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Sample records for vahur pik saima

  1. 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.

  2. 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"

  3. Reactor PIK construction

    International Nuclear Information System (INIS)

    Konoplev, Kir

    2003-01-01

    The construction work at the 100 MW researches reactor PIK in year 2002 was in progress. The main activity was concentrated on mechanical, ventilation and electrical equipment. Some systems and subsystems are under adjustment. Hydraulic driving gear for beam shutters are finished in installation, rinsing, and adjusting. Regulating rods test assembling was done. On the critical assembly the first reactor fueling was tested to evaluate the starting neutron source intensity and a sufficiency of existing control and instrument board. Mainline of the PIK facility design and neutron parameters are presented. (author)

  4. PIK reactor construction status

    International Nuclear Information System (INIS)

    Konoplev, K.A.; Smolsky, S.L.

    2001-01-01

    The 100MW reactor PIK for fundamental researches has a thermal neutron flux of more than 10 15 n/cm 2 sec. This presentation outlines the construction state as of 2001, its prospects and completion tactics in the conditions of unstable finance. Construction of the reactor started in 1976. In 1986 construction of the building was completed and significant part of the installation work fulfilled. Construction of cooling systems was finished, the control panel assembled, and adjustment of the pump and gate valve control circuits started. After Chernobyl catastrophe, the USSR nuclear reactor safety requirements were revised. The PIK design did not meet these requirements and underwent considerable revision. The reconstruction design resulted in double the initial cost. Creation of the containment was the bulkiest part of the reconstruction. It brought about the need to disassemble the roofing of the building, dismantle all the equipment of the two upper floors, and lay up the equipment of the lower floors. As of 2001, construction in accordance with the revised design is at the stage of assemblage of the most important units, i.e. reactor itself, cooling system, heavy water system, and a number of auxiliary systems, such as depleted fuel storage, emergency cooling system etc. (orig.)

  5. 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

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

    Index Scriptorium Estoniae

    2010-01-01

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

  7. Current status of the PIK Reactor

    International Nuclear Information System (INIS)

    Konoplev, K.A.

    1999-01-01

    At the end of 1998 the heads of the Russian Academy of Science, the Ministry of Science and Technology and the Ministry of Atomic Energy (the bodies involved in the research work with neutrons) declared the PIK-project as one of the objects of the first priority. They set a task to put it into operation in the next 3-4 years and to organize on its base an international center of neutron research. Realization of this task will depend on the real financing. In the last months there was a remarkable impulse in the construction work. In the frame of ISTC Project 321-96 Petersburg Nuclear Physics Institute and Research Institute of Technology developed functional training simulator (FTSC) for Reactor PIK. The utilization of FTSC for reactor PIK design examination began. (author)

  8. 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

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

    Index Scriptorium Estoniae

    Keller, Vahur, 1976-

    2011-01-01

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

  10. Gene of the month: PIK3CA.

    Science.gov (United States)

    Lai, K; Killingsworth, M C; Lee, C S

    2015-04-01

    PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which through its role in the PI3K/Akt pathway is important for the regulation of important cellular functions such as proliferation, metabolism and protein synthesis, angiogenesis and apoptosis. Mutations in PIK3CA are known to be involved in a wide range of human cancers and mutant PIK3CA is thought to act as an oncogene. The specific PIK3CA inhibitor, NVP-BYL719, has displayed promising results in cancer therapy and is currently under clinical trials. Furthermore, PI3K regulates autophagy, a cellular process that recycles proteins and organelles through lysosomal degradation and has recently been recognised as an attractive therapeutic target due to its pro- and anti-cancer properties. Several studies have attempted to investigate the effects of combining the inhibition of both PI3K and autophagy in cancer therapy, and an in vivo model has demonstrated that the combined use of a concomitant PI3K and autophagy inhibitor induced apoptosis in glioma cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  11. The state of the PIK reactor construction

    International Nuclear Information System (INIS)

    Konoplev, K.A.

    1995-01-01

    Principle concepts of the PIK reactor project were stated late in the 60's but its construction was started in 1976. By the year 1986 the initial project was realised by approximately 70% but then, after Chernobyl accident the construction was essentially frozen to adjust the project to the revised nuclear safety regulations. The revised project was approved only in 1990 when the country was on the threshold of serious economic problems. The PIK reactor is a source of neutrons placed in the heavy water reflector. The fuel is uranium-235 (90% enrichment) of total weight 27 kg. Light water is used as moderator and coolant. Design parameters: thermal power is 100 W; thermal neutron flux in the reflector is 1.2x10 15 n/cm 2 s; in the central vertical beam tube is 5x10 15 n/cm 2 s; number of horizontal beam tubes is 10; diameter of beam tubes is 10 cm, with the possibility of replacement with beam tubes up to 25 cm in diameter. The reactor will be equipped with sources of hot, cold, and ultracold neutrons to obtain beams in different intervals of energy spectrum. The low temperature circuit will enable to irradiate samples at helium temperatures. The reactor has three series cooling circuits. Emergency core cooling systems in LOCA are double and in emergency power supply system is triple. The PIK reactor has no single common containment but four separate systems: for pipelines and units of the first circuit, for heavy water reflector, for operating hall, and for experimental beam tubes hall

  12. Burnable absorber for the PIK reactor

    International Nuclear Information System (INIS)

    Gostev, V.V.; Smolskii, S.L.; Tchmshkyan, D.V.; Zakharov, A.S.; Zvezdkin, V.S.; Konoplev, K.A.

    1998-01-01

    In the reactor PIK design a burnable absorber is not used and the cycle duration is limited by the rods weight. Designed cycle time is two weeks and seams to be not enough for the 100 MW power research reactor equipped by many neutron beams and experimental facilities. Relatively frequent reloading reduces the reactor time on full power and in this way increases the maintenance expenses. In the reactor core fuel elements well mastered by practice are used and its modification was not approved. We try to find the possibilities of installation in the core separate burnable elements to avoid poison of the fuel. It is possible to replace a part of the fuel elements by absorbers, since the fuel elements are relatively small (diameter 5.15mm, uranium 235 content 7.14g) and there are more then 3800 elements in the core. Nevertheless, replacing decreases the fuel burnup and its consumption. In the PIK fuel assembles a little part of the volume is occupied by the dumb elements to create a complete package of the assembles shroud, that is necessary in the hydraulic reasons. In the presented report the assessment of such a replacement is done. As a burnable material Gadolinium was selected. The measurements or the beginning of cycle were performed on the critical facility PIK. The burning calculation was confirmed by measurements on the 18MW reactor WWR-M. The results give the opportunity to twice the cycle duration. The proposed modification of the fuel assembles does not lead to alteration in the other reactor systems, but it touch the burned fuel reprocessing technology. (author)

  13. Present status of PIK gadolinium control

    International Nuclear Information System (INIS)

    Petrov, Yu.V.; Garusov, E.A.; Shustov, V.A.

    1994-01-01

    A liquid control element (LCE) containing a water solution of gadolinium nitrate Gd(NO 3 ) 3 was originally planned for use at the PIK reactor for partial compensation of poisoning and fuel burnup [1-3]. However, a further analysis has shown that quick forcing-out, boiling up or flowing-out of the absorbing solution (though of low probability) can lead to the dangerous prompt overcriticality of the reactor. The results of the analysis are presented as well as the upper limit of the reactivity, quick insertion of which still is safe for the reactor (J.P.N.)

  14. SANA - project results and PIK contributions

    Energy Technology Data Exchange (ETDEWEB)

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

    1998-03-01

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

  15. 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

  16. The status of the PIK reactor

    Energy Technology Data Exchange (ETDEWEB)

    Petrov, Yu V [Academy of Sciences of Russia, Petersburg Nuclear Physics Institute, Gatchina, St. Petersburg (Russian Federation)

    1992-07-01

    This report describes the 100 MW research reactor PIK which is now under construction. The thermal neutron flux in the heavy water reflector exceeds 10{sup 15} cm{sup -2}s{sup -1}; in the light water trap, it is about 4{center_dot}10{sup 15} cm{sup -2}s{sup -1}. The replaceable core vessel allows to vary the parameters of the core over a wide range. The reactor provides sources of hot, cold and ultracold neutrons for 10 horizontal, 6 inclined neutron beams, and 8 neutron guides. At the ends of the beam tubes, the neutron flux is 10{sup 10} - 10{sup 11} cm{sup -2}s{sup -1}. The flux of the long wave neutrons exceeds 10{sup 9} cm{sup -2}s{sup -1}. To ensure precise measurements, the experimental hall is protected against vibrations. The project meets all modern safety requirements. The calculated parameters of the reactor were verified using a full-scale mock-up. Seventy percent of the reactor construction and installation were completed in the beginning of 1992. (author)

  17. Mutations in PIK3CA are infrequent in neuroblastoma

    International Nuclear Information System (INIS)

    Dam, Vincent; Morgan, Brian T; Mazanek, Pavel; Hogarty, Michael D

    2006-01-01

    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. 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. 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. These data suggest that activating

  18. Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells.

    Science.gov (United States)

    Gu, Mancang; Nishihara, Reiko; Chen, Yang; Li, Wanwan; Shi, Yan; Masugi, Yohei; Hamada, Tsuyoshi; Kosumi, Keisuke; Liu, Li; da Silva, Annacarolina; Nowak, Jonathan A; Twombly, Tyler; Du, Chunxia; Koh, Hideo; Li, Wenbin; Meyerhardt, Jeffrey A; Wolpin, Brian M; Giannakis, Marios; Aguirre, Andrew J; Bass, Adam J; Drew, David A; Chan, Andrew T; Fuchs, Charles S; Qian, Zhi Rong; Ogino, Shuji

    2017-10-20

    Evidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA -mutant colorectal carcinoma, but not in PIK3CA -wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA -mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA -mutant colon cancer cells than for PIK3CA -wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven PIK3CA -mutant and six PIK3CA -wild-type human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in PIK3CA mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose-dependent loss of cell viability in PIK3CA -mutant cells than in PIK3CA -wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in PIK3CA -mutant cells than in PIK3CA -wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA mutation, either c.3140A>G (p.H1047R) or c.1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in PIK3CA -mutated colon cancer cells than in PIK3CA -wild-type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA -mutant colon cancer.

  19. 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.

  20. PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival.

    Directory of Open Access Journals (Sweden)

    Christophe Rosty

    Full Text Available Mutations in PIK3CA are present in 10 to 15% of colorectal carcinomas. We aimed to examine how PIK3CA mutations relate to other molecular alterations in colorectal carcinoma, to pathologic phenotype and survival. PIK3CA mutation testing was carried out using direct sequencing on 757 incident tumors from the Melbourne Collaborative Cohort Study. The status of O-6-methylguanine-DNA methyltransferase (MGMT was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability, CpG island phenotype (CIMP, KRAS and BRAF V600E mutation status, and pathology review features were derived from previous reports. PIK3CA mutation was observed in 105 of 757 (14% of carcinomas, characterized by location in the proximal colon (54% vs. 34%; P<0.001 and an increased frequency of KRAS mutation (48% vs. 25%; P<0.001. High-levels of CIMP were more frequently found in PIK3CA-mutated tumors compared with PIK3CA wild-type tumors (22% vs. 11%; P = 0.004. There was no difference in the prevalence of BRAF V600E mutation between these two tumor groups. PIK3CA-mutated tumors were associated with loss of MGMT expression (35% vs. 20%; P = 0.001 and the presence of tumor mucinous differentiation (54% vs. 32%; P<0.001. In patients with wild-type BRAF tumors, PIK3CA mutation was associated with poor survival (HR 1.51 95% CI 1.04-2.19, P = 0.03. In summary, PIK3CA-mutated colorectal carcinomas are more likely to develop in the proximal colon, to demonstrate high levels of CIMP, KRAS mutation and loss of MGMT expression. PIK3CA mutation also contributes to significantly decreased survival for patients with wild-type BRAF tumors.

  1. 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 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.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.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.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.

  2. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA

    International Nuclear Information System (INIS)

    Lang, Qingbo; Ling, Changquan

    2012-01-01

    Highlights: ► PIK3CA is a novel target of miR-124 in HepG2 cells. ► MiR-124 suppresses cell proliferation by downregulating PIK3CA expression. ► MiR-124 regulates the PI3K/Akt pathway in HepG2 cells. ► MiR-124 overexpression inhibits the tumorigenesis in nude mice. -- Abstract: MicroRNAs (miRNAs) have crucial roles in the development and progression of human cancers, including hepatocellular carcinoma (HCC). Recent studies have shown that microRNA-124 (miR-124) was downregulated in HCC; however, the underlying mechanisms by which miR-124 suppresses tumorigenesis in HCC are largely unknown. In this study, we report that phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA) is a novel target of miR-124 in HepG2 cells. Overexpression of miR-124 resulted in decreased expression of PIK3CA at both mRNA and protein levels. We found that miR-124 overexpression markedly suppressed cell proliferation by inducing G1-phase cell-cycle arrest in vitro. Consistent with the restoring miR-124 expression, PIK3CA knockdown suppressed cell proliferation, whereas overexpression of PIK3CA abolished the suppressive effect of miR-124. Mechanistic studies showed that miR-124-mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. The expressions of Akt and mTOR, key components of the PI3K/Akt pathway, were all downregulated. Moreover, we found overexpressed miR-124 effectively repressed tumor growth in xenograft animal experiments. Taken together, our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA.

  3. p55PIK regulates alpha-fetoprotein expression through the NF-κB signaling pathway.

    Science.gov (United States)

    Ye, Guoguo; Sun, Ge; Cheng, Zhikui; Zhang, Lei; Hu, Kanghong; Xia, Xianmin; Zhou, Yin

    2017-12-15

    Alpha-fetoprotein (AFP) is regarded as a diagnostic and prognostic biomarker and a potential therapeutic target for hepatocellular carcinoma (HCC). However, the regulation of AFP expression in HCC remains poorly understood. This study aimed to investigate the mechanism by which AFP expression is regulated by p55PIK, an isoform of PI3K. Human HCC cell lines (HepG2 and Huh-7) were treated with p55PIK specific competitive inhibitor or shRNA, or p55PIK overexpression vector, in the absence or presence of NF-κB inhibitor PDTC. AFP expression was detected by quantitative real-time PCR and Western blotting. NF-κB responsive elements in AFP enhancer region were characterized by luciferase reporter assay. p55PIK significantly stimulated the expression of AFP by activating NF-κB signaling pathway in HCC cells. Furthermore, two NF-κB binding sites in AFP enhancer region were identified to be primarily responsible for p55PIK mediated upregulation of AFP expression. p55PIK/NF-κB signaling plays an important role in the upregulation of AFP expression in HCC. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    International Nuclear Information System (INIS)

    Serebrov, A. P.; Vassiljev, A. V.; Varlamov, V. E.; Geltenbort, P.; Gridnev, K. A.; Dmitriev, S. P.; Dovator, N. A.; Egorov, A. I.; Ezhov, V. F.; Zherebtsov, O. M.; Zinoviev, V. G.; Ivochkin, V. G.; Ivanov, S. N.; Ivanov, S. A.; Kolomensky, E. A.; Konoplev, K. A.; Krasnoschekova, I. A.; Lasakov, M. S.; Lyamkin, V. A.; Martemyanov, V. P.

    2016-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Serebrov, A. P., E-mail: serebrov@pnpi.spb.ru; Vassiljev, A. V.; Varlamov, V. E. [National Research Center Kurchatov Institute, Petersburg Nuclear Physics Institute (Russian Federation); Geltenbort, P. [Institut Laue-Langevin (France); Gridnev, K. A. [St. Petersburg State University (Russian Federation); Dmitriev, S. P.; Dovator, N. A. [Russian Academy of Sciences, Ioffe Physical-Technical Institute (Russian Federation); Egorov, A. I.; Ezhov, V. F.; Zherebtsov, O. M.; Zinoviev, V. G.; Ivochkin, V. G.; Ivanov, S. N.; Ivanov, S. A.; Kolomensky, E. A.; Konoplev, K. A.; Krasnoschekova, I. A.; Lasakov, M. S.; Lyamkin, V. A. [National Research Center Kurchatov Institute, Petersburg Nuclear Physics Institute (Russian Federation); Martemyanov, V. P. [National Research Center Kurchatov Institute (Russian Federation); and others

    2016-05-15

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

  6. 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.

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

    International Nuclear Information System (INIS)

    Murat, C.B.; Braga, P.B.S.; Fortes, M.A.H.Z.; Bronstein, M.D.; Corrêa-Giannella, M.L.C.; Giorgi, R.R.

    2012-01-01

    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

  8. 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.

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

    Science.gov (United States)

    Cossu-Rocca, Paolo; Orrù, Sandra; Muroni, Maria Rosaria; Sanges, Francesca; Sotgiu, Giovanni; Ena, Sara; Pira, Giovanna; Murgia, Luciano; Manca, Alessandra; Uras, Maria Gabriela; Sarobba, Maria Giuseppina; Urru, Silvana; De Miglio, Maria Rosaria

    2015-01-01

    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.

  10. 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

    2015-01-01

    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 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. PMID:25694549

  11. FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis.

    Science.gov (United States)

    Groesser, L; Herschberger, E; Landthaler, M; Hafner, C

    2012-04-01

    Benign lichenoid keratoses (BLKs) are solitary skin lesions which have been proposed to represent a regressive form of pre-existent epidermal tumours such as solar lentigo or seborrhoeic keratosis. However, the genetic basis of BLK is unknown. FGFR3, PIK3CA and RAS mutations have been shown to be involved in the pathogenesis of seborrhoeic keratosis and solar lentigo. We thus investigated whether these mutations are also present in BLK. After manual microdissection and DNA isolation, 52 BLKs were screened for FGFR3, PIK3CA and RAS hotspot mutations using SNaPshot(®) multiplex assays. We identified 6/52 (12%) FGFR3 mutations, 10/52 (19%) PIK3CA mutations, 6/52 (12%) HRAS mutations and 2/52 (4%) KRAS mutations. FGFR3 and RAS mutations were mutually exclusive. One BLK showed a simultaneous PIK3CA and HRAS mutation. In nine BLKs with a mutation, nonlesional control tissue from the epidermal margin and the dermal lymphocytic infiltrate were wild-type, indicating that these mutations are somatic. To demonstrate that these findings are specific, 10 samples of lichen planus were analysed without evidence for FGFR3, PIK3CA or RAS mutations. Our results indicate that FGFR3, PIK3CA and RAS mutations are present in approximately 50% of BLKs. These findings support the concept on the molecular genetic level that at least a proportion of BLKs represents regressive variants resulting from former benign epidermal tumours such as seborrhoeic keratosis and solar lentigo. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

  12. Tumor PIK3CA genotype and prognosis in early-stage breast cancer

    DEFF Research Database (Denmark)

    Zardavas, Dimitrios; Te Marvelde, Luc; Milne, Roger L.

    2018-01-01

    % in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P, .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR...... points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors....

  13. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA

    Energy Technology Data Exchange (ETDEWEB)

    Lang, Qingbo [Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Ling, Changquan, E-mail: lingchangquan@hotmail.com [Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China)

    2012-09-21

    Highlights: Black-Right-Pointing-Pointer PIK3CA is a novel target of miR-124 in HepG2 cells. Black-Right-Pointing-Pointer MiR-124 suppresses cell proliferation by downregulating PIK3CA expression. Black-Right-Pointing-Pointer MiR-124 regulates the PI3K/Akt pathway in HepG2 cells. Black-Right-Pointing-Pointer MiR-124 overexpression inhibits the tumorigenesis in nude mice. -- Abstract: MicroRNAs (miRNAs) have crucial roles in the development and progression of human cancers, including hepatocellular carcinoma (HCC). Recent studies have shown that microRNA-124 (miR-124) was downregulated in HCC; however, the underlying mechanisms by which miR-124 suppresses tumorigenesis in HCC are largely unknown. In this study, we report that phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA) is a novel target of miR-124 in HepG2 cells. Overexpression of miR-124 resulted in decreased expression of PIK3CA at both mRNA and protein levels. We found that miR-124 overexpression markedly suppressed cell proliferation by inducing G1-phase cell-cycle arrest in vitro. Consistent with the restoring miR-124 expression, PIK3CA knockdown suppressed cell proliferation, whereas overexpression of PIK3CA abolished the suppressive effect of miR-124. Mechanistic studies showed that miR-124-mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. The expressions of Akt and mTOR, key components of the PI3K/Akt pathway, were all downregulated. Moreover, we found overexpressed miR-124 effectively repressed tumor growth in xenograft animal experiments. Taken together, our results demonstrate that miR-124 functions as a growth-suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA.

  14. PIK3CA expression in diffuse large B cell lymphoma tissue and the effect of its knockdown in vitro

    Directory of Open Access Journals (Sweden)

    Cui W

    2017-04-01

    Full Text Available Wenli Cui,1–4,* Shutao Zheng,5,6,* Zebing Liu,1–3 Weige Wang,1–3 Ying Cai,1–3 Rui Bi,1–3 Bing Cao,1–3 Xiaoyan Zhou1–3 1Department of Pathology, Shanghai Cancer Center, Fudan University, 2Department of Oncology, Shanghai Medical College, Fudan University, 3Institute of Pathology, Fudan University, Shanghai, 4Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 5Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, 6State Key Lab Incubation Base of Xinjiang Major Diseases Research, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China *These authors contributed equally to this work Abstract: PIK3CA has been extensively investigated from its molecular mechanism perspective and epidemiological association with its mutations in different types of cancers. However, little has been reported regarding the clinicopathological significance of PIK3CA expression in diffuse large B cell lymphoma (DLBCL. In the present study, we investigated the clinicopathological significance of PIK3CA in DLBCL by performing immunohistochemical evaluation of PIK3CA in tissue microarrays consisting of 199 cases of DLBCL. Kaplan–Meier survival analysis was performed to analyze the association between PIK3CA expression and overall prognosis. To further investigate the role of PIK3CA mediated in the proliferation, cell cycle and apoptosis of DLBCL cells, Cell Counting Kit-8 (CCK-8 and flow cytometry assays were carried out in DLBCL cell lines after successful, stable knockdown of PIK3CA using lentiviral short hairpin RNA inference. Our results indicated that although PIK3CA was shown to be extensively expressed in DLBCL, no significant association was observed between PIK3CA expression and clinical outcome or between PIK3CA expression and other clinicopathological parameters, except between performance state (PS

  15. PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma

    International Nuclear Information System (INIS)

    Chiosea, Simion I; Nikiforova, Marina N; Grandis, Jennifer R; Lui, Vivian W Y; Diergaarde, Brenda; Maxwell, Jessica H; Ferris, Robert L; Kim, Seungwon W; Luvison, Alyssa; Miller, Megan

    2013-01-01

    Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma

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

  17. 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.

  18. 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.

  19. 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.

  20. CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS).

    Science.gov (United States)

    Martinez-Lopez, A; Blasco-Morente, G; Perez-Lopez, I; Herrera-Garcia, J D; Luque-Valenzuela, M; Sanchez-Cano, D; Lopez-Gutierrez, J C; Ruiz-Villaverde, R; Tercedor-Sanchez, J

    2017-01-01

    Overgrowth syndromes are characterized by global or localized disproportionate growth associated with other anomalies, including vascular malformations and neurological and/or visceral disorders. CLOVES (Congenital Lipomatous asymmetric Overgrowth of the trunk with lymphatic, capillary, venous, and combined-type Vascular malformations, Epidermal naevi, Scoliosis/Skeletal and spinal anomalies) is an overgrowth syndrome caused by mosaic activating mutation in gene PIK3CA, which gives rise to abnormal PI3K-AKT-mTOR pathway activation. These mutations are responsible for the clinical manifestations of the syndrome, which include low- and high-flow vascular malformations, thoracic lipomatous hyperplasia, asymmetric growth, and visceral and neurological disorders. These common anomalies are illustrated with figures from two personal cases. Identification of the clinical and genetic characteristics of CLOVES syndrome is crucial for the differential diagnosis with other overgrowth syndromes, such as Proteus or Klippel-Trenaunay (K-T) syndromes, and for the therapeutic management of the different anomalies. In this context, a new entity comprising different syndromes with phenotypic mutations in PIK3CA has been proposed, designated PIK3CA-related overgrowth spectrum (PROS), with the aim of facilitating clinical management and establishing appropriate genetic study criteria. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Mutant PIK3CA Induces EMT in a Cell Type Specific Manner.

    Directory of Open Access Journals (Sweden)

    Divya Bhagirath

    Full Text Available Breast cancer is characterized into different molecular subtypes, and each subtype is characterized by differential gene expression that are associated with distinct survival outcomes in patients. PIK3CA mutations are commonly associated with most breast cancer subtypes. More recently PIK3CA mutations have been shown to induce tumor heterogeneity and are associated with activation of EGFR-signaling and reduced relapse free survival in basal subtype of breast cancer. Thus, understanding what determines PIK3CA induced heterogeneity and oncogenesis, is an important area of investigation. In this study, we assessed the effect of mutant PIK3CA together with mutant Ras plus mutant p53 on oncogenic behavior of two distinct stem/progenitor breast cell lines, designated as K5+/K19- and K5+/K19+. Constructs were ectopically overexpressed in K5+/K19- and K5+/K19+ stem/progenitor cells, followed by various in-vitro and in-vivo analyses. Oncogene combination m-Ras/m-p53/m-PIK3CA efficiently transformed both K5+/K19- and K5+/K19+ cell lines in-vitro, as assessed by anchorage-independent soft agar colony formation assay. Significantly, while this oncogene combination induced a complete epithelial-to-mesenchymal transition (EMT in K5+/K19- cell line, mostly epithelial phenotype with minor EMT component was seen in K5+/K19+ cell line. However, both K5+/K19- and K5+/K19+ transformed cells exhibited increased invasion and migration abilities. Analyses of CD44 and CD24 expression showed both cell lines had tumor-initiating CD44+/CD24low cell population, however transformed K5+/K19- cells had more proportion of these cells. Significantly, both cell types exhibited in-vivo tumorigenesis, and maintained their EMT and epithelial nature in-vivo in mice tumors. Notably, while both cell types exhibited increase in tumor-initiating cell population, differential EMT phenotype was observed in these cell lines. These results suggest that EMT is a cell type dependent

  2. Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

    Directory of Open Access Journals (Sweden)

    Filip Janku

    2014-01-01

    Full Text Available Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589, and PTEN loss and/or mutation was found in 13% (149/1,157. In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

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

    International Nuclear Information System (INIS)

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

    2016-01-01

    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 application of this idea, which consists of installing "4He 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 "4He source with solid methane (CH_4) or/and liquid deuterium (D_2) moderator–reflector. We show that such a source with CH_4 moderator–reflector at the PIK reactor would provide the UCN density of ~1·10"5 cm"−"3, and the UCN production rate of ~2·10"7 s"−"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_2 moderator-reflector would reach the value of ~2·10"5 cm"−"3, and the UCN production rate would be equal ~8·10"7 s"−"1. Installation of such a source in a beam of CNs would slightly increase the density and production rate.

  4. Two design aspects connected with the safety of the PIK reactor presently under construction

    International Nuclear Information System (INIS)

    Gostev, V.V.; Zakharov, A.S.; Konoplev, K.A.; Levandovskii, N.V.; Ploshchanskii, L.M.; Smolsky, S.L.

    1993-01-01

    The PIK reactor is designed for physical research with neutron beams and sample irradiation. In the central trap the thermal neutrons flux is 4x10 15 n/cm 2 s. The reactor power is 100 MW, the thermal neutron flux in the reflector at the maximum of distribution is 1x10 15 n/cm 2 s. The core with a high uranium concentration of 600 g/l is light water-cooled, heavy water being used in the reflector. The Chernobyl disaster happened at the time of equipment installation at the PIK. The code revision, a change of the authors ideas about the safety, and a change of public attitude towards nuclear installations resulted in a stopping of construction and project revision. Reconstruction project has led to a change of all safety systems and involved in various degrees all essential reactor systems. The construction is presently resumed in spite of economic difficulties in Russia. The reactor was inspected by experts from a number of European countries, USA, and European Commission delegated by their governments to prepare a report on whether supporting the construction to its completion would be reasonable. In the course of inspection the experts from USA and EU expressed doubts concerning two systems, namely, the containment and scram. These two points are discussed in the present paper. Three type of containments are proposed and an analysis of their efficiency is presented. The PIK reactor is controlled by eight rods in the heavy-water reflector -and an absorbing cylinder at the boundary between the core and the central light-water neutron trap. The rods are used for emergency protection and reactor start-up. The central control cylinder called here the shutter serves several functions, namely, as scram, automatic control, and burnup compensation. The delay time before the onset of negative reactivity is 1.05 sec for rods and 0.25 sec for the shutter

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

    International Nuclear Information System (INIS)

    Ji, Meiju; Guan, Haixia; Gao, Cuixia; Shi, Bingyin; Hou, Peng

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    R. Winkelmann

    2011-09-01

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

  7. The Potsdam Parallel Ice Sheet Model (PISM-PIK) - Part 1: Model description

    Science.gov (United States)

    Winkelmann, R.; Martin, M. A.; Haseloff, M.; Albrecht, T.; Bueler, E.; Khroulev, C.; Levermann, A.

    2011-09-01

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

  8. 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.

  9. Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells

    Science.gov (United States)

    Arjumand, Wani; Merry, Cole D.; Wang, Chen; Saba, Elias; McIntyre, John B.; Fang, Shujuan; Kornaga, Elizabeth; Ghatage, Prafull; Doll, Corinne M.; Lees, Susan P.

    2016-01-01

    The phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signaling pathway is activated in many human cancers. Previously, we reported that patients with early stage cervical cancer whose tumours harbour PIK3CA exon 9 or 20 mutations have worse overall survival in response to treatment with radiation and cisplatin than patients with wild-type PIK3CA. The purpose of this study was to determine whether PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin and/or radiation, and whether PI3K inhibition reverses the phenotype. We found that CaSki cells that are heterozygous for the PIK3CA-E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA-E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. Our results suggests that cervical cancer patients whose tumours are positive for the PIK3CA-E545K mutation may benefit from PI3K inhibitor therapy in concert with standard cisplatin and radiation therapy. PMID:27489350

  10. The sensitivity and efficacy method of PIK3CA exon 9 E545A as a high diagnostic accuracy in breast cancer

    Directory of Open Access Journals (Sweden)

    Desriani

    2018-06-01

    Full Text Available The phosphatidylinositol 3-kinases (PIK3s are lipid kinases. Mutation in the exon 9 and exon 20 determined as a predictive factor in anti-HER-2 therapy. In some countries, such as Singapore, China, and Peru, PIK3CA exon 9 E545A was reported to produce the highest rate of mutation. In this research, we developed and optimized PIK3CA exon 9 E545A detection methods with intercalating dye SYBR Green I based on the Tm Shift approach by using prepared recombinant plasmid pGEMT-easy PIK3CA exon 9 and PIK3CA exon 9 E545A. Recombinant plasmid was used due to the limited number of samples. Methods: Recombinant plasmid was prepared based on manufactured procedures, and this process was then followed by Tm prediction with Poland software, Tm Shift SYBR Green I development, and its characterization (reproducibility, repeatability, sensitivity, qPCR efficiency, and qPCR amplification, respectively. Result: A method for PIK3CA E545A detection based on TM shift SYBR Green I has been successfully developed. The melting temperature for PIK3CA exon 9 was 78.1 ± 0.1 °C, while that for PIK3CA exon E545A was 80.20 °C. The Tm of mutant was the same as that predicted using Polland Software. The reproducibility of the methods was high, with the coefficient values for inter and intra assays were below 10% with a high sensitivity at 1%, while R2 0.99 and PCR efficiency was 97.75%. Conclusion: The results presented here demonstrate that the PIK3CA exon 9 E545A detection method has a good sensitivity and efficacy assay, which proves that the method has a high diagnostic accuracy in breast cancer. Keywords: SYBR Green I, PIK3CA E545A, Breast cancer, Real time PCR, Recombinant plasmid

  11. 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

  12. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

    NARCIS (Netherlands)

    Mirzaa, Ghayda; Timms, Andrew E.; Conti, Valerio; Boyle, Evan August; Girisha, Katta M.; Martin, Beth; Kircher, Martin; Olds, Carissa; Juusola, Jane; Collins, Sarah; Park, Kaylee; Carter, Melissa; Glass, Ian; Krägeloh-Mann, Inge; Chitayat, David; Parikh, Aditi Shah; Bradshaw, Rachael; Torti, Erin; Braddock, Stephen; Burke, Leah; Ghedia, Sondhya; Stephan, Mark; Stewart, Fiona; Prasad, Chitra; Napier, Melanie; Saitta, Sulagna; Straussberg, Rachel; Gabbett, Michael; O'Connor, Bridget C.; Keegan, Catherine E.; Yin, Lim Jiin; Lai, Angeline Hwei Meeng; Martin, Nicole; McKinnon, Margaret; Addor, Marie-Claude; Boccuto, Luigi; Schwartz, Charles E.; Lanoel, Agustina; Conway, Robert L.; Devriendt, Koenraad; Tatton-Brown, Katrina; Pierpont, Mary Ella; Painter, Michael; Worgan, Lisa; Reggin, James; Hennekam, Raoul; Tsuchiya, Karen; Pritchard, Colin C.; Aracena, Mariana; Gripp, Karen W.; Cordisco, Maria; Esch, Hilde Van; Garavelli, Livia; Curry, Cynthia; Goriely, Anne; Kayserilli, Hulya; Shendure, Jay; Graham, John; Guerrini, Renzo; Dobyns, William B.

    2016-01-01

    Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS

  13. Mass-spectrometer of knock-on nuclei for reactor 'Pik'

    International Nuclear Information System (INIS)

    Begzhanov, P.B.; Nazarov, A.G.; Petrov, G.A.; Pikul', V.P.

    1999-01-01

    For reactor 'Pik' (that is being built in St. Petersburg Institute of Nuclear Physics) there was designed a universal two shoulder mass-spectrometer for non-decelerated fission products (FP) of nuclei. The spectrometer helps to obtain different values of linear magnification, dispersion, aberration coefficients and transmission without making structural changes in the device. To separate FP for one shoulder of spectrometer we chose ion-optical scheme (IOS) consisting of three electrostatic analyzers and three-sectional magnet 'JOSEF' that had high dispersion by masses at small deflection radius. IOS calculations of mass-spectrometer were performed with the help of program TRANSVOL (transfer of phase volume) designed basing on TRIO program. The program allows calculating of complete IOS transmission with taking into account elements aperture and beam officering

  14. 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, 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

  15. Highly sensitive detection of the PIK3CAH1047R mutation in colorectal cancer using a novel PCR-RFLP method

    International Nuclear Information System (INIS)

    Li, Wan-Ming; Hu, Ting-Ting; Zhou, Lin-Lin; Feng, Yi-Ming; Wang, Yun-Yi; Fang, Jin

    2016-01-01

    The PIK3CA H1047R mutation is considered to be a potential predictive biomarker for EGFR-targeted therapies. In this study, we developed a novel PCR-PFLP approach to detect the PIK3CA H1047R mutation in high effectiveness. A 126-bp fragment of PIK3CA exon-20 was amplified by PCR, digested with FspI restriction endonuclease and separated by 3 % agarose gel electrophoresis for the PCR-RFLP analysis. The mutant sequence of the PIK3CA H1047R was spiked into the corresponding wild-type sequence in decreasing ratios for sensitivity analysis. Eight-six cases of formalin-fixed paraffin-embedded colorectal cancer (CRC) specimens were subjected to PCR-RFLP to evaluate the applicability of the method. The PCR-RFLP method had a capability to detect as litter as 0.4 % of mutation, and revealed 16.3 % of the PIK3CA H1047R mutation in 86 CRC tissues, which was significantly higher than that discovered by DNA sequencing (9.3 %). A positive association between the PIK3CA H1047R mutation and the patients’ age was first found, except for the negative relationship with the degree of tumor differentiation. In addition, the highly sensitive detection of a combinatorial mutation of PIK3CA, KRAS and BRAF was achieved using individual PCR-RFLP methods. We developed a sensitive, simple and rapid approach to detect the low-abundance PIK3CA H1047R mutation in real CRC specimens, providing an effective tool for guiding cancer targeted therapy

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

    Directory of Open Access Journals (Sweden)

    Anjali Tikoo

    Full Text Available 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  18. Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo.

    Science.gov (United States)

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

    2015-11-01

    HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu-amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0-G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy. ©2015 American Association for Cancer Research.

  19. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas.

    Science.gov (United States)

    Yamaguchi, Hiroshi; Kuboki, Yuko; Hatori, Takashi; Yamamoto, Masakazu; Shiratori, Keiko; Kawamura, Shunji; Kobayashi, Makio; Shimizu, Michio; Ban, Shinichi; Koyama, Isamu; Higashi, Morihiro; Shin, Nobuhiro; Ishida, Kazuyuki; Morikawa, Takanori; Motoi, Fuyuhiko; Unno, Michiaki; Kanno, Atsushi; Satoh, Kennichi; Shimosegawa, Tooru; Orikasa, Hideki; Watanabe, Tomoo; Nishimura, Kazuhiko; Harada, Youji; Furukawa, Toru

    2011-12-01

    Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P AKT was apparent in most ITPNs but only in a few IPMNs (P SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

  20. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution

    OpenAIRE

    Mirzaa, Ghayda; Timms, Andrew E.; Conti, Valerio; Boyle, Evan August; Girisha, Katta M.; Martin, Beth; Kircher, Martin; Olds, Carissa; Juusola, Jane; Collins, Sarah; Park, Kaylee; Carter, Melissa; Glass, Ian; Kr?geloh-Mann, Inge; Chitayat, David

    2016-01-01

    Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identifie...

  1. Measurement of glacier velocity at Pik Lenin, Tajikistan, by feature tracking

    Science.gov (United States)

    Kumari, S.; Ghosh, S. K.; Buchroithner, M. F.

    2014-11-01

    Glaciers, especially in mountain area are sensitive indicators of climate fluctuations and also contribute to present rates of sea level rise. In Central Asia, these glaciers are the primary resource for fresh water. Understanding the seasonal behavior of these glaciers would help to make efficient use of the available water reservoir. Different methods have been employed to study glacier displacements in past. The conventional survey techniques are very cost-intensive and highly depend on accessibility to high mountain glaciers also directs us to look for new ways to study these areas. Here remote sensing comes in handy with freely available data and a good coverage with high spatial and temporal resolution. Optical satellite imagery, available free can be effectively used for research purpose. The glacier in this region fed lake Karakul (380 km2), the largest Lake in Tajikistan. The objective is to study the displacement tendency of the Glacier in Pik Lenin area using Landsat 7 dataset. Normalized cross correlation algorithm has been implemented via CIAS to estimate the motion of glacier surface. A number of combination of reference block and search area size were tested for 30 m resolution dataset. As a result the specifications: reference block size of 15 pixels and search area size of 10 pixels was found out as the best set of parameters and considered for further processing. The study derives a reliable set of data depicting the velocities in the glacier which after post processing shows peak velocity of 121 m/y of the glacier.

  2. 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 To evaluate clinicopathologic and molecular features of patients with metastatic colorectal cancer (mCRC and their outcomes in early-phase trials using pathway-targeting agents.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.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.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.

  3. Oligonucleotide PIK3CA/Chromosome 3 Dual in Situ Hybridization Automated Assay with Improved Signals, One-Hour Hybridization, and No Use of Blocking DNA.

    Science.gov (United States)

    Zhang, Wenjun; Hubbard, Antony; Baca-Parkinson, Leslie; Stanislaw, Stacey; Vladich, Frank; Robida, Mark D; Grille, James G; Maxwell, Daniel; Tsao, Tsu-Shuen; Carroll, William; Gardner, Tracie; Clements, June; Singh, Shalini; Tang, Lei

    2015-09-01

    The PIK3CA gene at chromosome 3q26.32 was found to be amplified in up to 45% of patients with squamous cell carcinoma of the lung. The strong correlation between PIK3CA amplification and increased phosphatidylinositol 3-kinase (PI3K) pathway activities suggested that PIK3CA gene copy number is a potential predictive biomarker for PI3K inhibitors. Currently, all microscopic assessments of PIK3CA and chromosome 3 (CHR3) copy numbers use fluorescence in situ hybridization. PIK3CA probes are derived from bacterial artificial chromosomes whereas CHR3 probes are derived mainly from the plasmid pHS05. These manual fluorescence in situ hybridization assays mandate 12- to 18-hour hybridization and use of blocking DNA from human sources. Moreover, fluorescence in situ hybridization studies provide limited morphologic assessment and suffer from signal decay. We developed an oligonucleotide-based bright-field in situ hybridization assay that overcomes these shortcomings. This assay requires only a 1-hour hybridization with no need for blocking DNA followed by indirect chromogenic detection. Oligonucleotide probes produced discrete and uniform CHR3 stains superior to those from the pHS05 plasmid. This assay achieved successful staining in 100% of the 195 lung squamous cell carcinoma resections and in 94% of the 33 fine-needle aspirates. This robust automated bright-field dual in situ hybridization assay for the simultaneous detection of PIK3CA and CHR3 centromere provides a potential clinical diagnostic method to assess PIK3CA gene abnormality in lung tumors. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  4. PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

    OpenAIRE

    Anderson, Grace R.; Wardell, Suzanne E.; Cakir, Merve; Crawford, Lorin; Leeds, Jim C.; Nussbaum, Daniel P.; Shankar, Pallavi S.; Soderquist, Ryan S.; Stein, Elizabeth M.; Tingley, Jennifer P.; Winter, Peter S.; Zieser-Misenheimer, Elizabeth K.; Alley, Holly M.; Yllanes, Alexander; Haney, Victoria

    2016-01-01

    Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that the combined inhibition of BCL-XL and the mTOR/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses MCL-1 protein translation only in ...

  5. Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer

    DEFF Research Database (Denmark)

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

    2018-01-01

    investigated the association between RAS (KRAS or NRAS), BRAF, PIK3CA mutations and metastatic pattern in patients with metastatic (m) CRC. MATERIAL AND METHODS: This study reviewed Danish biobank and database of patients with mCRC who received cetuximab and irinotecan, independent of RAS mutation status...

  6. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells.

    Science.gov (United States)

    Pasquier, Benoit

    2015-04-03

    Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

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

    International Nuclear Information System (INIS)

    Velho, Sérgia; Moutinho, Cátia; Cirnes, Luís; Albuquerque, Cristina; Hamelin, Richard; Schmitt, Fernando; Carneiro, Fátima; Oliveira, Carla; Seruca, Raquel

    2008-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Schmitt Fernando

    2008-09-01

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

  9. 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.

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

    International Nuclear Information System (INIS)

    Naguib, Adam; Arends, Mark J; Cooke, James C; Happerfield, Lisa; Kerr, Lucy; Gay, Laura J; Luben, Robert N; Ball, Richard Y; Mitrou, Panagiota N; McTaggart, Alison

    2011-01-01

    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. 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. 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 < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). 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

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

    Science.gov (United States)

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

    2014-10-01

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

  12. Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas

    Directory of Open Access Journals (Sweden)

    Meagan B. Myers

    2016-04-01

    Full Text Available Mutant cancer subpopulations have the potential to derail durable patient responses to molecularly targeted cancer therapeutics, yet the prevalence and size of such subpopulations are largely unexplored. We employed the sensitive and quantitative Allele-specific Competitive Blocker PCR approach to characterize mutant cancer subpopulations in ductal carcinomas (DCs, examining five specific hotspot point mutations (PIK3CA H1047R, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E. As an approach to aid interpretation of the DC results, the mutations were also quantified in normal breast tissue. Overall, the mutations were prevalent in normal breast and DCs, with 9/9 DCs having measureable levels of at least three of the five mutations. HRAS G12D was significantly increased in DCs as compared to normal breast. The most frequent point mutation reported in DC by DNA sequencing, PIK3CA H1047R, was detected in all normal breast tissue and DC samples and was present at remarkably high levels (mutant fractions of 1.1 × 10−3 to 4.6 × 10−2 in 4/10 normal breast samples. In normal breast tissue samples, PIK3CA mutation levels were positively correlated with age. However, the PIK3CA H1047R mutant fraction distributions for normal breast tissues and DCs were similar. The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells.

