lk. 2. Saksamaa liidukantsleri Angela Merkeli visiidist Tallinna, kus kohtumisel peaminister Andrus Ansipiga arutati ka energeetikaküsimusi. A. Merkeli sõnul peab Venemaa täitma rahulepingut Gruusiaga ning peab rahvusvahelise õigusega ühildamatuks Lõuna-Osseetia ja Abhaasia sõltumatuse tunnustamist Venemaa poolt. Vt. samas: Lääneriikide esindajad mõistsid Venemaa sammu hukka. Juuresoleval fotol Angela Merkel ja president Toomas Hendrik Ilves ühisel jalutuskäigul Kumust presidendilossi. Vt. ka lk. 2 karikatuur Angela Merkelist, president T. H. Ilvesest ja peaminister Andrus Ansipist

  12. 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"

  13. Prantsuse uus armee - pisem, parem ja NATOs / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Prantsusmaal valminud valgest raamatust, kus on kirjas Prantsuse armee arengutendentsid, millest olulisim on liitumine Euroopa kaitsestruktuuridega. Vt. samas Karin Volmer. De Gaulle ambitsioonide ja hirmu piiril ; Kommentaarid Euroopa ajalehtedest

  14. Eestlased tulevad mitme maa ja mere tagant koju / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2010-01-01

    Islandi vulkaanituhast põhjustatud lennuliikluse ajutine seiskumine tingis riigijuhtide ja ametnike reisimise busside ja rongidega. Kaart; Diagramm. President Toomas Hendrik Ilves koos kaaskonnaga alustas tagasiteed Türgi-visiidilt autodega läbi Bulgaaria, Serbia, Ungari, Slovakkia, Poola, Leedu ja Läti. Eesti riigipea kohtus Serbia riigipea Boris Tadic'iga ning kavatseb 20. aprillil 2010 asetada pärja Poola presidendi Lech Kaczynski ja tema abikaasa hauale Krakowis. Vt. ka foto lk. 1. Ametlik visiit Türgi Vabariiki 15.-21.04.2010

  15. 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

  16. 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

  17. Rohelisi lõhestab isa kingitus pojale / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2010-01-01

    Erakond Eestimaa Rohelised otsustas anda erakonna liikme Valdur Lahtvee poja Rasmus Lahtvee firmale OÜ Ramses Grupp 115 000 krooni 2011. aasta riigikogu valimiste kampaania tehniliseks käivitamiseks. Erakonnas hiljuti toimunud võimupöörde eelne juhatus on varem seda lepingut keeldunud heaks kiitmast

  18. 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

  19. Euro pole enam mägede taga / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2003-01-01

    Ühisraha kasutuselevõtuks peab iga riik vastama majandus- ja rahapoliitilistele eeldustele, mis näitavad valmisolekut uuele rahale üleminekuks. Eestis tuleb euro kasutusele mitte varem kui 2006. a.

  20. Merkel kinnitab toetust Gruusiale / Vahur Koorits, Liisi Poll

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Ilmunud ka: Postimees : na russkom jazõke 27. aug. 2008, lk. 2. Saksamaa liidukantsleri Angela Merkeli visiidist Tallinna, kus kohtumisel peaminister Andrus Ansipiga arutati ka energeetikaküsimusi. A. Merkeli sõnul peab Venemaa täitma rahulepingut Gruusiaga ning peab rahvusvahelise õigusega ühildamatuks Lõuna-Osseetia ja Abhaasia sõltumatuse tunnustamist Venemaa poolt. Vt. samas: Lääneriikide esindajad mõistsid Venemaa sammu hukka. Juuresoleval fotol Angela Merkel ja president Toomas Hendrik Ilves ühisel jalutuskäigul Kumust presidendilossi. Vt. ka lk. 2 karikatuur Angela Merkelist, president T. H. Ilvesest ja peaminister Andrus Ansipist

  1. 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

  2. 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

  3. Nord Streami toetajad võtavad rivvi / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-

    2007-01-01

    Autor arutleb Vene-Saksa Läänemerre rajatava gaasijuhtme üle ja leiab, et Eesti ei peaks Nord Streamile merepõhja uuringuiks luba andma, sest see seaks meid sõltuvusse Venemaast. Vastukaja Andres Kasekampi artiklile 10. sept. Postimehes

  4. Sotsid kaotasid äsja saavutatud toetuse / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Turu-uuringute AS-i küsitluse tulemustest, mille järgi SDE toetus langes 4% võrra, mis võib olla tingitud suhtumise pärast töölepinguseadusesse ja vabadussamba küsimusse. Diagramm: IRL tõusis, sotsid langesid

  5. 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

  6. 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"

  7. 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

  8. 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

  9. Eestlased tulevad mitme maa ja mere tagant koju / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2010-01-01

    Islandi vulkaanituhast põhjustatud lennuliikluse ajutine seiskumine tingis riigijuhtide ja ametnike reisimise busside ja rongidega. Kaart; Diagramm. President Toomas Hendrik Ilves koos kaaskonnaga alustas tagasiteed Türgi-visiidilt autodega läbi Bulgaaria, Serbia, Ungari, Slovakkia, Poola, Leedu ja Läti. Eesti riigipea kohtus Serbia riigipea Boris Tadic'iga ning kavatseb 20. aprillil 2010 asetada pärja Poola presidendi Lech Kaczynski ja tema abikaasa hauale Krakowis. Vt. ka foto lk. 1. Ametlik visiit Türgi Vabariiki 15.-21.04.2010

  10. 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

  11. 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

  12. 高表达p55PIK细胞株的建立及其对结肠癌LoVo细胞周期的影响%Establishment of pS5PIK High-expression Cell Line and Its Effects on Cell Cycle of LoVo Cells

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    目的 构建p55PIK高表达的质粒,筛选稳定高表达p55PIK的LoVo细胞系,检测其对LoVo细胞周期的影响.方法 以基因组cDNA为模板,聚合酶链反应(PCR)扩增目的片段,通过限制性核酸内切酶进行酶切,T4 DNA连接酶将目的片段插入pcDNA3.1质粒中;将携带p55PIK基因的pcDNA3.1质粒转染LoVo细胞,加入适量的G418筛选(500μg/mL),并通过实时定量PCR(qPCR)和Western blot方法检测p55PIK mRNA水平和蛋白水平,进一步通过BrdU/PI掺入法检测p55PIK对LoVo细胞周期和DNA合成的影响.结果 成功构建了p55PIK高表达的质粒,并筛选出稳定高表达p55PIK的LoVo细胞系;在LoVo细胞中高表达p55PIK能够促进细胞S期的进程和DNA的合成.结论 成功构建了pcDNA3.1-p55PIK质粒,并筛选出p55PIK稳定高表达的LoVo细胞系,高表达p55PIK能够促进LoVo细胞S期的进程和DNA的合成.

  13. 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.

  14. Tõendid praktikasse / Ere Uibu, Ester Öpik

    Index Scriptorium Estoniae

    Uibu, Ere

    2016-01-01

    Eesti Õdede Liidu konverentsil tunnustati meditsiiniõdesid Sirje Kõvermäge, Kadri Piiri, Evelyn Evertit, Ere Uibut, Jane Freimani, Reet Tohvret, Teija Toivarit, Jane Remmerit, Ülle Tammsaart, Lily Parmu ja Kätlin Lünekundu

  15. 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...

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Seeder : Talleggi farmi kanu ootab tõenäoliselt ees hukkamine / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Newcastle'i tõppe nakatunud lindude tapmine on vajalik, sest vaid nii saab peatada ülinakkava taudi levikut, mis võib hävitada kogu nakatunud kanade populatsiooni. Põllumajandusminister Helir-Valdor Seederi esitatud ettepaneku kohaselt tuleb linnukasvatajatel hakata kanu laastava tõve vastu vaktsineerima. Lisa: Kanade teekond

  3. Jäätmeprobleem võib tuumaenergia kalliks ajada / Vahur Koorits ; kommenteerinud Ferran Tarradellas Espuny

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Kui Eestisse ehitatakse tuumajaam, tuleb rajada ka jäätmehoidla ohtlikest kõrgaktiivsetest tuumajäätmetest vabanemiseks. Kaart: Tuumajäätmete matmine Soome Olkiluotosse rajatava jäätmejaama näitel

  4. 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

  5. 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

  6. 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

  7. 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"

  8. Ränk linnuhaigus ähvardab Talleggi 200 000 kana surmaga gaasikambris / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Vt. ka Postimees : na russkom jazõke 23. okt., lk. 3. Eesti suurima linnulihatootja Talleggi lindla kanadel kahtlustatakse Newcastle'i tõbe, sulelistele ohtlikku nakkushaigust. Lisa: Inimestele ohutu Newcastle'i tõbi

  9. Korruptsioon ei valmista Eestis uuringu andmeil tõsist peavalu / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Ilmunud ka: Postimees : na russkom jazõke 7. nov. lk. 5. Organisatsiooni Transparency International 2006. aasta korruptsiooni tajumise indeksist. Ühingu Korruptsioonivaba Eesti tegevjuht Agu Laius tutvustab uuringut. Diagramm: Eesti tõusis korruptsiooni tajumise tabelis

  10. 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

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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"

  17. 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"

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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"

  3. ENPA president jätkas Tallinnaski Eesti-kriitikat / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Ilmunud ka: Postimees : na russkom jazõke, 20. sept. 2007, lk. 4. Postimees lüh. Euroopa Nõukogu Parlamentaarse Assamblee president Rene van der Linden külastas Eestit ja kritiseeris Eesti kodakondsuspoliitikat ja soovitas investeerida enam suhetesse Venemaaga. Välisminister Urmas Paeti ja ENPA delegatsiooni juhi Andres Herkeli seisukohad

  4. 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

  5. Lukas asub võitlusse kalliste kooliõpikutega / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2007-01-01

    Haridusminister Tõnis Lukas kirjutas alla määrusele, mille järgi tuleb kirjastustel esitada haridus- ja teadusministeeriumile alluvale eksami- ja kvalifikatsioonikeskusele õpiku või õppematerjali makett

  6. 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"

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Kaasaegne kunst ja selle kontsentratsioon hõimurahva pealinnas / Vahur Luhtsalu

    Index Scriptorium Estoniae

    Luhtsalu, Vahur

    2000-01-01

    Budapesti Sügisfestivalist, mille eesmärk on teha arusaadavaks kaasaegne kunst (muusika, teater, tantsukunst, kujutav kunst jm.) laiemale ringile. Pikemalt tantsu- ja muusikasündmustest. Széchenyi Kirjanduse ja Kunsti Akadeemiast.

  18. Ansip jäi küsitluses Savisaarele alla / 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 ebapopulaarseim avaliku elu tegelane. Kõige positiivsemaks avaliku elu tegelaseks peeti olümpiavõitja Gerd Kanterit, president Toomas Hendrik Ilvese poolt oli 7 % ja proua Evelin Ilvese poolt 3 % küsitletutest

  19. 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

  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. Korruptsioon ei valmista Eestis uuringu andmeil tõsist peavalu / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Ilmunud ka: Postimees : na russkom jazõke 7. nov. lk. 5. Organisatsiooni Transparency International 2006. aasta korruptsiooni tajumise indeksist. Ühingu Korruptsioonivaba Eesti tegevjuht Agu Laius tutvustab uuringut. Diagramm: Eesti tõusis korruptsiooni tajumise tabelis

  2. 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.

  3. V ozhidanii "tjomnoi loshadki" / Alla Plotkina

    Index Scriptorium Estoniae

    Plotkina, Alla

    2005-01-01

    7. juunil lõpeb alates 1995. a. Eesti Panka juhtinud Vahur Krafti ametiaeg. Eesti Panga presidendiks kandideerivad senine panga president Vahur Kraft ja Riigikogu liige Andres Lipstok. 2000. a. toimunud Eesti Panga presidendi valimistest

  4. V ozhidanii "tjomnoi loshadki" / Alla Plotkina

    Index Scriptorium Estoniae

    Plotkina, Alla

    2005-01-01

    7. juunil lõpeb alates 1995. a. Eesti Panka juhtinud Vahur Krafti ametiaeg. Eesti Panga presidendiks kandideerivad senine panga president Vahur Kraft ja Riigikogu liige Andres Lipstok. 2000. a. toimunud Eesti Panga presidendi valimistest

  5. 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

  6. Üks miin jälle lõhatud, paarkümmend tuhat veel / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Ilmunud ka: Postimees : na russkom jazõke 12. sept. lk. 3. Tallinna lahes toimunud miinitõrjeoperatsioonil Open Spirit lõhati miin kaitseminister Jürgen Ligi, ajakirjanike, mitmete riikide sõjaväelaste ja diplomaatide silme all

  7. 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

  8. "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

  9. 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"

  10. Omavalitsusjuhtide palgaralli jätkus täistuuridel / Vahur Koorits, Lauri Linnamäe, Gert Hankewitz

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2009-01-01

    Tähtsamate omavalitsusjuhtide, riigile kuuluvate ettevõtete juhtide ja pea kõigi oluliste infrastruktuuriettevõtete juhtide sissetulekud on tunduvalt tõusnud. Vt. samas: Riigi rahakotirauad avanesid ka mullu lahkelt enamikule tippjuhtidest; Aastal 2008 üle miljoni krooni teeninud riigipalgalised. Lisatud statistilised tabelid, kus on teiste seas ära toodud ka president Toomas Hendrik Ilvese palk 2007. ja 2008. a.

  11. 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"

  12. Tähtis on oskus lahendada klassikalisi küsimusi / Valdek Kulbach ; interv. Vahur Mägi

    Index Scriptorium Estoniae

    Kulbach, Valdek, 1927-

    2004-01-01

    Tallinna Tehnikaülikooli professor Valdek Kulbach on osalenud Tallinna ja Tartu laululava kõlaekraani, Tartu Jaani kiriku konstruktsioonide, Tartu jalakäijate ja Nõmme suusatajate terassilla arvutamisel ja ehitamisel, tegeleb Saaremaa püsiühendus teemaga, Suure väina silla ehitamise probleemidega

  13. 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

  14. 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

  15. 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

  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. Charmless decays B->pipi, piK and KK in broken SU(3)symmetry

    CERN Document Server

    Wu, Y L; Wu, Yue-Liang; Zhou, Yu-Feng

    2005-01-01

    Charmless B decay modes $B \\to \\pi \\pi, \\pi K$ and $KK$ aresystematically investigated with and without flavor SU(3) symmetry. Independent analyses on $\\pi \\pi$ and $\\pi K$ modes both favor a large ratio between color-suppressed tree ($C$) and tree ($T)$ diagram, which suggests that they are more likely to originate from long distance effects. The sizes of QCD penguin diagrams extracted individually from $\\pi\\pi$, $\\pi K$ and $KK$ modes are found to follow a pattern of SU(3) breaking in agreement with the naive factorization estimates. Global fits to these modes are done under various scenarios of SU(3)relations. The results show good determinations of weak phase $\\gamma$ in consistency with the Standard Model (SM), but a large electro-weak penguin $(P_{\\tmop{EW}})$ relative to $T + C$ with a large relative strong phase are favored, which requires an big enhancement of color suppressed electro-weak penguin ($P_{\\tmop{EW}}^C$) compatible in size but destructively interfering with $P_{\\tmop{EW}}$ within the SM,...

  19. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer.

    Science.gov (United States)

    De Roock, Wendy; De Vriendt, Veerle; Normanno, Nicola; Ciardiello, Fortunato; Tejpar, Sabine

    2011-06-01

    The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.

  20. Isospin breaking corrections to low-energy pi-K scattering

    CERN Document Server

    Nehme, A Z

    2002-01-01

    We evaluate the matrix elements for the processes pi^0 K^0 -> pi^0 K^0 and pi^- K^+ -> pi^0 K^0 in the presence of isospin breaking terms at leading and next-to-leading order. As a direct application the releveant combination of the S-wave scattering lengths involved in the pion-kaon atom lifetime is determined. We discuss the sensitivity of the results with respect to the input parameters.

  1. 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

  2. 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.

  3. 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.