  13. 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

  14. 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.

  15. Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study.

    Science.gov (United States)

    Mirzaa, Ghayda M; Conti, Valerio; Timms, Andrew E; Smyser, Christopher D; Ahmed, Sarah; Carter, Melissa; Barnett, Sarah; Hufnagel, Robert B; Goldstein, Amy; Narumi-Kishimoto, Yoko; Olds, Carissa; Collins, Sarah; Johnston, Kathreen; Deleuze, Jean-François; Nitschké, Patrick; Friend, Kathryn; Harris, Catharine; Goetsch, Allison; Martin, Beth; Boyle, Evan August; Parrini, Elena; Mei, Davide; Tattini, Lorenzo; Slavotinek, Anne; Blair, Ed; Barnett, Christopher; Shendure, Jay; Chelly, Jamel; Dobyns, William B; Guerrini, Renzo

    2015-12-01

    Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment, and epilepsy. The causes of BPP are heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic causes of BPP and characterise their frequency in this population. Children (aged ≤18 years) with polymicrogyria were enrolled into our research programme from July, 1980, to October, 2015, at two centres (Florence, Italy, and Seattle, WA, USA). We obtained samples (blood and saliva) throughout this period at both centres and did whole-exome sequencing on DNA from eight trios (two parents and one affected child) with BPP in 2014. After the identification of mosaic PIK3R2 mutations in two of these eight children, we performed targeted screening of PIK3R2 by two methods in a cohort of 118 children with BPP. First, we performed targeted sequencing of the entire PIK3R2 gene by single molecule molecular inversion probes (smMIPs) on 38 patients with BPP with normal to large head size. Second, we did amplicon sequencing of the recurrent PIK3R2 mutation (Gly373Arg) in 80 children with various types of polymicrogyria including BPP. One additional patient had clinical whole-exome sequencing done independently, and was included in this study because of the phenotypic similarity to our cohort. We identified a mosaic mutation (Gly373Arg) in a regulatory subunit of the PI3K-AKT-mTOR pathway, PIK3R2, in two children with BPP. Of the 38 patients with BPP and normal to large head size who underwent targeted next-generation sequencing by smMIPs, we identified constitutional and mosaic PIK3R2 mutations in 17 additional children. In parallel, one patient had the recurrent PIK3R2 mutation identified by clinical whole-exome sequencing. Seven of these 20 patients had BPP alone, and 13 had BPP in association with features of the

  16. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

    Science.gov (United States)

    Al-Shamsi, Humaid O.; Jones, Jeremy; Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Abdel-Wahab, Reham; Abousamra, Ahmed O. S.; Shaw, Kenna R.; Xiao, Lianchun; Hassan, Manal M.; Kipp, Benjamin R.; Kopetz, Scott; Soliman, Amr S.; McWilliams, Robert R.; Wolff, Robert A.

    2016-01-01

    Background The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. Methods Arab patients from the Arab Gulf region and a population of age- and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher’s exact test was used to determine the association between mutation status and clinical features. Results A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors. Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant. Conclusions This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation. PMID:28078112

  17. The Potsdam Parallel Ice Sheet Model (PISM-PIK – Part 2: Dynamic equilibrium simulation of the Antarctic ice sheet

    Directory of Open Access Journals (Sweden)

    M. A. Martin

    2011-09-01

    Full Text Available We present a dynamic equilibrium simulation of the ice sheet-shelf system on Antarctica with the Potsdam Parallel Ice Sheet Model (PISM-PIK. The simulation is initialized with present-day conditions for bed topography and ice thickness and then run to steady state with constant present-day surface mass balance. Surface temperature and sub-shelf basal melt distribution are parameterized. Grounding lines and calving fronts are free to evolve, and their modeled equilibrium state is compared to observational data. A physically-motivated calving law based on horizontal spreading rates allows for realistic calving fronts for various types of shelves. Steady-state dynamics including surface velocity and ice flux are analyzed for whole Antarctica and the Ronne-Filchner and Ross ice shelf areas in particular. The results show that the different flow regimes in sheet and shelves, and the transition zone between them, are captured reasonably well, supporting the approach of superposition of SIA and SSA for the representation of fast motion of grounded ice. This approach also leads to a natural emergence of sliding-dominated flow in stream-like features in this new 3-D marine ice sheet model.

  18. The Potsdam Parallel Ice Sheet Model (PISM-PIK) - Part 2: Dynamic equilibrium simulation of the Antarctic ice sheet

    Science.gov (United States)

    Martin, M. A.; Winkelmann, R.; Haseloff, M.; Albrecht, T.; Bueler, E.; Khroulev, C.; Levermann, A.

    2011-09-01

    We present a dynamic equilibrium simulation of the ice sheet-shelf system on Antarctica with the Potsdam Parallel Ice Sheet Model (PISM-PIK). The simulation is initialized with present-day conditions for bed topography and ice thickness and then run to steady state with constant present-day surface mass balance. Surface temperature and sub-shelf basal melt distribution are parameterized. Grounding lines and calving fronts are free to evolve, and their modeled equilibrium state is compared to observational data. A physically-motivated calving law based on horizontal spreading rates allows for realistic calving fronts for various types of shelves. Steady-state dynamics including surface velocity and ice flux are analyzed for whole Antarctica and the Ronne-Filchner and Ross ice shelf areas in particular. The results show that the different flow regimes in sheet and shelves, and the transition zone between them, are captured reasonably well, supporting the approach of superposition of SIA and SSA for the representation of fast motion of grounded ice. This approach also leads to a natural emergence of sliding-dominated flow in stream-like features in this new 3-D marine ice sheet model.

  19. microRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway.

    Science.gov (United States)

    Zhang, Junfeng; Zhang, Zongqi; Zhang, David Y; Zhu, Jianbing; Zhang, Tiantian; Wang, Changqian

    2013-01-01

    Endothelial progenitor cells (EPCs) are capable of proliferating and differentiating into mature endothelial cells, and they have been considered as potential candidates for coronary heart disease therapy. However, the transition of EPCs to mesenchymal cells is not fully understood. This study aimed to explore the role of microRNA 126 (miR-126) in the endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGFβ1). EndMT of rat bone marrow-derived EPCs was induced by TGFβ1 (5 ng/mL) for 7 days. miR-126 expression was depressed in the process of EPC EndMT. The luciferase reporter assay showed that the PI3K regulatory subunit p85 beta (PIK3R2) was a direct target of miR-126 in EPCs. Overexpression of miR-126 by a lentiviral vector (lenti-miR-126) was found to downregulate the mRNA expression of mesenchymal cell markers (α-SMA, sm22-a, and myocardin) and to maintain the mRNA expression of progenitor cell markers (CD34, CD133). In the cellular process of EndMT, there was an increase in the protein expression of PIK3R2 and the nuclear transcription factors FoxO3 and Smad4; PI3K and phosphor-Akt expression decreased, a change that was reversed markedly by overexpression of miR-126. Furthermore, knockdown of PIK3R2 gene expression level showed reversed morphological changes of the EPCs treated with TGFβ1, thereby giving the evidence that PIK3R2 is the target gene of miR-126 during EndMT process. These results show that miR-126 targets PIK3R2 to inhibit EPC EndMT and that this process involves regulation of the PI3K/Akt signalling pathway. miR-126 has the potential to be used as a biomarker for the early diagnosis of intimal hyperplasia in cardiovascular disease and can even be a therapeutic tool for treating cardiovascular diseases mediated by the EndMT process.

  20. microRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway.

    Directory of Open Access Journals (Sweden)

    Junfeng Zhang

    Full Text Available AIMS: Endothelial progenitor cells (EPCs are capable of proliferating and differentiating into mature endothelial cells, and they have been considered as potential candidates for coronary heart disease therapy. However, the transition of EPCs to mesenchymal cells is not fully understood. This study aimed to explore the role of microRNA 126 (miR-126 in the endothelial-to-mesenchymal transition (EndMT induced by transforming growth factor beta 1 (TGFβ1. METHODS AND RESULTS: EndMT of rat bone marrow-derived EPCs was induced by TGFβ1 (5 ng/mL for 7 days. miR-126 expression was depressed in the process of EPC EndMT. The luciferase reporter assay showed that the PI3K regulatory subunit p85 beta (PIK3R2 was a direct target of miR-126 in EPCs. Overexpression of miR-126 by a lentiviral vector (lenti-miR-126 was found to downregulate the mRNA expression of mesenchymal cell markers (α-SMA, sm22-a, and myocardin and to maintain the mRNA expression of progenitor cell markers (CD34, CD133. In the cellular process of EndMT, there was an increase in the protein expression of PIK3R2 and the nuclear transcription factors FoxO3 and Smad4; PI3K and phosphor-Akt expression decreased, a change that was reversed markedly by overexpression of miR-126. Furthermore, knockdown of PIK3R2 gene expression level showed reversed morphological changes of the EPCs treated with TGFβ1, thereby giving the evidence that PIK3R2 is the target gene of miR-126 during EndMT process. CONCLUSIONS: These results show that miR-126 targets PIK3R2 to inhibit EPC EndMT and that this process involves regulation of the PI3K/Akt signalling pathway. miR-126 has the potential to be used as a biomarker for the early diagnosis of intimal hyperplasia in cardiovascular disease and can even be a therapeutic tool for treating cardiovascular diseases mediated by the EndMT process.

  1. Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study

    Science.gov (United States)

    Mirzaa, Ghayda; Conti, Valerio; Timms, Andrew E.; Smyser, Christopher D.; Ahmed, Sarah; Carter, Melissa; Barnett, Sarah; Hufnagel, Robert B.; Goldstein, Amy; Narumi-Kishimoto, Yoko; Olds, Carissa; Collins, Sarah; Johnston, Kathreen; Deleuze, Jean-François; Nitschké, Patrick; Friend, Kathryn; Harris, Catharine; Goetsch, Allison; Martin, Beth; Boyle, Evan August; Parrini, Elena; Mei, Davide; Tattini, Lorenzo; Slavotinek, Anne; Blair, Ed; Barnett, Christopher; Shendure, Jay; Chelly, Jamel; Dobyns, William B.; Guerrini, Renzo

    2015-01-01

    SUMMARY Background Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment and epilepsy. BPP is etiologically heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic etiologies of BPP and delineate their frequency in this patient population. Methods We performed child-parent (trio)-based whole exome sequencing (WES) on eight children with BPP. Following the identification of mosaic PIK3R2 mutations in two of these eight children, we performed targeted screening of PIK3R2 in a cohort of 118 children with BPP who were ascertained from 1980 until 2015 using two methods. First, we performed targeted sequencing of the entire PIK3R2 gene by single molecule molecular inversion probes (smMIPs) on 38 patients with BPP with normal-large head size. Second, we performed amplicon sequencing of the recurrent PIK3R2 mutation (p.Gly373Arg) on 80 children with various types of polymicrogyria including BPP. One additional patient underwent clinical WES independently, and was included in this study given the phenotypic similarity to our cohort. All patients included in this study were children (BPP. Of the 38 patients with BPP and normal-large head size who underwent targeted next generation sequencing by smMIPs, we identified constitutional and mosaic PIK3R2 mutations in 17 additional children. In parallel, one patient was found to have the recurrent PIK3R2 mutation by clinical WES. Seven patients had BPP alone, and 13 had BPP in association with features of the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH). Nineteen patients had the same mutation (Gly373Arg), and one had a nearby missense mutation (p.Lys376Glu). Across the entire cohort, mutations were constitutional in 12 and mosaic in eight patients. Among mosaic patients, we observed substantial

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

    Directory of Open Access Journals (Sweden)

    Silvia N. Kariuki

    2010-01-01

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

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

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    Zacharenia Saridaki

    2011-01-01

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

  4. Pole demokraatiat, pole probleemi / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-2017

    2005-01-01

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

  5. Kotkapoja sünd / Vahur Made

    Index Scriptorium Estoniae

    Made, Vahur, 1971-2017

    2008-01-01

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

  6. 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

  7. Eesti paljastab kommunismi roimad / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Kommunismi Kuritegude Uurimise Sihtasutuse avatavast internetiportaalist, mis koondab infot kommunistliku ideoloogia tõttu maailmas toime pandud kuritegudest. Lisatud intervjuu Damian von Stauffenbergiga: tuleb taastada arusaam heast ja kurjast

  8. 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

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

    International Nuclear Information System (INIS)

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

    2015-01-01

    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. 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. 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. 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

  10. 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.

  11. 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.

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    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.

  12. 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

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    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.

  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

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    -stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600 mg/m(2)) before administration...... of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent...... activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab....

  15. 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"

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas.

    Science.gov (United States)

    Iwasaki, Takeshi; Matsushita, Michiko; Nonaka, Daisuke; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Nagata, Keiko; Nakajima, Hideki; Sano, Shigetoshi; Hayashi, Kazuhiko

    2015-02-01

    Merkel cell polyomavirus (MCPyV) integrates monoclonally into the genomes of approximately 80% of Merkel cell carcinomas (MCCs), affecting their clinicopathological features. The molecular mechanisms underlying MCC development after MCPyV infection remain unclear. We investigated the association of MCPyV infection with activation of the Akt/mammalian target of rapamycin (mTOR)/4E-binding protein 1 (4E-BP1) signaling pathway in MCCs to elucidate the role of these signal transductions and to identify molecular targets for treatment. We analyzed the molecular and pathological characteristics of 41 MCPyV-positive and 27 MCPyV-negative MCCs. Expression of mTOR, TSC1, and TSC2 messenger RNA was significantly higher in MCPyV-negative MCCs, and Akt (T308) phosphorylation also was significantly higher (92% vs 66%; P = .019), whereas 4E-BP1 (S65 and T70) phosphorylation was common in both MCC types (92%-100%). The expression rates of most other tested signals were high (60%-100%) and not significantly correlated with MCPyV large T antigen expression. PIK3CA mutations were observed more frequently in MCPyV-positive MCCs (6/36 [17%] vs 2/20 [10%]). These results suggest that protein expression (activation) of most Akt/mTOR/4E-BP1 pathway signals was not significantly different in MCPyV-positive and MCPyV-negative MCCs, although these 2 types may differ in tumorigenesis, and MCPyV-negative MCCs showed significantly more frequent p-Akt (T308) activation. Therefore, certain Akt/mTOR/4E-BP1 pathway signals could be novel therapeutic targets for MCC regardless of MCPyV infection status. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. 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...

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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"

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Tarifõ na teplo udarjat po koshelku / Hindrek Riikoja, Vahur Koorits

    Index Scriptorium Estoniae

    Riikoja, Hindrek

    2008-01-01

    1. oktoobrist hakkasid kehtima uued kütte- ja gaasihinnad. Vt. samas: Alo Raun ja Andrus Karnau. Elektrihinna kerkimine ohustab euro tulekut. Graafik: Elektri- ja gaasihinna tõus; Tabel: Toasooja kallinemine

  16. Eesti kunstnikud pidid teosed hõlma all Moskvasse toimetama / Vahur Koorits, Ksenia Repson

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Eesti kunstnike näitus "Paradise is not lost" Moskvas Zurab Tsereteli galeriis, kuraator Eha Komissarov. Vene tolliametnikud ei tahtnud lubada üle piiri Raul Meele ja Villem Jahu teoseid, kuna pidasid neid poliitiliselt sobimatuteks. Kommenteerib Eha Komissarov. Samal teemal ka Ksenia Repsoni repliik "Näitus kogub külastajaid"

  17. Kartinõ pribõli v Moskvu taikom / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    9. detsembril avati Moskvas Zurab Tsereteli galeriis eesti kunstnike näitus ±Paradise is not lost¬. Kuraator Eha Komissarov. Vene tolliametnikud ei lubanud üle piiri Raul Meele ja Villem Jahu teoseid, sest pidasid neid poliitiliselt sobimatuks. Kunstnikud viisid oma tööd Moskvasse isikliku pagasi hulgas. Kommenteerinud Ksenia Repson "Moskvitshi poznakomjatsja s estonskimi hudozhnikami"

  18. Sõjavägi võis salaja Estoniale sukelduda / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2006-01-01

    Rootsi parlamendisaadik Lars Angström väidab, et tuukrid käisid salaja Estonia vraki juures enne 2. okt. 1994, ja usub, et hukkumisööl veeti Estonial relvi, samuti soovib ta uut uurimist. Riigiprokurör Margus Kurmi seisukohad

  19. 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

  20. 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.

  1. 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

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

    Index Scriptorium Estoniae

    2013-01-01

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

  3. 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"

  4. 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

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

    Index Scriptorium Estoniae

    Keller, Vahur, 1976-

    2007-01-01

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

  6. 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

  7. 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.

  8. 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

  9. 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...

  10. Lennart Meri pühendusüritus tõi taas kokku kõlavad esinejad / Vahur Koorits

    Index Scriptorium Estoniae

    Koorits, Vahur, 1981-

    2008-01-01

    Tallinnas toimuvast president Lennart Meri nimelisest konverentsist teemal "Tabamata Euroopa". Esinejate seas on Euroopa Komisjoni asepresident Siim Kallas, president Toomas Hendrik Ilves, Venemaa presidendi Vladimir Putini majandusnõunik Andrei Illarionov ning ajakirja Economist Ida-Euroopa korrespondent Edward Lucas. Aruteluteemasid tutvustab konverentsi korraldava Rahvusvahelise Kaitseuuringute Keskuse juhataja Kadri Liik. Vt. samas: Euroopa sotsiaaldemokraadid peavad Eestis konverentsi. Tallinnas Reval Hotel Olümpia konverentsisaalis toimuva konverentsi "Sotsiaaldemokraatia perspektiivid 21. sajandi Euroopas" tervitussõnavõtu peab president Toomas Hendrik Ilves

  11. 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.

  12. 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

  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. 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"

  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. "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

  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. Maailma maksunduse trendid / Sulev Nõmmann, Olavi Kärsna, Paul Tammert, Lemmi Oro ... [jt.] ; eess.: Vahur Kraft

    Index Scriptorium Estoniae

    2003-01-01

    Maksukoormuse trendid, füüsilise isiku tulu- ja sotsiaalmaksu trendid, äriühingu kasumi maksustamine, omandi- ja isikumaksu trendid, tarbimismaksud, keskkonnaga seotud maksud, kontroll maksurahade kasutamise üle

  19. 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

  20. 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.

  1. Territorial Indicative Budget Ceilings (PIK as Instrument of Technocracy of Regional Development Planning

    Directory of Open Access Journals (Sweden)

    Sarjiyanto Sarjiyanto

    2017-03-01

    Full Text Available This research aims at analyzing the local government policy related to the local budget posture in the each territorial. There are uncertainty methods in dividing and formulating the local budget posture in each territorial in Indonesia. It is not depend on the actual economic variables of each territorial. This study uses the literature studies to collect the data of planning and budgeting. The content analysis of this local government economic policy is based on of the planning and budgeting process itself. The detailed information is found by observations and in-depth interview with the informants about the planning and budgeting process in Rembang. The result shows the variables that can determine the fair instrument in formulating the local budget posture some of which are: the number of population, the number of drop out (DO, the illiteracy (IR, the infant mortality rate (IMR, the malnutrition data, the number of poor (HCI, the economic growth, the damaged road infrastructure, the damaged irrigation system, the damaged schools, the land building tax, and the amount of retribution.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-11-01

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

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

    Index Scriptorium Estoniae

    Öpik, Ester

    2014-01-01

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

  4. 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.

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

    Index Scriptorium Estoniae

    Rand, Oliver, 1971-

    2007-01-01

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

  6. 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

  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. 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

  9. 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...

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

    Czech Academy of Sciences Publication Activity Database

    Oikonomou, E.; Koc, Michal; Šourková, Vladimíra; Anděra, Ladislav; Pintzas, A.

    2011-01-01

    Roč. 6, č. 6 (2011), e21632 E-ISSN 1932-6203 Grant - others:EK(XE) LSHC-CT-2006-037278 Institutional research plan: CEZ:AV0Z50520514 Keywords : 17- AAG * apoptosis * colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.092, year: 2011

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

    Data.gov (United States)

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

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

    Data.gov (United States)

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

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

    Czech Academy of Sciences Publication Activity Database

    Oikonomou, E.; Koc, Michal; Šourková, Vladimíra; Anděra, Ladislav; Pintzas, A.

    2011-01-01

    Roč. 6, č. 6 (2011), e21632 E-ISSN 1932-6203 Grant - others:EK(XE) LSHC-CT-2006-037278 Institutional research plan: CEZ:AV0Z50520514 Keywords : 17-AAG * apoptosis * colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.092, year: 2011

  14. 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.

  15. 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

  16. "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

  17. 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

  18. 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

  19. 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)

  20. 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

  1. Kolm debüüti / Jaak Urmet

    Index Scriptorium Estoniae

    Urmet, Jaak, 1979-

    2001-01-01

    Arvustus: Afanasjev, Vahur. Kandiline maailm. Tartu : Irboska Teataja Kirjastus, 2000 ; Ehin, Kristiina. Kevad Astrahanis : luuletusi 1992-1999. Tallinn : Huma, 2000 ; Kaldmaa, Jüri. Passioon. Tallinn : Huma, 2000

  2. 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.

  3. 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

  4. Dokfilm Mustjalast tõi võttegrupile ärakasutamissüüdistuse / Oliver Rand

    Index Scriptorium Estoniae

    Rand, Oliver, 1971-

    2007-01-01

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

  5. Kuusalus on kaks näitetruppi

    Index Scriptorium Estoniae

    1999-01-01

    Kuusalu rahvamaja näitering tõi lavale J. Patricku näidendi "Kummaline missis Savage". Lav. Vendo Peebo Kuusalu näitemänguselts esietendas I. Bresnani ""Hamleti" lavastamine Alamkolka külas". Lav. Saima Merivoo

  6. Characterization of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next generation sequencing study

    OpenAIRE

    Mirzaa, Ghayda; Conti, Valerio; Timms, Andrew E.; Smyser, Christopher D.; Ahmed, Sarah; Carter, Melissa; Barnett, Sarah; Hufnagel, Robert B.; Goldstein, Amy; Narumi-Kishimoto, Yoko; Olds, Carissa; Collins, Sarah; Johnston, Kathreen; Deleuze, Jean-Fran?ois; Nitschk?, Patrick

    2015-01-01

    Summary Background Bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment, and epilepsy. The causes of BPP are heterogeneous, but only a few genetic causes have been reported. The aim of this study was to identify additional genetic causes of BPP and characterise their frequency in this population. Methods Children (aged ≤18 years) with polymic...

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK a......BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS...

  8. 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

    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...

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

    NARCIS (Netherlands)

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

    2010-01-01

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

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

    Science.gov (United States)

    Zhang, Wei; Lv, Shengqing; Liu, Jun; Zang, Zhenle; Yin, Junyi; An, Ning; Yang, Hui; Song, Yechun

    2014-10-01

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

  11. 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

    venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S r...

  12. Kihelkonnamäng elust ja armastusest algab homme / Regina Lilleorg

    Index Scriptorium Estoniae

    Lilleorg, Regina

    2008-01-01

    Kuusalu kihelkonnamängust "Õhtune jalutuskäik Laane Leeni ja Oru Antoniga", mis käsitleb kirjanik Anton Hansen Tammsaare noorusaega Kuusalu mail Koitjärve lähistel. Kihelkonnamängu korraldab Kuusalu vallas tegutsev MTÜ Veljo Tormise Kultuuriselts (kihelkonnamänge korraldatakse 2000. aastast alates). N'äidendite autor on Saima Kallionsivu. Osalevad Kuusalu keskkooli näitering, õpetajad, kohalikud inimesed ja ka tallinlased

  13. Hoffmann - Eesti XIX sajandi külaolustiku jäädvustaja

    Index Scriptorium Estoniae

    2002-01-01

    1. II-5. V EKMi Rüütelkonna hoones baltisaksa maalikunstniku ja graafiku Oskar Hoffmanni teoste ülevaatenäitus "Hoffmann fecit". Kuraator Anne Lõugas, kujundaja Saima Veidenberg. Kunstnikust ja tema loomingust. Näitust saadab loengkontsertide sari "Maal ja muusika". 3. II A. Lõugase loeng O. Hoffmanni maalist "Talumees tubakakarbiga". Ilmub kommenteeritud arhiivipublikatsioon - Amanda Tõnissoni TÜs kaitstud seminaritöö O. Hoffmanni kohta.

  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. 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

  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. "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)

  18. 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

  19. 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

  20. 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

  1. Suurfirmade 2008. aasta eelarved kinnitavad majanduse jahtumist / Mikk Salu

    Index Scriptorium Estoniae

    Salu, Mikk, 1975-

    2008-01-01

    Eesti suurettevõtete juhid räägivad, kuidas nad oma ettevõtte uue aasta eelarvet on planeerinud, kui palju on arvestanud palgakasvuks. Pindi Kinnisvara arvestab oma tulude 20-protsendilise langusega. Peep Sooman, Enn Saar, Vahur Roossaar, Tarmo Noop, Siim Kallast ja Meelis Milder vastavad küsimusele, millist palgatõusu nad prognoosivad 2008. aastal

  2. 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

  3. 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

  4. 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

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

    Index Scriptorium Estoniae

    2010-01-01

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

  6. Noorte lühinäidendid jahmatasid publikut / Maria Uuetoa

    Index Scriptorium Estoniae

    Uuetoa, Maria

    2007-01-01

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

  7. 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

  8. 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

  9. 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

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

    Index Scriptorium Estoniae

    Feldmanis, Andris, 1982-

    2004-01-01

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

  11. Loodusõpetuse õppekomplekt IV klassile : (ilmub 2002.a. sügiseks) / Tiina Elvisto

    Index Scriptorium Estoniae

    Elvisto, Tiina, 1957-

    2002-01-01

    Kirjastuselt Avita ilmub 2002.a. sügiseks 4. klassi bioloogia õppekomplekt, autoriteks Mart Kuurme, Vahur Laug ja Tiina Elvisto. Samadelt autoritelt, neljas kaasautor Kadri Maaste, ilmub Avitalt 2002.a. "Loodusõpetuse õpik-tööraamat 2. klassile"

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

    Index Scriptorium Estoniae

    Valmas, Anne, 1941-2017

    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

  13. 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)

  14. 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"

  15. 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

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

    Directory of Open Access Journals (Sweden)

    James E Korkola

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

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

    DEFF Research Database (Denmark)

    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 colorectal cancers linked to hereditary nonpolyposis colorectal cancer (HNPCC). Sequencing was used to identify mutations in PIK3CA, a real-time PCR-based method to identify KRAS mutations, and immunohistochemical staining was used to evaluate the expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...

  18. Pengembangan Sistem Pengelolaan Informasi Pusat Informasi dan Konseling Remaja Kota Padang

    Directory of Open Access Journals (Sweden)

    Isra Wilna

    2017-04-01

    Full Text Available Salah satu fungsi dari Pusat Informasi dan Konseling Remaja (PIK Remaja adalah memberikan pelayanan informasi dan konseling tentang perencanaan kehidupan berkeluarga bagi remaja. PIK Remaja ini terdapat di lembaga pendidikan sepert sekolah dan perguruan tinggi maupun lembaga non pendidikan. Lokasinya tersebar di 11 kecamatan yang ada di Kota Padang. Setiap PIK, diharuskan menyampaikan laporan-nya secara kolektif dan berkala ke Badan Pemberdayaan Masyarakat, Perempuan dan Keluarga Berencana (BPMPKB  Padang,. Keterbatasan ruang dan waktu, menjadi kendala bagi BPMPKB dalam menjalan perannya sebagai pengawas. Disamping itu, perubahan alamat kantor PIK Remaja  banyak tidak terkelola karena tidak terdokumentasi dengan baik. Oleh karena itu dibangun sebuah sistem yang mampu menyelesaikan masalah tersebut. Sistem infomasi geografis menjadi pilihan karena mampu menyajikan informasi dengan referensi geografis. Dukungan teknologi web terhadap visualisasi geografis akan memudahkan pemangku kebijakan dalam pengembangan PIK Remaja di Kota Padang. Metode pengembangan aplikasi mengadopsi model waterfall. Aplikasi ini dibangun dengan fungsional pencarian PIK Remaja berdasarkan kategori, berdasarkan wilayah, pencarian PIK Remaja yang terdekat dari posisi pengguna, melihat rute menuju PIK Remaja yang dipilih. Disamping itu BPMPKB dapat mengelola data dan laporan  kegiatan PIK remaja. Disamping itu, PIK Remaja dapat mengelola data PIK-nya dan menyampaikan laporan kegiatan. Semua data tesimpan dalam database terdiri dari 9 tabel dengan  17 rancangan user interface aplikasi. Pengujian dilakukan dengan validasi fungsional aplikasi yang dirancang dengan aplikasi secara Blackbox testing. Pengujian ini  melibatkan 5 orang pengguna dengan hasil rekomendasi fungsional dari sistem telah berjalan sesuai dengan rancangan.   Kata kunci: PIK Remaja, Sistem Informasi Geografis.

  19. 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

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

    Index Scriptorium Estoniae

    Helme, Peeter, 1978-

    2010-01-01

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

  1. [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

  2. 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)

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

    Index Scriptorium Estoniae

    Toome, Hedi-Liis

    2009-01-01

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

  4. 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

  5. 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)

  6. Mida toob aasta 2014 välisilmas? / Jürgen Tamme

    Index Scriptorium Estoniae

    Tamme, Jürgen

    2014-01-01

    Küsimusele vastavad välisminister Urmas Paet, presidendi julgeolekunõunik Merle Maigre, riigikogu liikmed Marko Mihkelson, Mart Nutt ja Andres Herkel, suursaadik Tiit Matsulevitš, ajaloolane David Vseviov, TÜ rahvusvahelise õiguse professor Lauri Mälksoo, TLÜ Õigusakadeemia president Rein Müllerson, Eesti Diplomaatide Kooli asedirektor Vahur Made, Siim Kallase kabineti liige Juhan Lepassaar, publitsist Erkki Bahovski ja Kaitseväe Ühendatud Õppeasutuste dotsent Viljar Veebel

  7. Kolm sõjafilmi kolme aastaga / Küllo Arjakas

    Index Scriptorium Estoniae

    Arjakas, Küllo, 1959-

    2007-01-01

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

  8. 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. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  9. Prediction of Response to Therapy and Clinical Outcome through a Pilot Study of Complete Genetic Assessment of Ovarian Cancer

    Science.gov (United States)

    2015-12-01

    B, PIK3CA, BRCA2, ATM, SETD2, ATRX, MTOR, PIK3R1 Mucinous KRAS, TP53, CDKN2A, SMAD4 , TERT Carcinosarcoma TP53, RB1, APC Granulasa cell ATM...alterations in the PTEN- PI3K- AKT -mTOR pathway in a cohort of 379 ovarian cancer patients. Submitted to American Society of Clinical Oncology Annual meeting

  10. Biohuumus - looduslik, kuid tõhus lahendus mullaviljakuse tõstmiseks / Nadezda Knjazeva

    Index Scriptorium Estoniae

    Knjazeva, Nadezda

    2010-01-01

    Biohuumus "Green-PIK" on orgaaniliste jääkide tehnoloogiliste vihmaussidega "Staratel" ümbertöötlemise produkt. See kontsentreeritud väetis sisaldab tasakaalustatud kombinatsioonis tervet kompleksi vajalikke toitaineid ja mikroelemente, fermente, pinnasantibiootikume, vitamiine, taimede kasvu ja arengu hormoone. Väetamine muutub efektiivsemaks biohuumuse ja vedela kontsentraadi Gumistar "Grin-PIK" kompleksse kasutamise korral

  11. 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

  12. Mis tuleb

    Index Scriptorium Estoniae

    2004-01-01

    Detsembris Mahtra talurahvamuuseumis Atla mõisa keraamika- ja taimeseaderingi Takjanupud jõuluseadete näitus. 4. XII Tallinnas Säästva Renoveerimise Infokeskuses naturaalkrohvi töötuba. Kuni 4. XII Rapla keskraamatukogus Saima Randjärve näitus "Valguses". 9., 11., 17. ja 18. XII Säästva Renoveerimise Keskuses Jüri Kuusmanni loodusvärvide kursus. 11. XII Türi kultuurimajas tekstiilist kuuskede konkurss "Kuusepuu 2004". 14. XII Eesti Rahva Muuseumis 9. koolidevaheline jõuluteemaline võistujoonistamine. Tartu Mämguasjamuuseumis on 15.-23. XII avatud jõuluhõnguline mängutuba ja näitus Heli Männi mänguasjade kogust

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

    Index Scriptorium Estoniae

    Helme, Peeter, 1978-

    2008-01-01

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

  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. Möödunud aasta olulisimad kirjandusteosed

    Index Scriptorium Estoniae

    2007-01-01

    Eesti Kultuurkapitali kirjanduse sihtkapitali auhindade nominentide seas on Tiit Aleksejev, Nikolai Baturin, Jan Kaus, Peeter Sauter ja Mats Traat proosateoste eest, Vahur Afanasjev, Hasso Krull, Sven Kivisildnik, Mathura, Triin Soomets ja Indrek Ryytle luule eest, Jim Ashilevi, Andrus Kivirähk, Andrei Hvostov draamateoste eest ning Kristiina Kass, Andrus Kivirähk, Jaan Rannap, Üllar ja Rünno Saaremäe, Peeter Sauter lastekirjanduses. Vt. ka Eesti Ekspress, 8. veebr., lk. B11 ; Sirp, 9. veebr., lk. 8 ; Eesti Päevaleht : Arkaadia : [kirjanduslisa], 17. veebr., lk. 3

  16. 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

  17. Modernizing the 5G 100/8 piston compressor by means of directly streaming valves

    Energy Technology Data Exchange (ETDEWEB)

    Tsvetanov, Ts.; Stoyanov, I.

    1988-02-01

    Deals with 5G 100/8 air compressors which, despite long service and lack of spare parts, are still widely used in Bulgarian underground coal mines. K-4-10 ring-type valves are in particularly short supply; maintenance engineers have been forced to modify the compresors. Initially, Bulgarian KP-3.1 valves with direct air streaming replaced the K-4-10; these were later replaced by PIK-220 and PIK-220A valves. Tests on overhauled compressors have shown that replacing the KP-3.1 with the PIK-220 or PIK-220A can result in a saving of up to 100,000 kWh of electricity per compressor. Details of reconstruction and testing of piston compressors are included. 10 refs.

  18. "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

  19. 78 FR 37782 - Proposed Information Collection; Comment Request; Collection of State Level Data on Nutrition...

    Science.gov (United States)

    2013-06-24

    ... Food and Nutrition Service (FNS) of the United States Department of Agriculture (USDA) would like to... assign a PIK to each person record involves matching based on name, address, sex, date of birth, and...

  20. Multiple metabolic alterations exist in mutant PI3K cancers, but only glucose is essential as a nutrient source.

    Directory of Open Access Journals (Sweden)

    Rebecca Foster

    Full Text Available Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic

  1. 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

  2. Impact of KRAS, BRAF and PI3KCA mutations in rectal carcinomas treated with neoadjuvant radiochemotherapy and surgery

    International Nuclear Information System (INIS)

    Derbel, Olfa; La Fouchardière, Christelle de; Wang, Qing; Desseigne, Françoise; Rivoire, Michel; Meeus, Pierre; Peyrat, Patrice; Stella, Mattia; Martel-Lafay, Isabelle; Lemaistre, Anne-Isabelle

    2013-01-01

    Conventional treatment for locally advanced rectal cancer usually combines neoadjuvant radiochemotherapy and surgery. Until recently, there have been limited predictive factors (clinical or biological) for rectal tumor response to conventional treatment. KRAS, BRAF and PIK3CA mutations are commonly found in colon cancers. In this study, we aimed to determine the mutation frequencies of KRAS, BRAF and PIK3CA and to establish whether such mutations may be used as prognostic and/or predictive factors in rectal cancer patients. We retrospectively reviewed the clinical and biological data of 98 consecutive operated patients between May 2006 and September 2009. We focused in patients who received surgery in our center after radiochemotherapy and in which tumor samples were available. In the 98 patients with a rectal cancer, the median follow-up time was 28.3 months (4–74). Eight out of ninety-eight patients experienced a local recurrence (8%) and 17/98 developed distant metastasis (17%). KRAS, BRAF and PIK3CA were identified respectively in 23 (23.5%), 2 (2%) and 4 (4%) patients. As described in previous studies, mutations in KRAS and BRAF were mutually exclusive. No patient with local recurrence exhibited KRAS or PIK3CA mutation and one harbored BRAF mutation (12.5%). Of the seventeen patients with distant metastasis (17%), 5 were presenting KRAS mutation (29%), one BRAF (5%) and one PIK3CA mutation (5%). No relationship was seen between PIK3CA, KRAS or BRAF mutation and local or distant recurrences. The frequencies of KRAS, BRAF and PIK3CA mutations in our study were lower than the average frequencies reported in colorectal cancers and no significant correlation was found between local/distant recurrences and KRAS, BRAF or PIK3CA mutations. Future studies with greater number of patients, longer follow-up time and greater power to predict associations are necessary to fully understand this relationship

  3. Phosphoinositide Kinase-3 Status Associated With Presence or Absence of Human Papillomavirus in Head and Neck Squamous Cell Carcinomas

    International Nuclear Information System (INIS)

    Yarbrough, Wendell G.; Whigham, Amy; Brown, Brandee; Roach, Michael; Slebos, Robbert

    2007-01-01

    Purpose: To investigate phosphoinositide kinase-3 (PI3K) activation in relation to human papillomavirus (HPV) status in head and neck squamous cell carcinoma (HNSCC). Methods and Materials: Gene expression microarray data were analyzed to determine differentially expressed genes between HPV(+) and HPV(-) HNSCC. PIK3CA gene expression was confirmed by quantitative reverse transcriptase-polymerase chain reaction in seven HPV(+) and seven HPV(-) primary HNSCCs. PIK3CA mutation status in three HPV(+) and nine HPV(-) cell lines was determined by polymerase chain reaction amplification of hot spot exons (1, 9, 20) followed by direct sequencing. Results: PIK3CA was overexpressed in HPV(+)-associated HNSCC compared with the expression in HPV(-) HNSCC. Activation of PIK3CA by mutation was found in 1 of the 12 tested HNSCC cell lines. Conclusion: Activation of PI3K by mutation of PIK3CA is rare in HNSCC cell lines and was not found in three HPV(+) cell lines. One mechanism by which HPV-associated HNSCC might activate PI3K is increased expression of PIK3CA

  4. IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity

    Science.gov (United States)

    Chiang, Sarah; Weigelt, Britta; Wen, Huei-Chi; Pareja, Fresia; Raghavendra, Ashwini; Martelotto, Luciano G.; Burke, Kathleen A.; Basili, Thais; Li, Anqi; Geyer, Felipe C.; Piscuoglio, Salvatore; Ng, Charlotte K.Y.; Jungbluth, Achim A.; Balss, Jörg; Pusch, Stefan; Baker, Gabrielle M.; Cole, Kimberly S.; von Deimling, Andreas; Batten, Julie M.; Marotti, Jonathan D.; Soh, Hwei-Choo; McCalip, Benjamin L.; Serrano, Jonathan; Lim, Raymond S.; Siziopikou, Kalliopi P.; Lu, Song; Liu, Xiaolong; Hammour, Tarek; Brogi, Edi; Snuderl, Matija; Iafrate, A. John; Reis-Filho, Jorge S.; Schnitt, Stuart J.

    2017-01-01

    Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. PMID:27913435

  5. 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.

  6. 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...

  7. 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.

  8. The Effectiveness of Cognitive Reflection and Re-structurization on Career Decision Making of High School Students

    Directory of Open Access Journals (Sweden)

    Wagimin Wagimin

    2015-03-01

    Key Words: career decision making, CIP model, reflection, cognitive restructuring Abstrak: Penelitian ini bertujuan untuk menguji keefektifan  refleksi dan penstrukturan ulang kognitif guna meningkatkan pengambilan keputusan karier siswa SMA berdasarkan model PIK. Penelitian eksperimen ini menggunakan rancangan RCTs, dan subjek 40 orang siswa sebagai kelompok eksperi-men dan 40 sebagai kelompok kontrol. Sub-kemampuan pengambilan keputusan karier model PIK yang dikembangkan meliputi: memahami diri, memahami pilihan pekerjaan, komunikasi, analisis, sinte-sis, penilaian, pelaksanaan, dan proses pelaksanaan. Hasil penelitian menunjukkan bahwa ada perbeda-an kemampuan pengambilan keputusan karier antara siswa kelompok eksperimen dan kelompok kon-trol di mana kelompok eksperimen memiliki nilai rata-rata yang lebih tinggi. Informasi controlled trials menguatkan juga bahwa refleksi dan penstrukturan ulang kognitif  efektif untuk  meningkatkan kemampuan pengambilan keputusan karier siswa SMA. Kata kunci: pengambilan keputusan karier, model PIK, refleksi, penstrukturan ulang kognitif

  9. 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

  10. 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.

  11. 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.

  12. Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival.

    Science.gov (United States)

    Lin, Zhiqiang; Zhou, Pingzhu; von Gise, Alexander; Gu, Fei; Ma, Qing; Chen, Jinghai; Guo, Haidong; van Gorp, Pim R R; Wang, Da-Zhi; Pu, William T

    2015-01-02

    Yes-associated protein (YAP), the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEA (transcriptional enhancer activator)-domain sequence-specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. To identify direct YAP targets that mediate its mitogenic and antiapoptotic effects in the heart. We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP-bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase, as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEA-domain occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the phosphoinositol-3-kinase-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by adeno-associated virus-mediated Pik3cb expression. Pik3cb is a crucial direct target of YAP, through which the YAP activates phosphoinositol-3-kinase-AKT pathway and regulates cardiomyocyte proliferation and survival. © 2014 American Heart Association, Inc.

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

    Science.gov (United States)

    Zhu, Y; Lin, E C

    1988-05-01

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

  14. 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.

  15. Arstidel on keeruline võõrsilt naasta / Hanneli Rudi

    Index Scriptorium Estoniae

    Rudi, Hanneli

    2011-01-01

    Aastaid välismaal töötanud arstidel on raske Eestis tööd leida, sest vastavaid töökuulutusi Eesti Arstide Liidu ja haiglate kodulehed ei avalda. Eestisse tagasi tulla sooviv neuroloog Merle Ööpik ja lastepsühholoog Airiin Demir oma tööotsimiskogemustest

  16. Врачам сложно возвращаться в родную страну / Ханнели Руди

    Index Scriptorium Estoniae

    Руди, Ханнели

    2011-01-01

    Aastaid välismaal töötanud arstidel on raske Eestis tööd leida, sest vastavaid töökuulutusi Eesti Arstide Liidu ja haiglate kodulehed ei avalda. Eestisse tagasi tulla sooviv neuroloog Merle Ööpik ja lastepsühholoog Airiin Demir oma tööotsimiskogemustest

  17. 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

  18. 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...

  19. Genetics Home Reference: ovarian cancer

    Science.gov (United States)

    ... is most often associated with mutations in the MLH1 or MSH2 gene and accounts for between 10 ... AKT1 BARD1 BRCA1 BRCA2 BRIP1 CDH1 CHEK2 CTNNB1 MLH1 MRE11 MSH2 MSH6 NBN OPCML PALB2 PIK3CA PMS2 ...

  20. MAQUETTE ORL Décembre 2004

    African Journals Online (AJOL)

    35- Mtasiwa DM, Imamura N, Inda T et al. Immunophenotype, histology and cli- nical stage: their predictive value in the prognosis of non Hodgkin's lymphomas. Hiroshima J Med Sci 1990; 39(4): 95-102. 36- Hutchison RE, Berard CW, Shuster JJ, Link MP, Pik TE, Murphy SB; B-cell lineage confers a favorable outcome ...

  1. Energy fluxes and spectra for turbulent and laminar flows

    KAUST Repository

    Verma, Mahendra K.; Kumar, Abhishek; Kumar, Praveen; Barman, Satyajit; Chatterjee, Anando G.; Samtaney, Ravi

    2017-01-01

    spectrum $E(k)$ and energy flux $\\Pi(k)$ using spectral simulations on grids up to $4096^3$, and show consistency between the numerical results and predictions by the aforementioned models. We also construct a model for laminar flows that predicts $E(k

  2. Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups

    DEFF Research Database (Denmark)

    van Kessel, Kim E M; van der Keur, Kirstin A; Dyrskjøt, Lars

    2018-01-01

    prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated...

  3. 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.

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

    Czech Academy of Sciences Publication Activity Database

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

    2017-01-01

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

  5. Alternative splicing in colon, bladder, and prostate cancer identified by exon-array analysis

    DEFF Research Database (Denmark)

    Thorsen, Kasper; Sørensen, Karina D.; Brems-Eskildsen, Anne Sofie

    2008-01-01

    , PIK4CB, TPM1, and VCL). The validated tumor-specific splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases even of different tumor stages. A subset of the tumor-specific splicing alterations (ACTN1, CALD1, and VCL) was found in all three...

  6. 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...

  7. 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...

  8. JPRS Report: Environmental Issues

    Science.gov (United States)

    1993-05-28

    Enhanced Safety come in contact with its discharges. Lung diseases, 93WN0407A St. Petersburg CHAS PIK in Russian diseases of the larynx and asthma are...The contraband goods produced in the Far East consist of system of payments for pollution and the use of natural pelts and other parts of bears, tigers

  9. Molecular Profiles for Lung Cancer Pathogenesis and Detection in U.S. Veterans

    Science.gov (United States)

    2013-10-01

    independent survival and growth of cancer cells, including a catalytic subunit of phosphatidylinositol 3- kinase (PIK3CA) (33) and the SH2 -containg...comparative genomic hybridization: implications of the phosphatidylinositol 3- kinase pathway. Cancer Res. 2002;62:3636-40. 28. Massion PP, Zou Y, Uner

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

    Science.gov (United States)

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

    2015-09-01

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

  12. Molecular characterization of apocrine salivary duct carcinoma.

    Science.gov (United States)

    Chiosea, Simion I; Williams, Lindsay; Griffith, Christopher C; Thompson, Lester D R; Weinreb, Ilan; Bauman, Julie E; Luvison, Alyssa; Roy, Somak; Seethala, Raja R; Nikiforova, Marina N

    2015-06-01

    Contemporary classification and treatment of salivary duct carcinoma (SDC) require its thorough molecular characterization. Thirty apocrine SDCs were analyzed by the Ion Ampliseq Cancer HotSpot panel v2 for mutations in 50 cancer-related genes. Mutational findings were corroborated by immunohistochemistry (eg, TP53, BRAF, β-catenin, estrogen, and androgen receptors) or Sanger sequencing/SNaPshot polymerase chain reaction. ERBB2 (HER2), PTEN, FGFR1, CDKN2A/P16, CMET, EGFR, MDM2, and PIK3CA copy number changes were studied by fluorescence in situ hybridization. TP53 mutations (15/27, 56%), PTEN loss (11/29, 38%, including 2 cases with PTEN mutation), PIK3CA hotspot mutations (10/30, 33%), HRAS hotspot mutations (10/29; 34%), and ERBB2 amplification (9/29, 31%, including 1 case with mutation) represented the 5 most common abnormalities. There was no correlation between genetic changes and clinicopathologic parameters. There was substantial overlap between genetic changes: 8 of 9 cases with ERBB2 amplification also harbored a PIK3CA, HRAS, and TP53 mutation and/or PTEN loss. Six of 10 cases with PIK3CA mutation also had an HRAS mutation. These findings provide a molecular rationale for dual targeting of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways in SDC. FGFR1 amplification (3/29, 10%) represents a new potential target. On the basis of studies of breast carcinomas, the efficacy of anti-ERBB2 therapy will likely be decreased in SDC with ERBB2 amplification co-occurring with PIK3CA mutation or PTEN loss. Therefore, isolated ERBB2 testing is insufficient for theranostic stratification of apocrine SDC. On the basis of the prevalence and type of genetic changes, apocrine SDC appears to resemble one subtype of breast carcinoma-"luminal androgen receptor positive/molecular apocrine."

  13. 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.

  14. Evaluation of Seasonal, ANN, and Hybrid Models in Modeling Urban Water Consumption A Case Study of Rash City

    Directory of Open Access Journals (Sweden)

    Seyed Nematollah Mousavi

    2016-09-01

    Full Text Available Forecasting future water consumption in cities to plan for the required capacities in urban water supply systems (including water transmission networks and water treatment facilities depends on the application of behavioral models of uban water consumption. Being located in the North-South corridor, Rasht City is assuming a new role to play in the national economy as a foreign trade center. It will, thus, be necessary to review its present urban infrastructure in order to draft the required infrastructural development plans for meeting the city’s future water demands. The three Seasonal Autoregressive Integrated Moving Average (SARIMA, Artificial Neural Network (ANN, and SARIMABP approaches were employed in present study to model and forecast Rasht urban water consumption using monthly time series for the period 2001‒2008 of urban water consumption in Rasht. The seasonal unit root test was applied to develop the relevant SARIMA model. Results showed that all the seasonal and non-seasonal unit roots are present in all the frequencies in the monthly time series for Rasht urban water consumption. Using a proper filter, the SAIMA patterns were estimated. In a second stage the SARIMA output was used to determine the ANN output and the hybrid SARIMABP structure was accordingly constructed. The values for Rasht urban water consumption predicted by the three models indicated the superiority of the SARIMABP hybrid model as evidenced by the forecast error index of 0.41% obtained for this model. The other two models of SARIMA and ANN were, however, found to yield acceptable results for urban water managers since the forecasting error recorded for them was below 1%.

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

    Directory of Open Access Journals (Sweden)

    Ahmad J

    2015-11-01

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

  16. PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib

    International Nuclear Information System (INIS)

    Wang, Leiping; Hu, Xichun; Zhang, Qunling; Zhang, Jian; Sun, Si; Guo, Haiyi; Jia, Zhen; Wang, Biyun; Shao, Zhimin; Wang, Zhonghua

    2011-01-01

    Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or 'addictive' to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab. Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m 2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity. PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013). PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting

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

    Science.gov (United States)

    2013-04-01

    NDUFA12,CYC1,DHODH,NDUFA2,COX7C Melanoma Signaling 8.10E-01 6.52E-02 PIK3C3,CDK4,MDM2 Maturity Onset Diabetes of Young ( MODY ) Signaling 7.99E-01 6.45E...ACTG1,CACNA1A Inhibition of Angiogenesis by TSP1 1.63E+00 1.03E-01 CD47,SDC1,GUCY1A3,MAPK10 Type I Diabetes Mellitus Signaling 1.61E+00 6.67E-02...Pathway 5.02E-01 5.71E-02 CCNH,POLR2K Type II Diabetes Mellitus Signaling 4.89E-01 3.11E-02 MAP3K7,PIK3C3,MAPK10,SOCS5,PRKCB Hereditary Breast Cancer

  18. Energy fluxes and spectra for turbulent and laminar flows

    KAUST Repository

    Verma, Mahendra K.

    2017-05-14

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

  19. δ-Tocopherol inhibits receptor tyrosine kinase-induced AKT activation in prostate cancer cells.

    Science.gov (United States)

    Wang, Hong; Hong, Jungil; Yang, Chung S

    2016-11-01

    The cancer preventive activity of vitamin E is suggested by epidemiological studies and supported by animal studies with vitamin E forms, γ-tocopherol and δ-tocopherol (δ-T). Several recent large-scale cancer prevention trials with high dose of α-tocopherol, however, yielded disappointing results. Whether vitamin E prevents or promotes cancer is a serious concern. A better understanding of the molecular mechanisms of action of the different forms of tocopherols would enhance our understanding of this topic. In this study, we demonstrated that δ-T was the most effective tocopherol form in inhibiting prostate cancer cell growth, by inducing cell cycle arrest and apoptosis. By profiling the effects of δ-T on the cell signaling using the phospho-kinase array, we found that the most inhibited target was the phosphorylation of AKT on T308. Further study on the activation of AKT by EGFR and IGFR revealed that δ-T attenuated the EGF/IGF-induced activation of AKT (via the phosphorylation of AKT on T308 induced by the activation of PIK3). Expression of dominant active PIK3 and AKT in prostate cancer cell line DU145 in which PIK3, AKT, and PTEN are wild type caused the cells to be reflectory to the inhibition of δ-T, supporting that δ-T inhibits the PIK3-mediated activation of AKT. Our data also suggest that δ-T interferes with the EGF-induced EGFR internalization, which leads to the inhibition of the receptor tyrosine kinase-dependent activation of AKT. In summary, our results revealed a novel mechanism of δ-T in inhibiting prostate cancer cell growth, supporting the cancer preventive activity δ-T. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    2015-07-01

    medulloblastoma by activating N1ICD and PIK3CA in cerebellar NSCs and NPCs in the developing mouse brain. N1ICD models : We previously published...Aims: 1. Validate general applicability and clinical potential of SP66 as a theragnostic agent by measuring tumor uptake in PDX GBM models and a...spontaneous mouse medulloblastoma model ; 2. Evaluate the therapeutic potential of SP66 in vitro and in vivo. Overlap: None Contracting/ Grants

  1. Radioisotope dust pollution monitor

    International Nuclear Information System (INIS)

    Szepke, R.; Harasimczuk, J.; Dobrowiecki, J.

    1990-01-01

    Measuring principles and specification of two dust monitors: station-type AMIZ and portable-type PIK-10 for ambient air pollution are presented. The first one, a fully automatic instrument is destined for permanent monitoring of air pollution in preset sampling time from .25 to 24 hours. The second one was developed as a portable working model. Both instruments display their results in digital form in dust concentration units. (author)

  2. Q-balls of quasi-particles in a (2,0)-theory model of the fractional quantum Hall effect

    NARCIS (Netherlands)

    Ganor, O.J.; Hong, Y.P.; Moore, N.; Sun, H.Y.; Tan, H.S.; Torres-Chicon, N.R.

    2015-01-01

    A toy model of the fractional quantum Hall effect appears as part of the low-energy description of the Coulomb branch of the A(1) (2, 0)-theory formulated on (S-1 x R-2)/Z(k), where the generator of Z(k) acts as a combination of translation on S-1 and rotation by 2 pi/k on R-2. At low energy the

  3. 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

  4. Liigapörssi-pelin verkkopelaamisen työkalu

    OpenAIRE

    Finning, J. (Jaakko)

    2015-01-01

    Tiivistelmä Liigapörssin, ja saman valmistajan muiden vastaavien pelien, pelaaminen on suosittu harrastus penkkiurheilijoiden keskuudessa. Pelaaminen sisältää paljon haasteita. Ongelmia aiheuttavat jakson pelilistan läpikäynti, joukkueiden kokoaminen sekä vaihtojen tekeminen. Näitä haasteita kohdataan pelissä päivittäin. Monet yksittäiset pelaajat ovatkin laatineet itselleen alkeellisia tilastoja ja taulukoita, joiden avull...

  5. Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships.

    Science.gov (United States)

    Sakr, Rita A; Schizas, Michail; Carniello, Jose V Scarpa; Ng, Charlotte K Y; Piscuoglio, Salvatore; Giri, Dilip; Andrade, Victor P; De Brot, Marina; Lim, Raymond S; Towers, Russell; Weigelt, Britta; Reis-Filho, Jorge S; King, Tari A

    2016-02-01

    Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing. DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes. Single nucleotide variants and insertions and deletions were identified using state-of-the-art bioinformatics approaches. The constellation of somatic mutations found in LCIS (n = 34) and ILC (n = 21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1). LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  6. Stream Lifetimes Against Planetary Encounters

    Science.gov (United States)

    Valsecchi, G. B.; Lega, E.; Froeschle, Cl.

    2011-01-01

    We study, both analytically and numerically, the perturbation induced by an encounter with a planet on a meteoroid stream. Our analytical tool is the extension of pik s theory of close encounters, that we apply to streams described by geocentric variables. The resulting formulae are used to compute the rate at which a stream is dispersed by planetary encounters into the sporadic background. We have verified the accuracy of the analytical model using a numerical test.

  7. 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.

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

    KAUST Repository

    Mansour, Hicham; Incitti, Roberto; Bajic, Vladimir B.

    2014-01-01

    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.

  9. 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.

  10. Streso problema įvairiose ugdymo įstaigose

    OpenAIRE

    Charašauskienė, Vaiva

    2006-01-01

    Place of writing the study: Lithuanian university of agriculture. Institute of rural culture. Academy. 2006 years. Volume of work:57 pages There are:3 tables, 14 pictures, 5 appendices Bibliography:39 publications Object of research: Stress experienced by the the people at work in educational institutions Methods of research: 1. The analysis of bibliography. 2. The questionnaire about stress at work taken from J.Pikūnas, A.Palujanskienė‘s book „Stresas“ (2005), page...

  11. 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.

  12. On the Maximum Separation of Visual Binaries M. I. Nouh1,∗ & M. A. ...

    Indian Academy of Sciences (India)

    Stars, http://www.ad.usno.navy.mil/wds/orb6/orb6.html. Kuiper, G. P. 1935, Publ. Astron. Soc. Pacific., 47(15), 12. Öpik, E. 1924, Publ. Obs. Astro. Univ. Tartu., 25, 6. Press, W. H., Teukolsky, S. A., Vetterling, W. H., Flannery, B.P. 1992, Numerical Recipes. (Cambridge Univ. Press). Reed, B. C. 1984, J. R. Astron. Soc. Can.

  13. 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.

  14. Prognostic and predictive value of p-Akt, EGFR, and p-mTOR in early breast cancer

    International Nuclear Information System (INIS)

    Lazaridis, Georgios; Lambaki, Sofia; Karayannopoulou, Georgia; Eleftheraki, Anastasia G.; Papaspirou, Irene; Bobos, Mattheos; Efstratiou, Ioannis; Pentheroudakis, George; Zamboglou, Nikolaos; Fountzilas, George; Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki

    2014-01-01

    There are scarce data available on the prognostic/predictive value of p-Akt and p-mTOR protein expression in patients with high-risk early breast cancer. Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 997 patients participating in two adjuvant phase III trials were assessed for EGFR, PTEN, p-Akt, p-mTOR protein expression, and PIK3CA mutational status. These markers were evaluated for associations with each other and with selected patient and tumor characteristics, immunohistochemical subtypes, disease-free survival (DFS), and overall survival (OS). p-mTOR protein expression was negatively associated with EGFR and positively associated with PTEN, with p-Akt473, and with the presence of PIK3CA mutations. EGFR expression was positively associated with p-Akt473, p-Akt308, and PIK3CA wild-type tumors. Finally, p-Akt308 was positively associated with p-Akt473 expression. In univariate analysis, EGFR (p = 0.016) and the coexpression of EGFR and p-mTOR (p = 0.015) were associated with poor OS. Among patients with p-Akt308-negative or low-expressing tumors, those treated with hormonal therapy were associated with decreased risk for both relapse and death (p = 0.013 and p [de

  15. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.

    Science.gov (United States)

    Camps, Montserrat; Rückle, Thomas; Ji, Hong; Ardissone, Vittoria; Rintelen, Felix; Shaw, Jeffrey; Ferrandi, Chiara; Chabert, Christian; Gillieron, Corine; Françon, Bernard; Martin, Thierry; Gretener, Denise; Perrin, Dominique; Leroy, Didier; Vitte, Pierre-Alain; Hirsch, Emilio; Wymann, Matthias P; Cirillo, Rocco; Schwarz, Matthias K; Rommel, Christian

    2005-09-01

    Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

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

    Science.gov (United States)

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

    2015-01-01

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

  17. 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.

  18. Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan

    International Nuclear Information System (INIS)

    Kim, Seung Tae; Ahn, Tae Jin; Lee, Eunjin; Do, In-Gu; Lee, Su Jin; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Kim, Suk Hyeong; Lee, Jeeyun; Kim, Hee Cheol

    2015-01-01

    More than half of the patients selected based on KRAS mutation status fail to respond to the treatment with cetuximab in metastatic colorectal cancer (mCRC). We designed a study to identify additional biomarkers that could act as indicators for cetuximab treatment in mCRC. We investigated 58 tumor samples from wild type KRAS CRC patients treated with cetuximab plus irinotecan (CI). We conducted the genotyping for mutations in either BRAF or PIK3CA and profiled comprehensively the expression of 522 kinase genes. BRAF mutation was detected in 5.1 % (3/58) of patients. All 50 patients showed wild type PIK3CA. Gene expression patterns that categorized patients with or without the disease control to CI were compared by supervised classification analysis. PSKH1, TLK2 and PHKG2 were overexpressed significantly in patients with the disease control to IC. The higher expression value of PSKH1 (r = 0.462, p < 0.001) and TLK2 (r = 0.361, p = 0.005) had the significant correlation to prolonged PFS. The result of this work demonstrated that expression nature of kinase genes such as PSKH1, TLK2 and PHKG2 may be informative to predict the efficacy of CI in wild type KRAS CRC. Mutations in either BRAF or PIK3CA were rare subsets in wild type KRAS CRC

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

    Science.gov (United States)

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

    2016-10-01

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

  20. 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.)

  1. High-incidence of PTEN mutations in Chinese patients with primary small cell carcinoma of the esophagus

    International Nuclear Information System (INIS)

    Zhang, Zhimin; Wang, Ge; Xiao, Hualiang; Xie, Fei; Zhang, Hui; Chen, Chuan; Xiao, He; Yang, Zhenzhou; Wang, Dong; Li, Zengpeng

    2014-01-01

    Primary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive tumor with poor prognosis. The aim of this study was to investigate the existence of EGFR, KRAS, PIK3CA and PTEN mutations in PSCCE. Clinical–pathological data and paraffin-embedded specimens were collected from 38 patients. Exons 18 to 21 of EGFR, KRAS and PIK3CA status were analyzed by real-time PCR based on ARMS and Scorpion technology in all patients, and the PTEN gene was also screened using real-time PCR and high-resolution melting curve analysis (HRMA). Only 1 (2.63%) out of 38 patients had EGFR mutations in L858R missense, and KRAS and PIK3CA were not found in the mutational spot in all patients. However, PTEN mutations presented in 14 (36.84%) out of 38 patients, including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%). Concurrent mutations of these genes were not detected in all samples. No statistically significant associations were found between the clinicopathological features and the mutation status of PTEN. The incidence of PTEN mutations in Chinese patients with PSCCE was higher than that of previous reports in other histological subtypes of esophageal cancer

  2. Substantiation of the TVR-M reactor parameter selection and specific features of the research program

    International Nuclear Information System (INIS)

    Abov, Yu.G.; Kiselev, G.V.; Shvedov, O.V.

    1986-01-01

    Comparative analysis of characteristics of the T-VR-M(ITEP, USSR), GRHF(France) and PIK(LNPI USSR) high-flux heavy water cooled and moderated research reactors is given. The TVR-M reactor design concepts are mainly based on a 35-year experience in operating of the first Soviet heavy water research TVR reactor. As a result of the reactor reconstruction its thermal power will increase up to 25 MW neutron flux in experimental channels will increase 10 fold and reach 5.6x10 14 neutron/cm 2 xc. The TVR-M reactor has the quality value the ratio of maximum thermal neutron flux value the reflector to reactor power in practically the same as for the GRHF reactor (2.24x10 13 (neutron/cm 2 xc)/MW) which allows one to place it among the best research reactors in the world. Maximum fuel burnup of the order of 50% and minimum fuel loading are forseen for the TVR-M reactor which provides for operation cost minimum as compared to the GRHF and PIK reactors. The TVR-M reactor practically does not yield to the PIK and GRMF reactors in experimental channel quantity and exceeds the in the number of vertical channels. The TVR-M reactor experimental capabilities allow one to reduce measuring time and provide for conducting the experiments at a qualitatively new level. At the same time capabilities of radioactive nuclide production in qualitative and quantitative senses are increased

  3. The Prognostic Influence of BRAF Mutation and other Molecular, Clinical and Laboratory Parameters in Stage IV Colorectal Cancer.

    Science.gov (United States)

    Karadima, Maria L; Saetta, Angelica A; Chatziandreou, Ilenia; Lazaris, Andreas C; Patsouris, Efstratios; Tsavaris, Nikolaos

    2016-10-01

    Our aim was to evaluate the predictive and prognostic influence of BRAF mutation and other molecular, clinical and laboratory parameters in stage IV colorectal cancer (CRC). 60 patients were included in this retrospective analysis, and 17 variables were examined for their relation with treatment response and survival. KRAS mutation was identified in 40.3 % of cases, BRAF and PIK3CA in 8.8 % and 10.5 % respectively. 29.8 % of patients responded to treatment. Median survival time was 14.3 months. Weight loss, fever, abdominal metastases, blood transfusion, hypoalbuminaimia, BRAF and PIK3CA mutations, CRP and DNA Index were associated with survival. In multivariate analysis, male patients had 3.8 times higher probability of response, increased DNA Index was inversely correlated with response and one unit raise of DNA Index augmented 6 times the probability of death. Our findings potentiate the prognostic role of BRAF, PIK3CA mutations and ploidy in advanced CRC.

  4. 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)

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

    Directory of Open Access Journals (Sweden)

    Hamid S

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Yadav

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

  7. Value of preoperative enhanced multi-slice spiral CT scan for judging TNM staging of gastric cancer as well as its relationship with tumor marker and proliferation molecule expression

    Directory of Open Access Journals (Sweden)

    Ai-Jun Wu

    2016-12-01

    Full Text Available Objective: To study the value of preoperative enhanced multi-slice spiral CT scan for judging TNM staging of gastric cancer as well as its relationship with tumor marker and proliferation molecule expression. Methods: A total of 135 patients with gastric cancer who received surgical resection in our hospital between May 2012 and October 2015 were selected as the research subjects, preoperative enhanced multi-slice spiral CT scan was conducted to judge TNM staging, and serum was collected to determine the content of tumor markers; tumor tissue was collected after operation to determine the content of cytokines and pro-proliferation molecules. Results: CEA, CA199, CA153, CA125 and CA724 content in serum as well as TGFβ1, TGFβ2, VEGF, FGF2, PTP1B, PIK3CD, Survivin, Ezrin and YAP content in gastric cancer tissue of patients with TNM II, III and IV stage gastric cancer were significantly higher than those of patients with TNM I stage; CEA, CA199, CA153, CA125 and CA724 content in serum as well as TGFβ1, TGFβ2, VEGF, FGF2, PTP1B, PIK3CD, Survivin, Ezrin and YAP content in gastric cancer tissue of patients with TNM III and IV stage gastric cancer were significantly higher than those of patients with TNM II stage; CEA, CA199, CA153, CA125 and CA724 content in serum as well as TGFβ1, TGFβ2, VEGF, FGF2, PTP1B, PIK3CD, Survivin, Ezrin and YAP content in gastric cancer tissue of patients with TNM IV stage gastric cancer were significantly higher than those of patients with TNM III stage. Conclusions: TNM staging of gastric cancer decided by preoperative enhanced multi-slice spiral CT scan has good consistency with the content of tumor markers in serum and proliferation molecules in tumor lesion.

  8. Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Giselly Encinas

    2015-10-01

    Full Text Available Summary Objective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC or serous ovarian cancer (SOC. Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of PubMed was performed. Young age for BC and SOC patients was set at ≤35 and ≤40 years, respectively. Age groups were also classified in <30years and every 10 years thereafter. Results: twenty six (1,980 patients, 111 younger and 16 studies (598, 41 younger, were analyzed for BC and SOC, respectively. In BC, PIK3CA wild type tumor was associated with early onset, not confirmed in binary regression with estrogen receptor (ER status. In HER2-negative tumors, there was increased frequency of PIK3CA somatic mutation in older age groups; in ER-positive tumors, there was a trend towards an increased frequency of PIK3CA somatic mutation in older age groups. TP53 somatic mutation was described in 20% of tumors from both younger and older patients; PTEN, CDH1 and GATA3 somatic mutation was investigated only in 16 patients and PTEN mutation was detected in one of them. In SOC, TP53 somatic mutation was rather common, detected in more than 50% of tumors, however, more frequently in older patients. Conclusion: frequency of somatic mutations in specific genes was not associated with early-onset breast cancer. Although very common in patients with serous ovarian cancer diagnosed at all ages, TP53 mutation was more frequently detected in older women.

  9. Dynamic changes to survivin subcellular localization are initiated by DNA damage

    Directory of Open Access Journals (Sweden)

    Maritess Gay Asumen

    2010-07-01

    Full Text Available Maritess Gay Asumen1, Tochukwu V Ifeacho2, Luke Cockerham3, Christina Pfandl4, Nathan R Wall31Touro University’s College of Osteopathic Medicine, Vallejo, CA, USA; 2University of Southern California, Los Angeles, CA, USA; 3Center for Health Disparities Research and Molecular Medicine, Loma Linda University, CA, USA; 4Green Mountain Antibodies, Burlington, VT, USAAbstract: Subcellular distribution of the apoptosis inhibitor survivin and its ability to relocalize as a result of cell cycle phase or therapeutic insult has led to the hypothesis that these subcellular pools may coincide with different survivin functions. The PIK kinases (ATM, ATR and DNA-PK phosphorylate a variety of effector substrates that propagate DNA damage signals, resulting in various biological outputs. Here we demonstrate that subcellular repartitioning of survivin in MCF-7 cells as a result of UV light-mediated DNA damage is dependent upon DNA damage-sensing proteins as treatment with the pan PIK kinase inhibitor wortmannin repartitioned survivin in the mitochondria and diminished it from the cytosol and nucleus. Mitochondrial redistribution of survivin, such as was recorded after wortmannin treatment, occurred in cells lacking any one of the three DNA damage sensing protein kinases: DNA-PK, ATM or ATR. However, failed survivin redistribution from the mitochondria in response to low-dose UV occurred only in the cells lacking ATM, implying that ATM may be the primary kinase involved in this process. Taken together, this data implicates survivian’s subcellular distribution is a dynamic physiological process that appears responsive to UV light- initiated DNA damage and that its distribution may be responsible for its multifunctionality.Keywords: survivin, PIK kinases, ATM, ATR, DNA-PK

  10. Colorectal cancer cell-derived exosomes containing miR-10b regulate fibroblast cells via the PI3K/Akt pathway.

    Science.gov (United States)

    Dai, Guangyao; Yao, Xiaoguang; Zhang, Yubin; Gu, Jianbin; Geng, Yunfeng; Xue, Fei; Zhang, Jingcheng

    2018-04-01

    Cancer-associated fibroblasts (CAFs) contribute to the proliferation of colorectal cancer(CRC) cells. However, the mechanism by which CAFs develop in the tumor microenvironment remains unknown. Exosomes may be involved in activating CAFs. Using a miRNA expression profiling array, we determined the miRNA expression profile of secretory exosomes in CRC cells and then identified potential miRNAs with significant differential expression compared to normal cells via enrichment analysis. Predicted targets of candidate miRNAs were then assessed via bioinformatics analysis. Realtime qPCR, western blot, and cell cycle analyses were performed to evaluate the role of candidate exosomal miRNAs. Luciferase reporter assays were applied to confirm whether candidate exosomal miRNAs control target pathway expression. A CRC xenograft mouse model was constructed to evaluate tumor growth in vivo. Exosomes from CRC cells contained significantly higher levels of miR-10b than did exosomes from normal colorectal epithelial cells. Moreover, exosomes containing miR-10b were transferred to fibroblasts. Bioinformatics analysis identified PIK3CA, as a potential target of miR-10b. Luciferase reporter assays confirmed that miR-10b directly inhibited PIK3CA expression. Co-culturing fibroblasts with exosomes containing miR-10b significantly suppressed PIK3CA expression and decreased PI3K/Akt/mTOR pathway activity. Finally, exosomes containing miR-10b reduced fibroblast proliferation but promoted expression of TGF-β and SM α-actin, suggesting that exosomal miR-10b may activate fibroblasts to become CAFs that express myofibroblast markers. These activated fibroblasts were able to promote CRC growth in vitro and in vivo. CRC-derived exosomes actively promote disease progression by modulating surrounding stromal cells, which subsequently acquire features of CAFs. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

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

    Science.gov (United States)

    Yadav, Manoj Kumar; S, Aravindan; Ngangkham, Umakanta; Shubudhi, H N; Bag, Manas Kumar; Adak, Totan; Munda, Sushmita; Samantaray, Sanghamitra; Jena, Mayabini

    2017-01-01

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

  12. 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

  13. TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Zhang, L-H; Yin, A-A; Cheng, J-X; Huang, H-Y; Li, X-M; Zhang, Y-Q; Han, N; Zhang, X

    2015-01-29

    The tripartite motif protein TRIM24 (tripartite motif-containing 24) has been found to play distinct roles in tumor development and progression, according to different tumor contexts. However, it remains elusive whether TRIM24 plays a role in malignant gliomas that are the most common and deadly primary brain tumors in adults. We report here that TRIM24 expression is positively correlated with glioma malignancy and is negatively associated with prognosis of patients with newly diagnosed glioblastoma, which is the most malignant form of gliomas but displays highly heterogeneous clinical outcome. The multivariate Cox regression analysis demonstrates the independent predictive value of TRIM24 expression level for overall and progression-free survival. Knockdown of TRIM24 suppresses cell proliferation, cell cycle progression, clone formation and in vivo tumor development, whereas overexpression of TRIM24 promotes cell growth. Chromatin immunoprecipitation, real-time reverse transcription-PCR and mutation analyses demonstrate that TRIM24 binds to the PIK3CA promoter via its PHD-Bromo domain to activate the transcription of PIK3CA gene, thus enhancing phosphatidylinositide 3-kinase (PI3K)/Akt signaling. The pan-PI3K inhibitor LY294002 and small interfering RNA targeting PIK3CA both abrogate the growth-promoting effect of TRIM24. Moreover, TRIM24 regulates the expression of DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) through PI3K/Akt/nuclear factor-κB signaling transduction and enhances resistance to temozolomide, the standard chemotherapeutic agent for glioblastoma. Finally, glioblastoma patients with low TRIM24 expression benefit from chemotherapy, whereas those with high TRIM24 expression do not have such benefit. Our results suggest that TRIM24 might serve as a potential prognostic marker and therapeutic target for the management of malignant gliomas.

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

    International Nuclear Information System (INIS)

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

    2008-01-01

    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 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. 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. Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations.

    Science.gov (United States)

    Gollins, Simon; West, Nick; Sebag-Montefiore, David; Myint, Arthur Sun; Saunders, Mark; Susnerwala, Shabbir; Quirke, Phil; Essapen, Sharadah; Samuel, Leslie; Sizer, Bruce; Worlding, Jane; Southward, Katie; Hemmings, Gemma; Tinkler-Hundal, Emma; Taylor, Morag; Bottomley, Daniel; Chambers, Philip; Lawrie, Emma; Lopes, Andre; Beare, Sandy

    2017-10-24

    The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055). This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.

  16. The Genetic Landscape of Breast Carcinomas with Neuroendocrine Differentiation

    Science.gov (United States)

    Marchiò, Caterina; Geyer, Felipe C; Ng, Charlotte KY; Piscuoglio, Salvatore; De Filippo, Maria R; Cupo, Marco; Schultheis, Anne M; Lim, Raymond S; Burke, Kathleen A; Guerini-Rocco, Elena; Papotti, Mauro; Norton, Larry; Sapino, Anna; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    Neuroendocrine breast carcinomas (NBCs) account for 2–5% of all invasive breast cancers and are histologically similar to neuroendocrine tumours from other sites. They typically express oestrogen receptor (ER), are HER2-negative and of luminal 'intrinsic' subtype. Here we sought to define the mutational profile of NBCs, and to investigate whether NBCs and common forms of luminal (ER+/HER2-) breast cancer display distinct repertoires of somatic mutations. Eighteen ER+/HER2- NBCs, defined as harbouring >50% of tumour cells expressing chromogranin A and/or synaptophysin, and matched normal tissue were microdissected and subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in breast cancer and/or related to DNA repair. Their mutational repertoire was compared to that of ER+/HER2- (n=240), PAM50-defined luminal breast cancers (n=209 luminal A; n=111 luminal B) and invasive lobular carcinomas (n=127) from The Cancer Genome Atlas. NBCs were found to harbour a median of 4.5 (range 1-11) somatic mutations, similar to that of luminal B breast cancers (median=3, range 0-17) but significantly higher than that of luminal A breast cancers (median=3, range 0-18, p=0.02). The most frequently mutated genes were GATA3, FOXA1, TBX3, ARID1A (3/18, 17%), and PIK3CA, AKT1, CDH1 (2/18, 11%). NBCs less frequently harboured PIK3CA mutations than common forms of ER+/HER2, luminal A and invasive lobular carcinomas (pcancers. No TP53 somatic mutations were detected in NBCs. Compared to common forms of luminal breast cancers, NBCs display a distinctive repertoire of somatic mutations featuring lower frequency of TP53 and PIK3CA mutations, and enrichment for FOXA1, TBX3 mutations, and akin to neuroendocrine tumours from other sites, ARID1A mutations. PMID:27925203

  17. 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.

  18. 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.

  19. Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

    Directory of Open Access Journals (Sweden)

    Shang Guo

    Full Text Available While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%. No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma.

  20. Four MicroRNAs Promote Prostate Cell Proliferation with Regulation of PTEN and Its Downstream Signals In Vitro

    Science.gov (United States)

    Xue, Jing-lun; Chen, Jin-zhong

    2013-01-01

    Background Phosphatase and tensin homologue (PTEN), as a tumor suppressor, plays vital roles in tumorigenesis and progression of prostate cancer. However, the mechanisms of PTEN regulation still need further investigation. We here report that a combination of four microRNAs (miR-19b, miR-23b, miR-26a and miR-92a) promotes prostate cell proliferation by regulating PTEN and its downstream signals in vitro. Methodology/Principal Findings We found that the four microRNAs (miRNAs) could effectively suppress PTEN expression by directly interacting with its 3’ UTR in prostate epithelial and cancer cells. Under-expression of the four miRNAs by antisense neutralization up-regulates PTEN expression, while overexpression of the four miRNAs accelerates epithelial and prostate cancer cell proliferation. Furthermore, the expression of the four miRNAs could, singly or jointly, alter the expression of the key components in the phosphoinositide 3-kinase (PI3K)/Akt pathway, including PIK3CA, PIK3CD, PIK3R1 and Akt, along with their downstream signal, cyclin D1. Conclusions These results suggested that the four miRNAs could promote prostate cancer cell proliferation by co-regulating the expression of PTEN, PI3K/Akt pathway and cyclin D1 in vitro. These findings increase understanding of the molecular mechanisms of prostate carcinogenesis and progression, even provide valuable insights into the diagnosis, prognosis, and rational design of novel therapeutics for prostate cancer. PMID:24098737

  1. Hot spot mutations in Finnish non-small cell lung cancers.

    Science.gov (United States)

    Mäki-Nevala, Satu; Sarhadi, Virinder Kaur; Rönty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuuttila, Aija; Knuutila, Sakari

    2016-09-01

    Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Frequency of Somatic TP53 Mutations in Combination with Known Pathogenic Mutations in Colon Adenocarcinoma, Non–Small Cell Lung Carcinoma, and Gliomas as Identified by Next-Generation Sequencing

    Directory of Open Access Journals (Sweden)

    Zahra Shajani-Yi

    2018-03-01

    Full Text Available The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer. It encodes p53, a DNA-binding transcription factor that regulates multiple genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis, and senescence. TP53 is associated with human cancer by mutations that lead to a loss of wild-type p53 function as well as mutations that confer alternate oncogenic functions that enable them to promote invasion, metastasis, proliferation, and cell survival. Identifying the discrete TP53 mutations in tumor cells may help direct therapies that are more effective. In this study, we identified the frequency of individual TP53 mutations in patients with colon adenocarcinoma (48%, non–small cell lung carcinoma (NSCLC (36%, and glioma/glioblastoma (28% at our institution using next-generation sequencing. We also identified the occurrence of somatic mutations in numerous actionable genes including BRAF, EGFR, KRAS, IDH1, and PIK3CA that occurred concurrently with these TP53 mutations. Of the 480 tumors examined that contained one or more mutations in the TP53 gene, 219 were colon adenocarcinomas, 215 were NSCLCs, and 46 were gliomas/glioblastomas. Among the patients positive for TP53 mutations diagnosed with colon adenocarcinoma, 50% also showed at least one mutation in pathogenic genes of which 14% were BRAF, 33% were KRAS, and 3% were NRAS. Forty-seven percent of NSCLC patients harboring TP53 mutations also had a mutation in at least one actionable pathogenic variant with the following frequencies: BRAF: 4%, EGFR: 10%, KRAS: 28%, and PIK3CA: 4%. Fifty-two percent of patients diagnosed with glioma/glioblastoma with a positive TP53 mutation had at least one concurrent mutation in a known pathogenic gene of which 9% were CDKN2A, 41% were IDH1, and 11% were PIK3CA.

  3. 2005. aasta arhitektuurivõistlused

    Index Scriptorium Estoniae

    2005-01-01

    Tulemused: Viljandi Metsakalmistu kabel: I - Andres Lember (Male Arhitektid); Tartu Vabaduse sild: I - Stanislav Shulman, Oleg Samohhin (Peterburi, Transmost); Tartu Mõisavahe kvartali hoonestuskava: I .- Ott Kadarik, Villem Tomiste, Mihkel Tüür (Kosmos); Seewaldi ala planeerimine: I - Jüri Martson, Rasmus Reinolt, Ivo-Martin Veelma (Lokomotiiv); Rotermanni kvartali arhitektuurivõistlus: I - Kosmos; aasta betoonehitis 2004: Ülemiste hotell Tallinnas, Martin Aunin; Lasnamäe Jumalaema kirik: I - Oleg Zhemtshugov (AB Z-Projekt), Nikolai Djatko, Jevgeni Kolomenkin; Pärnu vanalinna ja rannapiirkonna tänavakaubanduse inventari ja jäätmejaamade kujundus: I - Peeter Varrak; Kihnu sadamaala planeerimise ja hoonestamise ideevõistlus: I - Siiri Vallner, Kaire Nõmm, Helina Lass, Anna-Liisa Unt (Kavakava); Narva kolledzhi uus hoone: I - Katrin Koov, S. Vallner (Kavakava) ja Indrek Peil (Head Arhitektid); Randvere algkooli hoone: II - Inga Raukas (Arhitektuuriagentuur); Tartu Toomemäe valgustuse ja arhitektuursete väikevormide ideevõistlus: II - K. Koov ja Heidi Urb (Kabvakava) ning Maarja Kask, Ralf Lõoke, Karli Luik (Salto); Metsakalmistu arhitektide kalmeala: I - M. Kask, R. Lõoke; Skoone bastioni ideevõistlus: I - M. Kask, R. Lõoke, K. Luik (Salto); Mahtra talurahvamuuseum: I -Tomomi Hayashi, Hanno Grossschmidt; parim eramu 2004-2005: metallmaja Tabasalus, Muru & Pere; Tallinna loomaaia läänevärav: I - I. Raukas, Monika Löve, Oliver Soomets; parim puitehitis 2005: Naba lasteaed Pirital, arhitektid Vahur Sova, Lauri Saar, sisearhitekt Mari Tosmin; Pae karjääri revitaliseerimine: III - Veronika Valk, Kerli Raamsalu

  4. 212ʻ Fahrenheiti : eesti luule 2006 / Piret Bristol

    Index Scriptorium Estoniae

    Bristol, Piret, 1968-

    2008-01-01

    Järgmistest 2006. a. ilmunud luulekogudest: Ryytle, Indrek. Inglid rokijaamas. Puhja : I. Rüütle ; Runnel, Hando. Viru veri ei värise. Tartu : Ilmamaa ; Vabat, Martin. Mina olengi kirjandusklassik. Tartu : Eesti Kirjanduse Selts ; Korts, Eliina. Lööklaused murravad metsi. Tartu : Eesti Kirjanduse Selts ; Koff, Indrek. Vana laul. Luige : Verb ; Teede, Andra. Takso Tallinna taevas. Luige : Verb ; Vusser, Kaspar. Vusserduste võnked. Tallinn : P. Kukk ; Elbing, Andrus. Siin Beebilõust, tere! : häired pimelinna tänavalt = Ciao, it's Babyface : trouble from the streets of a blind city. Tallinn : Epifanio ; Hint, Miina. Vabaduse vang, ehk, Põrandaalune kirjandus. Tallinn : MR ; Jüriado, Tiiu. Luule on ime. Habaja : Kentaur ; Ligi, Katre. Naabrivalve. Tartu : Ilmamaa ; Krull, Hasso. Talv. Tallinn : Tuum ; Mets, Mae. Pühapäeval on reede. Tartu : Ilmamaa ; Ploom, Ülar. Porr ja sorry. Tallinn : Tuum ; Hirv, Indrek, Surmapõletaja. Tallinn : Tuum ; Piir, Milvi Martina. Kõrkjavaas. Tartu : Fantaasia ; Soomets, Triin. Väljas. Tallinn : Tuum ; Mathura. Kohalolu. Rapla : Allikäärne ; Afanasjev, Vahur. Katedraal Emajões. Tartu ; Brüssel : ID Salong//Sild, Ivar. Spermaga ja puha. Pärnu : Jumalikud Ilmutused ; Meiel, Kaupo. Polügrafisti käsiraamat. Pärnu : Jumalikud Ilmutused ; Kivisildnik, Sven. Vägistatud jäämägi. Pärnu : Jumalikud Ilmutused ; Arder, Ott. Luule sünnib kus sünnib kui sünnib / koost. Leelo Tungal. Tallinn : Tänapäev ; Kompus, Marko. Vallaliste jõgede tõkkejooksja. Tartu : M. Kompus

  5. 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.

    1999-12-31

    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)

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

    DEFF Research Database (Denmark)

    Vestergaard, Anna Lindeløv

    2010-01-01

    endometriosis lesion. Human papillomavirus (HPV) is the causative agent of cervix cancer, and DNA viruses might play a role in endometriosis. DNA purified from tissue samples were subjected to highly sensitive PCR tests detecting HPV types, the herpes family viruses HSV-1 and -2, CMV, and EBV......, 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...

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

    Science.gov (United States)

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

  8. IGORR 2: Proceedings of the 2. meeting of the International Group On Research Reactors

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1992-07-01

    The International group on Research Reactors was formed to facilitate the sharing of knowledge and experience among those institutions and individuals who are actively working to design, build, and promote new research reactors or to make significant upgrades to existing facilities. Sessions during this second meeting were devoted to research reactor reports (GRENOBLE reactor, FRM-II, HIFAR, PIK, reactors at JAERI, MAPLE, ANS, NIST, MURR, TRIGA, BR-2, SIRIUS 2); other neutron sources; and two workshops were dealing with research and development results and needs and reports on progress in needed of R and D areas identified at IGORR 1.