  4. Characterization of rice blast resistance genes in rice germplasm with monogenic lines and pathogenicity assays

    Science.gov (United States)

    Resistance (R) genes have been effectively deployed in preventing rice crop losses due to the fungus Magnaporthe oryzae. In the present study, we studied the interaction between 24 monogenic lines carrying at least one major R gene, Pia, Pib, Pii, Pik, Pik-h, Pik-m, Pik-p, Pik-s, Pish, Pit, Pita, Pi...

  5. Identification of blast resistance genes for managing rice blast disease

    Science.gov (United States)

    Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most devastating diseases worldwide. In the present study, an international set of monogenic differentials carrying 24 major blast resistance (R) genes (Pia, Pib, Pii, Pik, Pik-h, Pik-m, Pik-p, Pik-s, Pish, Pit, Pita, Pita2,...

  6. 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

  7. 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

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

    Index Scriptorium Estoniae

    Made, Vahur, 1971-

    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.

  9. 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

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

    Index Scriptorium Estoniae

    Made, Vahur, 1971-

    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.

  11. 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

  12. 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

  13. Peagi Euroopa Liidu liikmeks saava väikeriigi finantssüsteemi stabiilsusele orienteeritud poliitikat mõjutavad tegurid - Eesti kogemus / Vahur Kraft

    Index Scriptorium Estoniae

    Kraft, Vahur, 1961-

    2003-01-01

    Ilmunud ka: Kroon & Economy nr. 3, lk. 9-16. Autor kirjeldab erinevaid tegureid, mis mõjutavad väikeriigi finantssektori poliitikat. Keskpanga rollist ja olulisematest ülesannetest finantsstabiilsuse tagamisel riigis, kus pangandus moodustab 80% kogu finantssektorist

  14. 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...

  15. An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia

    NARCIS (Netherlands)

    Jungerius, B. J.; Hoogendoorn, M. L. C.; Bakker, S. C.; van't Slot, R.; Bardoel, A. F.; Ophoff, R. A.; Wijmenga, C.; Kahn, R. S.; Sinke, R. J.

    2008-01-01

    Several lines of evidence, including expression analyses, brain imaging and genetic studies suggest that the integrity of myelin is disturbed in schizophrenia patients. In this study, we first reconstructed a pathway of 138 myelin-related genes, all involved in myelin structure, composition, develop

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

    Science.gov (United States)

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

  17. BEZ235 (PIK3/mTOR inhibitor Overcomes Pazopanib Resistance in Patient-Derived Refractory Soft Tissue Sarcoma Cells

    Directory of Open Access Journals (Sweden)

    Hee Kyung Kim

    2016-06-01

    Full Text Available BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients. METHODS: Patient derived tumor cells were collected from ascites at the time of progression to pazopanib and a 13-drug panel was tested for drug sensitivity. We confirmed the results using in vitro cell viability assay and immunoblot assay. We also performed the genomic profiling of PDX model. RESULTS: The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 μM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P = .0435. Similarly, 1.0 μM BEZ235 profoundly inhibited tumor cell growth in vitro when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, P < .0001. Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P = .0377. The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR. CONCLUSION: Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235. These molecules may be considered as treatment option in STS patient who have failed to pazopanib in the context of clinical trials.

  18. Somatic Mutations in the Notch, NF-KB, PIK3CA, and Hedgehog Pathways in Human Breast Cancers

    OpenAIRE

    Jiao, Xiang; Wood, Laura; Lindman, Monica; Jones, Sian,; Buckhaults, Phillip; Polyak, Kornelia; Sukumar, Saraswati; Carter, Hannah; Kim, Dewey; Karchin, Rachel; Sjöblom, Tobias

    2012-01-01

    Exome sequencing of human breast cancers has revealed a substantial number of candidate cancer genes with recurring but infrequent somatic mutations. To determine more accurately their mutation prevalence, we performed a mutation analysis of 36 novel candidate cancer genes in 96 human breast cancers. Somatic mutations with potential impact on protein function were observed in the genes ADAM12, CENTB1, CENTG1, DIP2C, GLI1, GRIN2D, HDLBP, IKBKB, KPNA5, NFKB1, NOTCH1, and OTOF. These findings st...

  19. 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

  20. Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110[alpha]/p85[alpha

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chuan-Hsiang; Mandelker, Diana; Gabelli, Sandra B.; Amzel, L.Mario (JHU)

    2011-07-14

    Phosphatidylinositide-3-kinases (PI3K) initiate a number of signaling pathways by recruiting other kinases, such as Akt, to the plasma membrane. One of the isoforms, PI3K{alpha}, is an oncogene frequently mutated in several cancer types. These mutations increase PI3K kinase activity, leading to increased cell survival, cell motility, cell metabolism, and cell cycle progression. The structure of the complex between the catalytic subunit of PI3K{alpha}, p110{alpha}, and a portion of its regulatory subunit, p85{alpha} reveals that the majority of the oncogenic mutations occur at the interfaces between p110 domains and between p110 and p85 domains. At these positions, mutations disrupt interactions resulting in changes in the kinase domain that may increase enzymatic activity. The structure also suggests that interaction with the membrane is mediated by one of the p85 domains (iSH2). These findings may provide novel structural loci for the design of new anti-cancer drugs.

  1. Efikasnost terapijskog monitoringa ciklosporina određivanjem C2 i PIK0−4 tokom prva 24 meseca posle transplantacije bubrega

    Directory of Open Access Journals (Sweden)

    Vavić Neven

    2008-01-01

    Full Text Available Background/Aim. Cyclosporine (CyA therapeutic drug monitoring (TDM through the measurement of drug concentration in blood two hours after the administration (C2, and/or according to the calculated value of the area under the concentration - time curve during the first four hours following administration (AUC0−4 shows favourable correlation with clinical manifestations in patients with kidney transplantation (Tx. The aim of this study was to analyze clinical efficiency and usability of TDM CyA through C2 and AUC0-4 in the group of our kidney transplanted patients during the first 24 months following Tx. Methods. The study included 50 patients who had undergone kidney Tx using living donors at the Clinic of Nephrology Military Medical Academy, from 1996 to 2003. The first group (group C2 consisted of 25 patients in whom CyA dose was adjusted according to the target C2 and AUC0−4 (calculated by the regression formula based on C1, C2 and C3, while the second group (group C0 consisted of 25 "historical" patients in whom the dose of this drug was adjusted according to C0. Results. On the 6th day the average daily dose of CyA in the group C2 was 10.1±0.8 mg/kg, while in the group C0 it was 7.6±1.6 (p < 0.05. One month following the Tx, daily drug doses were quite similar in the two observed groups (6.2 mg/kg in C0 and 6.6 mg/kg in group C2, p = NS. In the group C2, target C2/AUC 0−4 (C2 1 700 ng/ml, AUC0−4 4 400 ng·h/ml on the sixth day was achieved in 36.3%, and on day 14 in 76% of the patients. The target AUC 0−4, in relation with C2, in each observed time interval was reached in the higher number of patients. Maximum CyA concentrations in the group C2 were registered 2 hours following the administration (C2, when compared with the concentrations registered after the first and the third hour (C1 and C3. In relation with C1 and C3, C2 concentration correlated most favorably with AUC 0−4, both on the 6th (r = 0.85 and on the 9th day (r = 0.87. During the first three months following the Tx, in the group C0, 10 episodes (40% of acute cell rejection (AR were registered, while in the group C2, two episodes (8%, p = 0.07 were registered; in the observed period covering the first two years, a total of 13 (52% AR episodes in the group C0 and 5 AR episodes (20% in the group C2 (p = 0.03 were registered. All of five episodes of steroid resistant AR were registered in the group C0. In the group C2, all five patients with AR had lower C2 during AR: the average C2 at the moment of AR was 933.8 ng/ml, and in the patients without rejections was 1 364.2 ng/ml (p = 0.008. In the same group, the average C0 at the moment of AR was 263.2 ng/ml, and 240.0 ng/ml (p = 0,486 in the patients without AR. In the C0 group, average C0 concentration at the moment of AR was 227.1 ng/ml, while in the patients without AR it was 227.7 ng/ml (p = 0.95. Totally 68% of the patients showed signs of acute CyA nephrotoxicity during the first year in the group C2, and 52% in the group C0 (p = 0.38. In seven patients (28% of the group C2 and six patients of the group C0 (24%, p = 0.96 in the first two years following Tx, administration of CyA was interrupted due to nephrotoxicity. Overall graft function was good in both groups during the period of two years. One graft was lost in the group C0 due to chronic allograft nephropathy. The patients in the group C2 had better early and the same late graft function. Five patients in the group C2 who did not reach the target C2/AUC during the first 30 days, did not have more AR or worse graft function, comparing with the patients who reached the target concentrations. Conclusion. In the patients with CyA TDM through with the C2 and AUC0−4., AR frequency was considerably lower, and AR episodes had a milder flow than in those with CyA TDM through the C0. The drug concetration in blood two hours after administration (C2 was a good predictor of acute graft rejection, while C0 failed to point to the patients with the insufficient drug concentration. Higher drug doses were administered in the group C2 during the first month following Tx, and these patients did not show significantly higher frequency of acute nephrotoxicity and more frequent requirement of the drug use interruption. Graft function in both groups was good during the period of two years. CyA dose determination through C2 and AUC0-4 is efficient TDM method, relatively simple for use in day to day clinical practice.

  2. 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 ...

  3. 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).

  4. Tai sündmuste pärast asendatakse etendus

    Index Scriptorium Estoniae

    2008-01-01

    Eesti Draamateater asendab 30. nov. Salme Kultuurikeskuses etenduse "Voldemar" etendusega "Rahauputus", sest kolm näitlejat - Taavi Teplenkov, Britta Vahur ja Mari-Liis Lill - ei ole rahutuste tõttu Bangkokist tagasi Eestisse pääsenud

  5. Tuulelapsed loevad Tungalt / Riina Mägi

    Index Scriptorium Estoniae

    Mägi, Riina, 1957-

    2008-01-01

    Jõgeva Gümnaasiumis toimuvatest Betti Alverile pühendatud luulepäevadest Tuulelapsed, kus loetakse Leelo Tungla luulet. Korraldaja: Lianne Saage-Vahur. Žüriisse kuuluvad: Kersti Kreismann, Leelo Tungal, Toomas Lõhmuste ja Kalle Piiskoppel.

  6. 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.

  7. Tai sündmuste pärast asendatakse etendus

    Index Scriptorium Estoniae

    2008-01-01

    Eesti Draamateater asendab 30. nov. Salme Kultuurikeskuses etenduse "Voldemar" etendusega "Rahauputus", sest kolm näitlejat - Taavi Teplenkov, Britta Vahur ja Mari-Liis Lill - ei ole rahutuste tõttu Bangkokist tagasi Eestisse pääsenud

  8. 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

  9. 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

  10. 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)

  11. 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

  12. 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

  13. 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

  14. Kaire Kemp-Tishler : harmoonia moodsa ja vana vahel / Gitte Hint

    Index Scriptorium Estoniae

    Hint, Gitte

    2003-01-01

    Eramu sisekujundus. Sisearhitekt Kaire Kemp-Tishler, tema kommentaarid. Arhitekt Vahur Sova. Kamina sepised tegi Heigo Jelle. Trepihallis Tiit Pääsukese maal "Orasnzh". Ill.: I ja II korruse plaan, 14 värv. vaadet

  15. Kas on vaja piirata pornograafia levikut ? : pornograafia leviku reguleerimise seadus kitsendab pornograafiliste teoste esitamist ja eksponeerimist

    Index Scriptorium Estoniae

    1997-01-01

    Küsitlusele vastavad Riigikogu liige Rein Karemäe, Siseministeeriumi kantsler Vahur Glaase, seksuoloog Imre Rammul, ASi Guvatrak tegevdirektor Even Tudeberg, ASi Meediakorp meediadirektor Priit Hõbemägi

  16. 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

  17. Bank official shirks referendum

    Index Scriptorium Estoniae

    2005-01-01

    Eesti Panga presidendi Vahur Krafti ja rahandusministri Aivar Sõerdi sõnul ei ole vaja Eestis korraldada eurole üleminekuks referendumi, kuna Euroopa Liiduga liitudes kiitis Eesti euro kasutuselevõtu heaks

  18. Bank official shirks referendum

    Index Scriptorium Estoniae

    2005-01-01

    Eesti Panga presidendi Vahur Krafti ja rahandusministri Aivar Sõerdi sõnul ei ole vaja Eestis korraldada eurole üleminekuks referendumi, kuna Euroopa Liiduga liitudes kiitis Eesti euro kasutuselevõtu heaks

  19. 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

  20. Käsikäes elava esitlusega / Mart Ronver

    Index Scriptorium Estoniae

    Ronver, Mart

    2005-01-01

    Vokaalgrupp Vahur Soonbergi juhendamisel ja organistid Ene Salumäe ning Elke Unt andsid kontserte ja korraldajasid heliloojast Enn Võrgust lektooriume Raplamaal, viimasest lektooriumist 12. apr. Järvakandis

  1. "Kalevi naised" - mis asi see oli? / Andres Keil

    Index Scriptorium Estoniae

    Keil, Andres, 1974-

    2008-01-01

    Produtsent Kristian Taska Kalev Spordis näitamiseks valminud Venezuela seebiseriaali Eesti oludele mugandatud "Kalevi naised" esimene osa (lavastaja Ingomar Vihman, osades Maria Avdjushko, Jan Uuspõld, Britta Vahur)

  2. Nii halb, et täitsa hea / Verni Leivak

    Index Scriptorium Estoniae

    Leivak, Verni, 1966-

    2008-01-01

    Produtsent Kristian Taska Kalev Spordis näitamiseks valminud Venezuela seebiseriaali Eesti oludele mugandatud "Kalevi naised" esimene osa (lavastaja Ingomar Vihman, osades Maria Avdjushko, Jan Uuspõld, Britta Vahur)

  3. Usaldus juhi vastu tuleb taastada

    Index Scriptorium Estoniae

    2004-01-01

    Probleemsituatsioonist ettevõttes, kus juht on initsiatiivikate alluvate ideid alla surudes nendes umbusalduse pälvinud. Janek Kupper, Vahur Liivak, Tarmo Osman ja Helve Ulmas pakuvad võimalikke lahendusi

  4. Sto dnei, kotorõje ne potrjasli nikogo / Raivo Palmaru

    Index Scriptorium Estoniae

    Palmaru, Raivo, 1951-

    1999-01-01

    Mart Laari valitsuse tegevust kommenteerivad: Rein Taagepera, Raivo Vetik, Rein Ruutsoo, Anu Toots, Tiiu Pohl, Henn Käärik, Rein Toomla, Vahur Made. Tabelid: valitsuse tegevus erinevates valdkondades, ministrite pingerida, opositsioonierakondade tegevus

  5. Paarisrakendina rikkaks / Väinu Rozental

    Index Scriptorium Estoniae

    Rozental, Väinu, 1957-

    2008-01-01

    Balti Investeeringute Grupi Panga omanike Parvel Pruunsilla ja Vahur Volli elust ja tööst. Vt. samas: CV; Äripisik nakatas tudengieas. Kommenteerivad Juhani Jaeger, Ülar Tikk, Väino Peets ja Eero Palm

  6. "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

  7. Estonija, Slovenija i Litva rasshirjajut jevrozonu pervõmi / Jelizaveta Gavrilova

    Index Scriptorium Estoniae

    Gavrilova, Jelizaveta

    2004-01-01

    Euroopa Keskpank kiitis heaks Eesti liitumise vahetuskursimehhanismi ERM2-ga, mis tähendab eurole ülemineku võimalikkust aastatel 2006-2007. Eesti Panga president Vahur Kraft Eesti üleminekust eurole

  8. 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.