  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. IGORR 2: Proceedings of the 2. meeting of the International Group On Research Reactors

    International Nuclear Information System (INIS)

    1992-01-01

    The International group on Research Reactors was formed to facilitate the sharing of knowledge and experience among those institutions and individuals who are actively working to design, build, and promote new research reactors or to make significant upgrades to existing facilities. Sessions during this second meeting were devoted to research reactor reports (GRENOBLE reactor, FRM-II, HIFAR, PIK, reactors at JAERI, MAPLE, ANS, NIST, MURR, TRIGA, BR-2, SIRIUS 2); other neutron sources; and two workshops were dealing with research and development results and needs and reports on progress in needed of R and D areas identified at IGORR 1

  11. 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)

  12. Carpal Tunnel Syndrome in Aberrant Muscle Syndrome: A Case Report and Review of the Literature.

    Science.gov (United States)

    Steele, Jessica; Coombs, Christopher

    2018-06-01

    Aberrant Muscle Syndrome (AMS) is a rare congenital hand difference that is characterised by unilateral non-progressive muscular hyperplasia. The aetiology of aberrant muscle syndrome is not known, but a recently published case has shown a somatic PIK3CA activating mutation in a patient with AMS. Carpal tunnel syndrome (CTS) in children is rare. The most common causes are the mucopolysaccaridoses but space-occupying lesions have also been reported to cause CTS in children. We report the first case of CTS in a child with AMS successfully treated with open carpal tunnel release and excision of aberrant muscles.

  13. Mutational analysis of cutaneous squamous cell carcinomas and verrucal keratosis in patients taking BRAF inhibitors.

    Science.gov (United States)

    Anforth, Rachael; Tembe, Varsha; Blumetti, Tatiana; Fernandez-Peñas, Pablo

    2012-09-01

    B-RAF inhibitors (BRAFi) have been shown to improve rates of overall and progression-free survival in patients with stage IV metastatic melanoma positive for the BRAF V600E mutation. However, the main drawback is the development of verrucal keratosis (hyperkeratotic papules with verruca-like characteristics with benign histological findings) and cutaneous squamous cell carcinomas (cuSCC). We have found upstream mutations in RAS as well as PIK3CA in both verrucal keratosis and cuSCC. This suggests that verrucal keratosis is an early clinical presentation of cuSCC in patients on BRAFi. © 2012 John Wiley & Sons A/S.

  14. Molecular alterations and clinical prognostic factors for cholangiocarcinoma in Thai population

    Directory of Open Access Journals (Sweden)

    Trachu N

    2017-10-01

    Full Text Available N Trachu,1,2 E Sirachainan,3 N Larbcharoensub,4 W Rattanadech,3 S Detarkom,3 N Monnamo,1 K Kamprerasart,4 D MunTham,5 C Sukasem,6,7 T Reungwetwattana3 1Research Center, Faculty of Medicine Ramathibodi Hospital, 2Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, 3Division of Medical Oncology, Department of Medicine, 4Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 5Section for Mathematic, Faculty of Science and Technology, Rajamangala University of Technology Suvarnabhumi, 6Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, 7Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Abstract: This study explores genomic alterations in cholangiocarcinoma (CCC tissues in Thai patients. We identified and reviewed the records of patients who had been diagnosed with CCC and for whom sufficient tumor samples for DNA and RNA extraction were available in our database. The specimens were explored for EGFR, KRAS, BRAF, and PIK3CA mutations and ROS1 translocation in 81 samples. Immunohistochemistry staining for HER2, ALK, and Ki-67 expression was tested in 74 samples. Prevalence of EGFR, KRAS, and PIK3CA mutations in this study was 21%, 12%, and 16%, respectively. No BRAF V600 mutation or ROS1 translocation was found. Patients with T790M mutation had a significantly longer overall survival (18.84 months than those with the other types of EGFR mutations (4.08  months; hazard ratio [HR]: 0.26, P=0.038 and also had a significantly lower median Ki-67 (22.5% vs 80%, P=0.025. Furthermore, patients with PIK3CA mutations had a significantly longer median progression-free survival (15.87 vs 7.01 months; HR: 0.46, P=0.043. Strongly positive HER2 expression was found in only 1 patient, whereas ALK expression was not found. The presence of EGFR

  15. Synkkä turismi : Kärsimyksen aakkoset

    OpenAIRE

    Tahvanainen, Tuukka-Pekka

    2014-01-01

    Tiivistelmä Opinnäytetyössä tutustuttiin synkän turismin luonteeseen, teoriaan ja kohteisiin. Synkkä turismi ei ole laajuudestaan huolimatta kovin tiedostettu ilmiö, joten sen esitteleminen luo hyvän pohjan jatkotutkimuksille. Työhön kuului seuraavat osa-alueet: synkän turismin teorian esitteleminen ja perustavien termien läpikäyminen, valikoitujen kolmen synkän turismin kohteiden luokitteleminen synkän turismin kentälle ja synkän turismin kohteissa vierailevien matkailijoiden kertomu...

  16. 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...

  17. 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

  18. Whole genomes redefine the mutational landscape of pancreatic cancer.

    Science.gov (United States)

    Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K; Kassahn, Karin S; Bailey, Peter; Johns, Amber L; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C J; Robertson, Alan J; Fadlullah, Muhammad Z H; Bruxner, Tim J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J; Fink, J Lynn; Holmes, Oliver; Kazakoff, Stephen H; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Lee, Hong C; Jones, Marc D; Nagrial, Adnan M; Humphris, Jeremy; Chantrill, Lorraine A; Chin, Venessa; Steinmann, Angela M; Mawson, Amanda; Humphrey, Emily S; Colvin, Emily K; Chou, Angela; Scarlett, Christopher J; Pinho, Andreia V; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S; Kench, James G; Pettitt, Jessica A; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B; Graham, Janet S; Niclou, Simone P; Bjerkvig, Rolf; Grützmann, Robert; Aust, Daniela; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Zamboni, Giuseppe; Tortora, Giampaolo; Tempero, Margaret A; Gill, Anthony J; Eshleman, James R; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A; Pearson, John V; Biankin, Andrew V; Grimmond, Sean M

    2015-02-26

    Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

  19. The PRIMAP-hist national historical emissions time series

    Science.gov (United States)

    Gütschow, Johannes; Jeffery, M. Louise; Gieseke, Robert; Gebel, Ronja; Stevens, David; Krapp, Mario; Rocha, Marcia

    2016-11-01

    To assess the history of greenhouse gas emissions and individual countries' contributions to emissions and climate change, detailed historical data are needed. We combine several published datasets to create a comprehensive set of emissions pathways for each country and Kyoto gas, covering the years 1850 to 2014 with yearly values, for all UNFCCC member states and most non-UNFCCC territories. The sectoral resolution is that of the main IPCC 1996 categories. Additional time series of CO2 are available for energy and industry subsectors. Country-resolved data are combined from different sources and supplemented using year-to-year growth rates from regionally resolved sources and numerical extrapolations to complete the dataset. Regional deforestation emissions are downscaled to country level using estimates of the deforested area obtained from potential vegetation and simulations of agricultural land. In this paper, we discuss the data sources and methods used and present the resulting dataset, including its limitations and uncertainties. The dataset is available from doi:10.5880/PIK.2016.003 and can be viewed on the website accompanying this paper (de/primap-live/primap-hist/" target="_blank">http://www.pik-potsdam.de/primap-live/primap-hist/).

  20. Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.

    Science.gov (United States)

    Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F; Heukamp, Lukas C; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard; Odenthal, Margarete; Stenner, Markus

    2015-07-20

    Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.

  1. INFLUENCE OF EUROPEAN CORN BORER (Ostrinia nubilalis Hübner ON CORN HYBRIDS IN NORTH-WEST AND EASTERN CROATIA

    Directory of Open Access Journals (Sweden)

    Zvjezdana Augustinović

    2005-12-01

    Full Text Available European corn borer (Ostrinia nubilalis Hubner is one of the major corn pest in the world and in Croatia. Former investigations of corn borer in Croatia covered mostly its Eastern region. In trials conducted in 1998 and 1999 the research was extended to the North Western part of Croatia too. Macro trials were carried out with corn hybrids of FAO groups 200-600 at three localities: Križevci, Agricultural institute Osijek and at «Belje» PIK Karanac. In 1998 the intensity of the corn borer attack at the locality of «Belje» PIK Karanac was about 37.92% and in Agricultural institute Osijek 80.83%. In 1999 it varied between 37.08% at the locality of Agricultural Institute Osijek and 71.20% at the locality in Križevci. The estimated number of holes per plant in all three localities in both years was higher than the number of caterpillars. Length of damage per plant was between 0.38 and 18.80 cm. The data showed significant differences in the intensity of damaging effects on different localities while no significant differences concerning various hybrids were found. The statistical data concerning yield in both years showed significant differences among hybrids, localities and their interactions.

  2. Whole genomes redefine the mutational landscape of pancreatic cancer

    Science.gov (United States)

    Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K.; Kassahn, Karin S.; Bailey, Peter; Johns, Amber L.; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C. J.; Robertson, Alan J.; Fadlullah, Muhammad Z. H.; Bruxner, Tim J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J.; Fink, J. Lynn; Holmes, Oliver; Kazakoff, Stephen H.; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Lee, Hong C.; Jones, Marc D.; Nagrial, Adnan M.; Humphris, Jeremy; Chantrill, Lorraine A.; Chin, Venessa; Steinmann, Angela M.; Mawson, Amanda; Humphrey, Emily S.; Colvin, Emily K.; Chou, Angela; Scarlett, Christopher J.; Pinho, Andreia V.; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S.; Kench, James G.; Pettitt, Jessica A.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B.; Graham, Janet S.; Niclou, Simone P.; Bjerkvig, Rolf; Grützmann, Robert; Aust, Daniela; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Zamboni, Giuseppe; Tortora, Giampaolo; Tempero, Margaret A.; Gill, Anthony J.; Eshleman, James R.; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A.; Pearson, John V.; Biankin, Andrew V.; Grimmond, Sean M.

    2015-01-01

    Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded. PMID:25719666

  3. [Aspirin and colorectal cancer].

    Science.gov (United States)

    Grancher, Adrien; Michel, Pierre; Di Fiore, Frédéric; Sefrioui, David

    2018-02-01

    Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  4. mTOR inhibition elicits a dramatic response in PI3K-dependent colon cancers.

    Directory of Open Access Journals (Sweden)

    Dustin A Deming

    Full Text Available The phosphatidylinositide-3-kinase (PI3K signaling pathway is critical for multiple cellular functions including metabolism, proliferation, angiogenesis, and apoptosis, and is the most commonly altered pathway in human cancers. Recently, we developed a novel mouse model of colon cancer in which tumors are initiated by a dominant active PI3K (FC PIK3ca. The cancers in these mice are moderately differentiated invasive mucinous adenocarcinomas of the proximal colon that develop by 50 days of age. Interestingly, these cancers form without a benign intermediary or aberrant WNT signaling, indicating a non-canonical mechanism of tumorigenesis. Since these tumors are dependent upon the PI3K pathway, we investigated the potential for tumor response by the targeting of this pathway with rapamycin, an mTOR inhibitor. A cohort of FC PIK3ca mice were treated with rapamycin at a dose of 6 mg/kg/day or placebo for 14 days. FDG dual hybrid PET/CT imaging demonstrated a dramatic tumor response in the rapamycin arm and this was confirmed on necropsy. The tumor tissue remaining after treatment with rapamycin demonstrated increased pERK1/2 or persistent phosphorylated ribosomal protein S6 (pS6, indicating potential resistance mechanisms. This unique model will further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification.

  5. Targeting the PI3K signaling pathway in KRAS mutant colon cancer

    International Nuclear Information System (INIS)

    Hong, Suntaek; Kim, SoYoung; Kim, Hye Youn; Kang, Myunghee; Jang, Ho Hee; Lee, Won-Suk

    2015-01-01

    Metastatic colorectal cancer (CRC) patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to monoclonal antibody that targets the epidermal growth factor receptor such as cetuximab. BKM120 targets phosphatidylinositide-3-kinase (PIK3CA), but it is unknown whether BKM120 can reverse cetuximab resistance in KRAS mutant CRC. Human CRC cell lines with KRAS mutations (DLD-1, HCT116, and LoVo) were used to test the effect of cetuximab, BKM120, and cetuximab plus BKM120 on cell proliferation in vitro and in vivo. BKM120 reduced cell proliferation in a concentration-dependent manner in the LoVo (PI3KCA wild type) as well as the HCT116 and DLD1 cells (that carry a PI3KCA mutation). BKM120 only inhibited ERK phosphorylation in LoVo cells (PIK3CA wild type), but not in DLD1 or HCT116 cells at a concentration of 1 μmol/L. Treatment with cetuximab and BKM120 significantly reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (P = 0.034). BKM120 may overcome cetuximab resistance in colon cancer cells with KRAS mutation

  6. Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Wallin

    Full Text Available The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3 production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.

  7. Combined targeting of BRAF and CRAF or BRAF and PI3K effector pathways is required for efficacy in NRAS mutant tumors.

    Directory of Open Access Journals (Sweden)

    Bijay S Jaiswal

    Full Text Available BACKGROUND: Oncogenic RAS is a highly validated cancer target. Attempts at targeting RAS directly have so far not succeeded in the clinic. Understanding downstream RAS-effectors that mediate oncogenesis in a RAS mutant setting will help tailor treatments that use RAS-effector inhibitors either alone or in combination to target RAS-driven tumors. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have investigated the sufficiency of targeting RAS-effectors, RAF, MEK and PI3-Kinase either alone or in combination in RAS mutant lines, using an inducible shRNA in vivo mouse model system. We find that in colon cancer cells harboring a KRAS(G13D mutant allele, knocking down KRAS alone or the RAFs in combination or the RAF effectors, MEK1 and MEK2, together is effective in delaying tumor growth in vivo. In melanoma cells harboring an NRAS(Q61L or NRAS(Q61K mutant allele, we find that targeting NRAS alone or both BRAF and CRAF in combination or both BRAF and PIK3CA together showed efficacy. CONCLUSION/SIGNIFICANCE: Our data indicates that targeting oncogenic NRAS-driven melanomas require decrease in both pERK and pAKT downstream of RAS-effectors for efficacy. This can be achieved by either targeting both BRAF and CRAF or BRAF and PIK3CA simultaneously in NRAS mutant tumor cells.

  8. Unique molecular signatures as a hallmark of patients with metastatic breast cancer: implications for current treatment paradigms.

    Science.gov (United States)

    Wheler, Jennifer J; Parker, Barbara A; Lee, Jack J; Atkins, Johnique T; Janku, Filip; Tsimberidou, Apostolia M; Zinner, Ralph; Subbiah, Vivek; Fu, Siqing; Schwab, Richard; Moulder, Stacy; Valero, Vicente; Schwaederle, Maria; Yelensky, Roman; Miller, Vincent A; Stephens, M Philip J; Meric-Bernstam, Funda; Kurzrock, Razelle

    2014-05-15

    Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.

  9. Off-diagonal long-range order, cycle probabilities, and condensate fraction in the ideal Bose gas.

    Science.gov (United States)

    Chevallier, Maguelonne; Krauth, Werner

    2007-11-01

    We discuss the relationship between the cycle probabilities in the path-integral representation of the ideal Bose gas, off-diagonal long-range order, and Bose-Einstein condensation. Starting from the Landsberg recursion relation for the canonic partition function, we use elementary considerations to show that in a box of size L3 the sum of the cycle probabilities of length k>L2 equals the off-diagonal long-range order parameter in the thermodynamic limit. For arbitrary systems of ideal bosons, the integer derivative of the cycle probabilities is related to the probability of condensing k bosons. We use this relation to derive the precise form of the pik in the thermodynamic limit. We also determine the function pik for arbitrary systems. Furthermore, we use the cycle probabilities to compute the probability distribution of the maximum-length cycles both at T=0, where the ideal Bose gas reduces to the study of random permutations, and at finite temperature. We close with comments on the cycle probabilities in interacting Bose gases.

  10. MOLEKÜLER CIMBIZLAMAYA DAYALI YENİ BİR BISFENOL-BIPHENANTHROLINE SENTEZİ

    Directory of Open Access Journals (Sweden)

    Said nadeem

    2015-11-01

    Full Text Available 1,10-fenantrolin’den elde edilen "dugdugi" 8 molekülü sentezlendi ve NMR, EIMS ve UV kullanılarak yapısı aydınlatıldı. Bisfenol 8’I elde etmek için 1,3dibrompropan kullanılarak alkillendi ve 4-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-ylphenol ile reaksiyona sokuldu. Molekül 8’in 30 molL-1 çözeltisi %10 DMF içeren etanolde hazırlandı, ve etanol ile hazırlanmış 30 m L-1 Co2+, Cr3+, Cu2+, Fe3+, Mn2+, Ni2+, Ag+, and Zn2+ çözeltisi ile 30 dakika karıştırıldı.Kemosensör 8, Fe3+ varlığında pembe renk vererek çalışırken, diğer metallerin varlığında ayırt edici bir renk gözlenmedi. "Dugdugi" nin moleküler UV spektrumunda 279 nm’de bulunan pik Fe3+ ile etkileştirilince 290 nm’ye kaydı. Ayrıca, 524 nm’de yeni bir pik oluştuğu görüldü

  11. MDM2 Amplification and PI3KCA Mutation in a Case of Sclerosing Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Ken Kikuchi

    2013-01-01

    Full Text Available A rare sclerosing variant of rhabdomyosarcoma characterized by prominent hyalinization and pseudovascular pattern has recently been described as a subtype biologically distinct from embryonal, alveolar, and pleomorphic forms. We present cytogenetic and molecular findings as well as experimental studies of an unusual case of sclerosing rhabdomyosarcoma. The primary lesion arose within the plantar subcutaneous tissue of the left foot of an otherwise healthy 23-year-old male who eventually developed pulmonary nodules despite systemic chemotherapy. Two genetic abnormalities identified in surgical and/or autopsy samples of the tumor were introduced into 10T1/2 murine fibroblasts to determine whether these genetic changes cooperatively facilitated transformation and growth. Cytogenetic analysis revealed a complex abnormal hyperdiploid clone, and MDM2 gene amplification was confirmed by fluorescence in situ hybridization. Cancer gene mutation screening using a combination of multiplexed PCR and mass spectroscopy revealed a PIK3CA exon 20 H1047R mutation in the primary tumor, lung metastasis, and liver metastasis. However, this mutation was not cooperative with MDM2 overexpression in experimental assays for transformation or growth. Nevertheless, MDM2 and PIK3CA are genes worthy of further investigation in patients with sclerosing rhabdomyosarcoma and might be considered in the enrollment of these patients into clinical trials of targeted therapeutics.

  12. Inhibitors of EGFR and PI3K/Akt/mtor pathways for the treatment of head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Navarro Palomares, E. M.

    2015-07-01

    Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and although new therapeutic approaches have been recently evaluated, improvement in overall patient survival is still poor. For this reason, new effective and selective clinical treatments are urgently needed. Genomic analysis allowing the identification of differences between normal and tumor cells provides new therapeutic options identifying novel targets or drugs that have shown efficacy in other tumor types. In this sense, EGFR amplification and/or overexpression are frequent events in HNSCC; in fact, the only targeted therapy approved to treat HNSCC is the anti-EFGR antibody Cetuximab. Based on cell line drug screening studies we identified Bosutinib (SKI-606), a Src/Abl inhibitor, as a candidate drug to treat HNSCC. Using a panel of HNSCC cell lines we found that the treatment with Bosutinib was able to reduce cell proliferation and to induce apoptosis at higher doses. We verified that the drug rapidly inhibited EGFR phosphorylation, and sensitivity to Bosutinib correlated with the activation of EGFR in tumor-derived cell lines. Moreover, Bosutinib showed a synergistic effect on cell viability with the PI3K? inhibitor BYL719 only in those cell lines with mutations in PIK3CA. These results suggest that Bosutinib could be a new effective drug in the treatment of HNSCC cancer, especially in tumors with high activity of EGFR, and its combination with BYL719 could especially benefit those patients bearing activating mutations of PIK3CA. (Author)

  13. Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation

    Science.gov (United States)

    Sferruzzi-Perri, Amanda N.; López-Tello, Jorge; Fowden, Abigail L.; Constancia, Miguel

    2016-01-01

    Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, Pik3ca (encoding PIK3CA also known as p110α, α/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and α/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of α/+ fetuses. Despite its defective development, the α/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was α/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110α deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation. PMID:27621448

  14. Activation of the PI3K/AKT pathway in Merkel cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Christian Hafner

    Full Text Available Merkel cell carcinoma (MCC is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV. Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4% MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.

  15. Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics.

    Science.gov (United States)

    Cohen, Philip R; Tomson, Brett N; Elkin, Sheryl K; Marchlik, Erica; Carter, Jennifer L; Kurzrock, Razelle

    2016-04-26

    Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients.

  16. Modeling of transports of water and matter in landscape. Proceedings; Modellierung des Wasser- und Stofftransportes in grossen Einzugsgebieten. Beitraege

    Energy Technology Data Exchange (ETDEWEB)

    Bronstert, A.; Krysanova, V.; Schroeder, A.; Becker, A.; Bork, H.R. [eds.

    1998-04-01

    During recent years, the quantitative description of the water fluxes and the coupled transport of physical and chemical matter in the landscape has become steadily more and more important. The reasons for this are an increasing public awareness about the possible impacts of changes of land use, land cover, and of changes in regional and global climatic conditions together with a need for sound, multi-objective management of large river basins. The investigation areas of concern a usually much larger in extent than a typically sized hydrological investigation catchment. The tools primarily used in the quantification of the hydrological fluxes at the large scale are the so-called large-scale hydrological models. These models are comparatively new and still at the stage of development and improvement. The mentioned need for advanced large-scale hydrological models provided the reason for inviting scientists from German-speaking countries with experience in large-scale hydrological and hydro-meteorological models to exchange and discuss their modelling concepts and to identify research needs. The workshop was held at the Potsdam Institute for Climate Impact Research (PIK) on 15 and 16 December 1997, and was jointly organised by PIK, the University of Potsdam and the Centre for Agriculture and Land Use Research (ZALF). The workshop was attended by over 40 scientists, of whom 19 gave a presentation. (orig.)

  17. Participatory Design of an Online Self-Management Tool for Users With Spinal Cord Injury: Qualitative Study.

    Science.gov (United States)

    Allin, Sonya; Shepherd, John; Tomasone, Jennifer; Munce, Sarah; Linassi, Gary; Hossain, Saima Noreen; Jaglal, Susan

    2018-03-21

    general, participants indicated that they felt more confident with information received from trusted, in-person sources (eg, peers or health care professionals) than information found online. The discovery stage saw participants propose and discuss concepts to filter credible information and highlight community expertise, namely (1) a community-curated resource database, (2) online information navigators, and (3) group chats with peers. Several tools and techniques were collectively prototyped in an effort to foster trust and community; these are illustrated in the Results section. A PD process engaging users as codesigners, codevelopers, and informants can be used to identify design concerns and prototype online solutions to promote self-management after SCI. Future work will assess the usability of the collectively designed tools among a broad population of Canadians with SCI and the tools' impact on self-efficacy and health. ©Sonya Allin, John Shepherd, Jennifer Tomasone, Sarah Munce, Gary Linassi, Saima Noreen Hossain, Susan Jaglal. Originally published in JMIR Rehabilitation and Assistive Technology (http://rehab.jmir.org), 21.03.2018.

  18. Characterisation and dissolution studies on the uranium pyrochlore mineral betafite (Ca,U)_2(Nb,Ti,Ta)_2O_7

    International Nuclear Information System (INIS)

    McMaster, S.; Ram, R.; Tardio, J.; Bhargava, S.

    2014-01-01

    The pyrochlore group mineral, betafite (nominally (Ca,U)_2(Nb,Ti,Ta)_2O_7); is a refractory uranium mineral found in many ore deposits, including the currently mined deposit at Rössing, Namibia and the currently unmined deposit at Saima Massif, China. The decreasing abundance of “easy to leach” uranium minerals (i.e. uraninite), has led to interest in the extraction of uranium from refractory uranium minerals such as betafite. In the current study, three naturally occurring betafite mineral samples (obtained from Ambatofotsky and Miarinarivo, Madagascar (BAM and BMM respectively) and Silver Crater Mine, Canada (BSC)) were characterised using ex-situ high temperature X-Ray Diffraction (XRD), multi acid digestion / ICP-MS analysis (composition) and X-Ray Photoelectron Spectroscopy (XPS). Dissolution of the three samples was also investigated under conditions similar to those used in commercial tank based uranium leaching processes. XRD analysis showed that all three samples were highly metamict. Samples BMM and BSC showed no assignable diffraction lines before heat treating, whereas the XRD pattern obtained for sample BAM contained diffraction lines that confirmed the presence of crystalline anatase (TiO_2). Heat treatment studies on the samples showed that the betafite in the samples was converted into a crystalline form at 700°C in all 3 samples. Gangue minerals, rutile, Nb-rutile, UTiNb_2O_1_0, and studitite were also found to be present in the heat treated samples. Multi acid digestion ICP-MS analysis showed the natural samples contained between 16 and 26% w/w uranium as well as all the major elements present typically in betafite. XPS analysis was conducted on the unheated betafite samples. XPS analysis showed that the uranium in the samples was predominately in U"5"+ oxidation state. Some U"6"+ was also identified though this was most likely restricted to the outer surface of the samples. Dissolution studies (batch mode) were conducted under the following

  19. Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

    Directory of Open Access Journals (Sweden)

    Kenichi Konda

    Full Text Available Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs.We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI] and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers alterations in 158 CRNs including 56 polypoid neoplasms (PNs, 25 granular type laterally spreading tumors (LST-Gs, 48 non-granular type LSTs (LST-NGs, 19 depressed neoplasms (DNs and 10 small flat-elevated neoplasms (S-FNs on the basis of macroscopic appearance.S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs (P<0.001. By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively (P<0.007. We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively (P<0.005. Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05. PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41.We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

  20. The relationship of serum HE4, CP2 and HCgp-39 levels with tumor malignancy in patients with endometrial carcinoma

    Directory of Open Access Journals (Sweden)

    Yun-Xia Rao

    2017-04-01

    Full Text Available Objective: To study the relationship of serum human epididymis protein (HE4, cancer protein-2 (CP2 and human cartilage glycoprotein-39 (HCgp-39 levels with tumor malignancy in patients with endometrial carcinoma. Methods: A total of 90 patients with endometrial carcinoma treated in our hospital between May 2012 and August 2015 were collected and divided into early-to-mid (Ⅰ-Ⅲ stage endometrial carcinoma group (n=59 and advanced (Ⅳ stage endometrial carcinoma group (n=31 according to the pathological staging, and 34 patients with endometrial thickening who received uterine curettage in our hospital during the same period were selected as control group. The levels of HE4, CP2, HCgp-39 and tumor markers in serum as well as the mRNA expression of proliferation genes and invasion genes in tumor tissue were determined. Results: HE4, CP2, HCgp-39, CA125, CA19-9 and CEA levels in serum as well as Bcl2, Chk1, PIK1, HER2 and GDF-15 mRNA expression in tumor tissues of early-to-mid endometrial carcinoma group and advanced endometrial carcinoma group were significantly higher than those of control group while the miRNA-199a-3p, Bax, caspase3, BRCA1, Kiss-1 and KAI1 mRNA expression were lower than those of control group; HE4, CP2, HCgp-39, CA125, CA19-9 and CEA levels in serum as well as Bcl2, Chk1, PIK1, HER2 and GDF-15 mRNA expression in tumor tissues of advanced endometrial carcinoma group were significantly higher than those of early-to-mid endometrial carcinoma group while the miRNA-199a-3p, Bax, caspase3, BRCA1, Kiss-1 and KAI1 mRNA expression were lower than those of early-to-mid endometrial carcinoma group; serum HE4, CP2 and HCgp-39 levels were positively correlated with CA125, CA19-9, CEA, Bcl2, Chk1, PIK1, HER2 and GDF- 15, and negatively correlated with miRNA-199a-3p, Bax, caspase3, BRCA1, Kiss-1 and KAI1. Conclusion: Serum HE4, CP2 and HCgp-39 levels can directly reflect the tumor malignancy in patients with endometrial carcinoma, and are

  1. Genomic alterations in neuroendocrine cancers of the ovary.

    Science.gov (United States)

    Yaghmour, George; Prouet, Philippe; Wiedower, Eric; Jamy, Omer Hassan; Feldman, Rebecca; Chandler, Jason C; Pandey, Manjari; Martin, Mike G

    2016-08-26

    As we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. Patients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007-2015 were identified. Tumors were assessed with up to 21 IHC stains, in situ hybridization of cMET, EGFR, HER2 and PIK3CA, and next-generation sequencing (NGS) as well as Sanger sequencing of selected genes. Forty-six patients with SCCO (10 SCCO, 18 SCCO-HT, 18 NET-O) were identified as well as 58 patients with SCLC for comparison. Patients with SCCO and SCCO-HT were younger (median 42 years [range 12-75] and 26 years [range 8-40], respectively) than patients with NET-O 62 [range 13-76] or SCLC 66 [range 36-86]. SCCO patients were more likely to be metastatic (70 %) than SCCO-HT (50 %) or NET-O (33 %) patients, but at a similar rate to SCLC patients (65 %). PD1 expression varied across tumor type with SCCO (100 %), SCCO-HT (60 %), NET-O (33 %) vs SCLC (42 %). PDL1 expression also varied with SCCO (50 %), SCCO-HT (20 %), NET-O (33 %) and SCLC (0 %). No amplifications were identified in cMET, EGFR, or HER2 and only 1 was found in PIK3CA (NET-O). Actionable mutations were rare with 1 patient with SCCO having a BRCA2 mutation and 1 patient with NET-O having a PIK3CA mutation. No other actionable mutations were identified. No recurrent actionable mutations or rearrangements were identified using this platform in SCCO. IHC patterns may help guide the use of chemotherapy in these rare tumors.

  2. TU-CD-BRB-07: Identification of Associations Between Radiologist-Annotated Imaging Features and Genomic Alterations in Breast Invasive Carcinoma, a TCGA Phenotype Research Group Study

    Energy Technology Data Exchange (ETDEWEB)

    Rao, A; Net, J [University of Miami, Miami, Florida (United States); Brandt, K [Mayo Clinic, Rochester, Minnesota (United States); Huang, E [National Cancer Institute, NIH, Bethesda, MD (United States); Freymann, J; Kirby, J [Leidos Biomedical Research Inc., Frederick, MD (United States); Burnside, E [University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin (United States); Morris, E; Sutton, E [Memorial Sloan Kettering Cancer Center, New York, NY (United States); Bonaccio, E [Roswell Park Cancer Institute, Buffalo, NY (United States); Giger, M; Jaffe, C [Univ Chicago, Chicago, IL (United States); Ganott, M; Zuley, M [University of Pittsburgh Medical Center - Magee Womens Hospital, Pittsburgh, Pennsylvania (United States); Le-Petross, H [MD Anderson Cancer Center, Houston, TX (United States); Dogan, B [UT MDACC, Houston, TX (United States); Whitman, G [UTMDACC, Houston, TX (United States)

    2015-06-15

    Purpose: To determine associations between radiologist-annotated MRI features and genomic measurements in breast invasive carcinoma (BRCA) from the Cancer Genome Atlas (TCGA). Methods: 98 TCGA patients with BRCA were assessed by a panel of radiologists (TCGA Breast Phenotype Research Group) based on a variety of mass and non-mass features according to the Breast Imaging Reporting and Data System (BI-RADS). Batch corrected gene expression data was obtained from the TCGA Data Portal. The Kruskal-Wallis test was used to assess correlations between categorical image features and tumor-derived genomic features (such as gene pathway activity, copy number and mutation characteristics). Image-derived features were also correlated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) status. Multiple hypothesis correction was done using Benjamini-Hochberg FDR. Associations at an FDR of 0.1 were selected for interpretation. Results: ER status was associated with rim enhancement and peritumoral edema. PR status was associated with internal enhancement. Several components of the PI3K/Akt pathway were associated with rim enhancement as well as heterogeneity. In addition, several components of cell cycle regulation and cell division were associated with imaging characteristics.TP53 and GATA3 mutations were associated with lesion size. MRI features associated with TP53 mutation status were rim enhancement and peritumoral edema. Rim enhancement was associated with activity of RB1, PIK3R1, MAP3K1, AKT1,PI3K, and PIK3CA. Margin status was associated with HIF1A/ARNT, Ras/ GTP/PI3K, KRAS, and GADD45A. Axillary lymphadenopathy was associated with RB1 and BCL2L1. Peritumoral edema was associated with Aurora A/GADD45A, BCL2L1, CCNE1, and FOXA1. Heterogeneous internal nonmass enhancement was associated with EGFR, PI3K, AKT1, HF/MET, and EGFR/Erbb4/neuregulin 1. Diffuse nonmass enhancement was associated with HGF/MET/MUC20/SHIP

  3. Integrated genomic and immunophenotypic classification of pancreatic cancer reveals three distinct subtypes with prognostic/predictive significance.

    Science.gov (United States)

    Wartenberg, Martin; Cibin, Silvia; Zlobec, Inti; Vassella, Erik; Eppenberger-Castori, Serenella M M; Terracciano, Luigi; Eichmann, Micha; Worni, Mathias; Gloor, Beat; Perren, Aurel; Karamitopoulou, Eva

    2018-04-16

    Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC-cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings. A well-characterized PDAC-cohort (n=110) underwent next-generation sequencing with a hotspot cancer panel, while Next-generation Tissue-Microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM) and DNA mismatch-repair proteins. Previous data on FOXP3 were integrated. Immune-cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8. 2017), survival and epithelial-mesenchymal-transition (EMT)-like tumor budding.  Results: Three PDAC-subtypes were identified: the "immune-escape" (54%), poor in T- and B-cells and enriched in FOXP3+Tregs, with high-grade budding, frequent CDKN2A- , SMAD4- and PIK3CA-mutations and poor outcome; the "immune-rich" (35%), rich in T- and B-cells and poorer in FOXP3+Tregs, with infrequent budding, lower CDKN2A- and PIK3CA-mutation rate and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11, ATM) and the best outcome; and the "immune-exhausted" (11%) with immunogenic microenvironment and two subpopulations: one with PD-L1-expression and high PIK3CA-mutation rate and a microsatellite-unstable subpopulation with high prevalence of JAK3-mutations. The combination of low budding, low stromal FOXP3-counts, presence of TLTs and absence of CDKN2A-mutations confers significant survival advantage in PDAC-patients. Immune host responses correlate with tumor characteristics leading to morphologically recognizable PDAC-subtypes with prognostic/predictive significance. Copyright ©2018

  4. Lasteaia ja lõbumaja vahel : eesti proosa 2008 / Vaapo Vaher

    Index Scriptorium Estoniae

    Vaher, Vaapo, 1945-

    2009-01-01

    Ülevaade 2008. aasta eesti proosast. Pikemalt käsitletakse järgmisi autoreid ja nende teoseid: Mihkel Raud "Musta pori näkku", Olev Remsu "Musketäride muundumised", Rein Põder "Juba olnud", Juhan Nurme "Ligimene", Jaan Tangsoo "Méduse'i parv", Esta Aksli "Tare poole tõttaja", Mari Saat "Lasnamäe lunastaja", Peeter Morgen "Sõnum", Mait Raun "Dr. Mööbi seiklused Inglismaal", Andrei Hvostov "Võõrad lood" ja "Projektijuht Posse", Chaneldior "Kontrolli alt väljas", Vahur Afanasjev "Kosmos", Egon Ilisson "Isased", Jaak Leer "Kaks kabanossi ja Maaja", Kärt Hellerma "Sinine missa", Elo Viiding "Püha Maama", Toomas Raudam "Miks ma ei taha olla kirjanik?", Mart Kivastik "Kurb raamat", Jüri Tuulik "Räim, pisike kena kala", Tarmo Teder "12 jõulujuttu", Dagmar Lamp (koostaja) "Tule, ma jutustan sulle loo", Eia Uus "Kahe näoga jumal", Barthol Lo Mejor "Popdada 2007-2008", Anti Saar "Nemad kaks", Ketlin Priilinn "Liiseli võti" ja "Vaim", Aita Kivi "Lähedal", Marje Ernits "Hoia mu kätt", Kati Murutar "Naisena sündinud : kakskümmend aastat hiljem", Tuule Lind "Pööratud tuul", Siiri Laidla "Lihtne lugu, ehk, Senta suvepuhkus", Kätlin Padesaar "Veel üks paradiis", Aimée Beekman "Proovielu", Lehte Hainslau "Kolmkõla, ehk, 3 kõla", Ira Lember "Ööviiulid", Tamur Kusnets "Hundipäikese aeg : metsiku jahi algus", Kaupo Pähkel "Ehatähe rüütel", Arvo Valton "Ülemiste vanake", Tiit Aleksejev "Palveränd", Ants Eret "Afgaanide vang", Mario Merirand "Afganistani päevik", Leo Kunnas "Gort Ashryn", Rein Raud "Vend", Peeter Sauter "Beibi bluu", Marion Andra "Pimend", Kristjan Sander "13 talvist hetke", Helga Nõu "Peaaegu geenius, ehk, Schrödingeri kassi otsimas", Tiit Sepa "Eefa hüüdnimega Siug", Kaarel ja Klaara Kivi "Varandus seinal", Merike Jürjo "Mälestusteta maja", Rein Vahisalu "Viies kabinet", Aarne Biin "Mees otsib naist", Erik Tohvri "Ümberasujad" ja "Sulasest sai peremees", Arnold Laugus "Elav maa", Jüri v. Grauberg "Selguse poole", J

  5. Lasteaia ja lõbumaja vahel : Eesti proosa 2008 / Vaapo Vaher

    Index Scriptorium Estoniae

    Vaher, Vaapo, 1945-

    2012-01-01

    Ülevaade 2008. aasta eesti proosast. Pikemalt käsitletakse järgmisi autoreid ja nende teoseid: Mihkel Raud "Musta pori näkku", Olev Remsu "Musketäride muundumised", Rein Põder "Juba olnud", Juhan Nurme "Ligimene", Jaan Tangsoo "Méduse'i parv", Esta Aksli "Tare poole tõttaja", Mari Saat "Lasnamäe lunastaja", Peeter Morgen "Sõnum", Mait Raun "Dr. Mööbi seiklused Inglismaal", Andrei Hvostov "Võõrad lood" ja "Projektijuht Posse", Chaneldior "Kontrolli alt väljas", Vahur Afanasjev "Kosmos", Egon Ilisson "Isased", Jaak Leer "Kaks kabanossi ja Maaja", Kärt Hellerma "Sinine missa", Elo Viiding "Püha Maama", Toomas Raudam "Miks ma ei taha olla kirjanik?", Mart Kivastik "Kurb raamat", Jüri Tuulik "Räim, pisike kena kala", Tarmo Teder "12 jõulujuttu", Dagmar Lamp (koostaja) "Tule, ma jutustan sulle loo", Eia Uus "Kahe näoga jumal", Barthol Lo Mejor "Popdada 2007-2008", Anti Saar "Nemad kaks", Ketlin Priilinn "Liiseli võti" ja "Vaim", Aita Kivi "Lähedal", Marje Ernits "Hoia mu kätt", Kati Murutar "Naisena sündinud : kakskümmend aastat hiljem", Tuule Lind "Pööratud tuul", Siiri Laidla "Lihtne lugu, ehk, Senta suvepuhkus", Kätlin Padesaar "Veel üks paradiis", Aimée Beekman "Proovielu", Lehte Hainslau "Kolmkõla, ehk, 3 kõla", Ira Lember "Ööviiulid", Tamur Kusnets "Hundipäikese aeg : metsiku jahi algus", Kaupo Pähkel "Ehatähe rüütel", Arvo Valton "Ülemiste vanake", Tiit Aleksejev "Palveränd", Ants Eret "Afgaanide vang", Mario Merirand "Afganistani päevik", Leo Kunnas "Gort Ashryn", Rein Raud "Vend", Peeter Sauter "Beibi bluu", Marion Andra "Pimend", Kristjan Sander "13 talvist hetke", Helga Nõu "Peaaegu geenius, ehk, Schrödingeri kassi otsimas", Tiit Sepa "Eefa hüüdnimega Siug", Kaarel ja Klaara Kivi "Varandus seinal", Merike Jürjo "Mälestusteta maja", Rein Vahisalu "Viies kabinet", Aarne Biin "Mees otsib naist", Erik Tohvri "Ümberasujad" ja "Sulasest sai peremees", Arnold Laugus "Elav maa", Jüri v. Grauberg "Selguse poole", J

  6. Mastimännid ja muu mets : mitmekülgsuse võlu Eesti proosast aastal 2007 / Sirje Olesk

    Index Scriptorium Estoniae

    Olesk, Sirje, 1954-

    2008-01-01

    Ülevaade 2007. aasta eesti proosast. Käsitletakse järgimisi autoreid ja nende teoseid: Ene Mihkelson "Katkuhaud", Andrus Kivirähk "Mees, kes teadis ussisõnu", Jaan Kaplinski "Seesama jõgi", Tõnu Õnnepalu "Flandria päevik", Toomas Vint "Mäluauguga naine", Indrek Hargla "French ja Koulu Tarbatus", Kalle Käsper "Buridanid IV", Jaan Tooming "Teekond mäe südamesse", Ustav Mikelsaar "Tunnimehed", Henn Mikelsaar "Teema variatsioonidega", Reet Kudu "Pidupäevad võõrsil", Mara Maret Aronovich "Tagasikäiguga edasi", Aimée Beekman "Proovielu", Valentine Nõlvak "Ellujääja : mälestused", Mehis Heinsaar "Rändaja õnn", Maimu Berg "Unustatud inimesed", Mats Traat "Sarviku armastus : valik kultuuriloolisi novelle", Mihkel Mutt "Siseemigrant : novellid Rui taevalike kommentaaridega", Paavo Kivine "Kaks kavaleri", Kärt Hellerma "Ma armastasin David Copperfieldi", Piret Bristol "Paralleelmeri", Imre Siil "Mereröövlite loss", Kalju Saaber "Issanda loomaaed. Viru sektor", Veiko Märka "Lendas üle marmortahvli", Vahur Afanasjev "Kaadrid otsustavad, ehk, Sööbik ja Pisik seiklevad jälle, ehk, Eesti rahva lühike, kuid õnnelik ajalugu, Ehk kirjalik komejant tühjusest", Aarne Ruuben "Lugusid Anveltist ja Kingissepast", Epp Annus "Sina, Matilda", Peeter Helme "Puudutus", Ivar Sild "Tantsiv linn", Tui Hirv "Tähe tänav. Per musica ad astra", Tiina Laanem "Väikesed vanamehed", Angela Hofberg (pseud.) "Päev nagu elu", Marion Andra "Vähemalt...", Olle Lauli "Niguliste õpilased", Aarne Biin "Linna valitsemine", Erik Tohvri "Mürgiliblikas", Riina Kangur "Elisa", Kerttu Rakke "Küpsiseparadiis", Epp Petrone ja Dagmar Reintam "Õun ära süüa?", Elme Väljaste "Päriselu Proletariaadi puiesteel", Ketlin Priilinn "Hõbeingel", Ira Lember "Kohvik pärnade all", Paul Pajos "Krimijutud edasijõudnuile", Andres Anvelt "Punane elavhõbe", Klaara ja Kaarel Kivi "Mõrvasügis", Tiit Sepa "Hommik ühele", Lembit Uustulnd "Ruutuemanda sündroom : rahvusvaheline

  7. Intercomparison of four regional climate models for the German State of Saxonia

    Science.gov (United States)

    Kreienkamp, F.; Spekat, A.; Enke, W.