  9. 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)

  10. Läbirääkimised on türklaste rahvuslik hobi / Merit Raju

    Index Scriptorium Estoniae

    Raju, Merit

    2007-01-01

    Türgi ärikultuuri tutvustus. Kommenteerivad: Hansa Investeerimisfondi analüütik Pertti Rahnel. Türgis on piisavalt odavat tööjõudu;Vahur Luhtsalu Eesti Ankara suursaatkonnast.Kiiremini areneb kinnisvarasektor

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  17. Moldova president : SRÜ on minevik, EL meie tulevik / Vladimir Voronin ; interv. Toomas Sildam

    Index Scriptorium Estoniae

    Voronin, Vladimir

    2005-01-01

    Moldova president vastab küsimustele, mis puudutavad Moldova arengut, kommunistide võimul püsimist riigis, Moldova püüdlemisest Euroopa Liidu poole, Moldova ja Rumeenia suhteid, Moldovast eraldunud Transnistria tulevikku. Kaart: Moldova. Kommenteerib Eesti Diplomaatide Kooli asedirektor Vahur Made

  18. 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

  19. Liblikapüüdja uuslavastus : klassika kõverpeeglis / Riina Mägi

    Index Scriptorium Estoniae

    Mägi, Riina, 1957-

    2006-01-01

    Jõgeva Gümnaasiumi kooliteater Liblikapüüdja tõi lavale A. S. Pushkini "Kivist külalise". Lavastaja Lianne Saage-Vahur. Lavastus osales ka miniteatripäevadel Kuressaares, kus võideti klassika eripreemia

  20. Liblikapüüdjast täheks / Kaire-Külli Kuldbek

    Index Scriptorium Estoniae

    Kuldbek, Kaire-Külli, 1971-

    2007-01-01

    Tallinna Linnateatri näitlejanna Hele Kõre. Temast räägivad Jõgeva Gümnaasiumi emakeeleõpetaja, kooliteatri Liblikapüüdja juht Lianne Saage-Vahur ja sõbrannad-näitlejad Evelin Pang ja Karin Rask

  1. 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

  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. 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

  4. Ilmus artiklikogumik "Eesti teadlased paguluses" / Anne Valmas

    Index Scriptorium Estoniae

    Valmas, Anne, 1941-

    2009-01-01

    TLÜ AR väliseesti kirjanduse keskuse ja TTÜ Raamatukogu koostöös 24.03.2009 toimunud konverentsist "Eesti teadlased paguluses", mis tutvustas väliseesti teadlaste osa maailmateaduses. Ettekannete põhjal valminud artiklikogumikust "Eesti teadlased paguluses", koostajad Vahur Mägi ja Anne Valmas. Tallinn : Tallinna Ülikooli Kirjastus, 2009

  5. Eesti Panga salapärane ja suursugune elu / Kadri Jakobson

    Index Scriptorium Estoniae

    Jakobson, Kadri, 1970-

    2005-01-01

    Eesti Panga presidendi Vahur Krafti, asepresidentide Rein Minka, Märten Rossi, Andres Suti palgast, lisatasudest, preemiatest, riigi toetusest nende pensionikindlustusse. Eesti Panga nõukogu esimehe Mart Sõrgi, nõukogu liikmete töötasust. Eesti Panga pressiesindaja Silver Vohu kommentaare. Kommenteerib Tiit Made. Lisa: Mida teeb Eesti Panga nõukogu, nõukogu koosseis

  6. 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

  7. 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

  8. 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

  9. Vähinädal keskendub esmakordselt vere- ja lümfisüsteemi kasvajatele

    Index Scriptorium Estoniae

    2007-01-01

    3.-12. oktoobrini kestev rahvusvaheline vähinädal on seekord pühendatud vere- ja lümfisüsteemi kasvajatele. Kasvajate ravist räägivad Eesti Vähiliidu juhatuse esimees dr Vahur Valvere ning Tartu ülikooli kliinikumi hematoloogia-onkoloogia kliiniku juhataja professor Hele Everaus

  10. 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

  11. 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

  12. 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

  13. Igihaljas katus pole vaid moeröögatus / Ene Läkk

    Index Scriptorium Estoniae

    Läkk, Ene, 1957-

    1999-01-01

    Kivimaja, millel on hööveldamata laudadest hall vooder, toon heledamad aknaraamid, vaated merele. Garaaž ja rõdu kaetud kukeharjadega. Arhitekt Vahur Sova, katushaljastus Ülle Grishakov, Urmas Grišakov. Kommenteerivad projekteerijad ja Ökoloogiliste tehnoloogiate keskuse projektijuht T. Mauring

  14. 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

  15. Lipstok tahab nii asespiikriks kui ka Eesti Panga presidendiks / Rasmus Kagge

    Index Scriptorium Estoniae

    Kagge, Rasmus, 1977-

    2005-01-01

    Riigikogu liikmed Siim-Valmar Kiisler, Eiki Nestor, Peep Aru avaldavad arvamust Andres Lipstoki kandideerimise kohta nii Riigikogu aseesimeheks kui ka Eesti Panga presidendiks. Eesti Panga praeguse presidendi Vahur Krafti väidetavast plaanist kandideerida järgmistel Riigikogu valimistel

  16. Eesti Panga salapärane ja suursugune elu / Kadri Jakobson

    Index Scriptorium Estoniae

    Jakobson, Kadri, 1970-

    2005-01-01

    Eesti Panga presidendi Vahur Krafti, asepresidentide Rein Minka, Märten Rossi, Andres Suti palgast, lisatasudest, preemiatest, riigi toetusest nende pensionikindlustusse. Eesti Panga nõukogu esimehe Mart Sõrgi, nõukogu liikmete töötasust. Eesti Panga pressiesindaja Silver Vohu kommentaare. Kommenteerib Tiit Made. Lisa: Mida teeb Eesti Panga nõukogu, nõukogu koosseis

  17. 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

  18. Logistikateenuse hinda tõstab järgmisel aastal kütuse ja tööjõu kallinemine / Rivo Sarapik

    Index Scriptorium Estoniae

    Sarapik, Rivo, 1981-

    2005-01-01

    Ilmunud ka: Delovõje Vedomosti : Transport i Logistika 30. nov. lk. 2. Küsimustele logistikateenuste kallinemise kohta vastavad Ervin Hasselbach, Margus Tammaru, Evert Kreek, Mait Miller, Ants Ratas, Mike Neame, Vahur Oja, Kersti Orgma, Helena Roots ja Urmo Paluste

  19. Kiirete turusituatsiooni muutuste ajad saavad jätku 2007. aastal / Kristo Kiviorg

    Index Scriptorium Estoniae

    Kiviorg, Kristo

    2006-01-01

    Rünno Kaiva, Anton Juurik, Ervin Hasselbach, Raido Rebane, Ants Ratas, Helena Roots, Maanus Mätlik, Evert Kreek ja Vahur Oja analüüsivad tegureid, mis võivad mõjutada järgmisel aastal logistikateenuste hindu

  20. 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

  1. 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

  2. "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)

  3. 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

  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. 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

  6. 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"

  7. Kutsehariduskeskus areneb iga päevaga / Tõnis Lukas

    Index Scriptorium Estoniae

    Lukas, Tõnis, 1962-

    2009-01-01

    Minister Tõnis Lukase vastus Paide Kutsekeskkooli ning Türi Tehnika- ja Maamajanduskooli kolme endise direktori avalikule kirjale: Lugupeetud minister Tõnis Lukas : avalik kiri haridus- ja teadusministrile / Lembit Veermaa, Vahur Salom, Toomas Šadeiko // Järva Teataja (2009) 8. sept., lk. 2

  8. 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

  9. Side relvaliigi rollist kaitseväes / Villem Sedrik

    Index Scriptorium Estoniae

    Sedrik, Villem

    2007-01-01

    Autor annab ülevaate siderelvaliigi arengust kaitseväes ning rõhutab lahinguolukorras erinevate võitlevate partnerite infosüsteemide koostöö ja infovahetuse tähtsust tänapäeval. Vt. ka Sõdur nr. 2 lk. 12-15. Vahur Parve. Kiirpilk sidepidamise ajalukku

  10. Ülevaade maksukonfliktide konverentsist / Kalle Kägi

    Index Scriptorium Estoniae

    Kägi, Kalle, 1975-

    2003-01-01

    29. mail 2003. a. Tallinnas Eesti Maksuteadlaste Seltsi ja rahvusvahelise maksuõiguse ühingu IFA-Eesti poolt korraldatud maksukonverentsist. Ülevaade Kristi Lahesoo, Vello Vallaste, Kalle Kägi, Kaspar Lind'i, Martin Hubergi, Lasse Lehise, Aare Kuristi ja Vahur Kivistiku ettekannetest. Lisatud statistilised tabelid: maksuameti kohtuvaidlused; kohtueelsed kaebused/vaided 2000-2003

  11. Markuse evangeelium teatrilaval / Monika Reedik

    Index Scriptorium Estoniae

    Reedik, Monika

    2006-01-01

    Eesti Nuku- ja Noorsooteater tõi koostöös Eesti Piibliseltsi ja muusikaühinguga Crescendo 12. dets. välja Markuse evangeeliumi lavaversiooni, tegemist on monolavastusega Andres Roosilehe esituses. Evangeeliumi seadsid lavale Andres Roosileht ja Vahur Keller, mängupaigaks on Köismäe torn

  12. 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

  13. 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

  14. 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

  15. "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)

  16. 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

  17. [Raamatud] / Maarja Kangro

    Index Scriptorium Estoniae

    Kangro, Maarja, 1973-

    2007-01-01

    Tutvustus: Ehlvest, Jüri. Palverännak : [romaan]. Tallinn : Tuum, 2005 ; Krull, Hasso. Talv : [luuletused]. Tallinn : Tuum, 2006 ;Afanasjev, Vahur. Kaadrid otsustavad : [jutud, humoreskid. Tartu] : Irboska Teataja [Kirjastus], 2007 ; Pamuk, Orhan. Lumi : [romaan] / türgi keelest tõlkinud Ly Seppel. [Tallinn] : Pegasus, 2007

  18. Eesti Pank : kinnisvaraturg jaheneb / Anne Oja

    Index Scriptorium Estoniae

    Oja, Anne, 1970-

    2004-01-01

    Eesti Panga president Vahur Kraft prognoosis kinnisvaraturu jahenemist. Diagramm. Lisa: Kinnisvarakrahhist räägitud viimased kolm aastat. Vt. samas: Andris Feldmanis. Ehituse kallinemine pidurdas sektori kasvu; Liis Kängsepp. Ehitusfirmade juhid kasvu pidurdumist ei näe

  19. Characterization of breast cancers with PI3K mutations in an academic practice setting using SNaPshot profiling.

    Science.gov (United States)

    Abramson, Vandana G; Cooper Lloyd, M; Ballinger, Tarah; Sanders, Melinda E; Du, Liping; Lai, Darson; Su, Zengliu; Mayer, Ingrid; Levy, Mia; LaFrance, Delecia R; Vnencak-Jones, Cindy L; Shyr, Yu; Dahlman, Kimberly B; Pao, William; Arteaga, Carlos L

    2014-06-01

    Mutations in the PIK3CA gene are common in breast cancer and represent a clinically useful therapeutic target. Several larger, population-based studies have shown a positive prognostic significance associated with these mutations. This study aims to further identify characteristics of patients harboring PIK3CA mutations while evaluating the clinical impact of genomic testing for these mutations. Tumors from 312 patients at Vanderbilt-Ingram Cancer Center were analyzed for PIK3CA mutations using a multiplex screening assay (SNaPshot). Mutation rates, receptor status, histopathologic characteristics, and time to recurrence were assessed. The number of patients participating in clinical trials, specifically trials relating to the PIK3CA mutation, was examined. Statistically significant differences between wild-type and mutated tumors were determined using the Wilcoxon, Pearson, and Fischer exact tests. The PIK3CA mutation was found in 25 % of tumors tested. Patients with PIK3CA mutations were significantly more likely to express hormone receptors, be of lower combined histological grade, and have a reduced time to recurrence. Patients found to have a PIK3CA mutation were significantly more likely to enter a PIK3CA-specific clinical trial. In addition to confirming previously established positive prognostic characteristics of tumors harboring PIK3CA mutations, this study demonstrates the feasibility and utility of mutation profiling in a clinical setting. PIK3CA mutation testing impacted treatment and resulted in more patients entering mutation-specific clinical trials.

  20. 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.

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

    Science.gov (United States)

    2015-07-01

    progenitor cells (NPCs) by expressing an activated form of Notch1 (N1ICD) or oncogenic PIK3CA (PIK3CA*) in the developing mouse cerebellum, using cell...resistance, pediatric cancer, brain tumor, Notch1, PIK3CA, cell of origin, molecular subtypes, neural stem cells, neural progenitor cells, tumor initiation...neural progenitor cells, tumor initiation. 3. ACCOMPLISHMENTS: Major goals of the project: The stated goals of this project are to: 1) test the

  2. Transcription Factor Stat5 in Invasion and Metastasis of Human Breast Cancer

    Science.gov (United States)

    2005-05-01

    interacting proteins . Yeast-two-hybrid screening assay: I will use the commercially available BD MatchmakerTM Two-Hybrid System 3 (Clontech...Since I propose that p55pik is the bridge between CaM and Rb, and the interacting proteins ofp55pik are largely unknown, p55pik cDNA fused to the...project will identify the direct interaction between p55pik and CaM. Identification of direct interacting proteins provides a helpful hint in

  3. 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.

  4. GLYCINE-RICH RNA-BINDING PROTEIN1 interacts with RECEPTOR-LIKE CYTOPLASMIC PROTEIN KINASE1 and suppresses cell death and defense responses in pepper (Capsicum annuum).

    Science.gov (United States)

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

    2015-01-01

    Plants use a variety of innate immune regulators to trigger cell death and defense responses against pathogen attack. We identified pepper (Capsicum annuum) GLYCINE-RICH RNA-BINDING PROTEIN1 (CaGRP1) as a RECEPTOR-LIKE CYTOPLASMIC PROTEIN KINASE1 (CaPIK1)-interacting partner, based on bimolecular fluorescence complementation and coimmunoprecipitation analyses as well as gene silencing and transient expression analysis. CaGRP1 contains an N-terminal RNA recognition motif and a glycine-rich region at the C-terminus. The CaGRP1 protein had DNA- and RNA-binding activity in vitro. CaGRP1 interacted with CaPIK1 in planta. CaGRP1 and CaGRP1-CaPIK1 complexes were localized to the nucleus in plant cells. CaPIK1 phosphorylated CaGRP1 in vitro and in planta. Transient coexpression of CaGRP1 with CaPIK1 suppressed the CaPIK1-triggered cell death response, accompanied by a reduced CaPIK1-triggered reactive oxygen species (ROS) burst. The RNA recognition motif region of CaGRP1 was responsible for the nuclear localization of CaGRP1 as well as the suppression of the CaPIK1-triggered cell death response. CaGRP1 silencing in pepper conferred enhanced resistance to Xanthomonas campestris pv vesicatoria (Xcv) infection; however, CaPIK1-silenced plants were more susceptible to Xcv. CaGRP1 interacts with CaPIK1 and negatively regulates CaPIK1-triggered cell death and defense responses by suppressing ROS accumulation.

  5. 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

    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...

  6. 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....

  7. Parkimistrahvide aegumise küsimuses valitseb segadus / Sandra Maasalu

    Index Scriptorium Estoniae

    Maasalu, Sandra

    2007-01-01

    Justiitsministeerium peab vajalikuks täpsustada seadusi nii, et parkimistrahvi sissenõudmise aeg oleks täpselt määratletud. Kommenteerib justiitsminister Rein Lang. Vt ka: Koorits, Vahur. Röövimine aegub parkimistrahvist varem // Postimees 8. aug. 2007, lk. 3 ; Suik, Andres. Parkimistrahv aegub kiirelt : inimeste suhtes ei saa täita aegunud otsuseid // Postimees 14. aug. 2007, lk. 15

  8. Teater

    Index Scriptorium Estoniae

    2001-01-01

    Ülo Kriguli kosmogooniline muusikal "Põhjanaela paine" Arvo Valtoni lühijutu järgi, lavastaja Vahur Keller, kunstnik Hardi Volmer, koreograaf Kristina Pashkevièius. Esietendus 24. okt. Tallinna Linnateatris Euroopa Liidu programmi "El Phare/Tempus" raames. 2. nov. jõuab VAT Teatri mängukavva saksa näidend - Ingeborg von Zadowi "Pompeenia", lavastaja Mart Kampus

  9. 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

  10. 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)

  11. [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

  12. 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

  13. [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

  14. 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

  15. 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)

  16. 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

  17. 27. ja 28. IX toimus Narvas VII Eesti muuseumide näituste festival ja seminar

    Index Scriptorium Estoniae

    2004-01-01

    I koha pälvis ERMi ja Adamson-Ericu muuseumi koostööprojekt "Viinapuuväät. Maasikakiri II" (kontseptsiooni ja haridusprogrammi autorid Vaike Reemann, Ülle Kruus, Kersti Koll ja Kai Tuvik, kujundaja Denes Farkas, monteerija Vahur Puik), II - Tartu Kunstimuuseumi näitus "Muuseum muuseumis" (kontseptsiooni autorid ja teostajad Ahti Seppet, Hannes Varblane), III - Viljandi muuseumi näitus "Rõõmud lumel ja jääl" (idee autor Herki Helves)

  18. 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)

  19. 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

  20. Leedu president tuleb Eestisse

    Index Scriptorium Estoniae

    2005-01-01

    President Arnold Rüütli kutsel saabub Eestisse Leedu president valdas Adamkus, et tähistada Balti riikide NATO täisliikmeks saamise aastapäeva. Läti president Vaira Vike-Freiberga põhjendas kutsest äraütlemist varem kokku lepitud kohtumistega samal päeval. Diplomaatide kooli juhi Vahur Made kommentaar. Ilmunud ka Valgamaalane, 2005/Mar/29, lk. 6

  1. 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)

  2. 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)

  3. Role of Class III phosphoinositide 3-kinase in the brain development: possible involvement in specific learning disorders.

    Science.gov (United States)

    Inaguma, Yutaka; Matsumoto, Ayumi; Noda, Mariko; Tabata, Hidenori; Maeda, Akihiko; Goto, Masahide; Usui, Daisuke; Jimbo, Eriko F; Kikkawa, Kiyoshi; Ohtsuki, Mamitaro; Momoi, Mariko Y; Osaka, Hitoshi; Yamagata, Takanori; Nagata, Koh-Ichi

    2016-10-01

    Class III phosphoinositide 3-kinase (PIK3C3 or mammalian vacuolar protein sorting 34 homolog, Vps34) regulates vesicular trafficking, autophagy, and nutrient sensing. Recently, we reported that PIK3C3 is expressed in mouse cerebral cortex throughout the developmental process, especially at early embryonic stage. We thus examined the role of PIK3C3 in the development of the mouse cerebral cortex. Acute silencing of PIK3C3 with in utero electroporation method caused positional defects of excitatory neurons during corticogenesis. Time-lapse imaging revealed that the abnormal positioning was at least partially because of the reduced migration velocity. When PIK3C3 was silenced in cortical neurons in one hemisphere, axon extension to the contralateral hemisphere was also delayed. These aberrant phenotypes were rescued by RNAi-resistant PIK3C3. Notably, knockdown of PIK3C3 did not affect the cell cycle of neuronal progenitors and stem cells at the ventricular zone. Taken together, PIK3C3 was thought to play a crucial role in corticogenesis through the regulation of excitatory neuron migration and axon extension. Meanwhile, when we performed comparative genomic hybridization on a patient with specific learning disorders, a 107 Kb-deletion was identified on 18q12.3 (nt. 39554147-39661206) that encompasses exons 5-23 of PIK3C3. Notably, the above aberrant migration and axon growth phenotypes were not rescued by the disease-related truncation mutant (172 amino acids) lacking the C-terminal kinase domain. Thus, functional defects of PIK3C3 might impair corticogenesis and relate to the pathophysiology of specific learning disorders and other neurodevelopmental disorders. Acute knockdown of Class III phosphoinositide 3-kinase (PIK3C3) evokes migration defects of excitatory neurons during corticogenesis. PIK3C3-knockdown also disrupts axon outgrowth, but not progenitor proliferation in vivo. Involvement of PIK3C3 in neurodevelopmental disorders might be an interesting future

  4. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription.

    Science.gov (United States)

    Thomas, Daniel; Powell, Jason A; Vergez, Francois; Segal, David H; Nguyen, Nhu-Y N; Baker, Adele; Teh, Tse-Chieh; Barry, Emma F; Sarry, Jean-Emmanuel; Lee, Erwin M; Nero, Tracy L; Jabbour, Anissa M; Pomilio, Giovanna; Green, Benjamin D; Manenti, Stéphane; Glaser, Stefan P; Parker, Michael W; Lopez, Angel F; Ekert, Paul G; Lock, Richard B; Huang, David C S; Nilsson, Susie K; Récher, Christian; Wei, Andrew H; Guthridge, Mark A

    2013-08-01

    Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.

  5. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer

    Science.gov (United States)

    Ellis, Matthew J; Lin, Li; Crowder, Robert; Tao, Yu; Hoog, Jeremy; Snider, Jacqueline; Davies, Sherri; DeSchryver, Katherine; Evans, Dean B; Steinseifer, Jutta; Bandaru, Raj; Liu, WeiHua; Gardner, Humphrey; Semiglazov, Vladimir; Watson, Mark; Hunt, Kelly; Olson, John; Baselga, José

    2010-01-01

    Background Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in ~30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Methods Exon 9 (helical domain - HD) and Exon 20 (kinase domain- KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials. Interactions with clinical, pathological and biomarker response parameters were examined. Results A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected (N=235 P=<0.05), but not with treatment-induced changes in Ki67-based proliferation index (N=418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log rank P=0.02) in the P024 trial (N=153). The favorable prognostic effect was maintained in a multivariable analysis (N=125) that included the preoperative prognostic index (PEPI), an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9–105 P=0.01). Conclusion PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA kinase domain mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained. PMID:19844788

  6. p50PIK基因重组腺病毒的构建及对Hela细胞的影响%Construction of recombinant adenoviruses carrying p50 and Its effect on Hela cells

    Institute of Scientific and Technical Information of China (English)

    李进; 曹小年; 陈成; 杨锐; 胡俊波; 王晶

    2011-01-01

    Objective To construct recombinant adenovirus carrying p50PIK gene and examine the effect on cervix cancer Hela cell lines after transfection with Ad-p50PIK. Methods p50PIK cDNA was amplified by polymerase chain reaction (PCR), with the template PcDNA3. 1-p50PIK, then cloned into the shuttle plasmid pAdTrack-CMV. The plasmid pAdTrackCMV-p50 was linearized by PmeI, followed by homologous recombination with bone plasmid pAdEasy-1 in BJ5183, then identified by enzyme digestion.After linearized by PacI and transfection into HEK293 cells, recombinant adenovirus Ad-p50PIK were obtained in HEK293 cells then amplified by 3 circles. The green fluorescence in HEK293 cells was observed.Ad-p50PIK was transfected into Hela cells. The phosphorylation of Akt was detected by Western blotting.Results After double restriction enzyme digestion and agarose gel electrophoresis of The Ad-p50PIK-GFP,the 1400 bp purpose band was sequenced, Results was exactly the same with the sequence GeneBank had reported,indicating that the recombinant adenovirus Ad-p50PIK-GFP were successfully constructed; Then transfected into HEK293 cells, green fluorescence shows that Ad-p50PIK-GFP in HEK293 packaging cells successfully expressed; by SDS-PAGE electrophoresis was used to detect p50 on Akt phosphorylation, the Results show that high expression of p50 protein significantly increased AKT's Phosphorylated (Thr308).Conclusion Recombinant adenovirus Ad-p50PIK had been successfully constructed. Overexpression of p50PIK in Hela cell lines can promote phosphorylation of AKT.%目的 构建携带P50基因的重组腺病毒载体,观察其感染宫颈癌Hela细胞后对p-AKT(Thr308)的影响.方法 以PcDNA3.1-p50PIK质粒为模板,构建带有p50PIK基因的重组腺病毒质粒Ad-p50PIK-GFP,酶切鉴定后经PacI线性化后转染HEK293包装细胞,观察细胞内绿色荧光蛋白(GFP)表达情况,并进行3轮扩增,收获带有目的 片段的腺病毒.将重组腺病毒Ad-p50PIK

  7. "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

  8. "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

  9. 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

    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 v...... 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....

  10. Genome-wide analysis of the phosphoinositide kinome from two ciliates reveals novel evolutionary links for phosphoinositide kinases in eukaryotic cells.

    Directory of Open Access Journals (Sweden)

    George Leondaritis

    Full Text Available BACKGROUND: The complexity of phosphoinositide signaling in higher eukaryotes is partly due to expansion of specific families and types of phosphoinositide kinases (PIKs that can generate all phosphoinositides via multiple routes. This is particularly evident in the PI3Ks and PIPKs, and it is considered an evolutionary trait associated with metazoan diversification. Yet, there are limited comprehensive studies on the PIK repertoire of free living unicellular organisms. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a genome-wide analysis of putative PIK genes in two free living ciliated cells, Tetrahymena and Paramecium. The Tetrahymena thermophila and Paramecium tetraurelia genomes were probed with representative kinases from all families and types. Putative homologs were verified by EST, microarray and deep RNA sequencing database searches and further characterized for domain structure, catalytic efficiency, expression patterns and phylogenetic relationships. In total, we identified and characterized 22 genes in the Tetrahymena thermophila genome and 62 highly homologues genes in Paramecium tetraurelia suggesting a tight evolutionary conservation in the ciliate lineage. Comparison to the kinome of fungi reveals a significant expansion of PIK genes in ciliates. CONCLUSIONS/SIGNIFICANCE: Our study highlights four important aspects concerning ciliate and other unicellular PIKs. First, ciliate-specific expansion of PI4KIII-like genes. Second, presence of class I PI3Ks which, at least in Tetrahymena, are associated with a metazoan-type machinery for PIP3 signaling. Third, expansion of divergent PIPK enzymes such as the recently described type IV transmembrane PIPKs. Fourth, presence of possible type II PIPKs and presumably inactive PIKs (hence, pseudo-PIKs not previously described. Taken together, our results provide a solid framework for future investigation of the roles of PIKs in ciliates and indicate that novel functions and novel regulatory

  11. Crucial role of phosphatidylinositol 4-kinase IIIα in development of zebrafish pectoral fin is linked to phosphoinositide 3-kinase and FGF signaling

    OpenAIRE

    MA, HUI; Blake, Trevor; Chitnis, Ajay; Liu, Paul; Balla, Tamas

    2009-01-01

    Phosphatidylinositol 4-kinases (PI4Ks) catalyze the first committed step in the synthesis of phosphoinositides, important lipid regulators of signaling and trafficking pathways. Here we cloned Pik4a, one of the zebrafish PI4K enzymes, and studied its role(s) in vertebrate development using morpholino oligonucleotide-based gene silencing in zebrafish. Downregulation of Pik4a led to multiple developmental abnormalities, affecting the brain, heart, trunk and most prominen...

  12. Interspecies Complementation of the LuxR Family Pathway-Specific Regulator Involved in Macrolide Biosynthesis.

    Science.gov (United States)

    Mo, SangJoon; Yoon, Yeo Joon

    2016-01-01

    PikD is a widely known pathway-specific regulator for controlling pikromycin production in Streptomyces venezuelae ATCC 15439, which is a representative of the large ATP-binding regulator of the LuxR family (LAL) in Streptomyces sp. RapH and FkbN also belong to the LAL family of transcriptional regulators, which show greatest homology with the ATP-binding motif and helix-turn-helix DNA-binding motif of PikD. Overexpression of pikD and heterologous expression of rapH and fkbN led to enhanced production of pikromycin by approximately 1.8-, 1.6-, and 1.6-fold in S. venezuelae, respectively. Cross-complementation of rapH and fkbN in the pikD deletion mutant (ΔpikD) restored pikromycin and derived macrolactone production. Overall, these results show that heterologous expression of rapH and fkbN leads to the overproduction of pikromycin and its congeners from the pikromycin biosynthetic pathway in S. venezuelae, and they have the same functionality as the pathwayspecific transcriptional activator for the pikromycin biosynthetic pathway in the ΔpikD strain. These results also show extensive "cross-communication" between pathway-specific regulators of streptomycetes and suggest revision of the current paradigm for pathwayspecific versus global regulation of secondary metabolism in Streptomyces species.

  13. 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)

  14. 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"

  15. Eesti Parim Puitehitis 2005

    Index Scriptorium Estoniae

    2005-01-01

    Konkursi tulemused: parim puitehitis 2005 - lasteaed Naba Pirital (arhitektid Vahur Sova, Lauri Saar, insener Tõnu Peipman), äramärgitud inseneritöö - AS Palmako tootmishoone Kavastus (insener Paul Sõrmus, arhitekt Ott Ojamaa, Tartu Arhitektuuribüroo), äramärgitud ehitis - kortermaja Tabasalus Lucca külas (arhitekt Oliver Alver, insener Eino Hint), liimpuidu eriauhind - autode varjualune Õie t. Nõmmel (arhitekt Indrek Allmann, insener Indrek Einlo), vineeri eriauhind - Kuressaare Linnavalitsuse hoone fassaad (arhitektid Toomas Paavae, Terje Truumaa), voodrilaua eriauhind - Estonian Golf and Country Club Jõelähtmes (arhitekt Andres Siim, insenerid Villu Leppik, Ragnar Pabort, Alar Just)

  16. Kasum kerkis, aga valitsuse viletsus mõjutab majandust / Anvar Samost

    Index Scriptorium Estoniae

    Samost, Anvar, 1971-

    2005-01-01

    Lähtudes BNS/Faktumi majandusliku kindlustunde uuringute tulemustest ja Statistikaameti poolt avaldatud andmetest võib autori arvates 2005. aastat Eesti inimestele ja ettevõtetele lugeda üliedukaks, kuid praeguse valitsuse majandusotsused võivad saada takistuseks Eesti majanduse edasisele edenemisele. Vt. samas: Tiit Vähi. Eesti majandus muutub aina rahvusvahelisemaks; Maris Lauri. Parim aasta pärast taasiseseisvumist. Kommenteerivad EAKL-i esimees Harri Taliga, AS-i Rimi Eesti Food tegevdirektor Ruth Laatre, Hansapanga juhatuse esimees Erkki Raasuke, Riigikogu liige Liina Tõnisson, Nordea Panga Eesti filiaali juht Vahur Kraft

  17. 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

  18. 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"

  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. 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.

  1. 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.

  2. The effect of Phosphoinositide-3-kinase, regulatory subunit 3 in epithelial-mesenchymal transition and migration of non-small cell lung cancer%磷脂酰肌醇-3激酶调节亚基3在非小细胞肺癌上皮-间充质转化及迁移中的作用

    Institute of Scientific and Technical Information of China (English)

    杨熹; 胡福清; 李海杰; 兰静芩; 罗学来; 龚建平; 胡俊波

    2015-01-01

    Objective To test the expression of phosphoinositide-3-kinase,regulatory subunit 3 (PIK3R3) in the human non-small cell lung cancer (NSCLC) tissues,and to observe the effect of PIK3R3 on the epithelial-mesenchymal transition (EMT) and migration of NSCLC cell lines A549 and PC-9.Methods Total RNA and total protein lysate from the NSCLC tissues and paratumor tissues of 22 or 7 patients with NSCLC were prepared respectively,and the expression of PIK3R3 was tested by real-time quantitative polymerase chain reaction(Real-time PCR) and Western blotting; PIK3R3 was overexpressed or down-regulated by lentivirus infection,then the effect of PIK3R3 on the migration was detected by Transwell assay,and the expression of EMT related proteins were detected by Western blotting,and the binding of snail family zinc finger (SNAI) 1 and SNAI2 on the promoter of cadherin 1 (CDH1) were measured by chromatin immunoprecipitation assay (ChIP),and the transcription activity of CDH1 was detected by luciferase reporter assay.Results The expression of PIK3R3 was elevated in NSCLC patients' tumor tissues compared with the paratumor tissues; The migration of A549 and PC-9 cells was enhanced after PIK3R3 overexpression (A549 Control:46 ±3,PIK3R3:92 ±5; PC-9 Control:25 ±2,PIK3R3:53 ± 3),with the expression of CDH1 depressed and elevation of VIM,SNAI1 and SNAI2,which were related to the progress of EMT; The binding activity of SNAI1 and SNAI2 on the CDH1 promoter was elevated 9 times and 3.8 times,respectively,and the transcriptive activity of CDH1 was depressed to 30%.To the opposite,the migration of A.549 and PC-9 cells were inhibited after PIK3R3 down-regulated (A549 sh-Control:58 ± 5,sh-PIK3 R3:13-± 3 ; PC-9 sh-Control:28 ± 5,sh-PIK3 R3:10 ± 3),with the expression of CDH1 elevation and depressed of VIM,SNAI1 and SNAI2.The binding activity of SNAI1 and SNAI2 on the CDH1 promoter was reduced,and the transcriptive activity of CDH1 was increased 3.6 times.Conclusion The expression of PIK

  3. 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...