    2009-09-01

    Results from four regional climate models which focus on Central Europe are presented: CCLM, the climate version of the German Weather Service's Local Model - REMO, the regional dynamic model from the Max Planck Institute for Meteorology in Hamburg - STAR, the statistical model developed at the PIK Potsdam Institute and WETTREG, the statistic-dynamic model developed by the company CEC Potsdam. For the area of the German State of Saxonia a host of properties and indicators were analyzed aiming to show the models' abilities to reconstruct the current climate and compare climate model scenarios. These include a group of thermal indicators, such as the number of ice, frost, summer and hot days, the number of tropical nights; then there are hydrometeorological indicators such as the exceedance of low and high precipitation thresholds; humidity, cloudiness and wind indicators complement the array. A selection of them showing similarities and differences of the models investigated will be presented.

  8. Intact initiation of autophagy and mitochondrial fission by acute exercise in skeletal muscle of patientswith type 2 diabetes

    DEFF Research Database (Denmark)

    Kruse Sørensen, Rikke; Pedersen, Andreas James Thestrup; Kristensen, Jonas Møller

    2017-01-01

    AIMS: Type 2 diabetes (T2D) is characterized by insulin resistance, mitochondrial dysregulation, and, in some studies, exercise resistance in skeletal muscle. Regulation of autophagy and mitochondrial dynamics during exercise and recovery is important for skeletal muscle homeostasis......, and these responses may be altered in T2D. MATERIALS AND METHODS: We examined the effect of acute exercise on markers of autophagy and mitochondrial fusion and fission in skeletal muscle biopsies from patients with T2D (n=13) and weight-matched controls (n=14) before, immediately after and 3h after an acute bout...... of exercise. RESULTS: While mRNA levels of most markers of autophagy ( PIK3C, MAP1LC3B, SQSTM1, BNIP3, BNIP3L ) and mitochondrial dynamics ( OPA1, FIS1 ) remained unchanged, some either increased during and after exercise (GABARAPL1 ), decreased in the recovery period ( BECN1, ATG7, DNM1L ), or both ( MFN2...

  9. Strategi Komunikasi Badan Kependudukan dan Keluarga Berencana Nasional (BKKBN

    Directory of Open Access Journals (Sweden)

    Herdiana Ayu Susanti

    2015-01-01

    Full Text Available This study aims to determine communication strategy of Population and Family Planning Agency (BKKBN Special Region of Yogyakarta in disseminating Generation Program Planning (GenRe. The study uses descriptive qualitative method. The result shows that communication strategy undertaken by BKKBN Yogyakarta Province in disseminating the program GenRe is through Student Ambassador Selection genre, GenRe Goes To School and GenRe Goes To Campus, Genre Comedy Competition, Poster Competition genre, and Competition NGE - rap genre. BKKBN also uses mass media as a medium of socialization such as Public Service Announcements on television and radio, internet media by creating a website, blog, facebook, and twitter, as well as the use of billboards appeal board. BKKBN also works with schools and colleges to form the Youth Information and Counseling Center / Student (PIK R/M to get closer to teenagers and college students.

  10. ECR-MAPK regulation in liver early development.

    Science.gov (United States)

    Zhao, Xiu-Ju; Zhuo, Hexian

    2014-01-01

    Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region)-socs2 (-SH2-containing signals/receptor tyrosine kinases)-ppp2r2a/pik3c3 (MAPK signaling)-hsd3b5/cav2 (metabolism/organization) plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

  11. Measurement of $CP$ violation parameters in $B^0 \\to D K^{*0}$ decays

    CERN Document Server

    Aaij, Roel; Adinolfi, Marco; Affolder, Anthony; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Anderson, Jonathan; Andreassen, Rolf; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Aquines Gutierrez, Osvaldo; Archilli, Flavio; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Bachmann, Sebastian; Back, John; Badalov, Alexey; Balagura, Vladislav; Baldini, Wander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Batozskaya, Varvara; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Belogurov, Sergey; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Benton, Jack; Berezhnoy, Alexander; Bernet, Roland; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bien, Alexander; Bifani, Simone; Bird, Thomas; Bizzeti, Andrea; Bjørnstad, Pål Marius; Blake, Thomas; Blanc, Frédéric; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Borghi, Silvia; Borgia, Alessandra; Borsato, Martino; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Brambach, Tobias; van den Brand, Johannes; Bressieux, Joël; Brett, David; Britsch, Markward; Britton, Thomas; Brodzicka, Jolanta; Brook, Nicholas; Brown, Henry; Bursche, Albert; Busetto, Giovanni; Buytaert, Jan; Cadeddu, Sandro; Calabrese, Roberto; Calvi, Marta; Calvo Gomez, Miriam; Campana, Pierluigi; Campora Perez, Daniel; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cauet, Christophe; Cenci, Riccardo; Charles, Matthew; Charpentier, Philippe; Chen, Shanzhen; Cheung, Shu-Faye; Chiapolini, Nicola; Chrzaszcz, Marcin; Ciba, Krzystof; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Collins, Paula; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombes, Matthew; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Counts, Ian; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Cruz Torres, Melissa Maria; Cunliffe, Samuel; Currie, Robert; D'Ambrosio, Carmelo; Dalseno, Jeremy; David, Pascal; David, Pieter; Davis, Adam; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Silva, Weeraddana; De Simone, Patrizia; Decamp, Daniel; Deckenhoff, Mirko; Del Buono, Luigi; Déléage, Nicolas; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Di Canto, Angelo; Dijkstra, Hans; Donleavy, Stephanie; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Dossett, David; Dovbnya, Anatoliy; Dreimanis, Karlis; Dujany, Giulio; Dupertuis, Frederic; Durante, Paolo; Dzhelyadin, Rustem; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; El Rifai, Ibrahim; Elsasser, Christian; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Färber, Christian; Farinelli, Chiara; Farley, Nathanael; Farry, Stephen; Fay, Robert; Ferguson, Dianne; Fernandez Albor, Victor; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fontana, Marianna; Fontanelli, Flavio; Forty, Roger; Francisco, Oscar; Frank, Markus; Frei, Christoph; Frosini, Maddalena; Fu, Jinlin; Furfaro, Emiliano; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; García Pardiñas, Julián; Garofoli, Justin; Garra Tico, Jordi; Garrido, Lluis; Gaspar, Clara; Gauld, Rhorry; Gavardi, Laura; Gavrilov, Gennadii; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianelle, Alessio; Giani', Sebastiana; Gibson, Valerie; Giubega, Lavinia-Helena; Gligorov, Vladimir; Göbel, Carla; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gordon, Hamish; Gotti, Claudio; Grabalosa Gándara, Marc; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graziani, Giacomo; Grecu, Alexandru; Greening, Edward; Gregson, Sam; Griffith, Peter; Grillo, Lucia; Grünberg, Oliver; Gui, Bin; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hall, Samuel; Hamilton, Brian; Hampson, Thomas; Han, Xiaoxue; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; He, Jibo; Head, Timothy; Heijne, Veerle; Hennessy, Karol; Henrard, Pierre; Henry, Louis; Hernando Morata, Jose Angel; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hoballah, Mostafa; Hombach, Christoph; Hulsbergen, Wouter; Hunt, Philip; Hussain, Nazim; Hutchcroft, David; Hynds, Daniel; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jaeger, Andreas; Jalocha, Pawel; Jans, Eddy; Jaton, Pierre; Jawahery, Abolhassan; Jing, Fanfan; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kaballo, Michael; Kandybei, Sergii; Kanso, Walaa; Karacson, Matthias; Karbach, Moritz; Karodia, Sarah; Kelsey, Matthew; Kenyon, Ian; Ketel, Tjeerd; Khanji, Basem; Khurewathanakul, Chitsanu; Klaver, Suzanne; Klimaszewski, Konrad; Kochebina, Olga; Kolpin, Michael; Komarov, Ilya; Koopman, Rose; Koppenburg, Patrick; Korolev, Mikhail; Kozlinskiy, Alexandr; Kravchuk, Leonid; Kreplin, Katharina; Kreps, Michal; Krocker, Georg; Krokovny, Pavel; Kruse, Florian; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kurek, Krzysztof; Kvaratskheliya, Tengiz; La Thi, Viet Nga; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lambert, Dean; Lambert, Robert W; Lanfranchi, Gaia; Langenbruch, Christoph; Langhans, Benedikt; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; van Leerdam, Jeroen; Lees, Jean-Pierre; Lefèvre, Regis; Leflat, Alexander; Lefrançois, Jacques; Leo, Sabato; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Yiming; Likhomanenko, Tatiana; Liles, Myfanwy; Lindner, Rolf; Linn, Christian; Lionetto, Federica; Liu, Bo; Liu, Guoming; Lohn, Stefan; Longstaff, Iain; Lopes, Jose; Lopez-March, Neus; Lowdon, Peter; Lu, Haiting; Lucchesi, Donatella; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Machefert, Frederic; Machikhiliyan, Irina V; Maciuc, Florin; Maev, Oleg; Malde, Sneha; Manca, Giulia; Mancinelli, Giampiero; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marino, Pietro; Märki, Raphael; Marks, Jörg; Martellotti, Giuseppe; Martens, Aurelien; Martín Sánchez, Alexandra; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massafferri, André; Matev, Rosen; Mathe, Zoltan; Matteuzzi, Clara; Mazurov, Alexander; McCann, Michael; McCarthy, James; McNab, Andrew; McNulty, Ronan; McSkelly, Ben; Meadows, Brian; Meier, Frank; Meissner, Marco; Merk, Marcel; Milanes, Diego Alejandro; Minard, Marie-Noelle; Moggi, Niccolò; Molina Rodriguez, Josue; Monteil, Stephane; Morandin, Mauro; Morawski, Piotr; Mordà, Alessandro; Morello, Michael Joseph; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Müller, Katharina; Mussini, Manuel; Muster, Bastien; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Anh Duc; Nguyen, Thi-Dung; Nguyen-Mau, Chung; Nicol, Michelle; Niess, Valentin; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Novoselov, Alexey; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Oggero, Serena; Ogilvy, Stephen; Okhrimenko, Oleksandr; Oldeman, Rudolf; Onderwater, Gerco; Orlandea, Marius; Otalora Goicochea, Juan Martin; Owen, Patrick; Oyanguren, Maria Arantza; Pal, Bilas Kanti; Palano, Antimo; Palombo, Fernando; Palutan, Matteo; Panman, Jacob; Papanestis, Antonios; Pappagallo, Marco; Parkes, Christopher; Parkinson, Christopher John; Passaleva, Giovanni; Patel, Girish; Patel, Mitesh; Patrignani, Claudia; Pazos Alvarez, Antonio; Pearce, Alex; Pellegrino, Antonio; Pepe Altarelli, Monica; Perazzini, Stefano; Perez Trigo, Eliseo; Perret, Pascal; Perrin-Terrin, Mathieu; Pescatore, Luca; Pesen, Erhan; Petridis, Konstantin; Petrolini, Alessandro; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pilař, Tomas; Pinci, Davide; Pistone, Alessandro; Playfer, Stephen; Plo Casasus, Maximo; Polci, Francesco; Poluektov, Anton; Polycarpo, Erica; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Potterat, Cédric; Price, Eugenia; Prisciandaro, Jessica; Pritchard, Adrian; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Wenbin; Rachwal, Bartolomiej; Rademacker, Jonas; Rakotomiaramanana, Barinjaka; Rama, Matteo; Rangel, Murilo; Raniuk, Iurii; Rauschmayr, Nathalie; Raven, Gerhard; Reichert, Stefanie; Reid, Matthew; dos Reis, Alberto; Ricciardi, Stefania; Richards, Sophie; Rihl, Mariana; Rinnert, Kurt; Rives Molina, Vincente; Roa Romero, Diego; Robbe, Patrick; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Perez, Pablo; Roiser, Stefan; Romanovsky, Vladimir; Romero Vidal, Antonio; Rotondo, Marcello; Rouvinet, Julien; Ruf, Thomas; Ruffini, Fabrizio; Ruiz, Hugo; Ruiz Valls, Pablo; Saborido Silva, Juan Jose; Sagidova, Naylya; Sail, Paul; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santovetti, Emanuele; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saunders, Daniel Martin; Savrie, Mauro; Savrina, Darya; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Seco, Marcos; Semennikov, Alexander; Sepp, Indrek; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Shires, Alexander; Silva Coutinho, Rafael; Simi, Gabriele; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Anthony; Smith, Edmund; Smith, Eluned; Smith, Jackson; Smith, Mark; Snoek, Hella; Sokoloff, Michael; Soler, Paul; Soomro, Fatima; Souza, Daniel; Souza De Paula, Bruno; Spaan, Bernhard; Sparkes, Ailsa; Spradlin, Patrick; Sridharan, Srikanth; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Steinkamp, Olaf; Stenyakin, Oleg; Stevenson, Scott; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Straticiuc, Mihai; Straumann, Ulrich; Stroili, Roberto; Subbiah, Vijay Kartik; Sun, Liang; Sutcliffe, William; Swientek, Krzysztof; Swientek, Stefan; Syropoulos, Vasileios; Szczekowski, Marek; Szczypka, Paul; Szilard, Daniela; Szumlak, Tomasz; T'Jampens, Stephane; Teklishyn, Maksym; Tellarini, Giulia; Teubert, Frederic; Thomas, Christopher; Thomas, Eric; van Tilburg, Jeroen; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Torr, Nicholas; Tournefier, Edwige; Tourneur, Stephane; Tran, Minh Tâm; Tresch, Marco; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tuning, Niels; Ubeda Garcia, Mario; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vagnoni, Vincenzo; Valenti, Giovanni; Vallier, Alexis; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vázquez Sierra, Carlos; Vecchi, Stefania; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Vesterinen, Mika; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Vilasis-Cardona, Xavier; Vollhardt, Achim; Volyanskyy, Dmytro; Voong, David; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; Voss, Helge; de Vries, Jacco; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wandernoth, Sebastian; Wang, Jianchun; Ward, David; Watson, Nigel; Websdale, David; Whitehead, Mark; Wicht, Jean; Wiedner, Dirk; Wilkinson, Guy; Williams, Matthew; Williams, Mike; Wilson, Fergus; Wimberley, Jack; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wright, Simon; Wu, Suzhi; Wyllie, Kenneth; Xie, Yuehong; Xing, Zhou; Xu, Zhirui; Yang, Zhenwei; Yuan, Xuhao; Yushchenko, Oleg; Zangoli, Maria; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Wen Chao; Zhang, Yanxi; Zhelezov, Alexey; Zhokhov, Anatoly; Zhong, Liang; Zvyagin, Alexander

    2014-01-01

    An analysis of $B^0 \\to D K^{*0}$ decays is presented, where $D$ represents an admixture of $D^0$ and $\\overline{D}^0$ mesons reconstructed in four separate final states: $K^-\\pi^+$, $\\pi^-K^+$, $K^+ K^-$ and $\\pi^+\\pi^-$. The data sample corresponds to 3.0 fb$^-1$ of proton-proton collision, collected by the LHCb experiment. Measurements of several observables are performed, including $CP$ asymmetries. The most precise determination is presented of $r_B(DK^{*0})$, the magnitude of the ratio of the amplitudes of the decay $B^0 \\to D K^+ \\pi^-$ with a $b \\to u$ or a $b \\to c$ transition, in a $K \\pi$ mass region of $\\pm 50$ MeV/$c^2$ around the $K^*(892)$ mass and for an absolute value of the cosine of the $K^{*0}$ helicity angle larger than 0.4.

  12. Colorectal Liver Metastases: Does the Future of Precision Medicine Lie in Genetic Testing?

    Science.gov (United States)

    Barbon, Carlotta; Margonis, Georgios Antonios; Andreatos, Nikolaos; Rezaee, Neda; Sasaki, Kazunari; Buettner, Stefan; Damaskos, Christos; Pawlik, Timothy M; He, Jin; Wolfgang, Christopher L; Weiss, Matthew J

    2018-04-11

    Colorectal liver metastases (CRLM) present an important clinical challenge in both surgical and medical oncology. Despite improvements in management, survival among patients undergoing resection of CRLM is still very variable and there is a paucity of clinical trial data and reliable biomarkers that could guide prognostic forecasts, treatment selection, and follow-up. Fortunately, recent advances in molecular biology and tumor sequencing have identified a number of critical genetic loci and proliferation markers that may hold the key to understanding the biologic behavior of CRLM; specifically, mutations of KRAS, BRAF, TP53, PIK3CA, APC, expression of Ki-67, and the presence of microsatellite instability appear to have a decisive impact on prognosis and response to treatment in patients with CRLM. While the applicability of genetic biomarkers in everyday clinical practice remains conditional on the development of inexpensive bedside sequencing, targeted therapies, and the conduct of appropriate clinical trials, the promise of personalized treatment may be closer to realization than ever before.

  13. Progression inference for somatic mutations in cancer

    Directory of Open Access Journals (Sweden)

    Leif E. Peterson

    2017-04-01

    Full Text Available Computational methods were employed to determine progression inference of genomic alterations in commonly occurring cancers. Using cross-sectional TCGA data, we computed evolutionary trajectories involving selectivity relationships among pairs of gene-specific genomic alterations such as somatic mutations, deletions, amplifications, downregulation, and upregulation among the top 20 driver genes associated with each cancer. Results indicate that the majority of hierarchies involved TP53, PIK3CA, ERBB2, APC, KRAS, EGFR, IDH1, VHL, etc. Research into the order and accumulation of genomic alterations among cancer driver genes will ever-increase as the costs of nextgen sequencing subside, and personalized/precision medicine incorporates whole-genome scans into the diagnosis and treatment of cancer. Keywords: Oncology, Cancer research, Genetics, Computational biology

  14. Investigation of the effects of elevated atmospheric CO{sub 2} on a whet crop of the Free-Air Carbondioxide Enrichment (FACE) Experiment, Maricopa, USA. Final report; Untersuchung der Auswirkungen erhoehter atmosphaerischer CO{sub 2}-Konzentrationen auf Weizenbestaende des Free-Air Carbondioxid Enrichment (FACE)-Experimentes Maricopa (USA). Abschlussbericht

    Energy Technology Data Exchange (ETDEWEB)

    Kartschall, T; Grossman, S; Michaelis, P; Wechsung, F [Potsdam-Institut fuer Klimafolgenforschung e.V., Potsdam (Germany). Abt. Globaler Wandel und Natuerliche Systeme; Graefe, J; Waloszczyk, K [Professor-Hellriegel-Institut e.V., Bernburg (Germany); Wechsung, G [US Water-Conservation Lab., Phoenix, AZ (United States); Blum, E; Blum, M

    1998-02-01

    A version of the demeter model was developed which describes both the quantitative and qualitative effects of elevated atmospheric CO{sub 2} on a wheat crop under conditions of limited water and/or nitrogen supply. In the model`s photosynthesis and energy balance modules, first versions of components were developed which it should be possible to apply in further ecosystem models (starting with the cereals models of the demeter family). Experimental data from the Maricopa FACE wheat experiments 1992-1996, in which scientists from PIK were involved, were used for the development and testing of the model. Model solutions obtained were applied for the first time of central European climatic and site conditions as part of a regional yield study for the Federal State of Brandenburg. (orig.)

  15. Concordance of mutation detection in circulating tumor DNA in early clinical trials using different blood collection protocols

    DEFF Research Database (Denmark)

    Ahlborn, Lise B.; Madsen, Mette; Jonson, Lars

    2017-01-01

    in a clinical setting. Here we investigate the concordance between standard blood collection for molecular analysis using immediate separation of plasma, compared to the use of collection tubes allowing for delayed processing. Methods: In this study, we measured the fractional abundance of tumor specific...... patients with advanced solid cancers enrolled in early clinical trials. Results: Concordance in the fractional abundance of mutations in ctDNA isolated from blood collected in either K3EDTA or BCT tubes from patients with different solid cancers was observed. Conclusions: This study indicates that BCT...... mutations (BRAF p.V600E and PIK3CA p.H1047R) in ctDNA isolated from blood samples collected in either cell-stabilizing Cell-Free DNA BCT tubes (delayed processing within 72 hours) or standard K3EDTA tubes (immediate processing within 15 minutes). Twenty-five blood sample pairs (EDTA/BCT) were collected from...

  16. Metastatic Extramammary Paget’s Disease of Scrotum Responds Completely to Single Agent Trastuzumab in a Hemodialysis Patient: Case Report, Molecular Profiling and Brief Review of the Literature

    Directory of Open Access Journals (Sweden)

    Peter Barth

    2015-01-01

    metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%–40% in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options.

  17. Mõned erilised hetked EPIKoja võrgustiku tegemistest aastal 2016

    Index Scriptorium Estoniae

    2016-01-01

    Fotosid Eesti Puuetega Inimeste Koja liikmesorganisatsioonide üritustest 2016. aastal: Eesti Reumaliidu 17. käimispäev Tartus, puuetega noortele tervisepäev Pannjärve terviserajal, Eesti Autismiühingu korraldatud rahvusvahelisest autismipäevast Tallinna Tondi Põhikoolis, Eesti Tsöliaakia Seltsi suvelaager Tartumaal 8.-10. juulil, Vahtra Tantsud Tähtedega 2016 finaal, Tartu PIK-i projektis “Ajaga kaasa” osalejad Stenbocki maja, Eesti Pimedate Liit andis valge kepi päeva tänuseminaril üle tunnustused “Aasta tegu 2016”, Eesti Psoriaasiliit tähistas 26. märtsil oma 25. aastapäeva konverentsiga Tallinnas

  18. ECR-MAPK Regulation in Liver Early Development

    Directory of Open Access Journals (Sweden)

    Xiu-Ju Zhao

    2014-01-01

    Full Text Available Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region-socs2 (-SH2-containing signals/receptor tyrosine kinases-ppp2r2a/pik3c3 (MAPK signaling-hsd3b5/cav2 (metabolism/organization plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

  19. Statistic method of research reactors maximum permissible power calculation

    International Nuclear Information System (INIS)

    Grosheva, N.A.; Kirsanov, G.A.; Konoplev, K.A.; Chmshkyan, D.V.

    1998-01-01

    The technique for calculating maximum permissible power of a research reactor at which the probability of the thermal-process accident does not exceed the specified value, is presented. The statistical method is used for the calculations. It is regarded that the determining function related to the reactor safety is the known function of the reactor power and many statistically independent values which list includes the reactor process parameters, geometrical characteristics of the reactor core and fuel elements, as well as random factors connected with the reactor specific features. Heat flux density or temperature is taken as a limiting factor. The program realization of the method discussed is briefly described. The results of calculating the PIK reactor margin coefficients for different probabilities of the thermal-process accident are considered as an example. It is shown that the probability of an accident with fuel element melting in hot zone is lower than 10 -8 1 per year for the reactor rated power [ru

  20. RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics.

    Science.gov (United States)

    Best, Myron G; Sol, Nik; Kooi, Irsan; Tannous, Jihane; Westerman, Bart A; Rustenburg, François; Schellen, Pepijn; Verschueren, Heleen; Post, Edward; Koster, Jan; Ylstra, Bauke; Ameziane, Najim; Dorsman, Josephine; Smit, Egbert F; Verheul, Henk M; Noske, David P; Reijneveld, Jaap C; Nilsson, R Jonas A; Tannous, Bakhos A; Wesseling, Pieter; Wurdinger, Thomas

    2015-11-09

    Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies". Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

    DEFF Research Database (Denmark)

    Lescai, F; Als, T D; Li, Q

    2017-01-01

    Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations...... PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new...... risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder....

  2. Impact of rs361072 in the phosphoinositide 3-kinase p110beta gene on whole-body glucose metabolism and subunit protein expression in skeletal muscle

    DEFF Research Database (Denmark)

    Ribel-Madsen, Rasmus; Poulsen, Pernille; Holmkvist, Johan

    2010-01-01

    OBJECTIVE: Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110beta subunit, has previously been found to be associated with homeostasis model assessment for insulin resistance (HOMA-IR) in obese subjects...... infusion. rs361072 did not associate with insulin-stimulated peripheral glucose disposal despite a decreased muscle p85alpha:p110beta protein ratio (P(add) = 0.03) in G allele carriers. No association with HOMA-IR or type 2 diabetes (odds ratio 1.07, P = 0.5) was identified, and obesity did not interact...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    R cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin‐binding protein myristoylated alanine‐rich C‐kinase substrate (MARCKS) were increased two‐ and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in Tam......Acquired resistance to the anti‐estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen‐resistant MCF7 breast cancer cells (Tam...... was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell–cell and cell matrix‐initiated signalling. Consistent with known roles for Ras/MAPK and PI3‐kinase signalling in tamoxifen resistance, tyrosine‐phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in Tam...

  4. Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

    LENUS (Irish Health Repository)

    Toomey, Sinead

    2017-07-27

    The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K\\/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.

  5. Dynamic modeling of а heating system using geothermal energy and storage tank

    Directory of Open Access Journals (Sweden)

    Milanović Predrag D.

    2012-01-01

    Full Text Available This paper analyzes a greenhouse heating system using geothermal energy and storage tank and the possibility of utilization of insufficient amount of heat from geothermal sources during the periods with low outside air temperatures. Crucial for these analyses is modelling of the necessary yearly energy requirements for greenhouse heating. The results of these analyses enable calculation of an appropriate storage tank capacity so that the energy efficiency of greenhouse heating system with geothermal energy could be significantly improved. [Acknowledgement. This work was supported by Ministry of Science and Technology Development of the Republic of Serbia through the National Energy Efficiency Program (Grant 18234 A. The authors are thankful to the stuff and management of the Company “Farmakom MB PIK 7. juli - Debrc” for their assistance during the realization of this project.

  6. Time-dependent CP violation in $B^0_{(s)} \\to h^+h^-$ decays

    CERN Multimedia

    Fazzini, Davide

    2018-01-01

    The direct and mixing-induced CP-violating asymmetries in $B^0 \\to \\pi^+ \\pi^-$ and $B_s \\to K^+ K^-$ decays have been measured using a sample of pp collisions collected by the LHCb experiment during the Run1 of the LHC and corresponding to an integrated luminosity of 3.0 fb$^{-1}$.The time-integrated CP asymmetries in $B^0 \\to K^+ \\pi^-$ and $B_s \\to \\pi^+ K^-$ decays have also been measured, using the same data sample.The measurements of the CP-violating asymmetries of the $B^0 \\to \\pi^+ \\pi^-$, $B_s \\to K^+\\pi^-$ and $B_s \\to \\pi^+K^-$ decays are the most precise from a single experiment. The measurements of the CP-violating asymmetries of the Bs->KK decays are compatible with the previous results from LHCb.

  7. Multiscale Cues Drive Collective Cell Migration

    Science.gov (United States)

    Nam, Ki-Hwan; Kim, Peter; Wood, David K.; Kwon, Sunghoon; Provenzano, Paolo P.; Kim, Deok-Ho

    2016-07-01

    To investigate complex biophysical relationships driving directed cell migration, we developed a biomimetic platform that allows perturbation of microscale geometric constraints with concomitant nanoscale contact guidance architectures. This permits us to elucidate the influence, and parse out the relative contribution, of multiscale features, and define how these physical inputs are jointly processed with oncogenic signaling. We demonstrate that collective cell migration is profoundly enhanced by the addition of contract guidance cues when not otherwise constrained. However, while nanoscale cues promoted migration in all cases, microscale directed migration cues are dominant as the geometric constraint narrows, a behavior that is well explained by stochastic diffusion anisotropy modeling. Further, oncogene activation (i.e. mutant PIK3CA) resulted in profoundly increased migration where extracellular multiscale directed migration cues and intrinsic signaling synergistically conspire to greatly outperform normal cells or any extracellular guidance cues in isolation.

  8. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

    Directory of Open Access Journals (Sweden)

    Grace R. Anderson

    2017-07-01

    Full Text Available Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

  9. Identification of Top-ranked Proteins within a Directional Protein Interaction Network using the PageRank Algorithm: Applications in Humans and Plants.

    Science.gov (United States)

    Li, Xiu-Qing; Xing, Tim; Du, Donglei

    2016-01-01

    Somatic mutation of signal transduction genes or key nodes of the cellular protein network can cause severe diseases in humans but can sometimes genetically improve plants, likely because growth is determinate in animals but indeterminate in plants. This article reviews protein networks; human protein ranking; the mitogen-activated protein kinase (MAPK) and insulin (phospho- inositide 3kinase [PI3K]/phosphatase and tensin homolog [PTEN]/protein kinase B [AKT]) signaling pathways; human diseases caused by somatic mutations to the PI3K/PTEN/ AKT pathway; use of the MAPK pathway in plant molecular breeding; and protein domain evolution. Casitas B-lineage lymphoma (CBL), PTEN, MAPK1 and PIK3CA are among PIK3CA the top-ranked proteins in directional rankings. Eight proteins (ACVR1, CDC42, RAC1, RAF1, RHOA, TGFBR1, TRAF2, and TRAF6) are ranked in the top 50 key players in both signal emission and signal reception and in interaction with many other proteins. Top-ranked proteins likely have major impacts on the network function. Such proteins are targets for drug discovery, because their mutations are implicated in various cancers and overgrowth syndromes. Appropriately managing food intake may help reduce the growth of tumors or malformation of tissues. The role of the protein kinase C/ fatty acid synthase pathway in fat deposition in PTEN/PI3K patients should be investigated. Both the MAPK and insulin signaling pathways exist in plants, and MAPK pathway engineering can improve plant tolerance to biotic and abiotic stresses such as salinity.

  10. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

    Directory of Open Access Journals (Sweden)

    Maria Elena Maccari

    2018-03-01

    Full Text Available Activated phosphoinositide 3-kinase (PI3K δ Syndrome (APDS, caused by autosomal dominant mutations in PIK3CD (APDS1 or PIK3R1 (APDS2, is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2. Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission, while bowel inflammation (3 complete, 3 partial, 9 no remission and cytopenia (3 complete, 2 partial, 9 no remission responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

  11. Biomarker-driven trial in metastatic pancreas cancer: feasibility in a multicenter study of saracatinib, an oral Src inhibitor, in previously treated pancreatic cancer

    International Nuclear Information System (INIS)

    Arcaroli, John; Quackenbush, Kevin; Dasari, Arvind; Powell, Rebecca; McManus, Martine; Tan, Aik-Choon; Foster, Nathan R; Picus, Joel; Wright, John; Nallapareddy, Sujatha; Erlichman, Charles; Hidalgo, Manuel; Messersmith, Wells A

    2012-01-01

    Src tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib has shown antitumor activity in preclinical models of pancreas cancer. We performed a CTEP-sponsored Phase II clinical trial of saracatinib in previously treated pancreas cancer patients, with a primary endpoint of 6-month survival. A Simon MinMax two-stage phase II design was used. Saracatinib (175 mg/day) was administered orally continuously in 28-day cycles. In the unselected portion of the study, 18 patients were evaluable. Only two (11%) patients survived for at least 6 months, and three 6-month survivors were required to move to second stage of study as originally designed. The study was amended as a biomarker-driven trial (leucine rich repeat containing protein 19 [LRRC19] > insulin-like growth factor-binding protein 2 [IGFBP2] “top scoring pairs” polymerase chain reaction [PCR] assay, and PIK3CA mutant) based on preclinical data in a human pancreas tumor explant model. In the biomarker study, archival tumor tissue or fresh tumor biopsies were tested. Biomarker-positive patients were eligible for the study. Only one patient was PIK3CA mutant in a 3′ untranslated region (UTR) portion of the gene. This patient was enrolled in the study and failed to meet the 6-month survival endpoint. As the frequency of biomarker-positive patients was very low (<3%), the study was closed. Although we were unable to conclude whether enriching for a subset of second/third line pancreatic cancer patients treated with a Src inhibitor based on a biomarker would improve 6-month survival, we demonstrate that testing pancreatic tumor samples for a biomarker-driven, multicenter study in metastatic pancreas cancer is feasible

  12. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600–Mutant Colorectal Cancer

    Science.gov (United States)

    Corcoran, Ryan B.; Atreya, Chloe E.; Falchook, Gerald S.; Kwak, Eunice L.; Ryan, David P.; Bendell, Johanna C.; Hamid, Omid; Messersmith, Wells A.; Daud, Adil; Kurzrock, Razelle; Pierobon, Mariaelena; Sun, Peng; Cunningham, Elizabeth; Little, Shonda; Orford, Keith; Motwani, Monica; Bai, Yuchen; Patel, Kiran; Venook, Alan P.; Kopetz, Scott

    2015-01-01

    Purpose To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600–mutant metastatic colorectal cancer (mCRC). Patients and Methods A total of 43 patients with BRAF V600–mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft–bearing mice and the biopsied lesions from each corresponding patient. Conclusion The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600–mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted. PMID:26392102

  13. The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

    International Nuclear Information System (INIS)

    Pignochino, Ymera; Dell’Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M

    2015-01-01

    Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify ‘druggable’ pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in ‘hot spot’ regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. ERM and mTOR pathways are activated in MPM and ‘druggable’ by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM. The online version of this article (doi:10.1186/s12885-015-1363-1) contains supplementary material, which is available to authorized users

  14. Experimentally induced, synergistic late effects of a single dose of radiation and aging: significance in LKS fraction as compared with mature blood cells.

    Science.gov (United States)

    Hirabayashi, Yoko; Tsuboi, Isao; Nakachi, Kei; Kusunoki, Yoichiro; Inoue, Tohru

    2015-03-01

    The number of murine mature blood cells recovered within 6 weeks after 2-Gy whole-body irradiation at 6 weeks of age, whereas in the case of the undifferentiated hematopoietic stem/progenitor cell (HSC/HPC) compartment [cells in the lineage-negative, c-kit-positive and stem-cell-antigen-1-positive (LKS) fraction], the numerical differences between mice with and without irradiation remained more than a year, but conclusively the cells showed numerical recovery. When mice were exposed to radiation at 6 months of age, acute damages of mature blood cells were rather milder probably because of their maturation with age; but again, cells in the LKS fraction were specifically damaged, and their numerical recovery was significantly delayed probably as a result of LKS-specific cellular damages. Interestingly, in contrast to the recovery of the number of cells in the LKS fraction, their quality was not recovered, which was quantitatively assessed on the basis of oxidative-stress-related fluorescence intensity. To investigate why the recovery in the number of cells in the LKS fraction was delayed, expression levels of genes related to cellular proliferation and apoptosis of cells in the bone marrow and LKS fraction were analyzed by real-time polymerase chain reaction (RT-PCR). In the case of 21-month-old mice after radiation exposure, Ccnd1, PiK3r1 and Fyn were overexpressed solely in cells in the LKS fraction. Because Ccnd1and PiK3r1 upregulated by aging were further upregulated by radiation, single-dose radiation seemed to induce the acceleration of aging, which is related to the essential biological responses during aging based on a lifetime-dependent relationship between a living creature and xenobiotic materials. Copyright © 2014 John Wiley & Sons, Ltd.

  15. Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle

    Science.gov (United States)

    Lin, Frank Y.; Bergstrom, Katie; Person, Richard; Bavle, Abhishek; Ballester, Leomar Y.; Scollon, Sarah; Raesz-Martinez, Robin; Jea, Andrew; Birchansky, Sherri; Wheeler, David A.; Berg, Stacey L.; Chintagumpala, Murali M.; Adesina, Adekunle M.; Eng, Christine; Roy, Angshumoy; Plon, Sharon E.; Parsons, D. Williams

    2016-01-01

    The integration of genome-scale studies such as whole-exome sequencing (WES) into the clinical care of children with cancer has the potential to provide insight into the genetic basis of an individual's cancer with implications for clinical management. This report describes the results of clinical tumor and germline WES for a patient with a rare tumor diagnosis, rosette-forming glioneuronal tumor of the fourth ventricle (RGNT). Three pathogenic gene alterations with implications for clinical care were identified: somatic activating hotspot mutations in FGFR1 (p.N546K) and PIK3CA (p.H1047R) and a germline pathogenic variant in PTPN11 (p.N308S) diagnostic for Noonan syndrome. The molecular landscape of RGNT is not well-described, but these data are consistent with prior observations regarding the importance of the interconnected MAPK and PI3K/AKT/mTOR signaling pathways in this rare tumor. The co-occurrence of FGFR1, PIK3CA, and PTPN11 alterations provides further evidence for consideration of RGNT as a distinct molecular entity from pediatric low-grade gliomas and suggests potential therapeutic strategies for this patient in the event of tumor recurrence as novel agents targeting these pathways enter pediatric clinical trials. Although RGNT has not been definitively linked with cancer predisposition syndromes, two prior cases have been reported in patients with RASopathies (Noonan syndrome and neurofibromatosis type 1 [NF1]), providing an additional link between these tumors and the mitogen-activated protein kinase (MAPK) signaling pathway. In summary, this case provides an example of the potential for genome-scale sequencing technologies to provide insight into the biology of rare tumors and yield both tumor and germline results of potential relevance to patient care. PMID:27626068

  16. Interleukin 21 Controls mRNA and MicroRNA Expression in CD40-Activated Chronic Lymphocytic Leukemia Cells.

    Directory of Open Access Journals (Sweden)

    Loris De Cecco

    Full Text Available Several factors support CLL cell survival in the microenvironment. Under different experimental conditions, IL21 can either induce apoptosis or promote CLL cell survival. To investigate mechanisms involved in the effects of IL21, we studied the ability of IL21 to modulate gene and miRNA expressions in CD40-activated CLL cells. IL21 was a major regulator of chemokine production in CLL cells and it modulated the expression of genes involved in cell movement, metabolism, survival and apoptosis. In particular, IL21 down-regulated the expression of the chemokine genes CCL4, CCL3, CCL3L1, CCL17, and CCL2, while it up-regulated the Th1-related CXCL9 and CXCL10. In addition, IL21 down-regulated the expression of genes encoding signaling molecules, such as CD40, DDR1 and PIK3CD. IL21 modulated a similar set of genes in CLL and normal B-cells (e.g. chemokine genes, whereas other genes, including MYC, TNF, E2F1, EGR2 and GAS-6, were regulated only in CLL cells. An integrated analysis of the miRNome and gene expression indicated that several miRNAs were under IL21 control and these could, in turn, influence the expression of potential target genes. We focused on hsa-miR-663b predicted to down-regulate several relevant genes. Transfection of hsa-miR-663b or its specific antagonist showed that this miRNA regulated CCL17, DDR1, PIK3CD and CD40 gene expression. Our data indicated that IL21 modulates the expression of genes mediating the crosstalk between CLL cells and their microenvironment and miRNAs may take part in this process.

  17. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  18. LPJmL4 - a dynamic global vegetation model with managed land - Part 2: Model evaluation

    Science.gov (United States)

    Schaphoff, Sibyll; Forkel, Matthias; Müller, Christoph; Knauer, Jürgen; von Bloh, Werner; Gerten, Dieter; Jägermeyr, Jonas; Lucht, Wolfgang; Rammig, Anja; Thonicke, Kirsten; Waha, Katharina

    2018-04-01

    The dynamic global vegetation model LPJmL4 is a process-based model that simulates climate and land use change impacts on the terrestrial biosphere, agricultural production, and the water and carbon cycle. Different versions of the model have been developed and applied to evaluate the role of natural and managed ecosystems in the Earth system and the potential impacts of global environmental change. A comprehensive model description of the new model version, LPJmL4, is provided in a companion paper (Schaphoff et al., 2018c). Here, we provide a full picture of the model performance, going beyond standard benchmark procedures and give hints on the strengths and shortcomings of the model to identify the need for further model improvement. Specifically, we evaluate LPJmL4 against various datasets from in situ measurement sites, satellite observations, and agricultural yield statistics. We apply a range of metrics to evaluate the quality of the model to simulate stocks and flows of carbon and water in natural and managed ecosystems at different temporal and spatial scales. We show that an advanced phenology scheme improves the simulation of seasonal fluctuations in the atmospheric CO2 concentration, while the permafrost scheme improves estimates of carbon stocks. The full LPJmL4 code including the new developments will be supplied open source through https://gitlab.pik-potsdam.de/lpjml/LPJmL" target="_blank">https://gitlab.pik-potsdam.de/lpjml/LPJmL. We hope that this will lead to new model developments and applications that improve the model performance and possibly build up a new understanding of the terrestrial biosphere.

  19. LPJmL4 - a dynamic global vegetation model with managed land - Part 1: Model description

    Science.gov (United States)

    Schaphoff, Sibyll; von Bloh, Werner; Rammig, Anja; Thonicke, Kirsten; Biemans, Hester; Forkel, Matthias; Gerten, Dieter; Heinke, Jens; Jägermeyr, Jonas; Knauer, Jürgen; Langerwisch, Fanny; Lucht, Wolfgang; Müller, Christoph; Rolinski, Susanne; Waha, Katharina

    2018-04-01

    This paper provides a comprehensive description of the newest version of the Dynamic Global Vegetation Model with managed Land, LPJmL4. This model simulates - internally consistently - the growth and productivity of both natural and agricultural vegetation as coherently linked through their water, carbon, and energy fluxes. These features render LPJmL4 suitable for assessing a broad range of feedbacks within and impacts upon the terrestrial biosphere as increasingly shaped by human activities such as climate change and land use change. Here we describe the core model structure, including recently developed modules now unified in LPJmL4. Thereby, we also review LPJmL model developments and evaluations in the field of permafrost, human and ecological water demand, and improved representation of crop types. We summarize and discuss LPJmL model applications dealing with the impacts of historical and future environmental change on the terrestrial biosphere at regional and global scale and provide a comprehensive overview of LPJmL publications since the first model description in 2007. To demonstrate the main features of the LPJmL4 model, we display reference simulation results for key processes such as the current global distribution of natural and managed ecosystems, their productivities, and associated water fluxes. A thorough evaluation of the model is provided in a companion paper. By making the model source code freely available at https://gitlab.pik-potsdam.de/lpjml/LPJmL" target="_blank">https://gitlab.pik-potsdam.de/lpjml/LPJmL, we hope to stimulate the application and further development of LPJmL4 across scientific communities in support of major activities such as the IPCC and SDG process.

  20. Oncogene mutational profile in nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Zhang ZC

    2014-03-01

    Full Text Available Zi-Chen Zhang,1,* Sha Fu,1,* Fang Wang,1 Hai-Yun Wang,1 Yi-Xin Zeng,2 Jian-Yong Shao11Department of Molecular Diagnostics, 2Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China *These authors contributed equally to this work Abstract: Nasopharyngeal carcinoma (NPC is a common tumor in Southern China, but the oncogene mutational status of NPC patients has not been clarified. Using time-of-flight mass spectrometry, 238 mutation hotspots in 19 oncogenes were examined in 123 NPC patients. The relationships between mutational status and clinical data were assessed with a χ2 or Fisher's exact test. Survival analysis was performed using the Kaplan–Meier method with the log-rank test. In 123 patients, 21 (17.1% NPC tumors were positive for mutations in eight oncogenes: six patients had PIK3CA mutations (4.9%, five NRAS mutations (4.1%, four KIT mutations (3.3%, two PDGFRA mutations (1.6%, two ABL mutations (1.6%, and one with simultaneous mutations in HRAS, EGFR, and BRAF (1%. Patients with mutations were more likely to relapse or develop metastasis than those with wild-type alleles (P=0.019. No differences or correlations were found in other clinical characteristics or in patient survival. No mutations were detected in oncogenes AKT1, AKT2, CDK, ERBB2, FGFR1, FGFR3, FLT3, JAK2, KRAS, MET, and RET. These results demonstrate an association between NPC and mutations in NRAS, KIT, PIK3CA, PDGFRA, and ABL, which are associated with patient relapse and metastasis. Keywords: NPC, oncogene, mutation

  1. Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer.

    Science.gov (United States)

    Kim, Dalyong; Kim, Sun Young; Lee, Ji Sung; Hong, Yong Sang; Kim, Jeong Eun; Kim, Kyu-Pyo; Kim, Jihun; Jang, Se Jin; Yoon, Young-Kwang; Kim, Tae Won

    2017-11-23

    In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death. In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer.