  4. 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.

  5. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy.

    Science.gov (United States)

    Yu, Xinlei; Long, Yun Chau; Shen, Han-Ming

    2015-01-01

    Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiation and progression of autophagy. The class II enzyme emerged only recently as an alternative source of PtdIns3P and autophagic initiator. However, the orthodox paradigm is challenged by findings that the PIK3CB catalytic subunit of class I PI3K acts as a positive regulator of autophagy, and PIK3C3 was thought to be an amino acid sensor for MTOR, which curbs autophagy. At present, a number of PtdIns3K and PI3K inhibitors, including specific PIK3C3 inhibitors, have been developed for suppression of autophagy and for clinical applications in autophagy-related human diseases.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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

  14. miR-502 inhibits cell proliferation and tumor growth in hepatocellular carcinoma through suppressing phosphoinositide 3-kinase catalytic subunit gamma

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Suling, E-mail: suling_chen86@163.com [Department of Infectious Disease, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China); Li, Fang; Chai, Haiyun; Tao, Xin [Department of Infectious Disease, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China); Wang, Haili [Department of Hematology, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China); Ji, Aifang [Central Laboratory, Heping Hospital Attached to Changzhi Medical College, Changzhi 046000 (China)

    2015-08-21

    MicroRNAs (miRNAs) play a key role in carcinogenesis and tumor progression in hepatocellular carcinoma (HCC). In the present study, we demonstrated that miR-502 significantly inhibits HCC cell proliferation in vitro and tumor growth in vivo. G1/S cell cycle arrest and apoptosis of HCC cells were induced by miR-502. Phosphoinositide 3-kinase catalytic subunit gamma (PIK3CG) was identified as a direct downstream target of miR-502 in HCC cells. Notably, overexpression of PIK3CG reversed the inhibitory effects of miR-502 in HCC cells. Our findings suggest that miR-502 functions as a tumor suppressor in HCC via inhibition of PI3KCG, supporting its utility as a promising therapeutic gene target for this tumor type. - Highlights: • miR-502 suppresses HCC cell proliferation in vitro and tumorigenicity in vivo. • miR-502 regulates cell cycle and apoptosis in HCC cells. • PIK3CG is a direct target of miR-502. • miR-502 and PIK3CG expression patterns are inversely correlated in HCC tissues.

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

    Science.gov (United States)

    Lin, Jiong; Lin, Yao; Fan, Li; Kuang, Wei; Zheng, Liwei; Wu, Jiahua; Shang, Peng; Wang, Qiaofeng; Tan, Jiali

    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.

  16. 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

  17. 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...

  18. 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...

  19. CT assessment of early response to neoadjuvant therapy in colon cancer

    DEFF Research Database (Denmark)

    Rafaelsen, Søren Rafael; Dam, Claus; Lund-Rasmussen, Vera

    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...

  20. 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...

  1. 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

    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...

  2. Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness.

    Science.gov (United States)

    Tserga, Aggeliki; Chatziandreou, Ilenia; Michalopoulos, Nicolaos V; Patsouris, Efstratios; Saetta, Angelica A

    2016-07-01

    Deregulation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is closely associated with cancer development and cancer progression. PIK3CA, AKT1, and PTEN are the fundamental molecules of the PI3K/AKT pathway with increased mutation rates in cancer cases leading to aberrant regulation of the pathway. Even though molecular alterations of the PI3K/AKT pathway have been studied in breast cancer, correlations between specific molecular alterations and clinicopathological features remain contradictory. In this study, we examined mutations of the PI3K/AKT pathway in 75 breast carcinomas using high-resolution melting analysis and pyrosequencing, in parallel with analysis of relative expression of PIK3CA and AKT2 genes. Mutations of PIK3CA were found in our cohort in 21 cases (28 %), 10 (13 %) in exon 9 and 11(15 %) in exon 20. Mutation frequency of AKT1 and PTEN genes was 4 and 3 %, respectively. Overall, alterations in the PI3K/AKT signaling cascade were detected in 35 % of the cases. Furthermore, comparison of 50 breast carcinomas with adjacent normal tissues showed elevated PIK3CA messenger RNA (mRNA) levels in 18 % of tumor cases and elevated AKT2 mRNA levels in 14 %. Our findings, along with those of previous studies, underline the importance of the PI3K/AKT pathway components as potential biomarkers for breast carcinogenesis.

  3. Genetics Home Reference: ovarian cancer

    Science.gov (United States)

    ... mutations, are not inherited. Somatic mutations in the TP53 gene occur in almost half of all ovarian ... PALB2 PIK3CA PMS2 PRKN RAD50 RAD51C RAD51D STK11 TP53 Related Information What is a gene? What is ...

  4. Genetics Home Reference: head and neck squamous cell carcinoma

    Science.gov (United States)

    ... several of the genes associated with HNSCC, including TP53 , NOTCH1 , and CDKN2A , function as tumor suppressors, which ... cell carcinoma CDKN2A FAT1 HRAS NOTCH1 PIK3CA PTEN TP53 Related Information What is a gene? What is ...

  5. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus

    Science.gov (United States)

    Di Nicolantonio, Federica; Arena, Sabrina; Tabernero, Josep; Grosso, Stefano; Molinari, Francesca; Macarulla, Teresa; Russo, Mariangela; Cancelliere, Carlotta; Zecchin, Davide; Mazzucchelli, Luca; Sasazuki, Takehiko; Shirasawa, Senji; Geuna, Massimo; Frattini, Milo; Baselga, José; Gallicchio, Margherita; Biffo, Stefano; Bardelli, Alberto

    2010-01-01

    Personalized cancer medicine is based on the concept that targeted therapies are effective on subsets of patients whose tumors carry specific molecular alterations. Several mammalian target of rapamycin (mTOR) inhibitors are in preclinical or clinical trials for cancers, but the molecular basis of sensitivity or resistance to these inhibitors among patients is largely unknown. Here we have identified oncogenic variants of phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA) and KRAS as determinants of response to the mTOR inhibitor everolimus. Human cancer cells carrying alterations in the PI3K pathway were responsive to everolimus, both in vitro and in vivo, except when KRAS mutations occurred concomitantly or were exogenously introduced. In human cancer cells with mutations in both PIK3CA and KRAS, genetic ablation of mutant KRAS reinstated response to the drug. Consistent with these data, PIK3CA mutant cells, but not KRAS mutant cells, displayed everolimus-sensitive translation. Importantly, in a cohort of metastatic cancer patients, the presence of oncogenic KRAS mutations was associated with lack of benefit after everolimus therapy. Thus, our results demonstrate that alterations in the KRAS and PIK3CA genes may represent biomarkers to optimize treatment of patients with mTOR inhibitors. PMID:20664172

  6. Wess-Zumino-Witten model off criticality

    CERN Document Server

    Cabra, D C

    1994-01-01

    We study the renormalization group flow properties of the Wess-Zumino-Witten model in the region of couplings between $g^2=0$ and $g^2=4\\pi/k$, by evaluating the two-loop Zamolodchikov's $c$-function. We also discuss the region of negative couplings.

  7. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

    NARCIS (Netherlands)

    Smid, M.; Rodriguez-Gonzalez, F.G.; Sieuwerts, A.M.; Salgado, R.; Smissen, W.J. Prager-Van der; Vlugt-Daane, M.V.; Galen, A. van; Nik-Zainal, S.; Staaf, J.; Brinkman, A.B.; Vijver, M.J. van de; Richardson, A.L.; Fatima, A.; Berentsen, K.; Butler, A.; Martin, S.; Davies, H.R.; Debets, R.; Gelder, M.E. Meijer-van; Deurzen, C.H. van; MacGrogan, G.; Eynden, G.G. Van den; Purdie, C.; Thompson, A.M.; Caldas, C.; Span, P.N; Simpson, P.T.; Lakhani, S.R.; Laere, S. van; Desmedt, C.; Ringner, M.; Tommasi, S.; Eyford, J.; Broeks, A.; Vincent-Salomon, A.; Futreal, P.A.; Knappskog, S.; King, T.; Thomas, G; Viari, A.; Langerod, A.; Borresen-Dale, A.L.; Birney, E.; Stunnenberg, H.G.; Stratton, M.; Foekens, J.A.; Martens, J.W.M.

    2016-01-01

    A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA,

  8. Polyamine levels and tomato fruit development: possible interaction with ethylene.

    Science.gov (United States)

    Saftner, R A; Baldi, B G

    1990-02-01

    Fruits of tomato, Lycopersicon esculentum Mill. cv Liberty, ripen slowly and have a prolonged keeping quality. Ethylene production and the levels of polyamines in pericarp of cv Liberty, Pik Red, and Rutgers were measured in relation to fruit development. Depending on the stage of fruit development, Liberty produced between 16 and 38% of the ethylene produced by Pik Red and Rutgers. The polyamines putrescine, spermidine, and spermine were present in all cultivars. Cadaverine was detected only in Rutgers. Levels of putrescine and spermidine declined between the immature and mature green stages of development and prior to the onset of climacteric ethylene production. In Pik Red and Rutgers, the decline persisted, whereas in Liberty, the putrescine level increased during ripening. Ripe pericarp of Liberty contained about three and six times more free (unconjugated) polyamines than Pik Red and Rutgers, respectively. No pronounced changes in spermidine or cadaverine occurred during ripening. The increase in the free polyamine level in ripe pericarp of Liberty may account for the reduction of climacteric ethylene production, and prolonged storage life.

  9. 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.

  10. 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.

  11. 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...

  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

    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. What is your diagnosis?

    Science.gov (United States)

    Panteliades, Manuela; Silva, Claudia Marcia Resende; Gontijo, Bernardo

    2016-01-01

    CLOVES syndrome is a rare, newly described, and relatively unknown syndrome, related to somatic mutations of the PIK3CA gene. Clinical findings include adipose tissue overgrowth, vascular malformations, epidermal nevi, scoliosis, and spinal deformities. This report deals with a characteristic phenotype case, highlighting peculiar cutaneous and radiological changes. PMID:27438212

  14. 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

  15. EGFR related mutational status and association to clinical outcome of third-line cetuximab-irinotecan in metastatic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Frifeldt Sanne K

    2011-03-01

    Full Text Available Abstract Background As supplement to KRAS mutational analysis, BRAF and PIK3CA mutations as well as expression of PTEN may account for additional non-responders to anti-EGFR-MoAbs treatment. The aim of the present study was to investigate the utility as biomarkers of these mutations in a uniform cohort of patients with metastatic colorectal cancer treated with third-line cetuximab/irinotecan. Methods One-hundred-and-seven patients were prospectively included in the study. Mutational analyses of KRAS, BRAF and PIK3CA were performed on DNA from confirmed malignant tissue using commercially available kits. Loss of PTEN and EGFR was assessed by immunohistochemistry. Results DNA was available in 94 patients. The frequency of KRAS, BRAF and PIK3CA mutations were 44%, 3% and 14%, respectively. All were non-responders. EGF receptor status by IHC and loss of PTEN failed to show any clinical importance. KRAS and BRAF were mutually exclusive. Supplementing KRAS analysis with BRAF and PIK3CA indentified additional 11% of non-responders. Patient with any mutation had a high risk of early progression, whereas triple-negative status implied a response rate (RR of 41% (p Conclusion Triple-negative status implied a clear benefit from treatment, and we suggest that patient selection for third-line combination therapy with cetuximab/irinotecan could be based on triple mutational testing.

  16. Frequency of manure application in organic versus annual application of synthetic fertilizer in conventional vegetable production

    Science.gov (United States)

    Transporting manure is an input cost that can affect profit. Manure was applied either annually, or biannually, to bell pepper (Capsicum annuum L.), cv. Jupiter, cucumber (Cucumis sativus L.), cv. Earli Pik, and sweet corn (Zea mays var. rugosa Bonaf.), cv. Incredible (se endosperm genotype), grown...

  17. Pooled Analysis of Phosphatidylinositol 3-kinase Pathway Variants and Risk of Prostate Cancer

    Science.gov (United States)

    Koutros, Stella; Schumacher, Fredrick R.; Hayes, Richard B.; Ma, Jing; Huang, Wen-Yi; Albanes, Demetrius; Canzian, Federico; Chanock, Stephen J.; Crawford, E. David; Diver, W. Ryan; Feigelson, Heather Spencer; Giovanucci, Edward; Haiman, Christopher A.; Henderson, Brian E.; Hunter, David J.; Kaaks, Rudolf; Kolonel, Laurence N.; Kraft, Peter; Le Marchand, Loïc; Riboli, Elio; Siddiq, Afshan; Stampfer, Mier J.; Stram, Daniel O.; Thomas, Gilles; Travis, Ruth C.; Thun, Michael J.; Yeager, Meredith; Berndt, Sonja I.

    2010-01-01

    The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking and may impact prostate carcinogenesis. Thus, we explored the association between single nucleotide polymorphisms (SNPs) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk (ORper allele=1.08 (95% CI: 1.03, 1.14), p-trend = 0.0017) after adjustment for multiple testing (Padj=0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association (ORper allele=1.21 (95% CI: 1.09, 1.34); p-trend =0.0003). The adjusted association was stronger for men who were diagnosed before 65 years (ORper allele= 1.47 (95% CI: 1.20, 1.79), p-trend = 0.0001) or had a family history (ORper allele= 1.57 (95% CI: 1.11, 2.23), p-trend = 0.0114), and was strongest in those with both characteristics (ORper allele= 2.31 (95% CI: 1.07, 5.07), p-interaction = 0.005). Increased risks were observed among men in the top tertile of circulating insulin like growth factor-1 (IGF-1) levels (ORper allele= 1.46 (95% CI: 1.04, 2.06), p-trend=0.075). No differences were observed with disease aggressiveness (≥8/stage T3/T4/fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early onset disease, which may be attributable to IGF-dependent PI3K signaling. PMID:20197460

  18. Disulfiram Treatment Facilitates Phosphoinositide 3-Kinase Inhibition in Human Breast Cancer Cells In vitro and In vivo

    Science.gov (United States)

    Zhang, Haijun; Chen, Di; Ringler, Jonathan; Chen, Wei; Cui, Qiuzhi Cindy; Ethier, Stephen P.; Dou, Q. Ping; Wu, Guojun

    2013-01-01

    Frequent genetic alterations of the components in the phosphoinositide 3-kinase (PI3K)/PTEN/AKT signaling pathway contribute greatly to breast cancer initiation and progression, which makes targeting this signaling pathway a promising therapeutic strategy for breast cancer treatment. In this study, we showed that in the presence of copper (Cu), disulfiram (DSF), a clinically used antialcoholism drug, could potently inhibit breast cancer cell growth regardless of the PIK3CA status. Surprisingly, the treatment with a mixture of DSF and copper (DSF-Cu) led to the decreased expression of PTEN protein and the activation of AKT in a dose- and time-dependent manner in different cell lines with or without PIK3CA mutations. Treatment of breast cancer cell lines with a combination of DSF-Cu and LY294002, a pan-PI3K inhibitor, resulted in the significant inhibition of cell growth when compared with either drug alone. In addition, the combined treatment of DSF and LY294002 significantly inhibited the growth of the breast tumor xenograft in nude mice induced by MDA-MB-231 cells expressing mutant PIK3CA-H1047R and PIK3CA-E545K, whereas neither DSF nor LY294002 alone could significantly retard tumor growth. Finally, the observed in vivo inhibitory effects are found associated with aberrant signaling alterations and apoptosis-inducing activities in tumor samples. Thus, our finding shows for the first time that treatment of breast cancer with DSF results in a novel feedback mechanism that activates AKT signaling. Our study also suggests that the combination of DSF and a PI3K inhibitor may offer a new combinational treatment model for breast cancer, particularly for those with PIK3CA mutations. PMID:20424113

  19. Phosphatidylinositol-3-kinase pathway aberrations in gastric and colorectal cancer: meta-analysis, co-occurrence and ethnic variation.

    Science.gov (United States)

    Chong, Mei-Ling; Loh, Marie; Thakkar, Bhavin; Pang, Brendan; Iacopetta, Barry; Soong, Richie

    2014-03-01

    Inhibition of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a cancer treatment strategy that has entered into clinical trials. We performed a meta-analysis on the frequency of prominent genetic (PIK3CA mutation, PIK3CA amplification and PTEN deletion) and protein expression (high PI3K, PTEN loss and high pAkt) aberrations in the PI3K pathway in gastric cancer (GC) and colorectal cancer (CRC). We also performed laboratory analysis to investigate the co-occurrence of these aberrations. The meta-analysis indicated that East Asian and Caucasian GC patients differ significantly for the frequencies of PIK3CA Exon 9 and 20 mutations (7% vs. 15%, respectively), PTEN deletion (21% vs. 4%) and PTEN loss (47% vs. 78%), while CRC patients differed for PTEN loss (57% vs. 26%). High study heterogeneity (I(2) > 80) was observed for all aberrations except PIK3CA mutations. Laboratory analysis of tumors from East Asian patients revealed significant differences between GC (n = 79) and CRC (n = 116) for the frequencies of PIK3CA amplification (46% vs. 4%) and PTEN loss (54% vs. 78%). The incidence of GC cases with 0, 1, 2 and 3 concurrent aberrations was 14%, 52%, 27% and 8%, respectively, while for CRC it was 10%, 60%, 25% and 4%, respectively. Our study consolidates knowledge on the frequency, co-occurrence and clinical relevance of PI3K pathway aberrations in GC and CRC. Up to 86% of GC and 90% of CRC have at least one aberration in the PI3K pathway, and there are significant differences in the frequencies of these aberrations according to cancer type and ethnicity.

  20. 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

  1. Combination Patterns of Major R Genes Determine the Level of Resistance to the M. oryzae in Rice (Oryza sativa L..

    Directory of Open Access Journals (Sweden)

    Yunyu Wu

    Full Text Available Rice blast caused by Magnaporthe oryzae is the most devastating disease of rice and poses a serious threat to world food security. In this study, the distribution and effectiveness of 18 R genes in 277 accessions were investigated based on pathogenicity assays and molecular markers. The results showed that most of the accessions exhibited some degree of resistance (resistance frequency, RF >50%. Accordingly, most of the accessions were observed to harbor two or more R genes, and the number of R genes harbored in accessions was significantly positively correlated with RF. Some R genes were demonstrated to be specifically distributed in the genomes of rice sub-species, such as Pigm, Pi9, Pi5 and Pi1, which were only detected in indica-type accessions, and Pik and Piz, which were just harbored in japonica-type accessions. By analyzing the relationship between R genes and RF using a multiple stepwise regression model, the R genes Pid3, Pi5, Pi9, Pi54, Pigm and Pit were found to show the main effects against M. oryzae in indica-type accessions, while Pita, Pb1, Pik, Pizt and Pia were indicated to exhibit the main effects against M. oryzae in japonica-type accessions. Principal component analysis (PCA and cluster analysis revealed that combination patterns of major R genes were the main factors determining the resistance of rice varieties to M. oryzae, such as 'Pi9+Pi54', 'Pid3+Pigm', 'Pi5+Pid3+Pigm', 'Pi5+Pi54+Pid3+Pigm', 'Pi5+Pid3' and 'Pi5+Pit+Pid3' in indica-type accessions and 'Pik+Pib', 'Pik+Pita', 'Pik+Pb1', 'Pizt+Pia' and 'Pizt+Pita' in japonica-type accessions, which were able to confer effective resistance against M. oryzae. The above results provide good theoretical support for the rational utilization of combinations of major R genes in developing rice cultivars with broad-spectrum resistance.

  2. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Andrea Sartore-Bianchi

    Full Text Available BACKGROUND: KRAS mutations occur in 35-45% of metastatic colorectal cancers (mCRC and preclude responsiveness to EGFR-targeted therapy with cetuximab or panitumumab. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been found to give rise to resistance. We present a comprehensive analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression in mCRC patients treated with cetuximab or panitumumab, with the aim of clarifying the relative contribution of these molecular alterations to resistance. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively analyzed objective tumor response, progression-free (PFS and overall survival (OS together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non-responsive patients, 74 (70% had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43 among patients with no alterations, 4% (2/47 among patients with 1 alteration, and 0% (0/24 for patients with > or =2 alterations (p or =2 molecular alteration(s (p<0.001. CONCLUSIONS/SIGNIFICANCE: When expression of PTEN and mutations of KRAS, BRAF and PIK3CA are concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to anti-EGFR therapies can be identified. We propose to define as 'quadruple negative', the CRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA. Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab-based therapies.

  3. Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: A single center study

    Directory of Open Access Journals (Sweden)

    Ulivi Paola

    2012-05-01

    Full Text Available Abstract Background KRAS mutations negatively affect outcome after treatment with cetuximab in metastatic colorectal cancer (mCRC patients. As only 20% of KRAS wild type (WT patients respond to cetuximab it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding KRAS WT patients. We retrospectively analyzed objective tumor response rate, (ORR progression-free (PFS and overall survival (OS with respect to the mutational status of KRAS, BRAF, PIK3CA and PTEN expression in mCRC patients treated with a cetuximab-based regimen. Methods 67 mCRC patients were enrolled onto the study. DNA was extracted from paraffin-embedded sections derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were analyzed by direct sequencing, PIK3CA was evaluated by pyrosequencing and PTEN expression by immunohistochemistry. Results BRAF and PIK3CA mutations were independently associated with worse PFS (p = 0.006 and p = 0.028, respectively and OS (p = 0.008 and p = 0.029, respectively. No differences in clinical outcome were found between patients who were positive or negative for PTEN expression. Conversely, patients negative for KRAS, BRAF and PIK3CA mutations were characterized by significantly better ORR, PFS and OS than patients with at least one of these mutations. Conclusions BRAF and PIK3CA mutations would seem to be independent predictors of anti-EGFR therapy effectiveness and could be taken into consideration during treatment decision making.

  4. 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...... on the role of autophagy in CLL, and they may further represent targets of treatment....

  5. NRG-tehing võib lõppeda energiakriisiga / Endel Lippmaa ; interv. Aivar Reinap

    Index Scriptorium Estoniae

    Lippmaa, Endel, 1930-

    2001-01-01

    TA akadeemikute esindaja arvates peaks valitsus tunnistama NRG Energy tehingu ebaõnnestunuks ja kuulutama välja uue, avaliku erastamiskonkursi. Kommenteerivad: G. Okk, I. Öpik, V. Reiljan, M. Pärnoja. Avalik kiri Eesti elektrist lk. 24 - alla kirjutanud Eesti TA akadeemikud. Sama vt. vene keeles Estonija, 18. juuni 2001, lk.6. Parlamendisaadik (V. Reiljan). Ilmunud ka: Molodjozh Estonii, 30. juuni 2001, lk. 8

  6. 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.

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

    Science.gov (United States)

    2015-07-01

    selected based on bulk tumor cell analysis may be ineffective in eradicating CSCs. We showed in a SHH medulloblastoma model that responsiveness of...CSCs to SHH inhibitors therapies varied greatly depending on the cell type in which tumor initiation occurred in vivo. If this novel discovery were...hydrocephalus by weaning age. We validated elevated PIK3CA signaling in these brains by increased pAKT and pS6 expression in transgenic brains (Fig

  8. Assessing Dimensionality of a Set of Items - Comparison of Different Approaches

    Science.gov (United States)

    1992-08-10

    Paychologe Progam for Measurement Box 40 Tulan University University of Iowa X,%to’.n. PA 19400040 Ne Orleans, LA 70118 Iowa Cty. IA 52242 Dr. Williamn 0...University Dr. Osisneh Dodand Eshstios Fairfax, VA 2203 Educaional Testng Service Snoai Bldg. Ras. 123OP Princeton. NJ 06541 Uniiesity of Marylandl Dr...Haia 3199 Educationall Test Serviice Pittsburght. PA 15260 ISRAEL PrInceton NJ 08341 Dr. Susan R. Goldman Dr. Gregoty Candel11 Dr. Pik Drasgow, Peabody

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

    Directory of Open Access Journals (Sweden)

    Philipp A Jaeger

    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.

  10. 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.

  11. The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines.

    Science.gov (United States)

    Riquelme, Ismael; Tapia, Oscar; Espinoza, Jaime A; Leal, Pamela; Buchegger, Kurt; Sandoval, Alejandra; Bizama, Carolina; Araya, Juan Carlos; Peek, Richard M; Roa, Juan Carlos

    2016-10-01

    The PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism and angiogenesis. Emerging evidence has shown that deregulation of this pathway has a role promoting gastric cancer (GC). The aim was to assess the expression of genes involved in this pathway by qPCR in 23 tumor and 23 non-tumor gastric mucosa samples from advanced GC patients, and in AGS, MKN28 and MKN45 gastric cancer cell lines. Results showed a slight overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1, EIF4EBP1 and EIF4E genes, and a slightly decreased PTEN and TSC1 expression. In AGS, MKN28 and MKN45 cells a significant gene overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1 and EIF4E, and a significant repression of PTEN gene expression were observed. Immunoblotting showed that PI3K-β, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E and p-eIF4E proteins were present in cell lines at different levels, confirming activation of this pathway in vitro. This is the first time this extensive panel of 9 genes within PI3K/AKT/mTOR pathway has been studied in GC to clarify the biological role of this pathway in GC and develop new strategies for this malignancy.

  12. Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials.

    Science.gov (United States)

    Dienstmann, Rodrigo; Serpico, Danila; Rodon, Jordi; Saura, Cristina; Macarulla, Teresa; Elez, Elena; Alsina, Maria; Capdevila, Jaume; Perez-Garcia, Jose; Sánchez-Ollé, Gessamí; Aura, Claudia; Prudkin, Ludmila; Landolfi, Stefania; Hernández-Losa, Javier; Vivancos, Ana; Tabernero, Josep

    2012-09-01

    Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n = 10; or low PTEN, n = 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n = 10; or BRAF mutation, n = 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n = 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n = 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n = 5), and BRAF inhibitor (if BRAF mutation, n = 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P 16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit.

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

    Science.gov (United States)

    Jaeger, Philipp A; Pickford, Fiona; Sun, Chung-Huan; Lucin, Kurt M; Masliah, Eliezer; Wyss-Coray, Tony

    2010-06-15

    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.

  14. 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

  15. New Results from the FOCUS/E831 Experiment

    CERN Document Server

    Kim, D Y; Alimonti, G; Anjos, J C; Arena, V; Barberis, S; Bediaga, I; Benussi, L; Bertani, L; Bianco, S; Boca, G; Bonomi, G; Boschini, M; Butler, J N; Carrillo, S; Casimiro, E; Cawlfield, C; Cerutti, A; Cheung, H W K; Chiodini, G; Cho, K; Chung, Y S; Cinquini, L; Cuautle, E; Cumalat, J P; D'Angelo, P; Davenport, T F; De Miranda, J M; Di Corato, M; Dini, P; Dos Reis, A C; Edera, L; Engh, D; Erba, S; Fabbri, Franco Luigi; Gaines, I; Garbincius, P H; Gardner, R; Garren, L A; Giammarchi, M; Gianini, G; Gottschalk, E E; Green, S W; Göbel, C; Han, T; Hernández, H; Hosack, M; Inzani, P; Johns, W E; Kang, J S; Kasper, P H; Kim, D Y; Ko, B R; Kreymer, A E; Kryemadhi, A; Kutschke, R; Kwak, J W; Lee, K B; Leveraro, F; Liguori, G; Link, J M; Lopes-Pegna, D; Luiggi, E; López, A M; Magnin, J; Malvezzi, S; Massafferri, A; Menasce, D; Merlo, M M; Mezzadri, M; Mitchell, R; Moroni, L; Méndez, H; Nehring, M S; O'Reilly, B; Pantea, D; Paris, A; Park, H; Pedrini, D; Pepe, I M; Polycarpo, E; Pon, C; Prelz, F; Quinones, J; Rahimi, A; Ramírez, J E; Ratti, S P; Reyes, M; Riccardi, C; Rovere, M; Sala, S; Segoni, I; Sheaff, M; Sheldon, P D; Stenson, K; Sánchez-Hernández, A; Uribe, C; Vaandering, E W; Vitulo, P; Vázquez, F; Wahl, M; Wang, M; Webster, M; Wilson, J R; Wiss, J; Yager, P M; Zallo, A; Zhang, Y; Kim, Doris Yangsoo

    2003-01-01

    The E831/FOCUS experiment at Fermilab is a photoproduction experiment which generated high quality charm particles. During its run, we obtained a large data set, including more than 1 million charm mesons in the Kpi/K2pi/K3pi mode decays. The current analysis efforts by the collaboration members are quite active and diverse. I will summarize the recent papers published by the FOCUS group on topics of semileptonic decays of charm mesons.

  16. Prognostic factors in the myoepithelial-like spindle cell type of metaplastic breast cancer.

    Science.gov (United States)

    Leo, Fabian; Bartels, Stephan; Mägel, Lavinia; Framke, Theodor; Büsche, Guntram; Jonigk, Danny; Christgen, Matthias; Lehmann, Ulrich; Kreipe, Hans

    2016-08-01

    Metaplastic breast carcinoma (MBC) comprises a heterogeneous group of tumors with difficult to predict biological behavior. A subset of MBC, characterized by spindle-shaped tumor cells with a myoepithelial-like immunophenotype, was entered into a retrospective study (n = 42, median follow-up time 43 months). Molecular parameters (DNA sequences of mutation hot spots in AKT1, ALK, APC, BRAF, CDH1, CTNNB1, EGFR, ERBB2, FBXW7, FGFR2, FOXL2, GNAQ, GNAS, KIT, KRAS, MAP2K1, MET, MSH6, NRAS, PDGFRA, PIK3CA, PTEN, SF3B1, SMAD4, SRC, SRSF2, STK11, TP53, and U2AF1; copy numbers for EGFR, c-myc, FGFR, PLAG, c-met) were assessed. None of the patients had axillary lymph node involvement. In 13 cases, local recurrence developed after surgery (30.9 %). Distant metastasis occurred in seven patients (17 %; four after local recurrence). The most frequent genetic alteration was PIK3CA mutation (50 % of cases). None of the pathological parameters (size, grade, stage, Ki-67 labeling index) was significantly associated with disease-free survival (DFS) or overall survival (OS). PIK3CA mutation, especially the H1047R type, tended to adversely affect OS. Type of resection (mastectomy vs. breast-conserving therapy, width of margins) or adjuvant radiotherapy had no influence on DFS or OS, whereas in the group treated with radio-/chemotherapy, no local recurrence or metastasis and no death occurred. We conclude that the spindle cell type of MBC with myoepithelial features exhibits a higher frequency of PIK3CA mutation than other types of metaplastic or basal-like breast cancer and may benefit from combined radio-/chemotherapy. Classical pathological parameters are not helpful in identifying the high-risk tumors among this subgroup of MBC.

  17. Revealing the Effects of the Herbal Pair of Euphorbia kansui and Glycyrrhiza on Hepatocellular Carcinoma Ascites with Integrating Network Target Analysis and Experimental Validation.

    Science.gov (United States)

    Zhang, Yanqiong; Lin, Ya; Zhao, Haiyu; Guo, Qiuyan; Yan, Chen; Lin, Na

    2016-01-01

    Although the herbal pair of Euphorbia kansui (GS) and Glycyrrhiza (GC) is one of the so-called "eighteen antagonistic medicaments" in Chinese medicinal literature, it is prescribed in a classic Traditional Chinese Medicine (TCM) formula Gansui-Banxia-Tang for cancerous ascites, suggesting that GS and GC may exhibit synergistic or antagonistic effects in different combination designs. Here, we modeled the effects of GS/GC combination with a target interaction network and clarified the associations between the network topologies involving the drug targets and the drug combination effects. Moreover, the "edge-betweenness" values, which is defined as the frequency with which edges are placed on the shortest paths between all pairs of modules in network, were calculated, and the ADRB1-PIK3CG interaction exhibited the greatest edge-betweenness value, suggesting its crucial role in connecting the other edges in the network. Because ADRB1 and PIK3CG were putative targets of GS and GC, respectively, and both had functional interactions with AVPR2 approved as known therapeutic target for ascites, we proposed that the ADRB1-PIK3CG-AVPR2 signal axis might be involved in the effects of the GS-GC combination on ascites. This proposal was further experimentally validated in a H22 hepatocellular carcinoma (HCC) ascites model. Collectively, this systems-level investigation integrated drug target prediction and network analysis to reveal the combination principles of the herbal pair of GS and GC. Experimental validation in an in vivo system provided convincing evidence that different combination designs of GS and GC might result in synergistic or antagonistic effects on HCC ascites that might be partially related to their regulation of the ADRB1-PIK3CG-AVPR2 signal axis.