  2. Characterization of a naturally occurring breast cancer subset enriched in EMT and stem cell characteristics

    Energy Technology Data Exchange (ETDEWEB)

    Hennessy, Bryan T.; Gonzalez-Angulo, Ana-Maria; Stemke-Hale, Katherine; Gilcrease, Michael Z.; Krishnamurthy, Savitri; Lee, Ju-Seog; Fridlyand, Jane; Sahin, Aysegul; Agarwal, Roshan; Joy, Corwin; Liu, Wenbin; Stivers, David; Baggerly, Keith; Carey, Mark; Lluch, Ana; Monteagudo, Carlos; He, Xiaping; Weigman, Victor; Fan, Cheng; Palazzo, Juan; Hortobagyi, Gabriel N.; Nolden, Laura K.; Wang, Nicholas J.; Valero, Vicente; Gray, Joe W.; Perou, Charles M.; Mills, Gordon B.

    2009-05-19

    Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a 'tumorigenic' signature defined using CD44{sup +}/CD24{sup -} breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

  3. The influence of the CHIEF pathway on colorectal cancer-specific mortality.

    Directory of Open Access Journals (Sweden)

    Martha L Slattery

    Full Text Available Many components of the CHIEF (Convergence of Hormones, Inflammation, and Energy Related Factors pathway could influence survival given their involvement in cell growth, apoptosis, angiogenesis, and tumor invasion stimulation. We used ARTP (Adaptive Rank Truncation Product to test if genes in the pathway were associated with colorectal cancer-specific mortality. Colon cancer (n = 1555 and rectal cancer (n = 754 cases were followed over five years. Age, center, stage at diagnosis, and tumor molecular phenotype were considered when calculating ARTP p values. A polygenic risk score was used to summarize the magnitude of risk associated with this pathway. The JAK/STAT/SOC was significant for colon cancer survival (PARTP = 0.035. Fifteen genes (DUSP2, INFGR1, IL6, IRF2, JAK2, MAP3K10, MMP1, NFkB1A, NOS2A, PIK3CA, SEPX1, SMAD3, TLR2, TYK2, and VDR were associated with colon cancer mortality (PARTP < 0.05; JAK2 (PARTP  = 0.0086, PIK3CA (PARTP = 0.0098, and SMAD3 (PARTP = 0.0059 had the strongest associations. Over 40 SNPs were significantly associated with survival within the 15 significant genes (PARTP < 0.05. SMAD3 had the strongest association with survival (HRGG 2.46 95% CI 1.44,4.21 PTtrnd = 0.0002. Seven genes (IL2RA, IL8RA, IL8RB, IRF2, RAF1, RUNX3, and SEPX1 were significantly associated with rectal cancer (PARTP < 0.05. The HR for colorectal cancer-specific mortality among colon cancer cases in the upper at-risk alleles group was 11.81 (95% CI 7.07, 19. 74 and was 10.99 (95% CI 5.30, 22.78 for rectal cancer. These results suggest that several genes in the CHIEF pathway are important for colorectal cancer survival; the risk associated with the pathway merits validation in other studies.

  4. AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake.

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    Ramachandran Rashmi

    Full Text Available PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability.Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233* were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206 with or without the glucose analogue 2-deoxyglucose (2-DG. Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG. Cell migration was assessed by scratch assay.Activating PIK3CA (E545K, E542K and inactivating PTEN (R233* mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56% and MK-2206 (30 µM-49% treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.

  5. Analysis of genes involved in the PI3K/Akt pathway in radiation- and MNU-induced rat mammary carcinomas.

    Science.gov (United States)

    Showler, Kaye; Nishimura, Mayumi; Daino, Kazuhiro; Imaoka, Tatsuhiko; Nishimura, Yukiko; Morioka, Takamitsu; Blyth, Benjamin J; Kokubo, Toshiaki; Takabatake, Masaru; Fukuda, Maki; Moriyama, Hitomi; Kakinuma, Shizuko; Fukushi, Masahiro; Shimada, Yoshiya

    2017-03-01

    The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells. The negative pathway regulator Inpp4b was significantly downregulated in both groups, compared with in normal mammary tissue, and radiation-induced carcinomas also showed a significant decrease in Pten expression, while the chemically induced carcinomas showed a decrease in Pik3r1 and Pdk1. Significant upregulation of the positive regulators Erbb2 and Pik3ca was observed only in chemically induced carcinomas. However, no genes showed clear correlations with AKT phosphorylation levels, except in individual carcinomas. Only rare carcinomas showed mutations in PI3K/AKT pathway genes, yet these carcinomas did not exhibit stronger AKT phosphorylation. Thus, while AKT phosphorylation is a common feature of rat mammary carcinomas induced by radiation or a canonical chemical carcinogen, the mutation of key genes in the pathways or permanent changes to gene expression of particular signaling proteins do not explain the pathway activation in the advanced cancers. Although AKT signaling likely facilitates cancer development and growth in rat mammary carcinomas, it is unlikely that permanent disruption of the PI3K/AKT pathway genes is a major causal event in radiation carcinogenesis. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  6. Limited utility of tissue micro-arrays in detecting intra-tumoral heterogeneity in stem cell characteristics and tumor progression markers in breast cancer.

    Science.gov (United States)

    Kündig, Pascale; Giesen, Charlotte; Jackson, Hartland; Bodenmiller, Bernd; Papassotirolopus, Bärbel; Freiberger, Sandra Nicole; Aquino, Catharine; Opitz, Lennart; Varga, Zsuzsanna

    2018-05-08

    Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p < 0.05) with histopathological grading both in central and peripheral areas. Our results suggest that intra-tumoral heterogeneity of stem-cell and tumor-progression markers cannot be reliably addressed in tissue-micro-array samples in breast cancer. However, most markers correlated strongly with histopathological grading confirming prognostic information as expression profiles were independent on the site of the

  7. MERTK interactions with SH2-domain proteins in the retinal pigment epithelium.

    Science.gov (United States)

    Shelby, Shameka J; Colwill, Karen; Dhe-Paganon, Sirano; Pawson, Tony; Thompson, Debra A

    2013-01-01

    The receptor tyrosine kinase MERTK plays an essential role in the phagocytic uptake of shed photoreceptor membranes by the retinal pigment epithelium (RPE). A fundamental aspect of signal transduction by receptor tyrosine kinases involves autophosphorylation of tyrosine residues that recruit Src-homology 2 (SH2)-domain proteins to the receptor intracellular domain. The goal of the current study was to evaluate the interactions of human MERTK with SH2-domain proteins present in the RPE. The MERTK intracellular domain was expressed as a 6xHis-fusion protein (6xHis-rMERTK(571-999)), purified and phosphorylated. Ni(2+)-NTA pull downs were performed using 6xHis-rMERTK(571-999) in incubations with recombinant phosphotyrosine-recognition sequences expressed as GST-fusion proteins. In addition, pull downs of native SH2-domain proteins were performed using 6xHis-rMERTK(571-999) and protein homogenates from rat RPE/choroid. For both recombinant and native proteins, western analysis detected MERTK interactions with GRB2, PIK3R1 (P85α), VAV3, and SRC. Immunohistochemical analysis localized each protein to mouse RPE. In cultured RPE-J cells incubated with rod outer segments (OS), siRNA knockdown of Grb2 had no effect on OS binding, but significantly reduced OS uptake. Pik3r1 localized to early phagosomes along with Rab5 and Eea1. Phosphorylation and activation of Src was detected downstream of phagocytosis and Mertk activation. These findings suggest that MERTK signaling in the RPE involves a cohort of SH2-domain proteins with the potential to regulate both cytoskeletal rearrangement and membrane movement. Identification of the SH2-domain signaling partners of MERTK is an important step toward further defining the mechanism of RPE phagocytosis that is central to the function and survival of the retina.

  8. MERTK interactions with SH2-domain proteins in the retinal pigment epithelium.

    Directory of Open Access Journals (Sweden)

    Shameka J Shelby

    Full Text Available The receptor tyrosine kinase MERTK plays an essential role in the phagocytic uptake of shed photoreceptor membranes by the retinal pigment epithelium (RPE. A fundamental aspect of signal transduction by receptor tyrosine kinases involves autophosphorylation of tyrosine residues that recruit Src-homology 2 (SH2-domain proteins to the receptor intracellular domain. The goal of the current study was to evaluate the interactions of human MERTK with SH2-domain proteins present in the RPE. The MERTK intracellular domain was expressed as a 6xHis-fusion protein (6xHis-rMERTK(571-999, purified and phosphorylated. Ni(2+-NTA pull downs were performed using 6xHis-rMERTK(571-999 in incubations with recombinant phosphotyrosine-recognition sequences expressed as GST-fusion proteins. In addition, pull downs of native SH2-domain proteins were performed using 6xHis-rMERTK(571-999 and protein homogenates from rat RPE/choroid. For both recombinant and native proteins, western analysis detected MERTK interactions with GRB2, PIK3R1 (P85α, VAV3, and SRC. Immunohistochemical analysis localized each protein to mouse RPE. In cultured RPE-J cells incubated with rod outer segments (OS, siRNA knockdown of Grb2 had no effect on OS binding, but significantly reduced OS uptake. Pik3r1 localized to early phagosomes along with Rab5 and Eea1. Phosphorylation and activation of Src was detected downstream of phagocytosis and Mertk activation. These findings suggest that MERTK signaling in the RPE involves a cohort of SH2-domain proteins with the potential to regulate both cytoskeletal rearrangement and membrane movement. Identification of the SH2-domain signaling partners of MERTK is an important step toward further defining the mechanism of RPE phagocytosis that is central to the function and survival of the retina.

  9. Consistency and reproducibility of next-generation sequencing and other multigene mutational assays: A worldwide ring trial study on quantitative cytological molecular reference specimens.

    Science.gov (United States)

    Malapelle, Umberto; Mayo-de-Las-Casas, Clara; Molina-Vila, Miguel A; Rosell, Rafael; Savic, Spasenija; Bihl, Michel; Bubendorf, Lukas; Salto-Tellez, Manuel; de Biase, Dario; Tallini, Giovanni; Hwang, David H; Sholl, Lynette M; Luthra, Rajyalakshmi; Weynand, Birgit; Vander Borght, Sara; Missiaglia, Edoardo; Bongiovanni, Massimo; Stieber, Daniel; Vielh, Philippe; Schmitt, Fernando; Rappa, Alessandra; Barberis, Massimo; Pepe, Francesco; Pisapia, Pasquale; Serra, Nicola; Vigliar, Elena; Bellevicine, Claudio; Fassan, Matteo; Rugge, Massimo; de Andrea, Carlos E; Lozano, Maria D; Basolo, Fulvio; Fontanini, Gabriella; Nikiforov, Yuri E; Kamel-Reid, Suzanne; da Cunha Santos, Gilda; Nikiforova, Marina N; Roy-Chowdhuri, Sinchita; Troncone, Giancarlo

    2017-08-01

    Molecular testing of cytological lung cancer specimens includes, beyond epidermal growth factor receptor (EGFR), emerging predictive/prognostic genomic biomarkers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA). Next-generation sequencing (NGS) and other multigene mutational assays are suitable for cytological specimens, including smears. However, the current literature reflects single-institution studies rather than multicenter experiences. Quantitative cytological molecular reference slides were produced with cell lines designed to harbor concurrent mutations in the EGFR, KRAS, NRAS, BRAF, and PIK3CA genes at various allelic ratios, including low allele frequencies (AFs; 1%). This interlaboratory ring trial study included 14 institutions across the world that performed multigene mutational assays, from tissue extraction to data analysis, on these reference slides, with each laboratory using its own mutation analysis platform and methodology. All laboratories using NGS (n = 11) successfully detected the study's set of mutations with minimal variations in the means and standard errors of variant fractions at dilution points of 10% (P = .171) and 5% (P = .063) despite the use of different sequencing platforms (Illumina, Ion Torrent/Proton, and Roche). However, when mutations at a low AF of 1% were analyzed, the concordance of the NGS results was low, and this reflected the use of different thresholds for variant calling among the institutions. In contrast, laboratories using matrix-assisted laser desorption/ionization-time of flight (n = 2) showed lower concordance in terms of mutation detection and mutant AF quantification. Quantitative molecular reference slides are a useful tool for monitoring the performance of different multigene mutational

  10. Stage III & IV colon and rectal cancers share a similar genetic profile: a review of the Oregon Colorectal Cancer Registry.

    Science.gov (United States)

    Gawlick, Ute; Lu, Kim C; Douthit, Miriam A; Diggs, Brian S; Schuff, Kathryn G; Herzig, Daniel O; Tsikitis, Vassiliki L

    2013-05-01

    Determining the molecular profile of colon and rectal cancers offers the possibility of personalized cancer treatment. The purpose of this study was to determine whether known genetic mutations associated with colorectal carcinogenesis differ between colon and rectal cancers and whether they are associated with survival. The Oregon Colorectal Cancer Registry is a prospectively maintained, institutional review board-approved tissue repository with associated demographic and clinical information. The registry was queried for any patient with molecular analysis paired with clinical data. Patient demographics, tumor characteristics, microsatellite instability status, and mutational analysis for p53, AKT, BRAF, KRAS, MET, NRAS, and PIK3CA were analyzed. Categorical variables were compared using chi-square tests. Continuous variables between groups were analyzed using Mann-Whitney U tests. Kaplan-Meier analysis was used for survival studies. Comparisons of survival were made using log-rank tests. The registry included 370 patients: 69% with colon cancer and 31% with rectal cancer. Eighty percent of colon cancers and 68% of rectal cancers were stages III and IV. Mutational analysis found no significant differences in detected mutations between colon and rectal cancers, except that there were significantly more BRAF mutations in colon cancers compared with rectal cancers (10% vs 0%, P colon versus rectal cancers when stratified by the presence of KRAS, PIK3CA, and BRAF mutations. Stage III and IV colon and rectal cancers share similar molecular profiles, except that there were significantly more BRAF mutations in colon cancers compared with rectal cancers. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Prognostic and predictive value of p-Akt, EGFR, and p-mTOR in early breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lazaridis, Georgios; Lambaki, Sofia [Hospital, Department of Pathology, Thessaloniki (Greece); Karayannopoulou, Georgia [Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece). Dept. of Pathology; Eleftheraki, Anastasia G. [Data Office, Athens (Greece). Section of Biostatistics; Papaspirou, Irene [Alexandra Hospital, Athens (Greece). Dept. of Pathology; Bobos, Mattheos [Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece). Lab. of Molecular Oncology; Efstratiou, Ioannis [Papageorgiou Hospital, Thessaloniki (Greece). Dept. of Pathology; Pentheroudakis, George [Ioannina Univ. Hospital, Ioannina (Greece). Dept. of Medical Oncology; Zamboglou, Nikolaos [Klinikum Offenbach (Germany). Dept. of Radiation Oncology; Fountzilas, George [Hospital, Department of Pathology, Thessaloniki (Greece); Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece). Lab. of Molecular Oncology

    2014-07-15

    There are scarce data available on the prognostic/predictive value of p-Akt and p-mTOR protein expression in patients with high-risk early breast cancer. Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 997 patients participating in two adjuvant phase III trials were assessed for EGFR, PTEN, p-Akt, p-mTOR protein expression, and PIK3CA mutational status. These markers were evaluated for associations with each other and with selected patient and tumor characteristics, immunohistochemical subtypes, disease-free survival (DFS), and overall survival (OS). p-mTOR protein expression was negatively associated with EGFR and positively associated with PTEN, with p-Akt473, and with the presence of PIK3CA mutations. EGFR expression was positively associated with p-Akt473, p-Akt308, and PIK3CA wild-type tumors. Finally, p-Akt308 was positively associated with p-Akt473 expression. In univariate analysis, EGFR (p = 0.016) and the coexpression of EGFR and p-mTOR (p = 0.015) were associated with poor OS. Among patients with p-Akt308-negative or low-expressing tumors, those treated with hormonal therapy were associated with decreased risk for both relapse and death (p = 0.013 and p < 0.001, respectively). In the subgroup of patients with locoregional relapse, positive EGFR and mTOR protein expression was found to be associated with increased (p = 0.034) and decreased (p < 0.001) risk for earlier relapse, respectively. In multivariate analysis, low levels of p-Akt308 and the coexpression of EGFR and p-mTOR retained their prognostic value. Low protein expression of p-Akt308 was associated with improved DFS and OS among patients treated with hormonal therapy following adjuvant chemotherapy. Coexpression of EGFR and p-mTOR was associated with worse OS. (orig.) [German] Geringe Daten existieren ueber den prognostischen/praediktiven Wert der p-Akt- und p-mTOR-Proteinexpression bei Patienten mit ''High-risk''-Mammakarzinom im Fruehstadium

  12. The memorable service and monastic humility – the history of Stanisław Konarski’s heart

    Directory of Open Access Journals (Sweden)

    Ryszard Mączyński

    2016-12-01

    Full Text Available The article concentrates on an interesting 130-year-old artefact located in the Krakow church of Piarists – the decoration of the place where Stanisław Konarski’s (1700–1773 heart was buried. Konarski was a monk of the Pious Schools in the 18th century, as well as publisher of a collection of national laws Volumina legum, a bold commentator calling for strengthening royal power and abolishing liberum veto, reformer of the educational system and founder of the renowned, modern Collegium Nobilium. The circumstances of the discovery and relocation of the relic in 1882 from Warsaw to Krakow and the ceremony of its introduction to the monastic Church of the Transfiguration of Jesus on February 13 are also outlined. Three significant research issues are also discussed. The first one is the problem of the authenticity of the artefact, which was discovered more than a hundred years after Konarski’s death in the possession of a Warsaw optician Jakub Pik. It was then that the question started occupying the minds of researchers, including the rector of the Krakow college Adam Słotwiński. The question is made more relevant by the lack of any direct evidence from 1773 about the removal of Stanisław Konarski’s heart from his body after his death. The information gathered so far allow us to assume, with probability bordering on certainty, that it is authentic and the only surviving part of this famous monk’s body. Another question, totally absent from past reflections on the subject, is the reason why the heart was removed. This particular aspect turns our attention at a strikingly popular early-modern Polish tradition – first in royal families, later also among magnates and nobility – of burying hearts separately, usually by entombing them in a church founded by the deceased. It was found that a considerable number of hearts removed from bodies had been inhumed in Piarist churches (Rzeszów, Warsaw or Łowicz. This tradition, however, did

  13. S-02: Venöz Yetmezlikli Hastalarda Kalf Kası Egzersizlerinin Venöz Fonksiyona ve Kas Kuvvetine Etkisi

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    Sabriye Ercan

    2017-03-01

    Full Text Available Kronik venöz yetmezlik, alt ekstremitenin ilerleyici hipertansiyonu sebebiyle kalf kaslarında zayıflık ile giden bir hastalıktır. Erken tanı ve etkili konservatif tedaviler ile hastalığın ilerleyişi önlenebilir. Venöz geri dönüşü arttırmak ve kalf kas pompasını restore etmek için hastalara egzersiz önerilmektedir.Bu çalışmanın amacı; kronik venöz yetmezlikli hastalarda, iki farklı kalf egzersizi programının ayak bileği eklem hareket açıklığına, kuvvete, ağrıya, yaşam kalitesine ve venöz geri dolum zamanına etkisini analiz etmekti.Çalışmaya, kronik venöz yetmezlik tanılı 71 hasta alındı ve hastalar rasgele iki gruba ayrıldı. Ayak bileği eklem hareket açıklığı ölçümünde gonyometre, kas kuvveti ölçümünde izokinetik dinamometre kullanıldı. Venöz geri dolum zamanı, fotopletismografi kullanılarak ölçüldü. Vizüel Analog Skala değeri ağrı seviyesini, EQ-5D genel yaşam kalite ölçeği yaşam kalitesinin seviyesini tanımlamak için uygulandı. 12 hafta boyunca (3 seans/hafta Grup 1’deki hastalar ev tabanı kalf egzersizlerini, Grup 2’deki hastalar ise aynı egzersizleri ve izokinetik kalf kası egzersizlerini yaptı. Çalışmanın sonunda 42 hastanın kontrol verileri alındı. Kontrol değerleri karşılaştırıldığında gruplar arasında ağrı seviyesi ve kas kuvveti parametrelerinden ayak bileği plantarfleksiyon-dorsifleksiyon pik tork oranı ve toplam iş parametreleri açısından istatistiksel anlamlı fark tespit edildi (p<0,05. Başlangıç değerleri ile karşılaştırıldığında ise Grup 2’nin tüm ölçümlerinde, Grup 1’in ayak bileği dorsifleksör pik tork, pik tork/vücut ağırlığı ve venöz geri dolum zamanında istatistiksel anlamlı fark tespit edildi (p<0,05.Kronik venöz yetmezliği olan hastalarda egzersizin venöz fonksiyonu düzenlemedeki etkisi çalışmamızla bir kez daha ortaya konmuş, izokinetik egzersizin etkisi ise literat

  14. Mutational status of synchronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Quéré, Gilles; Descourt, Renaud; Robinet, Gilles; Autret, Sandrine; Raguenes, Odile; Fercot, Brigitte; Alemany, Pierre; Uguen, Arnaud; Férec, Claude; Quintin-Roué, Isabelle; Le Gac, Gérald

    2016-01-01

    Despite reported discordance between the mutational status of primary lung cancers and their metastases, metastatic sites are rarely biopsied and targeted therapy is guided by genetic biomarkers detected in the primary tumor. This situation is mostly explained by the apparent stability of EGFR-activating mutations. Given the dramatic increase in the range of candidate drugs and high rates of drug resistance, rebiopsy or liquid biopsy may become widespread. The purpose of this study was to test genetic biomarkers used in clinical practice (EGFR, ALK) and candidate biomarkers identified by the French National Cancer Institute (KRAS, BRAF, PIK3CA, HER2) in patients with metastatic non-small-cell lung cancer for whom two tumor samples were available. A retrospective study identified 88 tumor samples collected synchronously or metachronously, from the same or two different sites, in 44 patients. Mutation analysis used SNaPshot (EGFR, KRAS, BRAF missense mutations), pyrosequencing (EGFR and PIK3CA missense mutations), sizing assays (EGFR and HER2 indels) and IHC and/or FISH (ALK rearrangements). About half the patients (52 %) harbored at least one mutation. Five patients had an activating mutation of EGFR in both the primary tumor and the metastasis. The T790M resistance mutation was detected in metastases in 3 patients with acquired resistance to EGFR tyrosine kinase inhibitors. FISH showed discordance in ALK status between a small biopsy sample and the surgical specimen. KRAS mutations were observed in 36 % of samples, six patients (14 %) having discordant genotypes; all discordances concerned sampling from different sites. Two patients (5 %) showed PI3KCA mutations. One metastasis harbored both PI3KCA and KRAS mutations, while the synchronously sampled primary tumor was mutation free. No mutations were detected in BRAF and HER2. This study highlighted noteworthy intra-individual discordance in KRAS mutational status, whereas EGFR status was stable. Intratumoral

  15. Screening for susceptibility genes in hereditary non-polyposis colorectal cancer.

    Science.gov (United States)

    Yu, Li; Yin, Bo; Qu, Kaiying; Li, Jingjing; Jin, Qiao; Liu, Ling; Liu, Chunlan; Zhu, Yuxing; Wang, Qi; Peng, Xiaowei; Zhou, Jianda; Cao, Peiguo; Cao, Ke

    2018-06-01

    In the present study, hereditary non-polyposis colorectal cancer (HNPCC) susceptibility genes were screened for using whole exome sequencing in 3 HNPCC patients from 1 family and using single nucleotide polymorphism (SNP) genotyping assays in 96 other colorectal cancer and control samples. Peripheral blood was obtained from 3 HNPCC patients from 1 family; the proband and the proband's brother and cousin. High-throughput sequencing was performed using whole exome capture technology. Sequences were aligned against the HAPMAP, dbSNP130 and 1,000 Genome Project databases. Reported common variations and synonymous mutations were filtered out. Non-synonymous single nucleotide variants in the 3 HNPCC patients were integrated and the candidate genes were identified. Finally, SNP genotyping was performed for the genes in 96 peripheral blood samples. In total, 60.4 Gb of data was retrieved from the 3 HNPCC patients using whole exome capture technology. Subsequently, according to certain screening criteria, 15 candidate genes were identified. Among the 96 samples that had been SNP genotyped, 92 were successfully genotyped for 15 gene loci, while genotyping for HTRA1 failed in 4 sporadic colorectal cancer patient samples. In 12 control subjects and 81 sporadic colorectal cancer patients, genotypes at 13 loci were wild-type, namely DDX20, ZFYVE26, PIK3R3, SLC26A8, ZEB2, TP53INP1, SLC11A1, LRBA, CEBPZ, ETAA1, SEMA3G, IFRD2 and FAT1 . The CEP290 genotype was mutant in 1 sporadic colorectal cancer patient and was wild-type in all other subjects. A total of 5 of the 12 control subjects and 30 of the 81 sporadic colorectal cancer patients had a mutant HTRA1 genotype. In all 3 HNPCC patients, the same mutant genotypes were identified at all 15 gene loci. Overall, 13 potential susceptibility genes for HNPCC were identified, namely DDX20, ZFYVE26, PIK3R3, SLC26A8, ZEB2, TP53INP1, SLC11A1, LRBA, CEBPZ, ETAA1, SEMA3G, IFRD2 and FAT1 .

  16. Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

    Science.gov (United States)

    Millis, Sherri Z.; Kimbrough, Jeffery; Doll, Nancy; Von Hoff, Daniel; Ramanathan, Ramesh K.

    2017-01-01

    Background Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei (PMP), goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. Methods Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. A total of 588 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age =55). Sixty-two percent of samples were adenocarcinomas (used for analysis); the rest consisted of 9% goblet cell, 15% mucinous; 6% pseudomyxoma, and less than 5% carcinoids and 2% neuroendocrine. Tests included sequencing [Sanger, next generation sequencing (NGS)], protein expression/immunohistochemistry (IHC), and gene amplification [fluorescent in situ hybridization (FISH) or CISH]. Results Profiling across all appendiceal cancer histological subtypes for IHC revealed: 97% BRCP, 81% MRP1, 81% COX-2, 71% MGMT, 56% TOPO1, 5% PTEN, 52% EGFR, 40% ERCC1, 38% SPARC, 35% PDGFR, 35% TOPO2A, 25% RRM1, 21% TS, 16% cKIT, and 12% for TLE3. NGS revealed mutations in the following genes: 50.4% KRAS, 21.9% P53, 17.6% GNAS, 16.5% SMAD4, 10% APC, 7.5% ATM, 5.5% PIK3CA, 5.0% FBXW7, and 1.8% BRAF. Conclusions Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins (BCRP and MRP1), which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment. The incidence of low TS (79%) could be used as a backbone of therapy (using inhibitors such as 5FU/capecitabine or newer agents). Therapeutic options includeTOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temozolomide). Clinical trials targeting pathways involving KRAS, p53, GNAS, SMAD4, APC, ATM, PIK3CA, FBXW7, and

  17. Pemikiran Pengarang Peranakan Tionghoa di Surabaya dan Malang Periode 1870-1942

    Directory of Open Access Journals (Sweden)

    Dwi Susanto

    2013-06-01

    Full Text Available Penelitian ini bertujuan menemukan pemikiran yang dominan dalam kesusastraan peranakan pada periode 1870-1942 di Surabaya dan Malang dan memberikan uraian mengenai sebab perubahan tersebut. Penelitian ini berjenis penelitian kualitatif dengan teknik analisis data sesuai dengan prosedur dalam ranah teori sejarah intelektual sebagaimana sastra adalah produk sosial. Pemikiran yang berkembang dalam periode tersebut terbagi dalam tiga bagian. Pemikiran pertama adalah pemikiran yang bersifat konservatif yang dicirikan dengan kembali pada ajaran Khonghucu (1870-1910. Pemikiran ini diwakili oleh Oei Soei Tiong, Ang Siong Tiauw, Tan Khing Tian, dan Tjap Goan Thay. Pemikiran kedua adalah pemikiran yang mempertanyakan gerakan ka um konservatif sehingga terjebak pada keraguan antara menuju moderat dan konservatif (1911-1920. Pemikiran ini diwakili oleh figur Liem Sim Djiwie. Pemikiran ketiga adalah pemikiran yang bersifat moderat dan adaptif, yakni menerima unsur lokalitas sebagai bagian dari identitas Tionghoa, tetapi menolak unsur Barat. Pemikiran ini diwakili Liem Khing Hoo dan Njoo Cheong Seng (1921-1935-­‐an. Sementara itu, Ong Pik Lok menempati struktur eskapisme modern. Ke lompok ini tidak mempersoalkan pilihan identitas, melakukan pelarian dari dunia realitas, dan menjadi korban materialisme dan individualisme (1935-1942. Abstract: The paper aims to find the dominant thoughts in Indonesian Chinese literature and to describe the impact and cause of this changes in the 1870-1942 period. The paper uses qualita tive method research based on the sociological literature, collaborated especially with the intellectual history studies. The thoughts in 1870-1942 can be divided into three. The first is conservatism. As a mainstream in early periods, it characterized the movement of Chinese traditional culture or custom of Confucianism (1870-1910. The actors in this period were Oei Soei Tiong, Ang Siong Tiauw, Tan Khing Tian, and Tjap Goan Thay. Second, in

  18. A functional proteogenomic analysis of endometrioid and clear cell carcinomas using reverse phase protein array and mutation analysis: protein expression is histotype-specific and loss of ARID1A/BAF250a is associated with AKT phosphorylation

    International Nuclear Information System (INIS)

    Wiegand, Kimberly C; Lu, Yiling; Zhang, Fan; Anglesio, Michael S; Gilks, Blake; Mills, Gordon B; Huntsman, David G; Carey, Mark S; Hennessy, Bryan T; Leung, Samuel; Wang, Yemin; Ju, Zhenlin; McGahren, Mollianne; Kalloger, Steve E; Finlayson, Sarah; Stemke-Hale, Katherine

    2014-01-01

    Ovarian cancer is now recognized as a number of distinct diseases primarily defined by histological subtype. Both clear cell ovarian carcinomas (CCC) and ovarian endometrioid carcinomas (EC) may arise from endometriosis and frequently harbor mutations in the ARID1A tumor suppressor gene. We studied the influence of histological subtype on protein expression with reverse phase protein array (RPPA) and assessed proteomic changes associated with ARID1A mutation/BAF250a expression in EC and CCC. Immunohistochemistry (IHC) for BAF250a expression was performed on 127 chemotherapy-naive ovarian carcinomas (33 CCC, 29 EC, and 65 high-grade serous ovarian carcinomas (HGSC)). Whole tumor lysates were prepared from frozen banked tumor samples and profiled by RPPA using 116 antibodies. ARID1A mutations were identified by exome sequencing, and PIK3CA mutations were characterized by MALDI-TOF mass spectrometry. SAM (Significance Analysis of Microarrays) was performed to determine differential protein expression by histological subtype and ARID1A mutation status. Multivariate logistic regression was used to assess the impact of ARID1A mutation status/BAF250a expression on AKT phosphorylation (pAKT). PIK3CA mutation type and PTEN expression were included in the model. BAF250a knockdown was performed in 3 clear cell lines using siRNA to ARID1A. Marked differences in protein expression were observed that are driven by histotype. Compared to HGSC, SAM identified over 50 proteins that are differentially expressed in CCC and EC. These included PI3K/AKT pathway proteins, those regulating the cell cycle, apoptosis, transcription, and other signaling pathways including steroid hormone signaling. Multivariate models showed that tumors with loss of BAF250a expression showed significantly higher levels of AKT-Thr 308 and AKT-Ser 473 phosphorylation (p < 0.05). In 31 CCC cases, pAKT was similarly significantly increased in tumors with BAF250a loss on IHC. Knockdown of BAF250a by siRNA in

  19. Molecular profiling of appendiceal epithelial tumors using massively parallel sequencing to identify somatic mutations.

    Science.gov (United States)

    Liu, Xiaoying; Mody, Kabir; de Abreu, Francine B; Pipas, J Marc; Peterson, Jason D; Gallagher, Torrey L; Suriawinata, Arief A; Ripple, Gregory H; Hourdequin, Kathryn C; Smith, Kerrington D; Barth, Richard J; Colacchio, Thomas A; Tsapakos, Michael J; Zaki, Bassem I; Gardner, Timothy B; Gordon, Stuart R; Amos, Christopher I; Wells, Wendy A; Tsongalis, Gregory J

    2014-07-01

    Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts

  20. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer.

    Science.gov (United States)

    Rothé, F; Laes, J-F; Lambrechts, D; Smeets, D; Vincent, D; Maetens, M; Fumagalli, D; Michiels, S; Drisis, S; Moerman, C; Detiffe, J-P; Larsimont, D; Awada, A; Piccart, M; Sotiriou, C; Ignatiadis, M

    2014-10-01

    Molecular screening programs use next-generation sequencing (NGS) of cancer gene panels to analyze metastatic biopsies. We interrogated whether plasma could be used as an alternative to metastatic biopsies. The Ion AmpliSeq™ Cancer Hotspot Panel v2 (Ion Torrent), covering 2800 COSMIC mutations from 50 cancer genes was used to analyze 69 tumor (primary/metastases) and 31 plasma samples from 17 metastatic breast cancer patients. The targeted coverage for tumor DNA was ×1000 and for plasma cell-free DNA ×25 000. Whole blood normal DNA was used to exclude germline variants. The Illumina technology was used to confirm observed mutations. Evaluable NGS results were obtained for 60 tumor and 31 plasma samples from 17 patients. When tumor samples were analyzed, 12 of 17 (71%, 95% confidence interval (CI) 44% to 90%) patients had ≥1 mutation (median 1 mutation per patient, range 0-2 mutations) in either p53, PIK3CA, PTEN, AKT1 or IDH2 gene. When plasma samples were analyzed, 12 of 17 (71%, 95% CI: 44-90%) patients had ≥1 mutation (median 1 mutation per patient, range 0-2 mutations) in either p53, PIK3CA, PTEN, AKT1, IDH2 and SMAD4. All mutations were confirmed. When we focused on tumor and plasma samples collected at the same time-point, we observed that, in four patients, no mutation was identified in either tumor or plasma; in nine patients, the same mutations was identified in tumor and plasma; in two patients, a mutation was identified in tumor but not in plasma; in two patients, a mutation was identified in plasma but not in tumor. Thus, in 13 of 17 (76%, 95% CI 50% to 93%) patients, tumor and plasma provided concordant results whereas in 4 of 17 (24%, 95% CI 7% to 50%) patients, the results were discordant, providing complementary information. Plasma can be prospectively tested as an alternative to metastatic biopsies in molecular screening programs. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology

  1. Genome-Wide Association Study and Transcriptome Analysis Provide New Insights into the White/Red Earlobe Color Formation in Chicken.

    Science.gov (United States)

    Luo, Wei; Xu, Jiguo; Li, Zhenhui; Xu, Haiping; Lin, Shudai; Wang, Jiaying; Ouyang, Hongjia; Nie, Qinghua; Zhang, Xiquan

    2018-04-25

    Earlobe color is a typical external trait in chicken. There are some previous studies showing that the chicken white/red earlobe color is a polygenic and sex-linked trait in some breeds, but its molecular genetic and histological mechanisms still remain unclear. We herein utilized histological section, genome-wide association study (GWAS) and RNA-seq, further to investigate the potential histological and molecular genetic mechanisms of white/red earlobe formation in Qiangyuan Partridge chicken (QYP). through histological section analysis, we found the dermal papillary layer of red earlobes had many more blood vessels than that of white earlobes. And we identified a total of 44 SNPs from Chromosome 1, 2, 3, 4, 9, 10, 11, 13, 19, 20, 23 and Z, that was significantly associated with the chicken white/red earlobe color from GWAS, along with 73 significantly associated genes obtained (e.g., PIK3CB, B4GALT1 and TP63), supporting the fact that the white/red earlobe color was also polygenic and sex-linked in QYP. Importantly, PIK3CB and B4GALT1 are both involved in the biological process of angiogenesis, which may directly give rise to the chicken white earlobe formation through regulating blood vessel density in chicken earlobe. Additionally, through contrast of RNA-seq profiles between white earlobe skins and red earlobe skins, we further identified TP63 and CDH1 differentially expressed. Combined with the existing knowledge of TP63 in epithelial development and tumor angiogenesis, we propose that down-regulated TP63 in white earlobes may play roles in thickening the skin and decreasing the vessel numbers in dermal papillary layer, thereby contributing to the white earlobe formation via paling the redness of the skin in QYP, but the specific mechanism remains to be further clarified. our findings advance the existing understanding of the white earlobe formation, as well as provide new clues to understand the molecular mechanism of chicken white/red earlobe color

  2. KRAS Mutation Status and Clinical Outcome of Preoperative Chemoradiation With Cetuximab in Locally Advanced Rectal Cancer: A Pooled Analysis of 2 Phase II Trials

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Young; Shim, Eun Kyung [Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Yeo, Hyun Yang [Division of Translational and Clinical Research I, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Baek, Ji Yeon [Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Hong, Yong Sang [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Dae Yong [Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Division of Translational and Clinical Research I, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Kim, Tae Won [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Jee Hyun [Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam (Korea, Republic of); Im, Seock-Ah [Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jung, Kyung Hae [Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Chang, Hee Jin, E-mail: heejincmd@yahoo.com [Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of); Division of Translational and Clinical Research I, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of)

    2013-01-01

    Purpose: Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. Methods and Materials: We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m{sup 2} weekly and 1650 mg/m{sup 2}/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m{sup 2} on 1 week before radiation, and 250 mg/m{sup 2} weekly thereafter. Results: Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. Conclusions: In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with

  3. Avirulence (AVR) Gene-Based Diagnosis Complements Existing Pathogen Surveillance Tools for Effective Deployment of Resistance (R) Genes Against Rice Blast Disease.

    Science.gov (United States)

    Selisana, S M; Yanoria, M J; Quime, B; Chaipanya, C; Lu, G; Opulencia, R; Wang, G-L; Mitchell, T; Correll, J; Talbot, N J; Leung, H; Zhou, B

    2017-06-01

    Avirulence (AVR) genes in Magnaporthe oryzae, the fungal pathogen that causes the devastating rice blast disease, have been documented to be major targets subject to mutations to avoid recognition by resistance (R) genes. In this study, an AVR-gene-based diagnosis tool for determining the virulence spectrum of a rice blast pathogen population was developed and validated. A set of 77 single-spore field isolates was subjected to pathotype analysis using differential lines, each containing a single R gene, and classified into 20 virulent pathotypes, except for 4 isolates that lost pathogenicity. In all, 10 differential lines showed low frequency (95%), inferring the effectiveness of R genes present in the respective differential lines. In addition, the haplotypes of seven AVR genes were determined by polymerase chain reaction amplification and sequencing, if applicable. The calculated frequency of different AVR genes displayed significant variations in the population. AVRPiz-t and AVR-Pii were detected in 100 and 84.9% of the isolates, respectively. Five AVR genes such as AVR-Pik-D (20.5%) and AVR-Pik-E (1.4%), AVRPiz-t (2.7%), AVR-Pita (0%), AVR-Pia (0%), and AVR1-CO39 (0%) displayed low or even zero frequency. The frequency of AVR genes correlated almost perfectly with the resistance frequency of the cognate R genes in differential lines, except for International Rice Research Institute-bred blast-resistant lines IRBLzt-T, IRBLta-K1, and IRBLkp-K60. Both genetic analysis and molecular marker validation revealed an additional R gene, most likely Pi19 or its allele, in these three differential lines. This can explain the spuriously higher resistance frequency of each target R gene based on conventional pathotyping. This study demonstrates that AVR-gene-based diagnosis provides a precise, R-gene-specific, and differential line-free assessment method that can be used for determining the virulence spectrum of a rice blast pathogen population and for predicting the

  4. A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes

    International Nuclear Information System (INIS)

    Fumagalli, Debora; Gavin, Patrick G; Taniyama, Yusuke; Kim, Seung-Il; Choi, Hyun-Joo; Paik, Soonmyung; Pogue-Geile, Katherine L

    2010-01-01

    An increasing number of studies show that genetic markers can aid in refining prognostic information and predicting the benefit from systemic therapy. Our goal was to develop a high throughput, cost-effective and simple methodology for the detection of clinically relevant hot spot mutations in colon cancer. The Maldi-Tof mass spectrometry platform and OncoCarta panel from Sequenom were used to profile 239 colon cancers and 39 metastatic lymph nodes from NSABP clinical trial C-07 utilizing routinely processed FFPET (formalin-fixed paraffin-embedded tissue). Among the 238 common hot-spot cancer mutations in 19 genes interrogated by the OncoCarta panel, mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples. Twenty-four assays that detected mutations in more than 1% of the samples were reconfigured into a new multiplexed panel, termed here as ColoCarta. Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta, demonstrating that this methodology was reproducible. Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC (Catalog of Somatic Mutations in Cancer) database. The frequencies were 43.5% for KRAS, 20.1% for PIK3CA, and 12.1% for BRAF. In addition, infrequent mutations in NRAS, AKT1, ABL1, and MET were detected. Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7% concordant. All mutations found in the lymph nodes were also found in the corresponding primary tumors, but in 4 cases a mutation was present in the primary tumor only. This study describes a high throughput technology that can be used to interrogate DNAs isolated from routinely processed FFPET and identifies the specific mutations that are common to colon cancer. The development of this technology and the Colo

  5. Monte Carlo methods to calculate impact probabilities

    Science.gov (United States)

    Rickman, H.; Wiśniowski, T.; Wajer, P.; Gabryszewski, R.; Valsecchi, G. B.

    2014-09-01

    Context. Unraveling the events that took place in the solar system during the period known as the late heavy bombardment requires the interpretation of the cratered surfaces of the Moon and terrestrial planets. This, in turn, requires good estimates of the statistical impact probabilities for different source populations of projectiles, a subject that has received relatively little attention, since the works of Öpik (1951, Proc. R. Irish Acad. Sect. A, 54, 165) and Wetherill (1967, J. Geophys. Res., 72, 2429). Aims: We aim to work around the limitations of the Öpik and Wetherill formulae, which are caused by singularities due to zero denominators under special circumstances. Using modern computers, it is possible to make good estimates of impact probabilities by means of Monte Carlo simulations, and in this work, we explore the available options. Methods: We describe three basic methods to derive the average impact probability for a projectile with a given semi-major axis, eccentricity, and inclination with respect to a target planet on an elliptic orbit. One is a numerical averaging of the Wetherill formula; the next is a Monte Carlo super-sizing method using the target's Hill sphere. The third uses extensive minimum orbit intersection distance (MOID) calculations for a Monte Carlo sampling of potentially impacting orbits, along with calculations of the relevant interval for the timing of the encounter allowing collision. Numerical experiments are carried out for an intercomparison of the methods and to scrutinize their behavior near the singularities (zero relative inclination and equal perihelion distances). Results: We find an excellent agreement between all methods in the general case, while there appear large differences in the immediate vicinity of the singularities. With respect to the MOID method, which is the only one that does not involve simplifying assumptions and approximations, the Wetherill averaging impact probability departs by diverging toward

  6. Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

    Science.gov (United States)

    Tang, Yew Chung; Ho, Szu-Chi; Tan, Elisabeth; Ng, Alvin Wei Tian; McPherson, John R; Goh, Germaine Yen Lin; Teh, Bin Tean; Bard, Frederic; Rozen, Steven G

    2018-03-22

    Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers. To discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data. The screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets. Six genes showed PTEN

  7. A novel fully automated molecular diagnostic system (AMDS for colorectal cancer mutation detection.

    Directory of Open Access Journals (Sweden)

    Shiro Kitano

    Full Text Available BACKGROUND: KRAS, BRAF and PIK3CA mutations are frequently observed in colorectal cancer (CRC. In particular, KRAS mutations are strong predictors for clinical outcomes of EGFR-targeted treatments such as cetuximab and panitumumab in metastatic colorectal cancer (mCRC. For mutation analysis, the current methods are time-consuming, and not readily available to all oncologists and pathologists. We have developed a novel, simple, sensitive and fully automated molecular diagnostic system (AMDS for point of care testing (POCT. Here we report the results of a comparison study between AMDS and direct sequencing (DS in the detection of KRAS, BRAF and PI3KCA somatic mutations. METHODOLOGY/PRINCIPAL FINDING: DNA was extracted from a slice of either frozen (n = 89 or formalin-fixed and paraffin-embedded (FFPE CRC tissue (n = 70, and then used for mutation analysis by AMDS and DS. All mutations (n = 41 among frozen and 27 among FFPE samples detected by DS were also successfully (100% detected by the AMDS. However, 8 frozen and 6 FFPE samples detected as wild-type in the DS analysis were shown as mutants in the AMDS analysis. By cloning-sequencing assays, these discordant samples were confirmed as true mutants. One sample had simultaneous "hot spot" mutations of KRAS and PIK3CA, and cloning assay comfirmed that E542K and E545K were not on the same allele. Genotyping call rates for DS were 100.0% (89/89 and 74.3% (52/70 in frozen and FFPE samples, respectively, for the first attempt; whereas that of AMDS was 100.0% for both sample sets. For automated DNA extraction and mutation detection by AMDS, frozen tissues (n = 41 were successfully detected all mutations within 70 minutes. CONCLUSIONS/SIGNIFICANCE: AMDS has superior sensitivity and accuracy over DS, and is much easier to execute than conventional labor intensive manual mutation analysis. AMDS has great potential for POCT equipment for mutation analysis.