  18. The semileptonic decays $B/B_s \\to (\\pi, K)(l^+l^-,l\

    CERN Document Server

    Wang, Wen-Fei

    2012-01-01

    In this paper we first calculate the form factors of $B \\to (\\pi,K)$ and $B_s \\to K $ transitions by employing the perturbative QCD (pQCD) factorization approach with the inclusion of the next-to-leading-order(NLO) corrections, and then we calculate the branching ratios of the corresponding semileptonic decays $B/B_s \\to (\\pi, K)(l^+l^-,l\

  19. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer

    Science.gov (United States)

    Domingo, Enric; Ramamoorthy, Rajarajan; Oukrif, Dahmane; Rosmarin, Daniel; Presz, Michal; Wang, Haitao; Pulker, Hannah; Lockstone, Helen; Hveem, Tarjei; Cranston, Treena; Danielsen, Havard; Novelli, Marco; Davidson, Brian; Xu, Zheng-Zhou; Molloy, Peter; Johnstone, Elaine; Holmes, Christopher; Midgley, Rachel; Kerr, David; Sieber, Oliver; Tomlinson, Ian

    2013-01-01

    Abstract Molecular classification of colorectal cancer (CRC) is currently based on microsatellite instability (MSI), KRAS or BRAF mutation and, occasionally, chromosomal instability (CIN). Whilst useful, these categories may not fully represent the underlying molecular subgroups. We screened 906 stage II/III CRCs from the VICTOR clinical trial for somatic mutations. Multivariate analyses (logistic regression, clustering, Bayesian networks) identified the primary molecular associations. Positive associations occurred between: CIN and TP53 mutation; MSI and BRAF mutation; and KRAS and PIK3CA mutations. Negative associations occurred between: MSI and CIN; MSI and NRAS mutation; and KRAS mutation, and each of NRAS, TP53 and BRAF mutations. Some complex relationships were elucidated: KRAS and TP53 mutations had both a direct negative association and a weaker, confounding, positive association via TP53–CIN–MSI–BRAF–KRAS. Our results suggested a new molecular classification of CRCs: (1) MSI+ and/or BRAF-mutant; (2) CIN+ and/or TP53– mutant, with wild-type KRAS and PIK3CA; (3) KRAS- and/or PIK3CA-mutant, CIN+, TP53-wild-type; (4) KRAS– and/or PIK3CA-mutant, CIN–, TP53-wild-type; (5) NRAS-mutant; (6) no mutations; (7) others. As expected, group 1 cancers were mostly proximal and poorly differentiated, usually occurring in women. Unexpectedly, two different types of CIN+ CRC were found: group 2 cancers were usually distal and occurred in men, whereas group 3 showed neither of these associations but were of higher stage. CIN+ cancers have conventionally been associated with all three of these variables, because they have been tested en masse. Our classification also showed potentially improved prognostic capabilities, with group 3, and possibly group 1, independently predicting disease-free survival. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:23165447

  20. 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

  1. Installation Restoration Program. Phase 2. Confirmation/Quantification. Stage 1. Air Force Plant 6, Cobb County, Georgia. Volume 2.

    Science.gov (United States)

    1986-08-09

    03 4 0 1 s 20 30 AO 60 so 100 -Z - BMA.CKAN ’,;HT VERY SLT .4.10531.8 O7B ’-44’ -~F-1 19.0 - - - -e N 101.5DE~s AN V Y DESE ROWN PIK,% %- TEST BORING...before the water quality change graphic analysis of fatty acids from landfill sites ., was noticed. Dynamiting during the prospetn Inter. J . Environ

  2. Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.

    Science.gov (United States)

    Ducker, G S; Atreya, C E; Simko, J P; Hom, Y K; Matli, M R; Benes, C H; Hann, B; Nakakura, E K; Bergsland, E K; Donner, D B; Settleman, J; Shokat, K M; Warren, R S

    2014-03-20

    The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new adenosine triphosphate (ATP) competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, whereas those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor eIF4E-binding protein 1 (4E-BP1), but not ribosomal protein S6 (rpS6). In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242-induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared with KRAS wild-type controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1.

  3. Resonances in coupled {\\pi}K,{\\eta}K scattering from quantum chromodynamics

    CERN Document Server

    Dudek, Jozef J; Thomas, Christopher E; Wilson, David J

    2014-01-01

    Using first-principles calculation within Quantum Chromodynamics, we are able to reproduce the pattern of experimental strange resonances which appear as complex singularities within coupled {\\pi}K, {\\eta}K scattering amplitudes. We make use of numerical computation within the lattice discretized approach to the quantum field theory, extracting the energy dependence of scattering amplitudes through their relationship to the discrete spectrum of the theory in a finite-volume, which we map out in unprecedented detail.

  4. 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.)

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer.

    Science.gov (United States)

    van Ginkel, Joost H; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M

    2016-09-20

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC. Furthermore, we assessed prevalence, co-occurrence, and synonymy of gene mutations in (matched) tumor samples. TP53 was found mutated the most frequent with mutation rates of up to 83% in all tumors, compared to mutation rates of between 0 and 21% of CDKN2A, PIK3CA, HRAS, CDK4, FBXW7 and RB1. Mutational co-occurrence predominantly existed between TP53 and PIK3CA, TP53 and CDKN2A, and HRAS and PIK3CA. Mutational synonymy between primary tumor and associated metastasis and recurrence was present in respectively 88% and 89%. TP53 mutations were concordantly mutated in 95% of metastases and in 91% of recurrences. This indicates TP53 mutations to be highly prevalent and concordant in primary tumors and associated locoregional metastases and recurrences. In turn, this provides ground for further investigating the use of TP53 mutations as diagnostic biomarkers in HNSCC patients.

  7. 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(+)/PIK3CA(H1047R) 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(+)/PIK3CA(H1047R) 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.

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

    Directory of Open Access Journals (Sweden)

    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. 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.

    Directory of Open Access Journals (Sweden)

    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

  10. Kuidas sünnib pealkiri? / Pärt Lias

    Index Scriptorium Estoniae

    Lias, Pärt

    2002-01-01

    Pealkiri, pühendus, moto, joonealune märge, ees- ja järelsõna on teose teksti manused, mis ei kuulu otse teksti, kuid selgitavad, täiendavad ja täpsustavad seda. Gerard Genette on need teksti lisandid koondanud üldnimetuse paratekstid alla. Eesti kirjanikud vastavad Pärt Liase küsimusele oma teoste pealkirjade saamisloo kohta: Aimee Beekman, Henn-Kaarel Hellat, Joel Sang ja Arvo Mägi (4); Lennart Meri, Heino Kiik ja Fanny de Sivers (5); Helga Nõu, Ülle Kauksi, Maie Kalda ja Cornelius Hasselblatt (6); Debora Vaarandi, Vaino Vahing, Arved Viirlaid ja Wimberg (7); Vahur Afanasjev, Matt Barker, Andrus Kivirähk, Jürgen Rooste ja Contra (8); Elin Toona, Jaak Rähesoo, Enn Soosaar, Juhan Peegel ja Toomas Kall (9); Kerttu Rakke, Aare Pilv, Aarne Ruben, Indrek Hargla, Jan Kaus ja Karen Orlau (10); Ene Mihkelson, Mats Traat ja Boriss Baljasnõi (11); Maimu Berg, Ain Kaalep, Enn Nõu ja Madis Kõiv (12)

  11. Kuidas sünnib pealkiri? / Pärt Lias

    Index Scriptorium Estoniae

    Lias, Pärt

    2002-01-01

    Pealkiri, pühendus, moto, joonealune märge, ees- ja järelsõna on teose teksti manused, mis ei kuulu otse teksti, kuid selgitavad, täiendavad ja täpsustavad seda. Gerard Genette on need teksti lisandid koondanud üldnimetuse paratekstid alla. Eesti kirjanikud vastavad Pärt Liase küsimusele oma teoste pealkirjade saamisloo kohta: Aimee Beekman, Henn-Kaarel Hellat, Joel Sang ja Arvo Mägi (4); Lennart Meri, Heino Kiik ja Fanny de Sivers (5); Helga Nõu, Ülle Kauksi, Maie Kalda ja Cornelius Hasselblatt (6); Debora Vaarandi, Vaino Vahing, Arved Viirlaid ja Wimberg (7); Vahur Afanasjev, Matt Barker, Andrus Kivirähk, Jürgen Rooste ja Contra (8); Elin Toona, Jaak Rähesoo, Enn Soosaar, Juhan Peegel ja Toomas Kall (9); Kerttu Rakke, Aare Pilv, Aarne Ruben, Indrek Hargla, Jan Kaus ja Karen Orlau (10); Ene Mihkelson, Mats Traat ja Boriss Baljasnõi (11); Maimu Berg, Ain Kaalep, Enn Nõu ja Madis Kõiv (12)

  12. Phosphatidylinositol 3-kinase p85 regulatory subunit gene and spinal muscular atrophy disease

    Directory of Open Access Journals (Sweden)

    Monica STAVARACHI

    2009-11-01

    Full Text Available Spinal muscular atrophy (SMA is a frequent neuromuscular disorder caused by motoneuronal apoptosis, as a result of SMN (Survival Motor Neuron protein deficiency. Although the SMA determining gene was identified, the molecular mechanism of the disease is not clearly understood, due to the heterogeneity of clinical manifestations. Trying to complete the molecular describing SMA picture, by identifying potential modulators factors, we investigated the relationship between phosphatidylinositol 3-kinase p85 regulatory subunit gene (PIK3R1 and SMA pathology. As IGF signaling pathway has been reported to play an important role in motoneurons survival and PIK3 is a key element of this cascade signaling, we focused on the relationship between PIK3R1 gene Met326Ile polymorphism and SMA type I, the most severe form of the disease. A total of 80 subjects (40 SMA type I patients and 40 unrelated healthy controls were included in the study. The statistical analyzes performed consequently to the genotyping by mismatch PCR-RFLP method, revealed that Met326Ile polymorphism is not associated with SMA type I disease: ORMet/Met = 0.398 with a p = 0.072 meanwhile ORMet = 0.495, p = 0.063. However, the Cochrane – Armitage test indicated that there is a statistically association trend between the analyzed polymorphism and SMA type I pathology: ORMet = 0.438, p = 0.032. We concluded that additional researches with an increased subjects number and replicates studies in other populations will clarify the investigated relationship and it may contribute to the SMA molecular mechanism understanding.

  13. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients.

    Science.gov (United States)

    van den Hurk, Karin; Balint, Balazs; Toomey, Sinead; O'Leary, Patrick C; Unwin, Louise; Sheahan, Kieran; McDermott, Enda W; Murphy, Ian; van den Oord, Joost J; Rafferty, Mairin; FitzGerald, Dara M; Moran, Julie; Cummins, Robert; MacEneaney, Owen; Kay, Elaine W; O'Brien, Cathal P; Finn, Stephen P; Heffron, Cynthia C B B; Murphy, Michelle; Yela, Ruben; Power, Derek G; Regan, Padraic J; McDermott, Clodagh M; O'Keeffe, Allan; Orosz, Zsolt; Donnellan, Paul P; Crown, John P; Hennessy, Bryan T; Gallagher, William M

    2015-06-01

    Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (PBRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

  14. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  16. Association between germline single nucleotide polymorphisms in the PI3K-AKT-mTOR pathway, obesity, and breast cancer disease-free survival.

    Science.gov (United States)

    Pande, Mala; Bondy, Melissa L; Do, Kim-Anh; Sahin, Aysegul A; Ying, Jun; Mills, Gordon B; Thompson, Patricia A; Brewster, Abenaa M

    2014-09-01

    Obesity-related hormones and cytokines alter PI3 K-AKT-mTOR pathway activation in breast tumors contributing to poorer disease-free survival (DFS) and decreased responsiveness to tamoxifen and trastuzumab. We hypothesized that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3 K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway with DFS in a sample of 1,019 women with stage I-II breast cancer. SNPs significantly associated with DFS in any genetic model (additive, dominant, or recessive) after correcting for false discovery rate (FDR = 0.10) were included in Cox proportional hazards multivariable analyses. After adjusting for race/ethnicity, age at diagnosis, tumor stage, and treatment, rs1063539 in ADIPOQ, rs11585329 in LEPR, and rs2519757 in TSC1 were associated with improved DFS, and rs1520220 in IGF1 and rs2677760 in PIK3CA were associated with worse DFS. The associations were not significantly modified by the type of systemic treatment received or body mass index. The SNPs were not associated with tumor characteristics such as tumor size, lymph node status, nuclear grade, or hormone receptor status. In this study, germline SNPs in the PI3 K-AKT-mTOR pathway were associated with breast cancer DFS and may be potential prognostic markers. Future studies are needed to replicate our results and to evaluate the relationship between these polymorphisms and activation of the PI3 K-AKT-mTOR pathway in breast tumors.

  17. Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations.

    Science.gov (United States)

    Deb, S; Wong, S Q; Li, J; Do, H; Weiss, J; Byrne, D; Chakrabarti, A; Bosma, T; Fellowes, A; Dobrovic, A; Fox, S B

    2014-12-09

    Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers. Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes. Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours. This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.

  18. Preclinical evaluation of PI3K inhibitor BYL719 as a single agent and its synergism in combination with cisplatin or MEK inhibitor in nasopharyngeal carcinoma (NPC)

    Science.gov (United States)

    Wong, Chi Hang; Ma, Brigette Buig Yue; Cheong, Hio Teng; Hui, Connie Wun Chun; Hui, Edwin Pun; Chan, Anthony Tak Cheung

    2015-01-01

    Nasopharyngeal carcinoma (NPC) is endemic to Southeast Asia and over 40% of NPC tissues harbor PIK3CA amplifications. This study aims to study the preclinical activity of a novel PI3K inhibitor, BYL719, in 6 NPC cell lines: C666-1, CNE-2, HK1, HK1-EBV, HONE-1 and HONE-1-LMP1. Over 70% of growth inhibition was attained when NPC cell lines were exposed to increasing concentrations of BYL719, with IC50 values at the low micro-molar range. Two BYL719-sensitive cell lines that harbor PIK3CA mutations, CNE-2 and HONE-1, were selected for further analysis on the effect of BYL719 on cell cycle progression, apoptosis and PI3K signaling. BYL719 significantly reduced the phosphorylation of Akt, and the Akt-mTOR axis downstream effector S6 in these 2 cell lines, but a feedback activation of MAPK was observed at 72 hours post-treatment. BYL719 induced G0/G1 cell cycle arrest and apoptosis in both cell lines. In 3D cell culture models, the growth of NPC spheroids was significantly inhibited in a dose-depending manner. When BYL719 was combined with a MEK inhibitor (AZD6244) in a 3D cell culture system, strong synergism on NPC cell growth was observed with attenuation of MAPK activation. A synergistic inhibitory effect on growth was observed when BYL719 was combined with higher dose levels of cisplatin. These data suggest that BYL719 has preclinical activity in NPC cell lines especially in those which harbor PIK3CA mutation. Combination with a MEK inhibitor maybe a useful strategy that warrants further investigation. PMID:26101713

  19. Combined treatment with everolimus and fulvestrant reversed anti-HER2 resistance in a patient with refractory advanced breast cancer: a case report

    Directory of Open Access Journals (Sweden)

    Sun B

    2016-07-01

    Full Text Available Bing Sun,1 Lijuan Ding,1 Shikai Wu,1 Xiangying Meng,1 Santai Song2 1Department of Radiotherapy, 2Department of Breast Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People’s Republic of China Background: Everolimus, an inhibitor of the mammalian target of rapamycin, shows promising antitumor activity when combined with trastuzumab and chemotherapy for human epidermal growth factor receptor-2 (HER2-positive breast cancer or when combined with endocrine agents for hormone receptor (HR-positive tumors. However, data are limited regarding the effect of everolimus in combination with endocrine drugs in HER2-positive advanced breast cancer regardless of the HR status.Case presentation: A 44-year-old female was diagnosed with recurrent HER2-positive breast cancer. The primary tumor was HR positive; however, the metastatic tumor was HR negative. The patient was resistant to classical chemotherapeutic agents and anti-HER2 treatment. Thus, the combination of everolimus and fulvestrant, a selective estrogen receptor downregulator, was chosen to reverse the resistance to anti-HER2 therapy. Indeed, the patient experienced long-term disease stabilization. Adverse events associated with the treatment were manageable by dose adjustments. We performed genetic testing of the metastatic tumor, which harbored a PIK3CA gene mutation but was positive for phosphatase and tensin homologue expression, which might result in resistance to the mammalian target of rapamycin inhibitor.Conclusion: This case study indicates that combined treatment with everolimus and fulvestrant might be a viable option for the treatment of metastatic breast cancer patients who are HER2 positive and carry a PIK3CA gene mutation but are resistant to anti-HER2 therapy and classical chemotherapeutic agents. Further prospective randomized trials are needed to confirm this finding. Keywords: mTOR inhibitor, PIK3CA gene, genetic testing, PI3K Akt mTOR pathway

  20. Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest

    Science.gov (United States)

    Wang, Peng; Ye, Jing-An; Hou, Chong-Xian; Zhou, Dong; Zhan, Sheng-Quan

    2016-01-01

    Temozolomide (TMZ) is approved for use as first-line treatment for glioblastoma multiforme (GBM). However, GBM shows chemoresistance shortly after the initiation of treatment. In order to detect whether silencing of human protein phosphatase 1D magnesium dependent (PPM1D) gene could increase the effects of TMZ in glioma cells, glioma cells U87-MG were infected with lentiviral shRNA vector targeting PPM1D silencing. After PPM1D silencing was established, cells were treated with TMZ. The multiple functions of human glioma cells after PPM1D silencing and TMZ chemotherapy were detected by flow cytometry and MTT assay. Significantly differentially expressed genes were distinguished by microarray-based gene expression profiling and analyzed by gene pathway enrichment analysis and ontology assessment. Western blotting was used to establish the protein expression of the core genes. PPM1D gene silencing improves TMZ induced cell proliferation and induces cell apoptosis and cell cycle arrest. When PPM1D gene silencing combined with TMZ was performed in glioma cells, 367 genes were upregulated and 444 genes were downregulated compared with negative control. The most significant differential expression pathway was pathway in cancer and IGFR1R, PIK3R1, MAPK8 and EP300 are core genes in the network. Western blotting showed that MAPK8 and PIK3R1 protein expression levels were upregulated and RB1 protein expression was decreased. It was consistent with that detected in gene expression profiling. In conclusion, PPM1D gene silencing combined with TMZ eradicates glioma cells through cell apoptosis and cell cycle arrest. PIK3R1/AKT pathway plays a role in the multiple functions of glioma cells after PPM1D silencing and TMZ chemotherapy. PMID:27633132

  1. FEASIBILITY OF INDUCTION DOCETAXEL, CISPLATIN, 5-FLUOROURACIL, CETUXIMAB (TPF-C FOLLOWED BY CONCURRENT CETUXIMAB RADIOTHERAPY FOR LOCALLY ADVANCED HEAD AND NECK SQUAMOUS CELL CARCINOMA

    Directory of Open Access Journals (Sweden)

    Nikolaos eCharalambakis

    2013-01-01

    Full Text Available Purpose: To report our experience with a sequential regimen of induction TPF-C followed by radioimmunotherapy with cetuximab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC. Patients and Methods: Toxicity and outcome was retrospectively analyzed in 22 patients receiving sequential therapy with induction TPF-C followed by radioimmunotherapy between October 2008 and December 2011. Outcome was estimated using Kaplan-Meier analyses. In addition, we performed mutation analysis for PIK3CA genes and high-risk HPV-DNA detection using PCR. Results: Median follow-up was 16 months. Six patients were TNM Stage III, 15 patients IV (IVA or IVB and 1 patient Stage II with bulky disease. During TPF-C, Grade 3 and 4 toxicities occurred in 8 patients (36.4%, dose modifications in 7 (31.8%, delays in 1 (4.5%, and unplanned admissions in 5 (22.7%. Clinical tumor response was documented in 18 of the 21 patients who completed at least 3 cycles of TPF-C (85.7% with 3 patients developing complete response and 15 partial responses. Grade 3/4 mucositis was observed in 6 (31.6% patients. At a median follow up of 19 months, 13 patients were alive and 9 (40.9% had died including 7 patients as a result of disease persistence or recurrence and two as a result of unrelated causes. PIK3CA mutations were not identified and our 2 oropharynx cases were HPV negative.Conclusions: The combination of induction TPF-C with concurrent cetuximab radioimmunotherapy in patients with locally advanced HNSCC is tolerable, with encouraging efficacy.Keywords: HNSCC, TPF-C, cetuximab radiotherapy, toxicity and outcome, mutation analysis, PIK3CA, HPV-DNA.

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

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background 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. Methods 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. Results Eighteen (37% of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours 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: tumours 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. Conclusion 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.

  3. H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation via heregulin production and activation of HER3

    Science.gov (United States)

    Chakrabarty, Anindita; Rexer, Brent N.; Wang, Shizhen Emily; Cook, Rebecca S.; Engelman, Jeffrey A.; Arteaga, Carlos, L.

    2010-01-01

    Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110α subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K but not E545K PI3K markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors. PMID:20581867

  4. 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.

  5. 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.

  6. Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma.

    Science.gov (United States)

    Paula, Luciana Marques; De Moraes, Luis Henrique Ferreira; Do Canto, Abaeté Leite; Dos Santos, Laurita; Martin, Airton Abrahão; Rogatto, Silvia Regina; De Azevedo Canevari, Renata

    2017-01-01

    Nodal status is the most significant independent prognostic factor in breast cancer. Identification of molecular markers would allow stratification of patients who require surgical assessment of lymph nodes from the large numbers of patients for whom this surgical procedure is unnecessary, thus leading to a more accurate prognosis. However, up to now, the reported studies are preliminary and controversial, and although hundreds of markers have been assessed, few of them have been used in clinical practice for treatment or prognosis in breast cancer. The purpose of the present study was to determine whether protein phosphatase Mg2+/Mn2+ dependent 1D, β-1,3-N-acetylglucosaminyltransferase, neural precursor cell expressed, developmentally down-regulated 9, prohibitin, phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5), phosphatidylinositol-5-phosphate 4-kinase type IIα, TRF1-interacting ankyrin-related ADP-ribose polymerase 2, BCL2 associated agonist of cell death, G2 and S-phase expressed 1 and PAX interacting protein 1 genes, described as prognostic markers in breast cancer in a previous microarray study, are also predictors of lymph node involvement in breast carcinoma Reverse transcription-quantitative polymerase chain reaction analysis was performed on primary breast tumor tissues from women with negative lymph node involvement (n=27) compared with primary tumor tissues from women with positive lymph node involvement (n=23), and was also performed on primary tumors and paired lymph node metastases (n=11). For all genes analyzed, only the PIK3R5 gene exhibited differential expression in samples of primary tumors with positive lymph node involvement compared with primary tumors with negative lymph node involvement (P=0.0347). These results demonstrate that the PIK3R5 gene may be considered predictive of lymph node involvement in breast carcinoma. Although the other genes evaluated in the present study have been previously characterized to be involved with

  7. Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma

    Science.gov (United States)

    Paula, Luciana Marques; De Moraes, Luis Henrique Ferreira; Do Canto, Abaeté Leite; Dos Santos, Laurita; Martin, Airton Abrahão; Rogatto, Silvia Regina; De Azevedo Canevari, Renata

    2017-01-01

    Nodal status is the most significant independent prognostic factor in breast cancer. Identification of molecular markers would allow stratification of patients who require surgical assessment of lymph nodes from the large numbers of patients for whom this surgical procedure is unnecessary, thus leading to a more accurate prognosis. However, up to now, the reported studies are preliminary and controversial, and although hundreds of markers have been assessed, few of them have been used in clinical practice for treatment or prognosis in breast cancer. The purpose of the present study was to determine whether protein phosphatase Mg2+/Mn2+ dependent 1D, β-1,3-N-acetylglucosaminyltransferase, neural precursor cell expressed, developmentally down-regulated 9, prohibitin, phosphoinositide-3-kinase regulatory subunit 5 (PIK3R5), phosphatidylinositol-5-phosphate 4-kinase type IIα, TRF1-interacting ankyrin-related ADP-ribose polymerase 2, BCL2 associated agonist of cell death, G2 and S-phase expressed 1 and PAX interacting protein 1 genes, described as prognostic markers in breast cancer in a previous microarray study, are also predictors of lymph node involvement in breast carcinoma Reverse transcription-quantitative polymerase chain reaction analysis was performed on primary breast tumor tissues from women with negative lymph node involvement (n=27) compared with primary tumor tissues from women with positive lymph node involvement (n=23), and was also performed on primary tumors and paired lymph node metastases (n=11). For all genes analyzed, only the PIK3R5 gene exhibited differential expression in samples of primary tumors with positive lymph node involvement compared with primary tumors with negative lymph node involvement (P=0.0347). These results demonstrate that the PIK3R5 gene may be considered predictive of lymph node involvement in breast carcinoma. Although the other genes evaluated in the present study have been previously characterized to be involved with

  8. Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Yasutaka Sukawa; Hiroyuki Yamamoto; Katsuhiko Nosho; Hiroaki Kunimoto; Hiromu Suzuki; Yasushi Adachi; Mayumi Nakazawa

    2012-01-01

    AIM:To investigate human epidermal growth factor receptor 2 (HER2)-phosphatidylinositol 3-kinase (PI3K)-v-Akt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry (IHC) using the HercepTestTM kit.Standard criteria for HER2 positivity (0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt (pAkt)was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide (PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus (EBV)infection was analyzed by in situ hybridization targeting EBV-encoded small RNA (EBER) with an EBER-RNA probe.Microsatellite instability (MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167 (72%),32 (14%),12 (5%) and 20 (8.7%) samples,respectively.HER2 overexpression (IHC 3+) significantly correlated with intestinal histological type (15/20 vs 98/205,P =0.05).PIK3CA mutations were present in 20 cases (8.7%) and significantly correlated with MSI (10/20 vs 9/211,P < 0.01).The mutation frequency was high (21%) in T4 cancers and very low (6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5 (2%),9 (4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R (6/20,30%) in exon20.Eighteen cancers (8%) were EBV-positive and this

  9. 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.

  10. Endometriosis and Type I Interferon & Characterization of a Mammalian Flippase

    DEFF Research Database (Denmark)

    Vestergaard, Anna Lindeløv

    2010-01-01

    , and ERa, when analyzed by bisulfate PCR and melting curve analysis. Also, no mutations of BRAF, HRAS, NRAS, CTNNB1, CDK4, FGFR3, PIK3CA, P53, and PTEN were detected by PCR denaturing gradient gel electrophoresis analysis. A well-known cancer-associated mutation in KRAS was detected in a single...... protein family are believed to be chaperones or additional subunits to these enzymes. The molecular mechanism of the flippases is currently unknown, and whereas studies of the yeast family members have provided some functional knowledge on the matter, the mammalian homologs are still fairly...

  11. The optical model potential of the $\\Sigma$ hyperon in nuclear matter

    OpenAIRE

    Dabrowski, J; Rozynek, J.

    2009-01-01

    We present our attempts to determine the optical model potential $U_\\Sigma = V_\\Sigma -iW_\\Sigma$ of the $\\Sigma$ hyperon in nuclear matter. We analyze the following sources of information on $U_\\Sigma$: $\\Sigma N$ scattering, $\\Sigma^-$ atoms, and final state interaction of $\\Sigma$ hyperons in the $(\\pi,K^+)$ and $(K^-.\\pi)$ reactions on nuclear targets. We conclude that $V_\\Sigma$ is repulsive inside the nucleus and has a shallow a tractive pocket at the nuclear surface. These features of ...

  12. 50 CFR 680.42 - Limitations on use of QS, PQS, IFQ, and IPQ.

    Science.gov (United States)

    2010-10-01

    ...,000 4.0% = 36,000 (F) Percent of the initial QS pool for SMB 2.0% = 582,000 4.0% = 36,000 (G) Percent... 2,910,000 (F) 10.0 percent of the initial QS pool for SMB 2,910,000 (G) 20.0 percent of the initial... initial QS pool for PIK 1,455,000 (F) 5.0 percent of the initial QS pool for SMB 1,455,000 (G) 5.0 percent...

  13. A calculation of the three-loop helicity-dependent splitting functions in QCD

    CERN Document Server

    Vogt, A; Vermaseren, J A M

    2014-01-01

    We have calculated the complete matrix of three-loop helicity-difference (`polarized') splitting functions Delta P_ik^(2), i,k = q,g, in massless perturbative QCD. In this note we briefly discuss some properties of the polarized splitting functions and our non-standard determination of the hitherto missing lower-row quantities Delta P_gq^(2) and Delta P_gg^(2). The resulting next-to-next-to-leading order (NNLO) corrections to the evolution of polarized parton distributions are illustrated and found to be small even at rather large values of the strong coupling constant alpha_s.

  14. Hathayoga in history and practice : Classical hathayoga in modern Varanasi

    OpenAIRE

    Poulsen, Gitte

    2013-01-01

    Abstract: The study investigates the field of haṭha yoga as it is described in the medieval Haṭhayogapradīpikā, a work on yoga composed in Sanskrit from the Nāth tradition. The study have then compared these practices, practitioners and the attitudes towards them, with interviews conducted in modern Varanasi, India. The focus in the assignment is the connection between haṭha yoga and tantric practices since tantra has been crucial in the forming of the early haṭha yoga and classical haṭha yo...

  15. 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...

  16. Prejunctional Muscarinic Receptors in the Deep Muscular Plexus of Canine Ileum: Comparison with Smooth Muscle Receptors

    Science.gov (United States)

    1992-01-01

    These receptors showed a high affinity for the M,/M,-selective antagonist 4-DAMP (pK, = 7.41); in contrast, the PIK, values of pirenzepine (5.60...and oxotremorine. Based on pirenzepine (5.60), methoctramine (5.65) and AF-DX 116 (5.21) the pharmacological observations presented here, the preiunc...ito the "Guide for the tare anid Vse of having a high affinity for pirenzepine . are located postsynapr- L~aboratorv Aninials," preparedl Iw the C

  17. Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

    DEFF Research Database (Denmark)

    Feng, Yongjia; Demehri, Farok R; Xiao, Weidong

    2017-01-01

    BACKGROUND & AIMS: Total parenteral nutrition (TPN), a crucial treatment for patients who cannot receive enteral nutrition, is associated with mucosal atrophy, barrier dysfunction, and infectious complications. Glucagon-like peptide-2 (GLP-2) and epidermal growth factor (EGF) improve intestinal...... deprived of enteral nutrition. METHODS: Adult C57BL/6J, IEC-Egfr(knock out (KO)) and IEC-pik3r1(KO) mice receiving TPN or enteral nutrition were treated with EGF or GLP-2 alone or in combination with reciprocal receptor inhibitors, GLP-2(3-33) or gefitinib. Jejunum was collected and mucosal atrophy and IEC...

  18. Development of a full-scale training simulator for an 800-MW power unit

    Science.gov (United States)

    Zhuravlev, S. K.; Andreev, A. M.

    2013-07-01

    Stages of work involving preparation of requirements specification, development, and subsequent implementation of a project for constructing a full-scale training simulator of an 800-MW power unit are considered. The training simulator is constructed using the Kosmotronika-Venets computerized automation system developed by PIK Progress (Moscow). The entire personnel training system, the arrangement of drills, and the concept of structuring the entire personnel education system at the Surgut GRES-2 district power station, a branch of E.ON Rossiya, had to be touched in drawing up the requirements specification for elaborating the training simulator. The article describes how these problems were solved.

  19. 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)

  20. 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