  8. KRAS Mutation Status and Clinical Outcome of Preoperative Chemoradiation With Cetuximab in Locally Advanced Rectal Cancer: A Pooled Analysis of 2 Phase II Trials

    International Nuclear Information System (INIS)

    Kim, Sun Young; Shim, Eun Kyung; Yeo, Hyun Yang; Baek, Ji Yeon; Hong, Yong Sang; Kim, Dae Yong; Kim, Tae Won; Kim, Jee Hyun; Im, Seock-Ah; Jung, Kyung Hae; Chang, Hee Jin

    2013-01-01

    Purpose: Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. Methods and Materials: We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m 2 weekly and 1650 mg/m 2 /day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m 2 on 1 week before radiation, and 250 mg/m 2 weekly thereafter. Results: Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. Conclusions: In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with irinotecan plus

  9. Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options.

    Science.gov (United States)

    Gay, Laurie M; Kim, Sungeun; Fedorchak, Kyle; Kundranda, Madappa; Odia, Yazmin; Nangia, Chaitali; Battiste, James; Colon-Otero, Gerardo; Powell, Steven; Russell, Jeffery; Elvin, Julia A; Vergilio, Jo-Anne; Suh, James; Ali, Siraj M; Stephens, Philip J; Miller, Vincent A; Ross, Jeffrey S

    2017-07-01

    Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA , NF1 , CDKN2A , and CDKN2C occurring in 7% of samples. We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered

  10. Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines

    International Nuclear Information System (INIS)

    Kim, Ji Eun; Stones, Clare; Joseph, Wayne R; Leung, Euphemia; Finlay, Graeme J; Shelling, Andrew N; Phillips, Wayne A; Shepherd, Peter R; Baguley, Bruce C

    2012-01-01

    The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metastatic malignant melanoma of known PIK3CA, PTEN, NRAS and BRAF mutational status. Western blotting was used to compare the phosphorylation status of components of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways, as indices of pathway utilisation. Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways. Utilisation of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways in melanoma, as determined by phosphorylation of signalling components, varies widely across a series of cell lines, and does not directly reflect mutation of genes coding these components. The main difference between cultured normal melanocytes and melanoma cells is not the pathway utilisation itself, but rather in the serum dependence of pathway utilisation

  11. Therapeutic strategies and genetic profile comparisons in small cell carcinoma and large cell neuroendocrine carcinoma of the lung using next-generation sequencing.

    Science.gov (United States)

    Ito, Masaoki; Miyata, Yoshihiro; Hirano, Shoko; Kimura, Shingo; Irisuna, Fumiko; Ikeda, Kyoko; Kushitani, Kei; Tsutani, Yasuhiro; Ueda, Daisuke; Tsubokawa, Norifumi; Takeshima, Yukio; Okada, Morihito

    2017-12-12

    Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of target therapy has not been established in these tumors. This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, and explore the possibility of target therapy using next-generation sequencing. In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. The case harboring EGFR mutation showed response to EGFR-tyrosine kinase inhibitor. However, there are no clinicopathological features associated with therapeutically targetable cases. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types. In conclusion, although patients with SCLC and LCNEC may benefit from target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.

  12. Mutational profiling of non-small-cell lung cancer patients resistant to first-generation EGFR tyrosine kinase inhibitors using next generation sequencing

    Science.gov (United States)

    Jin, Ying; Shao, Yang; Shi, Xun; Lou, Guangyuan; Zhang, Yiping; Wu, Xue; Tong, Xiaoling; Yu, Xinmin

    2016-01-01

    Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is secondary EGFR-T790M mutation. Other mechanisms, such as HER2 and MET amplifications, and PIK3CA mutations, were also reported. However, the mechanisms in the remaining patients are still unknown. In this study, we performed mutational profiling in a cohort of 83 NSCLC patients with TKI-sensitizing EGFR mutations at diagnosis and acquired resistance to three different first-generation EGFR TKIs using targeted next generation sequencing (NGS) of 416 cancer-related genes. In total, we identified 322 genetic alterations with a median of 3 mutations per patient. 61% of patients still exhibit TKI-sensitizing EGFR mutations, and 36% of patients acquired EGFR-T790M. Besides other known resistance mechanisms, we identified TET2 mutations in 12% of patients. Interestingly, we also observed SOX2 amplification in EGFR-T790M negative patients, which are restricted to Icotinib treatment resistance, a drug widely used in Chinese NSCLC patients. Our study uncovered mutational profiles of NSCLC patients with first-generation EGFR TKIs resistance with potential therapeutic implications. PMID:27528220

  13. Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition

    Science.gov (United States)

    Rodríguez-Cortez, Virginia C.; del Pino-Molina, Lucia; Rodríguez-Ubreva, Javier; Ciudad, Laura; Gómez-Cabrero, David; Company, Carlos; Urquiza, José M.; Tegnér, Jesper; Rodríguez-Gallego, Carlos; López-Granados, Eduardo; Ballestar, Esteban

    2015-01-01

    Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals. PMID:26081581

  14. Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy.

    Science.gov (United States)

    Bonechi, Martina; Galardi, Francesca; Biagioni, Chiara; De Luca, Francesca; Bergqvist, Mattias; Neumüller, Magnus; Guarducci, Cristina; Boccalini, Giulia; Gabellini, Stefano; Migliaccio, Ilenia; Di Leo, Angelo; Pestrin, Marta; Malorni, Luca

    2018-03-27

    The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1 / PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients.

  15. Clinical potential of meningioma genomic insights: a practical review for neurosurgeons.

    Science.gov (United States)

    Karsy, Michael; Azab, Mohammed A; Abou-Al-Shaar, Hussam; Guan, Jian; Eli, Ilyas; Jensen, Randy L; Ormond, D Ryan

    2018-06-01

    Meningiomas are among the most common intracranial pathological conditions, accounting for 36% of intracranial lesions treated by neurosurgeons. Although the majority of these lesions are benign, the classical categorization of tumors by histological type or World Health Organization (WHO) grade has not fully captured the potential for meningioma progression and recurrence. Many targeted treatments have failed to generate a long-lasting effect on these tumors. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor 4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least 6 distinct mutational classes of meningiomas. In addition, 6 methylation classes of meningioma have been appreciated, enabling improved prediction of prognosis compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin. However, despite these exciting findings, the clinical relevance of these findings remains elusive. The authors review the key findings from recent genomic studies in meningiomas, specifically focusing on how these findings relate to clinical insights for the practicing neurosurgeon.

  16. Challenging a dogma: co-mutations exist in MAPK pathway genes in colorectal cancer.

    Science.gov (United States)

    Grellety, Thomas; Gros, Audrey; Pedeutour, Florence; Merlio, Jean-Philippe; Duranton-Tanneur, Valerie; Italiano, Antoine; Soubeyran, Isabelle

    2016-10-01

    Sequencing of genes encoding mitogen-activated protein kinase (MAPK) pathway proteins in colorectal cancer (CRC) has established as dogma that of the genes in a pathway only a single one is ever mutated. We searched for cases with a mutation in more than one MAPK pathway gene (co-mutations). Tumor tissue samples of all patients presenting with CRC, and referred between 01/01/2008 and 01/06/2015 to three French cancer centers for determination of mutation status of RAS/RAF+/-PIK3CA, were retrospectively screened for co-mutations using Sanger sequencing or next-generation sequencing. We found that of 1791 colorectal patients with mutations in the MAPK pathway, 20 had a co-mutation, 8 of KRAS/NRAS, and some even with a third mutation. More than half of the mutations were in codons 12 and 13. We also found 3 cases with a co-mutation of NRAS/BRAF and 9 with a co-mutation of KRAS/BRAF. In 2 patients with a co-mutation of KRAS/NRAS, the co-mutation existed in the primary as well as in a metastasis, which suggests that co-mutations occur early during carcinogenesis and are maintained when a tumor disseminates. We conclude that co-mutations exist in the MAPK genes but with low frequency and as yet with unknown outcome implications.

  17. Lactic Acidosis in Prostate Cancer: Consider the Warburg Effect

    Directory of Open Access Journals (Sweden)

    Johannes C. van der Mijn

    2017-11-01

    Full Text Available Lactic acidosis is a commonly observed clinical condition that is associated with a poor prognosis, especially in malignancies. We describe a case of an 81-year-old patient who presented with symptoms of tachypnea and general discomfort. Arterial blood gas analysis showed a high anion gap acidosis with a lactate level of 9.5 mmol/L with respiratory compensation. CT scanning showed no signs of pulmonary embolism or other causes of impaired tissue oxygenation. Despite treatment with sodium bicarbonate, the patient developed an adrenalin-resistant cardiac arrest, most likely caused by the acidosis. Autopsy revealed Gleason score 5 + 5 metastatic prostate cancer as the most probable cause of the lactic acidosis. Next-generation sequencing indicated a nonsense mutation in the TP53 gene (887delA and an activating mutation in the PIK3CA gene (1634A>G as candidate molecular drivers. This case demonstrates the prevalence and clinical relevance of metabolic reprogramming, frequently referred to as “the Warburg effect,” in patients with prostate cancer.

  18. Commentary on "Integrative clinical genomics of advanced prostate cancer". Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM.Cell. 21 May 2015;161(5):1215-1228.

    Science.gov (United States)

    Freedland, Stephen J; Aronson, William J

    2017-08-01

    Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. A total of 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could affect treatment decisions for these affected individuals. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Cinnamon extract regulates glucose transporter and insulin-signaling gene expression in mouse adipocytes.

    Science.gov (United States)

    Cao, Heping; Graves, Donald J; Anderson, Richard A

    2010-11-01

    Cinnamon extracts (CE) are reported to have beneficial effects on people with normal and impaired glucose tolerance, the metabolic syndrome, type 2 diabetes, and insulin resistance. However, clinical results are controversial. Molecular characterization of CE effects is limited. This study investigated the effects of CE on gene expression in cultured mouse adipocytes. Water-soluble CE was prepared from ground cinnamon (Cinnamomum burmannii). Quantitative real-time PCR was used to investigate CE effects on the expression of genes coding for adipokines, glucose transporter (GLUT) family, and insulin-signaling components in mouse 3T3-L1 adipocytes. CE (100 μg/ml) increased GLUT1 mRNA levels 1.91±0.15, 4.39±0.78, and 6.98±2.18-fold of the control after 2-, 4-, and 16-h treatments, respectively. CE decreased the expression of further genes encoding insulin-signaling pathway proteins including GSK3B, IGF1R, IGF2R, and PIK3R1. This study indicates that CE regulates the expression of multiple genes in adipocytes and this regulation could contribute to the potential health benefits of CE. Published by Elsevier GmbH.

  20. Molecular characteristics of endometrial cancer coexisting with peritoneal malignant mesothelioma in Li-Fraumeni-like syndrome.

    Science.gov (United States)

    Chao, Angel; Lai, Chyong-Huey; Lee, Yun-Shien; Ueng, Shir-Hwa; Lin, Chiao-Yun; Wang, Tzu-Hao

    2015-01-15

    Endometrial cancer that occurs concurrently with peritoneal malignant mesothelioma (PMM) is difficult to diagnose preoperatively. A postmenopausal woman had endometrial cancer extending to the cervix, vagina and pelvic lymph nodes, and PMM in bilateral ovaries, cul-de-sac, and multiple peritoneal sites. Adjuvant therapies included chemotherapy and radiotherapy. Targeted, massively parallel DNA sequencing and molecular inversion probe microarray analysis revealed a germline TP53 mutation compatible with Li-Fraumeni-like syndrome, somatic mutations of PIK3CA in the endometrial cancer, and a somatic mutation of GNA11 and JAK3 in the PMM. Large-scale genomic amplifications and some deletions were found in the endometrial cancer. The patient has been stable for 24 months after therapy. One of her four children was also found to carry the germline TP53 mutation. Molecular characterization of the coexistent tumors not only helps us make the definite diagnosis, but also provides information to select targeted therapies if needed in the future. Identification of germline TP53 mutation further urged us to monitor future development of malignancies in this patient and encourage cancer screening in her family.

  1. Update on Sporadic Colorectal Cancer Genetics.

    Science.gov (United States)

    Hardiman, Karin M

    2018-05-01

    Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/β-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.

  2. Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients

    International Nuclear Information System (INIS)

    Diaz Rubio Garcia, E.

    2009-01-01

    The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the antiEGFR monoclonal antibodies (cetuximab and panitumumab) have emerged in combination with the standard cytotoxic chemotherapy (FOLFOX and FOLFIRI). However, the benefit from cetuximab and panitumumab is only confined to KRAS-wild type (KRAS-wt) colorectal tumors, while KRAS mutated tumors do not respond to these drugs. The 65 % of colorectal tumors are KRAS-wt tumors, but efficacy of antiEGFR therapies is detected only in 60-70 % of these KRAS-wt tumors. Other biomarkers and molecular pathways must be involved in the response of the antiEGFR therapies for the KRAS-wt colorectal tumors, such as the EGFR ligands, the EGFR-phosphorilated levels, the number of EGFR copies, the status of the KRAS effected B-RAF and the alternative intracellular signaling pathways PIK3CA/PTEN/AKT and JAK/STAT. A battery of these biomarkers is needed to select the most sensitive patients to the antiEGFR therapies. This pattern may represent a novel favorable cost-effectiveness tool to develop tailored treatments. A review of these biomarkers and molecular pathways, involved in the antiEGFR therapies response, is performed. (Author) 68 refs.

  3. Endometrial cancer and somatic G>T KRAS transversion in patients with constitutional MUTYH biallelic mutations.

    Science.gov (United States)

    Tricarico, Rossella; Bet, Paola; Ciambotti, Benedetta; Di Gregorio, Carmela; Gatteschi, Beatrice; Gismondi, Viviana; Toschi, Benedetta; Tonelli, Francesco; Varesco, Liliana; Genuardi, Maurizio

    2009-02-18

    MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for PTEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis.

  4. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

    Science.gov (United States)

    Cristofanilli, Massimo; Turner, Nicholas C; Bondarenko, Igor; Ro, Jungsil; Im, Seock-Ah; Masuda, Norikazu; Colleoni, Marco; DeMichele, Angela; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Zhang, Ke; Theall, Kathy Puyana; Jiang, Yuqiu; Bartlett, Cynthia Huang; Koehler, Maria; Slamon, Dennis

    2016-04-01

    In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Between Oct 7, 2013, and Aug 26, 2014, 521 patients were

  5. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.

    Science.gov (United States)

    O'Leary, Ben; Hrebien, Sarah; Morden, James P; Beaney, Matthew; Fribbens, Charlotte; Huang, Xin; Liu, Yuan; Bartlett, Cynthia Huang; Koehler, Maria; Cristofanilli, Massimo; Garcia-Murillas, Isaac; Bliss, Judith M; Turner, Nicholas C

    2018-03-01

    CDK4/6 inhibition substantially improves progression-free survival (PFS) for women with advanced estrogen receptor-positive breast cancer, although there are no predictive biomarkers. Early changes in circulating tumor DNA (ctDNA) level may provide early response prediction, but the impact of tumor heterogeneity is unknown. Here we use plasma samples from patients in the randomized phase III PALOMA-3 study of CDK4/6 inhibitor palbociclib and fulvestrant for women with advanced breast cancer and show that relative change in PIK3CA ctDNA level after 15 days treatment strongly predicts PFS on palbociclib and fulvestrant (hazard ratio 3.94, log-rank p = 0.0013). ESR1 mutations selected by prior hormone therapy are shown to be frequently sub clonal, with ESR1 ctDNA dynamics offering limited prediction of clinical outcome. These results suggest that early ctDNA dynamics may provide a robust biomarker for CDK4/6 inhibitors, with early ctDNA dynamics demonstrating divergent response of tumor sub clones to treatment.

  6. Biological and Molecular Effects of Small Molecule Kinase Inhibitors on Low-Passage Human Colorectal Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Falko Lange

    2014-01-01

    Full Text Available Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC patients, to evaluate effects of the small molecule kinase inhibitors (SMI vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models.

  7. Chemotherapeutics-resistance "arms" race: An update on mechanisms involved in resistance limiting EGFR inhibitors in lung cancer.

    Science.gov (United States)

    Singh, Pankaj Kumar; Silakari, Om

    2017-10-01

    Clinical reports suggest that EGFR-mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate-keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc., in the development of tolerance towards the EGFR TKI's, along with other commonly known mechanisms, such as amplification of signalling pathways such as, c-MET, Erbb2, AXL, additional acquired secondary mutations (PIK3CA, BRAF), or phenotypic transformation (small cell or epithelial to mesenchymal transitions). Interestingly, a recent study showed development of resistance via another point mutation, C797S, in case of tumors which were previously resistant and were administered agents capable of overcoming T790M gatekeeper mutation based resistance. Thus, raising serious concern over the direction of drug development involving tyrosine kinases such as EGFR. Current approaches focussing on development of third generation inhibitors, dual inhibitors or inhibitors of HSP90 have shown significant activity but do not answer the long term question of resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Precision measurement of the $\\Lambda_b^0$ baryon lifetime

    CERN Document Server

    INSPIRE-00258707; Adeva, B; Adinolfi, M; Adrover, C; 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; Anderlini, L; Anderson, J; Andreassen, R; 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; Baesso, C; Balagura, V; Baldini, W; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; 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; 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; Burducea, I; 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Williams, M; Wilson, F F; Wimberley, J; Wishahi, J; Wislicki, W; Witek, M; Wotton, S A; Wright, S; Wu, S; Wyllie, K; Xie, Y; Xing, Z; Yang, Z; Young, R; 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

    2013-01-01

    The ratio of the $\\Lambda_b^0$ baryon lifetime to that of the $\\overline{B}^0$ meson is measured using 1.0 fb$^{-1}$ of integrated luminosity in 7 TeV center-of-mass energy $pp$ collisions at the LHC. The $\\Lambda_b^0$ baryon is observed for the first time in the decay mode $\\Lambda_b^0 \\to J/\\psi p K^-$, while the $\\overline{B}^0$ meson decay used is the well known $\\overline{B}^0 \\to J/\\psi \\pi^+ K^-$ mode, where the $\\pi^+K^-$ mass is consistent with that of the $\\bar{K}^{*0}(892)$ meson. The ratio of lifetimes is measured to be $0.976\\pm0.012\\pm0.006$, in agreement with theoretical expectations based on the heavy quark expansion. Using previous determinations of the $\\overline{B}^0$ meson lifetime, the $\\Lambda_b^0$ lifetime is found to be $1.482 \\pm 0.018 \\pm 0.012$ ps. In both cases the first uncertainty is statistical and the second systematic.

  9. Precision measurement of the ratio of the $\\Lambda^0_b$ to $\\overline{B}^0$ lifetimes

    CERN Document Server

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Pearce, Alex; Pellegrino, Antonio; Pepe Altarelli, Monica; Perazzini, Stefano; Perez Trigo, Eliseo; Perret, Pascal; Perrin-Terrin, Mathieu; Pescatore, Luca; Pesen, Erhan; Pessina, Gianluigi; Petridis, Konstantin; Petrolini, Alessandro; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pilař, Tomas; Pinci, Davide; Pistone, Alessandro; Playfer, Stephen; Plo Casasus, Maximo; Polci, Francesco; Poluektov, Anton; Polycarpo, Erica; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Potterat, Cédric; Powell, Andrew; Prisciandaro, Jessica; Pritchard, Adrian; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Wenbin; Rachwal, Bartolomiej; Rademacker, Jonas; Rakotomiaramanana, Barinjaka; Rama, Matteo; Rangel, Murilo; Raniuk, Iurii; Rauschmayr, Nathalie; Raven, Gerhard; Reichert, Stefanie; Reid, Matthew; dos Reis, Alberto; Ricciardi, Stefania; Richards, Alexander; Rinnert, Kurt; Rives Molina, Vincente; Roa Romero, Diego; Robbe, Patrick; Roberts, Douglas; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Perez, Pablo; Roiser, Stefan; Romanovsky, Vladimir; Romero Vidal, Antonio; Rotondo, Marcello; Rouvinet, Julien; Ruf, Thomas; Ruffini, Fabrizio; Ruiz, Hugo; Ruiz Valls, Pablo; Sabatino, Giovanni; Saborido Silva, Juan Jose; Sagidova, Naylya; Sail, Paul; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santovetti, Emanuele; Sapunov, Matvey; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Savrie, Mauro; Savrina, Darya; Schiller, Manuel; Schindler, Heinrich; Schlupp, Maximilian; Schmelling, Michael; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Seco, Marcos; Semennikov, Alexander; Senderowska, Katarzyna; Sepp, Indrek; Serra, Nicola; Serrano, Justine; Seyfert, Paul; Shapkin, Mikhail; Shapoval, Illya; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Oksana; Shevchenko, Vladimir; Shires, Alexander; Silva Coutinho, Rafael; Simi, Gabriele; Sirendi, Marek; Skidmore, Nicola; Skwarnicki, Tomasz; Smith, Anthony; Smith, Edmund; Smith, Eluned; Smith, Jackson; Smith, Mark; Snoek, Hella; Sokoloff, Michael; Soler, Paul; Soomro, Fatima; Souza, Daniel; Souza De Paula, Bruno; Spaan, Bernhard; Sparkes, Ailsa; Spinella, Franco; Spradlin, Patrick; Stagni, Federico; Stahl, Sascha; Steinkamp, Olaf; Stevenson, Scott; Stoica, Sabin; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Straticiuc, Mihai; Straumann, Ulrich; Stroili, Roberto; Subbiah, Vijay Kartik; Sun, Liang; Sutcliffe, William; Swientek, Stefan; Syropoulos, Vasileios; Szczekowski, Marek; Szczypka, Paul; Szilard, Daniela; Szumlak, Tomasz; T'Jampens, Stephane; Teklishyn, Maksym; Tellarini, Giulia; Teodorescu, Eliza; Teubert, Frederic; Thomas, Christopher; Thomas, Eric; van Tilburg, Jeroen; Tisserand, Vincent; Tobin, Mark; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Topp-Joergensen, Stig; Torr, Nicholas; Tournefier, Edwige; Tourneur, Stephane; Tran, Minh Tâm; Tresch, Marco; Tsaregorodtsev, Andrei; Tsopelas, Panagiotis; Tuning, Niels; Ubeda Garcia, Mario; Ukleja, Artur; Ustyuzhanin, Andrey; Uwer, Ulrich; Vagnoni, Vincenzo; Valenti, Giovanni; Vallier, Alexis; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vázquez Sierra, Carlos; Vecchi, Stefania; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Vesterinen, Mika; Viaud, Benoit; Vieira, Daniel; Vilasis-Cardona, Xavier; Vollhardt, Achim; Volyanskyy, Dmytro; Voong, David; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; Voss, Helge; de Vries, Jacco; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Wandernoth, Sebastian; Wang, Jianchun; Ward, David; Watson, Nigel; Webber, Adam Dane; Websdale, David; Whitehead, Mark; Wicht, Jean; Wiechczynski, Jaroslaw; Wiedner, Dirk; Wilkinson, Guy; Williams, Matthew; Williams, Mike; Wilson, Fergus; Wimberley, Jack; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wright, Simon; Wu, Suzhi; Wyllie, Kenneth; Xie, Yuehong; Xing, Zhou; Yang, Zhenwei; Yuan, Xuhao; Yushchenko, Oleg; Zangoli, Maria; Zavertyaev, Mikhail; Zhang, Feng; Zhang, Liming; Zhang, Wen Chao; Zhang, Yanxi; Zhelezov, Alexey; Zhokhov, Anatoly; Zhong, Liang; Zvyagin, Alexander

    2014-01-01

    The LHCb measurement of the lifetime ratio of the $\\Lambda^0_b$ to the $\\overline{B}^0$ meson is updated using data corresponding to an integrated luminosity of 3.0 fb$^{-1}$ collected using 7 and 8 TeV centre-of-mass energy $pp$ collisions at the LHC. The decay modes used are $\\overline{\\Lambda}^0_b \\to J/\\psi p K^-$ and $\\overline{B}^0 \\to J/\\psi \\pi^+ K^-$, where the $\\pi^+K^-$ mass is consistent with that of the $\\overline{K}^{*0}(892)$ meson. The lifetime ratio is determined with unprecedented precision to be $0.974\\pm0.006\\pm0.004$, where the first uncertainty is statistical and the second systematic. This result is in agreement with original theoretical predictions based on the heavy quark expansion. Using the current world average of the $\\overline{B}^0$ lifetime, the $\\Lambda^0_b$ lifetime is found to be $1.479 \\pm 0.009 \\pm 0.010$ ps.

  10. Adhesion and degranulation promoting adapter protein (ADAP is a central hub for phosphotyrosine-mediated interactions in T cells.

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    Marc Sylvester

    Full Text Available TCR stimulation leads to an increase in cellular adhesion among other outcomes. The adhesion and degranulation promoting adapter protein (ADAP is known to be rapidly phosphorylated after T cell stimulation and relays the TCR signal to adhesion molecules of the integrin family. While three tyrosine phosphorylation sites have been characterized biochemically, the binding capabilities and associated functions of several other potential phosphotyrosine motifs remain unclear. Here, we utilize in vitro phosphorylation and mass spectrometry to map novel phosphotyrosine sites in the C-terminal part of human ADAP (486-783. Individual tyrosines were then mutated to phenylalanine and their relevance for cellular adhesion and migration was tested experimentally. Functionally important tyrosine residues include two sites within the folded hSH3 domains of ADAP and two at the C-terminus. Furthermore, using a peptide pulldown approach in combination with stable isotope labeling in cell culture (SILAC we identified SLP-76, PLCgamma, PIK3R1, Nck, CRK, Gads, and RasGAP as phospho-dependent binding partners of a central YDDV motif of ADAP. The phosphorylation-dependent interaction between ADAP and Nck was confirmed by yeast two-hybrid analysis, immunoprecipitation and binary pulldown experiments, indicating that ADAP directly links integrins to modulators of the cytoskeleton independent of SLP-76.

  11. POLE somatic mutations in advanced colorectal cancer.

    Science.gov (United States)

    Guerra, Joana; Pinto, Carla; Pinto, Diana; Pinheiro, Manuela; Silva, Romina; Peixoto, Ana; Rocha, Patrícia; Veiga, Isabel; Santos, Catarina; Santos, Rui; Cabreira, Verónica; Lopes, Paula; Henrique, Rui; Teixeira, Manuel R

    2017-12-01

    Despite all the knowledge already gathered, the picture of somatic genetic changes in colorectal tumorigenesis is far from complete. Recently, germline and somatic mutations in the exonuclease domain of polymerase epsilon, catalytic subunit (POLE) gene have been reported in a small subset of microsatellite-stable and hypermutated colorectal carcinomas (CRCs), affecting the proofreading activity of the enzyme and leading to misincorporation of bases during DNA replication. To evaluate the role of POLE mutations in colorectal carcinogenesis, namely in advanced CRC, we searched for somatic mutations by Sanger sequencing in tumor DNA samples from 307 cases. Microsatellite instability and mutation analyses of a panel of oncogenes were performed in the tumors harboring POLE mutations. Three heterozygous mutations were found in two tumors, the c.857C>G, p.Pro286Arg, the c.901G>A, p.Asp301Asn, and the c.1376C>T, p.Ser459Phe. Of the POLE-mutated CRCs, one tumor was microsatellite-stable and the other had low microsatellite instability, whereas KRAS and PIK3CA mutations were found in one tumor each. We conclude that POLE somatic mutations exist but are rare in advanced CRC, with further larger studies being necessary to evaluate its biological and clinical implications. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  12. Genomic rearrangements of PTEN in prostate cancer

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    Sopheap ePhin

    2013-09-01

    Full Text Available The phosphatase and tensin homolog gene on chromosome 10q23.3 (PTEN is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in-situ hybridization (FISH assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, AR, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

  13. Detection of somatic mutations by high-resolution DNA melting (HRM) analysis in multiple cancers.

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    Gonzalez-Bosquet, Jesus; Calcei, Jacob; Wei, Jun S; Garcia-Closas, Montserrat; Sherman, Mark E; Hewitt, Stephen; Vockley, Joseph; Lissowska, Jolanta; Yang, Hannah P; Khan, Javed; Chanock, Stephen

    2011-01-17

    Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM) curve analysis represents a fast, post-PCR high-throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each). HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples.

  14. Detection of somatic mutations by high-resolution DNA melting (HRM analysis in multiple cancers.

    Directory of Open Access Journals (Sweden)

    Jesus Gonzalez-Bosquet

    Full Text Available Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM curve analysis represents a fast, post-PCR high-throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each. HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples.

  15. Use of the Ion PGM and the GeneReader NGS Systems in Daily Routine Practice for Advanced Lung Adenocarcinoma Patients: A Practical Point of View Reporting a Comparative Study and Assessment of 90 Patients

    Directory of Open Access Journals (Sweden)

    Simon Heeke

    2018-03-01

    Full Text Available Background: With the integration of various targeted therapies into the clinical management of patients with advanced lung adenocarcinoma, next-generation sequencing (NGS has become the technology of choice and has led to an increase in simultaneously interrogated genes. However, the broader adoption of NGS for routine clinical practice is still hampered by sophisticated workflows, complex bioinformatics analysis and medical interpretation. Therefore, the performance of the novel QIAGEN GeneReader NGS system was compared to an in-house ISO-15189 certified Ion PGM NGS platform. Methods: Clinical samples from 90 patients (60 Retrospectively and 30 Prospectively with lung adenocarcinoma were sequenced with both systems. Mutations were analyzed and EGFR, KRAS, BRAF, NRAS, ALK, PIK3CA and ERBB2 genes were compared and sampling time and suitability for clinical testing were assessed. Results: Both sequencing systems showed perfect concordance for the overlapping genes. Correlation of allele frequency was r2 = 0.93 for the retrospective patients and r2 = 0.81 for the prospective patients. Hands-on time and total run time were shorter using the PGM system, while the GeneReader platform provided good traceability and up-to-date interpretation of the results. Conclusion: We demonstrated the suitability of the GeneReader NGS system in routine practice in a clinical pathology laboratory setting.

  16. Non-filtration method of processing of uranium ores

    International Nuclear Information System (INIS)

    Laskorin, B.N.; Vodolazov, L.I.; Tokarev, N.N.; Vyalkov, V.I.; Goldobina, V.A.; Gosudarstvennyj Komitet po Ispol'zovaniyu Atomnoj Ehnergii SSSR, Moscow)

    1977-01-01

    The development of the filterless sorption method has lead to working out the sorption leaching process and the process of extraction desorption, which has made possible to intensify the process of uranium ore working and to improve greatly the technical economic indexes by liquidating the complex method of multiple filtration and repulping of cakes. This method makes possible to involve more poor uranium raw materials and at the same time to extract valuable components: molybdenum, vanadium, copper, etc. Great industrial experience has been accumulating in sorption of dense pulp with the ratio of solid phase to liquid one equal to 1:1. This has lead to the increase of productivity of working plants by 1,5-3,0 times, the increase of uranium extraction by 5-10%, the increase of labour capacity of main workers by 2-3 times, and to the decrease of reagents expense, auxiliary materials, electric energy and vapour by several times. In fact the developed technology is continuous in all its steps with complete complex automatization of the process with the help of the most simple and available means of regulation and controlling. The process is equipped with high productivity apparatuses of great power with mechanic and pneumatic mixing for high density pulps, and with the columns KDS, KDZS, KNSPR and PIK for the regeneration of saturated sorbent in the counterflow regime. The exploitation of fine-granular hydrophilic ion-exchange resins in hydrophobized state is foreseen [ru

  17. Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a Caucasian family.

    Science.gov (United States)

    De Summa, Simona; Guida, Michele; Tommasi, Stefania; Strippoli, Sabino; Pellegrini, Cristina; Fargnoli, Maria Concetta; Pilato, Brunella; Natalicchio, Iole; Guida, Gabriella; Pinto, Rosamaria

    2017-05-02

    Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology.To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes.In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree.From the analysis of the pedigree, we were able to identify a "protective" haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model.

  18. ATM is required for the repair of Topotecan-induced replication-associated double-strand breaks

    International Nuclear Information System (INIS)

    Köcher, Sabrina; Spies-Naumann, Anja; Kriegs, Malte; Dahm-Daphi, Jochen; Dornreiter, Irena

    2013-01-01

    Purpose: DNA replication is a promising target for anti-cancer therapies. Therefore, the understanding of replication-associated DNA repair mechanisms is of great interest. One key factor of DNA double-strand break (DSB) repair is the PIK kinase Ataxia-Telangiectasia Mutated (ATM) but it is still unclear whether ATM is involved in the repair of replication-associated DSBs. Here, we focused on the involvement of ATM in homology-directed repair (HDR) of indirect DSBs associated with replication. Material and methods: Experiments were performed using ATM-deficient and -proficient human cells. Replication-associated DSBs were induced with Topotecan (TPT) and compared with γ-irradiation (IR). Cell survival was measured by clonogenic assay. Overall DSB repair and HDR were evaluated by detecting residual γH2AX/53BP1 and Rad51 foci, respectively. Cell cycle distribution was analysed by flow cytometry and protein expression by Western blot. Results: ATM-deficiency leads to enhanced numbers of residual DSBs, resulting in a pronounced S/G2-block and decreased survival upon TPT-treatment. In common with IR, persisting Rad51 foci were detected following TPT-treatment. Conclusions: These results demonstrate that ATM is essentially required for the completion of HR-mediated repair of TPT-induced DSBs formed indirectly at replication forks

  19. The Wnt/β-catenin pathway is deregulated in cemento-ossifying fibromas.

    Science.gov (United States)

    Pereira, Thaís Dos Santos Fontes; Diniz, Marina Gonçalves; França, Josiane Alves; Moreira, Rennan Garcias; Menezes, Grazielle Helena Ferreira de; Sousa, Sílvia Ferreira de; Castro, Wagner Henriques de; Gomes, Carolina Cavaliéri; Gomez, Ricardo Santiago

    2018-02-01

    The molecular pathogenesis of cemento ossifying fibroma (COF) is unclear. The purpose of this study was to investigate mutations in 50 oncogenes and tumor suppressor genes, including APC and CTNNB1, in which mutations in COF have been previously reported. In addition, we assessed the transcriptional levels of the Wnt/β-catenin pathway genes in COF. We used a quantitative polymerase chain reaction array to evaluate the transcriptional levels of 44 Wnt/β-catenin pathway genes in 6 COF samples, in comparison with 6 samples of healthy jaws. By using next-generation sequencing (NGS) in 7 COF samples, we investigated approximately 2800 mutations in 50 genes. The expression assay revealed 12 differentially expressed Wnt/β-catenin pathway genes in COF, including the upregulation of CTNNB1, TCF7, NKD1, and WNT5 A, and downregulation of CTNNBIP1, FRZB, FZD6, RHOU, SFRP4, WNT10 A, WNT3 A, and WNT4, suggesting activation of the Wnt/β-catenin signaling pathway. NGS revealed 5 single nucleotide variants: TP53 (rs1042522), PIK3 CA (rs2230461), MET (rs33917957), KIT (rs3822214), and APC (rs33974176), but none of them was pathogenic. Although NGS detected no oncogenic mutation, deregulation of key Wnt/β-catenin signaling pathway genes appears to be relevant to the molecular pathogenesis of COF. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Bayesian phylogeny analysis of vertebrate serpins illustrates evolutionary conservation of the intron and indels based six groups classification system from lampreys for ∼500 MY

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    Abhishek Kumar

    2015-06-01

    Full Text Available The serpin superfamily is characterized by proteins that fold into a conserved tertiary structure and exploits a sophisticated and irreversible suicide-mechanism of inhibition. Vertebrate serpins are classified into six groups (V1–V6, based on three independent biological features—genomic organization, diagnostic amino acid sites and rare indels. However, this classification system was based on the limited number of mammalian genomes available. In this study, several non-mammalian genomes are used to validate this classification system using the powerful Bayesian phylogenetic method. This method supports the intron and indel based vertebrate classification and proves that serpins have been maintained from lampreys to humans for about 500 MY. Lampreys have fewer than 10 serpins, which expand into 36 serpins in humans. The two expanding groups V1 and V2 have SERPINB1/SERPINB6 and SERPINA8/SERPIND1 as the ancestral serpins, respectively. Large clusters of serpins are formed by local duplications of these serpins in tetrapod genomes. Interestingly, the ancestral HCII/SERPIND1 locus (nested within PIK4CA possesses group V4 serpin (A2APL1, homolog of α2-AP/SERPINF2 of lampreys; hence, pointing to the fact that group V4 might have originated from group V2. Additionally in this study, details of the phylogenetic history and genomic characteristics of vertebrate serpins are revisited.

  1. Next-generation sequencing for molecular diagnosis of lung adenocarcinoma specimens obtained by fine needle aspiration cytology

    Science.gov (United States)

    Qiu, Tian; Guo, Huiqin; Zhao, Huan; Wang, Luhua; Zhang, Zhihui

    2015-06-01

    Identification of multi-gene variations has led to the development of new targeted therapies in lung adenocarcinoma patients, and identification of an appropriate patient population with a reliable screening method is the key to the overall success of tumor targeted therapies. In this study, we used the Ion Torrent next-generation sequencing (NGS) technique to screen for mutations in 89 cases of lung adenocarcinoma metastatic lymph node specimens obtained by fine-needle aspiration cytology (FNAC). Of the 89 specimens, 30 (34%) were found to harbor epidermal growth factor receptor (EGFR) kinase domain mutations. Seven (8%) samples harbored KRAS mutations, and three (3%) samples had BRAF mutations involving exon 11 (G469A) and exon 15 (V600E). Eight (9%) samples harbored PIK3CA mutations. One (1%) sample had a HRAS G12C mutation. Thirty-two (36%) samples (36%) harbored TP53 mutations. Other genes including APC, ATM, MET, PTPN11, GNAS, HRAS, RB1, SMAD4 and STK11 were found each in one case. Our study has demonstrated that NGS using the Ion Torrent technology is a useful tool for gene mutation screening in lung adenocarcinoma metastatic lymph node specimens obtained by FNAC, and may promote the development of new targeted therapies in lung adenocarcinoma patients.

  2. Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors.

    Science.gov (United States)

    Shao, Yi; Zhong, Dian-Sheng

    2018-04-01

    Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8-16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.

  3. A Comparison of Fresh Frozen vs. Formalin-Fixed, Paraffin-Embedded Specimens of Canine Mammary Tumors via Branched-DNA Assay

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    Florenza Lüder Ripoli

    2016-05-01

    Full Text Available Mammary neoplasms are the tumors most affecting female dogs and women. Formalin-fixed, paraffin-embedded (FFPE tissues are an invaluable source of archived biological material. Fresh frozen (FF tissue is considered ideal for gene expression analysis. However, strategies based on FFPE material offer several advantages. Branched-DNA assays permit a reliable and fast workflow when analyzing gene expression. The aim of this study was to assess the comparability of the branched-DNA assay when analyzing certain gene expression patterns between FF and FFPE samples in canine mammary tumors. RNA was isolated from 109 FFPE samples and from 93 FF samples of different canine mammary tissues. Sixteen (16 target genes (Tp53; Myc; HMGA1; Pik3ca; Mcl1; MAPK3; FOXO3; PTEN; GATA4; PFDN5; HMGB1; MAPK1; BRCA2; BRCA1; HMGA2; and Her2 were analyzed via branched-DNA assay (b-DNA. ACTB, GAPDH, and HPRT1 were used as data normalizers. Overall, the relative gene expression of the two different origins of samples showed an agreement of 63%. Still, care should be taken, as FFPE specimens showed lower expression of the analyzed targets when compared to FF samples. The fact that the gene expression in FFPE proved to be lower than in FF specimens is likely to have been caused by the effect of storage time. ACTB had the best performance as a data normalizer.

  4. Improvement of Learning and Memory Induced by Cordyceps Polypeptide Treatment and the Underlying Mechanism

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    Guangxin Yuan

    2018-01-01

    Full Text Available Our previous research revealed that Cordyceps militaris can improve the learning and memory, and although the main active ingredient should be its polypeptide complexes, the underlying mechanism of its activity remains poorly understood. In this study, we explored the mechanisms by which Cordyceps militaris improves learning and memory in a mouse model. Mice were given scopolamine hydrobromide intraperitoneally to establish a mouse model of learning and memory impairment. The effects of Cordyceps polypeptide in this model were tested using the Morris water maze test; serum superoxide dismutase activity; serum malondialdehyde levels; activities of acetyl cholinesterase, Na+-k+-ATPase, and nitric oxide synthase; and gamma aminobutyric acid and glutamate contents in brain tissue. Moreover, differentially expressed genes and the related cellular signaling pathways were screened using an mRNA expression profile chip. The results showed that the genes Pik3r5, Il-1β, and Slc18a2 were involved in the effects of Cordyceps polypeptide on the nervous system of these mice. Our findings suggest that Cordyceps polypeptide may improve learning and memory in the scopolamine-induced mouse model of learning and memory impairment by scavenging oxygen free radicals, preventing oxidative damage, and protecting the nervous system.

  5. Association of body mass index with ER, PR and 14-3-3σ expression in tumor and stroma of type I and type II endometrial carcinoma.

    Science.gov (United States)

    Peevey, Joseph F; Seagle, Brandon-Luke L; Maniar, Kruti P; Kim, J Julie

    2017-06-27

    Obesity is a prominent risk factor for endometrial cancer (EC) and can impede on surgical and hormonal treatments. Markers of EC, estrogen receptor (ER), progesterone receptor (PR), phospho(Ser473)-AKT (pAKT) and 14-3-3 sigma (14-3-3σ) were measured in EC tissues in both the tumor and stroma and grouped by body mass index (BMI). Immunohistochemical scoring of 82 cases of Type 1 and Type II EC tissues revealed a significantly increased tumor expression of ER, PR and 14-3-3σ in women with Type I (BMI PR and 14-3-3σ in the tumor epithelium was significantly higher in Type I than Type II. In particular, Type I EC exhibited significantly increased levels of only PR from patients with BMI > 40 compared to BMI PR, PIK3CA, PTEN and SFN (gene for 14-3-3σ) confirmed increased PR expression in EC of obese women. In conclusion, ER, PR and 14-3-3σ are differentially regulated in Type I compared to Type II EC while PR is dysregulated in obese women with Type I EC. These findings have potential implications for efficacy of progestin treatment in obese women.

  6. Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients; Biomarcadores y terapeutica ANTI-EGFR en el cancer colorrectal metastasico en pacientes con K-Ras no mutado

    Energy Technology Data Exchange (ETDEWEB)

    Diaz Rubio Garcia, E

    2009-07-01

    The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have emerged in combination with the standard cytotoxic chemotherapy (FOLFOX and FOLFIRI). However, the benefit from cetuximab and panitumumab is only confined to KRAS-wild type (KRAS-wt) colorectal tumors, while KRAS mutated tumors do not respond to these drugs. The 65 % of colorectal tumors are KRAS-wt tumors, but efficacy of antiEGFR therapies is detected only in 60-70 % of these KRAS-wt tumors. Other biomarkers and molecular pathways must be involved in the response of the antiEGFR therapies for the KRAS-wt colorectal tumors, such as the EGFR ligands, the EGFR-phosphorilated levels, the number of EGFR copies, the status of the KRAS effected B-RAF and the alternative intracellular signaling pathways PIK3CA/PTEN/AKT and JAK/STAT. A battery of these biomarkers is needed to select the most sensitive patients to the antiEGFR therapies. This pattern may represent a novel favorable cost-effectiveness tool to develop tailored treatments. A review of these biomarkers and molecular pathways, involved in the antiEGFR therapies response, is performed. (Author) 68 refs.

  7. Exosomal protein interactors as emerging therapeutic targets in urothelial bladder cancer

    International Nuclear Information System (INIS)

    Kumari, N.; Saxena, S.; Agrawal, U.

    2015-01-01

    Background: Exosomes are rich sources of biological material (proteins and nucleic acids) secreted by both tumor and normal cells, and found in urine of urinary bladder cancer patients. Objective: The objective of the study was to identify interacting exosomal proteins in bladder cancer for future use in targeted therapy. Methods: The Exocarta database (www.exocarta.org) was mined for urinary bladder cancer specific exosomal proteins. The urinary bladder cancer specific exosomal proteins (n = 248) were analyzed to identify enriched pathways by Onto-tool Pathway Express (http://vortex.cs.wayne.edu/ ontoexpress). Results: Enriched pathways included cellular architecture, motility, cell to cell adhesion, tumorigenesis and metastasis. Proteins in the 9 top-ranked pathways included CTNNA1 (alpha-catenin), CTNNB1 (beta-catenin), VSAP, ITGA4, PAK1, DDR1, CDC42, RHOA, NRAS, RHO, PIK3AR1, MLC1, MMRN1, and CTTNBP2 and network analysis revealed 10 important hub proteins and identified inferred interactor NF2. Conclusions: The importance of identifying interactors is that that they can be used as targets for therapy, for example, using Bevacizumab (avastin - an angiogenesis inhibitor) against NF2 to inhibit protein-protein interactions will inhibit tumor growth and progression by hindering the exosome biogenesis

  8. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

    Science.gov (United States)

    Wain, Louise V; Verwoert, Germaine C; O’Reilly, Paul F; Shi, Gang; Johnson, Toby; Johnson, Andrew D; Bochud, Murielle; Rice, Kenneth M; Henneman, Peter; Smith, Albert V; Ehret, Georg B; Amin, Najaf; Larson, Martin G; Mooser, Vincent; Hadley, David; Dörr, Marcus; Bis, Joshua C; Aspelund, Thor; Esko, Tõnu; Janssens, A Cecile JW; Zhao, Jing Hua; Heath, Simon; Laan, Maris; Fu, Jingyuan; Pistis, Giorgio; Luan, Jian’an; Arora, Pankaj; Lucas, Gavin; Pirastu, Nicola; Pichler, Irene; Jackson, Anne U; Webster, Rebecca J; Zhang, Feng; Peden, John F; Schmidt, Helena; Tanaka, Toshiko; Campbell, Harry; Igl, Wilmar; Milaneschi, Yuri; Hotteng, Jouke-Jan; Vitart, Veronique; Chasman, Daniel I; Trompet, Stella; Bragg-Gresham, Jennifer L; Alizadeh, Behrooz Z; Chambers, John C; Guo, Xiuqing; Lehtimäki, Terho; Kühnel, Brigitte; Lopez, Lorna M; Polašek, Ozren; Boban, Mladen; Nelson, Christopher P; Morrison, Alanna C; Pihur, Vasyl; Ganesh, Santhi K; Hofman, Albert; Kundu, Suman; Mattace-Raso, Francesco US; Rivadeneira, Fernando; Sijbrands, Eric JG; Uitterlinden, Andre G; Hwang, Shih-Jen; Vasan, Ramachandran S; Wang, Thomas J; Bergmann, Sven; Vollenweider, Peter; Waeber, Gérard; Laitinen, Jaana; Pouta, Anneli; Zitting, Paavo; McArdle, Wendy L; Kroemer, Heyo K; Völker, Uwe; Völzke, Henry; Glazer, Nicole L; Taylor, Kent D; Harris, Tamara B; Alavere, Helene; Haller, Toomas; Keis, Aime; Tammesoo, Mari-Liis; Aulchenko, Yurii; Barroso, Inês; Khaw, Kay-Tee; Galan, Pilar; Hercberg, Serge; Lathrop, Mark; Eyheramendy, Susana; Org, Elin; Sõber, Siim; Lu, Xiaowen; Nolte, Ilja M; Penninx, Brenda W; Corre, Tanguy; Masciullo, Corrado; Sala, Cinzia; Groop, Leif; Voight, Benjamin F; Melander, Olle; O’Donnell, Christopher J; Salomaa, Veikko; d’Adamo, Adamo Pio; Fabretto, Antonella; Faletra, Flavio; Ulivi, Sheila; Del Greco, M Fabiola; Facheris, Maurizio; Collins, Francis S; Bergman, Richard N; Beilby, John P; Hung, Joseph; Musk, A William; Mangino, Massimo; Shin, So-Youn; Soranzo, Nicole; Watkins, Hugh; Goel, Anuj; Hamsten, Anders; Gider, Pierre; Loitfelder, Marisa; Zeginigg, Marion; Hernandez, Dena; Najjar, Samer S; Navarro, Pau; Wild, Sarah H; Corsi, Anna Maria; Singleton, Andrew; de Geus, Eco JC; Willemsen, Gonneke; Parker, Alex N; Rose, Lynda M; Buckley, Brendan; Stott, David; Orru, Marco; Uda, Manuela; van der Klauw, Melanie M; Zhang, Weihua; Li, Xinzhong; Scott, James; Chen, Yii-Der Ida; Burke, Gregory L; Kähönen, Mika; Viikari, Jorma; Döring, Angela; Meitinger, Thomas; Davies, Gail; Starr, John M; Emilsson, Valur; Plump, Andrew; Lindeman, Jan H; ’t Hoen, Peter AC; König, Inke R; Felix, Janine F; Clarke, Robert; Hopewell, Jemma C; Ongen, Halit; Breteler, Monique; Debette, Stéphanie; DeStefano, Anita L; Fornage, Myriam; Mitchell, Gary F; Smith, Nicholas L; Holm, Hilma; Stefansson, Kari; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Samani, Nilesh J; Preuss, Michael; Rudan, Igor; Hayward, Caroline; Deary, Ian J; Wichmann, H-Erich; Raitakari, Olli T; Palmas, Walter; Kooner, Jaspal S; Stolk, Ronald P; Jukema, J Wouter; Wright, Alan F; Boomsma, Dorret I; Bandinelli, Stefania; Gyllensten, Ulf B; Wilson, James F; Ferrucci, Luigi; Schmidt, Reinhold; Farrall, Martin; Spector, Tim D; Palmer, Lyle J; Tuomilehto, Jaakko; Pfeufer, Arne; Gasparini, Paolo; Siscovick, David; Altshuler, David; Loos, Ruth JF; Toniolo, Daniela; Snieder, Harold; Gieger, Christian; Meneton, Pierre; Wareham, Nicholas J; Oostra, Ben A; Metspalu, Andres; Launer, Lenore; Rettig, Rainer; Strachan, David P; Beckmann, Jacques S; Witteman, Jacqueline CM; Erdmann, Jeanette; van Dijk, Ko Willems; Boerwinkle, Eric; Boehnke, Michael; Ridker, Paul M; Jarvelin, Marjo-Riitta; Chakravarti, Aravinda; Abecasis, Goncalo R; Gudnason, Vilmundur; Newton-Cheh, Christopher; Levy, Daniel; Munroe, Patricia B; Psaty, Bruce M; Caulfield, Mark J; Rao, Dabeeru C

    2012-01-01

    Numerous genetic loci influence systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans 1-3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N=74,064) and follow-up studies (N=48,607), we identified at genome-wide significance (P= 2.7×10-8 to P=2.3×10-13) four novel PP loci (at 4q12 near CHIC2/PDGFRAI, 7q22.3 near PIK3CG, 8q24.12 in NOV, 11q24.3 near ADAMTS-8), two novel MAP loci (3p21.31 in MAP4, 10q25.3 near ADRB1) and one locus associated with both traits (2q24.3 near FIGN) which has recently been associated with SBP in east Asians. For three of the novel PP signals, the estimated effect for SBP was opposite to that for DBP, in contrast to the majority of common SBP- and DBP-associated variants which show concordant effects on both traits. These findings indicate novel genetic mechanisms underlying blood pressure variation, including pathways that may differentially influence SBP and DBP. PMID:21909110

  9. Molecular biomarkers for progression of intraductal papillary mucinous neoplasm of the pancreas.

    Science.gov (United States)

    Kuboki, Yuko; Shimizu, Kyoko; Hatori, Takashi; Yamamoto, Masakazu; Shibata, Noriyuki; Shiratori, Keiko; Furukawa, Toru

    2015-03-01

    We aimed to identify molecular biomarkers for assessing the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN). We retrospectively investigated molecular aberrations and their associations with clinicopathological features in 172 IPMNs. GNAS and KRAS mutations were detected in 48% and 56% of IPMNs, respectively. No mutations of EGFR, PIK3CA GNAO1, GNAQ, or GNAI2 were observed. Significant associations were observed between IPMN morphological types and GNAS mutations, KRAS mutations, the expression of phosphorylated MAPK (pMAPK), AKT, and phosphorylated AKT (pAKT), nuclear accumulation of β-catenin, SMAD4 loss, and TP53 overexpression; histological grades and the expression of EGFR, pMAPK, AKT, and pAKT, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression; invasive phenotypes and KRAS mutations, the nuclear β-catenin, and SMAD4 loss; and prognosis and SMAD4 loss and TP53 overexpression. Multivariate analysis to compare prognostic impacts of multiple molecular features revealed that TP53 overexpression was an independent prognostic factor (P = 0.030; hazard ratio, 5.533). These results indicate that mutations in GNAS and KRAS, the expression of EGFR and pMAPK, the nuclear β-catenin, SMAD4 loss, and TP53 overexpression may be relevant for assessing the clinical course of IPMN, including its progression into different morphological types, invasion, and prognosis.

  10. Epidermal growth factor receptor signaling pathway is frequently altered in ampullary carcinoma at protein and genetic levels.

    Science.gov (United States)

    Mikhitarian, Kaidi; Pollen, Maressa; Zhao, Zhiguo; Shyr, Yu; Merchant, Nipun B; Parikh, Alexander; Revetta, Frank; Washington, M Kay; Vnencak-Jones, Cindy; Shi, Chanjuan

    2014-05-01

    Our objective was to explore alteration of the epidermal growth factor receptor (EGFR) signaling pathway in ampullary carcinoma. Immunohistochemical studies were employed to evaluate expression of amphiregulin as well as expression and activation of EGFR. A lab-developed assay was used to identify mutations in the EGFR pathway genes, including KRAS, BRAF, PIK3CA, PTEN, and AKT1. A total of 52 ampullary carcinomas were identified, including 25 intestinal-type and 24 pancreatobiliary-type tumors, with the intestinal type being associated with a younger age at diagnosis (P=0.03) and a better prognosis (PSMAD4 and BRAF. KRAS mutations at codons 12 and 13 did not adversely affect overall survival. In conclusion, EGFR expression and activation were different between intestinal- and pancreatobiliary-type ampullary carcinoma. KRAS mutation was common in both histologic types; however, the incidence appeared to be lower in the pancreatobiliary type compared with its pancreatic counterpart, pancreatic ductal adenocarcinoma. Mutational analysis of the EGFR pathway genes may provide important insights into personalized treatment for patients with ampullary carcinoma.

  11. Mutational Context and Diverse Clonal Development in Early and Late Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Iver Nordentoft

    2014-06-01

    Full Text Available Bladder cancer (or urothelial cell carcinoma [UCC] is characterized by field disease (malignant alterations in surrounding mucosa and frequent recurrences. Whole-genome, exome, and transcriptome sequencing of 38 tumors, including four metachronous tumor pairs and 20 superficial tumors, identified an APOBEC mutational signature in one-third. This was biased toward the sense strand, correlated with mean expression level, and clustered near breakpoints. A > G mutations were up to eight times more frequent on the sense strand (p < 0.002 in [ACG]AT contexts. The patient-specific APOBEC signature was negatively correlated to repair-gene expression and was not related to clinicopathological parameters. Mutations in gene families and single genes were related to tumor stage, and expression of chromatin modifiers correlated with survival. Evolutionary and subclonal analyses of early/late tumor pairs showed a unitary origin, and discrete tumor clones contained mutated cancer genes. The ancestral clones contained Pik3ca/Kdm6a mutations and may reflect the field-disease mutations shared among later tumors.

  12. Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR

    Science.gov (United States)

    Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S.; Liu, Qingsong

    2016-01-01

    Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors. PMID:27077655

  13. Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel.

    Directory of Open Access Journals (Sweden)

    Aldo Scarpa

    Full Text Available Identification of driver mutations in lung adenocarcinoma has led to development of targeted agents that are already approved for clinical use or are in clinical trials. Therefore, the number of biomarkers that will be needed to assess is expected to rapidly increase. This calls for the implementation of methods probing the mutational status of multiple genes for inoperable cases, for which limited cytological or bioptic material is available. Cytology specimens from 38 lung adenocarcinomas were subjected to the simultaneous assessment of 504 mutational hotspots of 22 lung cancer-associated genes using 10 nanograms of DNA and Ion Torrent PGM next-generation sequencing. Thirty-six cases were successfully sequenced (95%. In 24/36 cases (67% at least one mutated gene was observed, including EGFR, KRAS, PIK3CA, BRAF, TP53, PTEN, MET, SMAD4, FGFR3, STK11, MAP2K1. EGFR and KRAS mutations, respectively found in 6/36 (16% and 10/36 (28% cases, were mutually exclusive. Nine samples (25% showed concurrent alterations in different genes. The next-generation sequencing test used is superior to current standard methodologies, as it interrogates multiple genes and requires limited amounts of DNA. Its applicability to routine cytology samples might allow a significant increase in the fraction of lung cancer patients eligible for personalized therapy.

  14. Hyperon Beam Experiment

    CERN Multimedia

    2002-01-01

    The experiment WA89 uses the upgraded Omega facility together with a hyperon beam installed at the end of the H1 beamline. The beam can deliver 2~10$ ^{5} \\% Sigma ^- $ per machine burst at 330 GeV/c with a background of 5 10$ ^{5} \\% \\pi ^- $. \\\\ \\\\ The goals of the experiment are: observation of charmed particles, mainly the charmed-strange baryons and measurements of their production in the kinematical range x$ _{F} $~$>$~0.2, and their decay properties, a search for exotic states such as U(3100) observed in the previous CERN hyperon beam experiment WA62, measurements of hyperon polarization and production properties. \\\\ \\\\ A vertex detector consisting of 24 silicon microstrip planes with 25~$\\mu$m pitch and 6~planes with 50~$\\mu$m pitch provides track measurements of sufficient accuracy to identify the decays of short living charmed particles and measure their lifetimes. A RICH detector provides good $\\pi$/K separation for momenta up to 100~GeV/c and $\\pi$/p separation up to 150~GeV/c. Photons are detecte...

  15. RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemotherapy sensitivity in acute megakaryocytic leukemia.

    Science.gov (United States)

    Edwards, Holly; Xie, Chengzhi; LaFiura, Katherine M; Dombkowski, Alan A; Buck, Steven A; Boerner, Julie L; Taub, Jeffrey W; Matherly, Larry H; Ge, Yubin

    2009-09-24

    RUNX1 (AML1) encodes the core binding factor alpha subunit of a heterodimeric transcription factor complex which plays critical roles in normal hematopoiesis. Translocations or down-regulation of RUNX1 have been linked to favorable clinical outcomes in acute leukemias, suggesting that RUNX1 may also play critical roles in chemotherapy responses in acute leukemias; however, the molecular mechanisms remain unclear. The median level of RUNX1b transcripts in Down syndrome (DS) children with acute megakaryocytic leukemia (AMkL) were 4.4-fold (P regulation of PIK3CD by RUNX1 was further confirmed by chromatin immunoprecipitation and promoter reporter gene assays. Further, a PI3-kinase inhibitor, LY294002, and cytosine arabinoside synergized in antileukemia effects on Meg-01 and primary pediatric AMkL cells. Our results suggest that RUNX1 may play a critical role in chemotherapy response in AMkL by regulating the PI3-kinase/Akt pathway. Thus, the treatment of AMkL may be improved by integrating PI3-kinase or Akt inhibitors into the chemotherapy of this disease.

  16. Start of operation of the barrel measuring facility II-01. Implementation into operational processes

    International Nuclear Information System (INIS)

    Buesing, B.; Escher, M.

    2013-01-01

    For the operation of the barrel measuring facility (FAME) II-01 a variety requirements to the measuring techniques were defined and tested in the frame of start-up. The used mechanical engineering and measuring technique complies with the state-of-the-art. Using the barrel measuring facility quality assured determinations of the dose rate and the nuclide-specific activity inventory were performed. For the evaluation of the gamma spectrometric measurements of FAME II-01 appropriately qualified personnel is available. The implementation of the facility in combination with the connection to the data base system PIK-AS and AVK it guaranteed that important data are available in real-time for the measuring process and the subsequent work steps. Besides this it is guaranteed that using the import/export functions relevant data are reviewed, supplemented and exchanged between the systems without transfer errors. The determined data of the dose rate and gamma spectrometric measurements allow an activity determination of the waste package with quality assurance and close to reality. Conservative assumptions in the frame of activity calculations for the later final disposal can be reduced. The automated operation of FAME allows also the reduction of radiation exposure of the personnel.

  17. Female Aging Alters Expression of Human Cumulus Cells Genes that Are Essential for Oocyte Quality

    Directory of Open Access Journals (Sweden)

    Tamadir Al-Edani

    2014-01-01

    Full Text Available Impact of female aging is an important issue in human reproduction. There was a need for an extensive analysis of age impact on transcriptome profile of cumulus cells (CCs to link oocyte quality and developmental potential with patient’s age. CCs from patients of three age groups were analyzed individually using microarrays. RT-qPCR validation was performed on independent CC cohorts. We focused here on pathways affected by aging in CCs that may explain the decline of oocyte quality with age. In CCs collected from patients >37 years, angiogenic genes including ANGPTL4, LEPR, TGFBR3, and FGF2 were significantly overexpressed compared to patients of the two younger groups. In contrast genes implicated in TGF-β signaling pathway such as AMH, TGFB1, inhibin, and activin receptor were underexpressed. CCs from patients whose ages are between 31 and 36 years showed an overexpression of genes related to insulin signaling pathway such as IGFBP3, PIK3R1, and IGFBP5. A bioinformatic analysis was performed to identify the microRNAs that are potential regulators of the differentially expressed genes of the study. It revealed that the pathways impacted by age were potential targets of specific miRNAs previously identified in our CCs small RNAs sequencing.

  18. Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort.

    Science.gov (United States)

    Rae, William; Ward, Daniel; Mattocks, Christopher J; Gao, Yifang; Pengelly, Reuben J; Patel, Sanjay V; Ennis, Sarah; Faust, Saul N; Williams, Anthony P

    2017-09-01

    Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG , CTLA4 , NFKB1 , GATA2 , CD40LG and TAZ as well as previously reported pathogenic variants in STAT3 , PIK3CD , STAT1 , NFKB2 and STXBP2 . AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

  19. HER2 activating mutations are targets for colorectal cancer treatment.

    Science.gov (United States)

    Kavuri, Shyam M; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M; Migliardi, Giorgia; Searleman, Adam C; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A; Bertotti, Andrea; Bose, Ron

    2015-08-01

    The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs. HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. ©2015 American Association for Cancer Research.

  20. Engineering progress of CNS concept in Hanaro

    International Nuclear Information System (INIS)

    Choi, C.O.; Park, K.N.; Park, S.H.

    1997-01-01

    The Korea Atomic Energy research Institute (KAERI) strives to provide utilizing facilities on and around the Hanaro reactor in order to activate advanced researches by neutron application. As one of the facilities to be installed, the conceptual design work of CNS was started in 1996 with a project schedule of 5 years so that its installation work can be finished by the year 2000. And the major engineering targets of this CNS facility are established for a minimum physical interference with the present facilities of the Hanaro, a reach-out of very-high-gain factors in the cold neutron flux, a simplicity of the maintenance of the facility, and a safety in the operation of the facility as well as the reactor. For the conceptual design of Hanaro CNS, the experience of utilization and production of cold neutron at WWR-M reactor Gatchina, Russia has been used with that of elaborations for PIK reactor in design for neutron guide systems and instruments. (author)

  1. Basaloid carcinoma of the pancreas--clinicopathological presentation and oncogenetic snapshot of a rare entity.

    Science.gov (United States)

    Szasz, A Marcell; Szirtes, Ildiko; Tihanyi, Balazs; Barkaszi, Bernadett; Baranyai, Zsolt; Tihanyi, Tibor; Harsanyi, Laszlo; Timar, Jozsef; Kulka, Janina

    2015-02-01

    We report a case of basaloid pancreatic carcinoma with clinical, pathological, and genomic data. The 73-year-old male patient had jaundice, acholic stool, diarrhea, weight loss, and a large, painless gall bladder. His GGT was highly elevated. The pancreatic head contained a tumor, which was resected by partial pancreatoduodenectomy with pancreato-gastric anastomosis, cholecystectomy, and lymphadenectomy. On gross examination, a 3.8-cm white firm nodule was found, which microscopically was composed of basaloid cell nests with a less than usual desmoplastic stromal background and focally PANIN. Immunohistochemical profile displayed strong CK5/6, CK19, p63, EGFR, vimentin, and evident CK14 expression and absence of expression of CK7, chromogranin, synaptophysin, and BRCA1. A high Ki-67 index and p53 expression were noted. Sequencing of the most frequent 46 oncogenes with ionTorrent (AmpliSeq PCR) method identified PIK3CA, KRAS, and TP53 genes as drivers and variants of the FGFR3, PDGFRA, KIT, KDR, EGFR, RET, and ATM genes. The tumor we report displays histopathological appearances similar to the previously described case and a genomic landscape fitting to the general population of pancreatic carcinomas. We hypothesize that this tumor may belong to the group of DNA damage repair-deficient pancreatic carcinoma subgroup.

  2. KIF26B, a novel oncogene, promotes proliferation and metastasis by activating the VEGF pathway in gastric cancer.

    Science.gov (United States)

    Zhang, H; Ma, R-R; Wang, X-J; Su, Z-X; Chen, X; Shi, D-B; Guo, X-Y; Liu, H-T; Gao, P

    2017-10-05

    Tumor metastasis is the main reason of cancer-related death for gastric cancer (GC) patients and gene expression microarray data indicate that kinesin family member 26B (KIF26B) is one of the most upregulated genes in metastatic GC samples. Specifically, KIF26B expression was upregulated in a stepwise manner from non-tumorous gastric mucosa, primary GC tissues without metastasis, via primary GC tissues with metastasis, to secondary lymph node metastatic (LNM) foci. Increased expression of KIF26B was correlated with tumor size, positive LNM or distant metastases and poor prognosis. KIF26B, negatively regulated by miR-372, promoted GC cell proliferation and metastasis in vitro and in vivo. Mechanistic investigations confirmed that the main target of KIF26B was the vascular endothelial growth factor (VEGF) signaling pathway, particularly by inhibition or overexpression of VEGFA, PXN, FAK, PIK3CA, BCL2 and CREB1. Thus, KIF26B, a novel oncogene regulated by miR-372, promotes proliferation and metastasis through the VEGF pathway in GC.

  3. Developmental programming: effect of prenatal steroid excess on intraovarian components of insulin signaling pathway and related proteins in sheep.

    Science.gov (United States)

    Ortega, Hugo H; Rey, Florencia; Velazquez, Melisa M L; Padmanabhan, Vasantha

    2010-06-01

    Prenatal testosterone (T) excess increases ovarian follicular recruitment, follicular persistence, insulin resistance, and compensatory hyperinsulinemia. Considering the importance of insulin in ovarian physiology, in this study, using prenatal T- and dihydrotestosterone (DHT, a nonaromatizable androgen)-treated female sheep, we tested the hypothesis that prenatal androgen excess alters the intraovarian insulin signaling cascade and metabolic mediators that have an impact on insulin signaling. Changes in ovarian insulin receptor (INSRB), insulin receptor substrate 1 (IRS1), mammalian target of rapamycin (MTOR), phosphatidylinositol 3-kinase (PIK3), peroxisome proliferator-activated receptor-gamma (PPARG), and adiponectin proteins were determined at fetal (Days 90 and 140), postpubertal (10 mo), and adult (21 mo) ages by immunohistochemistry. Results indicated that these proteins were expressed in granulosa, theca, and stromal compartments, with INSRB, IRS1, PPARG, and adiponectin increasing in parallel with advanced follicular differentiation. Importantly, prenatal T excess induced age-specific changes in PPARG and adiponectin expression, with increased PPARG expression evident during fetal life and decreased antral follicular adiponectin expression during adult life. Comparison of developmental changes in prenatal T and DHT-treated females found that the effects on PPARG were programmed by androgenic actions of T, whereas the effects on adiponectin were likely by its estrogenic action. These results suggest a role for PPARG in the programming of ovarian disruptions by prenatal T excess, including a decrease in antral follicular adiponectin expression and a contributory role for adiponectin in follicular persistence and ovulatory failure.

  4. A Network Pharmacology Approach to Uncover the Multiple Mechanisms of Hedyotis diffusa Willd. on Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Xinkui Liu

    2018-01-01

    Full Text Available Background. As one of the most frequently diagnosed cancer diseases globally, colorectal cancer (CRC remains an important cause of cancer-related death. Although the traditional Chinese herb Hedyotis diffusa Willd. (HDW has been proven to be effective for treating CRC in clinical practice, its definite mechanisms have not been completely deciphered. Objective. The aim of our research is to systematically explore the multiple mechanisms of HDW on CRC. Methods. This study adopted the network pharmacology approach, which was mainly composed of active component gathering, target prediction, CRC gene collection, network analysis, and gene enrichment analysis. Results. The network analysis showed that 10 targets might be the therapeutic targets of HDW on CRC, namely, HRAS, PIK3CA, KRAS, TP53, APC, BRAF, GSK3B, CDK2, AKT1, and RAF1. The gene enrichment analysis implied that HDW probably benefits patients with CRC by modulating pathways related to cancers, infectious diseases, endocrine system, immune system, nervous system, signal transduction, cellular community, and cell motility. Conclusions. This study partially verified and predicted the pharmacological and molecular mechanism of HDW against CRC from a holistic perspective, which will also lay a foundation for the further experimental research and clinical rational application of HDW.

  5. Gene Mutation Profiles in Primary Diffuse Large B Cell Lymphoma of Central Nervous System: Next Generation Sequencing Analyses

    Science.gov (United States)

    Todorovic Balint, Milena; Jelicic, Jelena; Mihaljevic, Biljana; Kostic, Jelena; Stanic, Bojana; Balint, Bela; Pejanovic, Nadja; Lucic, Bojana; Tosic, Natasa; Marjanovic, Irena; Stojiljkovic, Maja; Karan-Djurasevic, Teodora; Perisic, Ognjen; Rakocevic, Goran; Popovic, Milos; Raicevic, Sava; Bila, Jelena; Antic, Darko; Andjelic, Bosko; Pavlovic, Sonja

    2016-01-01

    The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach. PMID:27164089

  6. Molecular alterations in lesions of anogenital mammary-like glands and their mammary counterparts including hidradenoma papilliferum, intraductal papilloma, fibroadenoma and phyllodes tumor.

    Science.gov (United States)

    Konstantinova, Anastasia M; Vanecek, Tomas; Martinek, Petr; Kyrpychova, Liubov; Spagnolo, Dominic V; Stewart, Colin J R; Portelli, Francesca; Michal, Michal; Kazakov, Dmitry V

    2017-06-01

    Lesions affecting anogenital mammary-like glands (AGMLG) are histopathologically very similar to those seen in the breast but whether this morphological similarity is also reflected at the genetic level is unknown. To compare the underlying molecular mechanisms in lesions of AGMLG and their mammary counterparts, we analyzed the mutational profile of 16 anogenital neoplasms including 5 hidradenomas papilliferum (HP), 1 lesion with features of HP and fibroadenoma (FA), 7 FA, 3 phyllodes tumors (PhT)) and 18 analogous breast lesions (6 intraductal papillomas (IDP), 9 FA, and 3 PhT) by high-coverage next generation sequencing (NGS) using a panel comprising 50 cancer-related genes. Additionally, all cases were analyzed for the presence of a mutation in the MED12 gene. All detected mutations with allele frequencies over 20% were independently validated by Sanger sequencing (concordance: 100%). Mutations in PIK3CA, AKT1, MET, ABL1 and TP53 genes were found in lesions of AGMLG and also their mammary counterparts. The PI3K-AKT cascade plays a role in tumors arising at both sites. It appears that some histopathologically similar anogenital and breast lesions develop along similar molecular pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. The challenge of reducing scientific complexity for different target groups (without losing the essence) - experiences from interdisciplinary audio-visual media production

    Science.gov (United States)

    Hezel, Bernd; Broschkowski, Ephraim; Kropp, Jürgen

    2013-04-01

    The Climate Media Factory originates from an interdisciplinary media lab run by the Film and Television University "Konrad Wolf" Potsdam-Babelsberg (HFF) and the Potsdam Institute for Climate Impact Research (PIK). Climate scientists, authors, producers and media scholars work together to develop media products on climate change and sustainability. We strive towards communicating scientific content via different media platforms reconciling the communication needs of scientists and the audience's need to understand the complexity of topics that are relevant in their everyday life. By presenting four audio-visual examples, that have been designed for very different target groups, we show (i) the interdisciplinary challenges during the production process and the lessons learnt and (ii) possibilities to reach the required degree of simplification without the need for dumbing down the content. "We know enough about climate change" is a short animated film that was produced for the German Agency for International Cooperation (GIZ) for training programs and conferences on adaptation in the target countries including Indonesia, Tunisia and Mexico. "Earthbook" is a short animation produced for "The Year of Science" to raise awareness for the topics of sustainability among digital natives. "What is Climate Engineering?". Produced for the Institute for Advanced Sustainability Studies (IASS) the film is meant for an informed and interested public. "Wimmelwelt Energie!" is a prototype of an iPad application for children from 4-6 years of age to help them learn about different forms of energy and related greenhouse gas emissions.

  8. Measurement of Telomere Length in Colorectal Cancers for Improved Molecular Diagnosis

    Directory of Open Access Journals (Sweden)

    Eric Le Balc’h

    2017-08-01

    Full Text Available All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs using TRF (Telomere Restriction Fragment analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B, PIK3CA (phosphatidylinositol 3-kinase catalytic subunit, or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor.

  9. Rapid targeted somatic mutation analysis of solid tumors in routine clinical diagnostics.

    Science.gov (United States)

    Magliacane, Gilda; Grassini, Greta; Bartocci, Paola; Francaviglia, Ilaria; Dal Cin, Elena; Barbieri, Gianluca; Arrigoni, Gianluigi; Pecciarini, Lorenza; Doglioni, Claudio; Cangi, Maria Giulia

    2015-10-13

    Tumor genotyping is an essential step in routine clinical practice and pathology laboratories face a major challenge in being able to provide rapid, sensitive and updated molecular tests. We developed a novel mass spectrometry multiplexed genotyping platform named PentaPanel to concurrently assess single nucleotide polymorphisms in 56 hotspots of the 5 most clinically relevant cancer genes, KRAS, NRAS, BRAF, EGFR and PIK3CA for a total of 221 detectable mutations. To both evaluate and validate the PentaPanel performance, we investigated 1025 tumor specimens of 6 different cancer types (carcinomas of colon, lung, breast, pancreas, and biliary tract, and melanomas), systematically addressing sensitivity, specificity, and reproducibility of our platform. Sanger sequencing was also performed for all the study samples. Our data showed that PentaPanel is a high throughput and robust tool, allowing genotyping for targeted therapy selection of 10 patients in the same run, with a practical turnaround time of 2 working days. Importantly, it was successfully used to interrogate different DNAs isolated from routinely processed specimens (formalin-fixed paraffin embedded, frozen, and cytological samples), covering all the requirements of clinical tests. In conclusion, the PentaPanel platform can provide an immediate, accurate and cost effective multiplex approach for clinically relevant gene mutation analysis in many solid tumors and its utility across many diseases can be particularly relevant in multiple clinical trials, including the new basket trial approach, aiming to identify appropriate targeted drug combination strategies.

  10. A side-effect free method for identifying cancer drug targets.

    Science.gov (United States)

    Ashraf, Md Izhar; Ong, Seng-Kai; Mujawar, Shama; Pawar, Shrikant; More, Pallavi; Paul, Somnath; Lahiri, Chandrajit

    2018-04-27

    Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

  11. A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas.

    Directory of Open Access Journals (Sweden)

    Chao Ling

    Full Text Available Previous genetic studies on colorectal carcinomas (CRC have identified multiple somatic mutations in four candidate pathways (TGF-β, Wnt, P53 and RTK-RAS pathways on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

  12. The organization of the fuc regulon specifying L-fucose dissimilation in Escherichia coli K12 as determined by gene cloning.

    Science.gov (United States)

    Chen, Y M; Zhu, Y; Lin, E C

    1987-12-01

    In Escherichia coli the six known genes specifying the utilization of L-fucose as carbon and energy source cluster at 60.2 min and constitute a regulon. These genes include fucP (encoding L-fucose permease), fucI (encoding L-fucose isomerase), fucK (encoding L-fuculose kinase), fucA (encoding L-fuculose 1-phosphate aldolase), fucO (encoding L-1,2-propanediol oxidoreductase), and fucR (encoding the regulatory protein). In this study the fuc genes were cloned and their positions on the chromosome were established by restriction endonuclease and complementation analyses. Clockwise, the gene order is: fucO-fucA-fucP-fucI-fucK-fucR. The operons comprising the structural genes and the direction of transcription were determined by complementation analysis and Southern blot hybridization. The fucPIK and fucA operons are transcribed clockwise. The fucO operon is transcribed counterclockwise. The fucR gene product activates the three structural operons in trans.

  13. Investigating the role of class-IA PI 3-kinase isoforms in adipocyte differentiation

    International Nuclear Information System (INIS)

    Kim, Ji Eun; Shepherd, Peter R.; Chaussade, Claire

    2009-01-01

    PI 3-kinases, in particular class-IA, are key signalling molecules controlling many cellular processes including growth, proliferation, migration and differentiation. In this study, we have used a collection of isoform selective PI 3-kinase inhibitors to determine whether attenuation of signalling through class-IA PI 3-kinase isoforms will impact adipocyte differentiation. First, we analysed the expression profiles and found that fibroblastic pre-adipocytes express detectable levels of p110α and p110δ and that after differentiation, p110δ levels fall while p110α levels rise, together with C/EBPα and PPARγ. When using specific inhibitors during the differentiation process, we observed that neither p110β nor p110δ inhibition, had any significant effect. In contrast PIK-75, a selective p110α inhibitor completely abolished adipocyte differentiation as assessed by morphology, transcript and protein levels of adipocyte markers. These results indicate that long term treatment with p110α inhibitors could potentially have a severe impact on fat cell numbers in vivo.

  14. Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis.

    Science.gov (United States)

    Ruprecht, Benjamin; Zaal, Esther A; Zecha, Jana; Wu, Wei; Berkers, Celia R; Kuster, Bernhard; Lemeer, Simone

    2017-04-15

    HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases, and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an extensive and exclusively phosphorylation-mediated reprogramming of glycolytic activity, supported additionally by widespread changes of corresponding metabolites and an increased sensitivity towards glycolysis inhibition. Collectively, our multi-omic analysis offers deeper perspectives on cancer drug resistance and suggests new biomarkers and treatment options for lapatinib-resistant cancers. Cancer Res; 77(8); 1842-53. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. PI3K inhibition to overcome endocrine resistance in breast cancer.

    Science.gov (United States)

    Keegan, Niamh M; Gleeson, Jack P; Hennessy, Bryan T; Morris, Patrick G

    2018-01-01

    Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

  16. A spectral algorithm for the seriation problem

    Energy Technology Data Exchange (ETDEWEB)

    Atkins, J.E. [Michigan Univ., Ann Arbor, MI (United States). Dept. of Mathematics; Boman, E.G. [Stanford Univ., CA (United States). Dept. of Computer Science; Hendrickson, B. [Sandia National Labs., Albuquerque, NM (United States)

    1994-11-01

    Given a set of objects and a correlation function f reflecting the desire for two items to be near each other, find all sequences {pi} of the items so that correlation preferences are preserved; that is if {pi}(i) < {pi}(j) < {pi}(k) then f(i,j) {ge} f(i,k) and f(j,k) {ge} f(i,k). This seriation problem has numerous applications, for instance, solving it yields a solution to the consecutive ones problem. We present a spectral algorithm for this problem that has a number of interesting features. Whereas most previous applications of spectral techniques provided bounds or heuristics, our result is an algorithm for a nontrivial combinatorial problem. Our analysis introduces powerful tools from matrix theory to the theoretical computer science community. Also, spectral methods are being applied as heuristics for a variety of sequencing problems and our result helps explain and justify these applications. Although the worst case running time for our approach is not competitive with that of existing methods for well posed problem instances, unlike combinatorial approaches our algorithm remains a credible heuristic for the important cases where there are errors in the data.

  17. ECONOMIC UNITY OF PRODUCTION AND TRADE OF SLAUGHTER ANIMALS AND MEAT (PATHS OF INITIATION OF LONG TERM SOLUTIONS IN CROATIAN ANIMAL BREEDING

    Directory of Open Access Journals (Sweden)

    Krsto Benčević

    2000-06-01

    Full Text Available For starting a long term programmes in Croatian animal production, formation of "economic unities" is necessary. Presentation and explanation of production and trade unity for animal production and marketing with subjects and phases is given here. It is pointed out that production of slaughter animals and meat is key interest of market and economic policy as well as of development of agricultural country. It seems that production and trade of meat in Croatia is not organized enough in overall market competition and in meat processing. Creating the economic unity of production and trade of slaughter animals can help in relative fast and efficient solving of problems accumulated in agriculture, especialy in meat production (PIK Vrbovec, Danica, Bejle etc. For initiating and getting in function the phases of production and trade of slaughter animals and meat, proper legislation should be introduced. This legislation should comprehencively define the idea of agricultural economy as a subject of legislative and normisation acts for overall, process and market oriented functioning of multidisciplinary agricultural systems. Additionaly, law on trade of slaughter animals, meat and agricultural products should be introduced in order to form a market and determine the share and obligations of certain participants in structure of such market.

  18. Surgical trauma induces overgrowth in lower limb gigantism: regulation with use of rapamycin is promising.

    Science.gov (United States)

    Pinto, Rohan Sebastian; Harrison, William David; Graham, Kenneth; Nayagam, Durai

    2018-01-04

    We describe an unclassified overgrowth syndrome characterised by unregulated growth of dermal fibroblasts in the lower limbs of a 35-year-old woman. A PIK3CA gene mutation resulted in lower limb gigantism. Below the waist, she weighed 117 kg with each leg measuring over 100 cm in circumference. Her total adiposity was 50% accounted for by her legs mainly. Liposuction and surgical debulking were performed to reduce the size of the limbs but had exacerbated the overgrowth in her lower limbs. Systemic sepsis from an infected foot ulcer necessitated treatment by an above-knee amputation. Postoperatively, the stump increased in size by 19 kg. A trial of rapamycin to reverse the growth of the stump has shown promise. We discuss the clinical and genetic features of this previously unclassified disorder and the orthopaedic considerations involved. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Capture-based next-generation sequencing reveals multiple actionable mutations in cancer patients failed in traditional testing.

    Science.gov (United States)

    Xie, Jing; Lu, Xiongxiong; Wu, Xue; Lin, Xiaoyi; Zhang, Chao; Huang, Xiaofang; Chang, Zhili; Wang, Xinjing; Wen, Chenlei; Tang, Xiaomei; Shi, Minmin; Zhan, Qian; Chen, Hao; Deng, Xiaxing; Peng, Chenghong; Li, Hongwei; Fang, Yuan; Shao, Yang; Shen, Baiyong

    2016-05-01

    Targeted therapies including monoclonal antibodies and small molecule inhibitors have dramatically changed the treatment of cancer over past 10 years. Their therapeutic advantages are more tumor specific and with less side effects. For precisely tailoring available targeted therapies to each individual or a subset of cancer patients, next-generation sequencing (NGS) has been utilized as a promising diagnosis tool with its advantages of accuracy, sensitivity, and high throughput. We developed and validated a NGS-based cancer genomic diagnosis targeting 115 prognosis and therapeutics relevant genes on multiple specimen including blood, tumor tissue, and body fluid from 10 patients with different cancer types. The sequencing data was then analyzed by the clinical-applicable analytical pipelines developed in house. We have assessed analytical sensitivity, specificity, and accuracy of the NGS-based molecular diagnosis. Also, our developed analytical pipelines were capable of detecting base substitutions, indels, and gene copy number variations (CNVs). For instance, several actionable mutations of EGFR,PIK3CA,TP53, and KRAS have been detected for indicating drug susceptibility and resistance in the cases of lung cancer. Our study has shown that NGS-based molecular diagnosis is more sensitive and comprehensive to detect genomic alterations in cancer, and supports a direct clinical use for guiding targeted therapy.

  20. EVA1A/TMEM166 Regulates Embryonic Neurogenesis by Autophagy

    Directory of Open Access Journals (Sweden)

    Mengtao Li

    2016-03-01

    Full Text Available Self-renewal and differentiation of neural stem cells is essential for embryonic neurogenesis, which is associated with cell autophagy. However, the mechanism by which autophagy regulates neurogenesis remains undefined. Here, we show that Eva1a/Tmem166, an autophagy-related gene, regulates neural stem cell self-renewal and differentiation. Eva1a depletion impaired the generation of newborn neurons, both in vivo and in vitro. Conversely, overexpression of EVA1A enhanced newborn neuron generation and maturation. Moreover, Eva1a depletion activated the PIK3CA-AKT axis, leading to the activation of the mammalian target of rapamycin and the subsequent inhibition of autophagy. Furthermore, addition of methylpyruvate to the culture during neural stem cell differentiation rescued the defective embryonic neurogenesis induced by Eva1a depletion, suggesting that energy availability is a significant factor in embryonic neurogenesis. Collectively, these data demonstrated that EVA1A regulates embryonic neurogenesis by modulating autophagy. Our results have potential implications for understanding the pathogenesis of neurodevelopmental disorders caused by autophagy dysregulation.

  1. Mutational Analysis of Merkel Cell Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Erstad, Derek J. [Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States); Cusack, James C. Jr., E-mail: jcusack@mgh.harvard.edu [Division of Surgical Oncology, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (United States)

    2014-10-17

    Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge.