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PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide)

Identity

Other namesEC 2.7.1.153
MGC142161
MGC14216
PI3K
p110-alpha
HGNC (Hugo) PIK3CA
LocusID (NCBI) 5290
Location 3q26.32
Location_base_pair Starts at 178866311 and ends at 178952497 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order centromere-KCNMB2-ZMAT3-BC032034-PIK3CA-KCNMB3-ZNF639-MFN1-GNB4- telomere

DNA/RNA

 
  Relative size of the 21 exons of PIK3CA. The entire exon 1 is UTR (untranslated region). Exon numeration corresponds to the prevalent transcript (NM-006218).
Description The PIK3CA gene spans a total genomic size of 86,190 bases and is composed of 21 exons, 20 of them coding exons of varying lengths. Putative pseudogenes of PIK3CA have been described on chromosomes 16 (gi 28913054) and 22q11.2 (gi 5931525), the later one in the Cat Eye Syndrome region. These regions are highly homolog to the sequences of exons 9 and 11-13 of the PIK3CA gene.
Transcription The human PIK3CA transcript has an open reading frame of 3,207-bp, predicting a protein of 1,068 amino acid residues.

Protein

 
  p110alpha conserved domains. Through its adaptor binding domain p110alpha interacts with the regulatory subunit. C2 domain, protein-kinase-C-homology-2 domain.
Description The PIK3CA gene encodes the p110alpha protein which is a catalytic subunit of the class I PI 3-kinases (PI3K). Class I PI3K are heterodimeric molecules composed of a catalytic subunit, a p110, and a regulatory subunit. There are three possible calatytic subunits p110alpha, beta or delta.
Expression Widely expressed.
Localisation The p110alpha localizes in the cytoplasm.
Function Class I PI 3-kinases (PI3K) are linked to many cellular functions, including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. PI3K convert PI(4,5)P2 to PI(3,4,5)P3 on the inner leaflet of the plasma membrane. The PI(3,4,)P3 provokes the recruitment to cellular membranes of a variety of signalling proteins, containing PX domain, pleckstrin homology domains (PH domains), FYVE domains and other phosphoinositide-binding domains. One of these is the protein kinase B (PKB/AKT) a very well known protein that is activated as a result of its translocation to the cell membrane where it is then phosphorylated and activated by another kinase, called phosphoinositide dependent kinase 1 (PDK1). The phosphorylation of AKT leads to the activation of the TSC/mTOR pathway. PTEN, a tumor suppressor inactivated in many cancers counteracts the action of PI3K by dephosphorylating the phosphoinositide-3,4,5-trisphosphate (PIP3) (Lee et al., 2007).The PI3K are inhibited by the drugs wortmannin and LY294002 although to various degree of sensitivity among the different classes.

Mutations

Somatic Somatic mutations at the PIK3CA gene have been found in tumors and thus, it can be considered a bona fide oncogene (Samuels et al., 2004). Most of the mutations cluster in hotspots within the helical or the catalytic domains.

Implicated in

Entity A wide variety of human cancers
Note (for example, colon, breast, endometrial, ovarian, brain, lung, thyroid, head and neck and stomach).

PIK3CA mutations lead to constitutive activation of p110alpha enzymatic activity, stimulate AKT signaling, and allow growth factor-independent growth (Bader et al., 2005). In addition, when expressed in normal cells, these mutations allow anchorage-independent growth, further attesting to their important role in cancer development (Kang et al., 2005). PIK3CA somatic mutations are frequent in a variety of human primary tumors and cancer cell lines such as, among others, those of the colon, breast, and stomach (Samuels et al., 2004). However, in other tumors, i.e. those of the lung, head and neck, brain, endometrium, ovary, prostate, osteosarcoma and pancreas, hematopoietic malignancies, PIK3CA mutations are not as common (Angulo et al., 2008; Qiu et al., 2006; Muller et al., 2007; Samuels et al., 2004; Schonleben et al., 2006). PIK3CA gene amplification has also been proposed as a mechanism for oncogene activation in some tumors (Angulo et al., 2008). Because PIK3CA is now considered an important oncogene implicated in the development of a wide variety of human cancers, efforts are now being directed towards the development of molecules that inhibit the activity of PI3K (Garcia-Echeverria et al., 2008). These could be efficient in the treatment of those tumors carrying constitutive activation of PI3K pathway. PTEN is a well known tumor suppressor that counteracts the action of PI3K by dephosphorylating the phosphoinositide-3,4,5-trisphosphate (PIP3). Thus, the treatment with drugs that inhibit p110alpha activity would be also potentially efficient in patients whose tumors carry genetic alterations at PTEN.
It has recently been reported that activation of the PI3K pathway in breast tumors with concomitant ERBB2 gene amplification, either through PIK3CA mutations or PTEN inactivation, underlies trastuzumab resistance. These findings may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy (Berns et al., 2007).

  

To be noted

Recent evidence has shown that the PIK3CA gene is mutated and amplified in a range of human cancers. Due to that p110alpha is believed to be a promising drug target. A number of pharmaceutical companies are currently designing and charactering potential p110alpha isoform specific inhibitors.

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

External links

Nomenclature
HGNC (Hugo)PIK3CA   8975
Cards
AtlasPIK3CAID415ch3q26
Entrez_Gene (NCBI)PIK3CA  5290  phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
GeneCards (Weizmann)PIK3CA
Ensembl (Hinxton) [Gene_View]  chr3:178866311-178952497 [Contig_View]  PIK3CA [Vega]
cBioPortalPIK3CA
AceView (NCBI)PIK3CA
Genatlas (Paris)PIK3CA
WikiGenes5290
SOURCE (Princeton)NM_006218
Genomic and cartography
GoldenPath (UCSC)PIK3CA  -  3q26.32   chr3:178866311-178952497 +  3q26.3   [Description]    (hg19-Feb_2009)
EnsemblPIK3CA - 3q26.3 [CytoView]
Mapping of homologs : NCBIPIK3CA [Mapview]
OMIM114480   114500   114550   162900   167000   171834   182000   211980   602501   603387   612918   613659   615108   
Gene and transcription
Genbank (Entrez)AB210020 AK292940 AK297203 AK302608 AU129890
RefSeq transcript (Entrez)NM_006218
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_012113 NT_005612 NW_001838884 NW_004929311
Consensus coding sequences : CCDS (NCBI)PIK3CA
Cluster EST : UnigeneHs.715194 [ NCBI ]
CGAP (NCI)Hs.715194
Alternative Splicing : Fast-db (Paris)GSHG0021342
Gene ExpressionPIK3CA [ NCBI-GEO ]     PIK3CA [ SEEK ]   PIK3CA [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP42336 (Uniprot)
NextProtP42336  [Medical]
With graphics : InterProP42336
Splice isoforms : SwissVarP42336 (Swissvar)
Catalytic activity : Enzyme2.7.1.153 [ Enzyme-Expasy ]   2.7.1.1532.7.1.153 [ IntEnz-EBI ]   2.7.1.153 [ BRENDA ]   2.7.1.153 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PI3_4_KINASE_1 (PS00915)    PI3_4_KINASE_2 (PS00916)    PI3_4_KINASE_3 (PS50290)    PI3K_ABD (PS51544)    PI3K_C2 (PS51547)    PI3K_RBD (PS51546)    PIK_HELICAL (PS51545)   
Domains : Interpro (EBI)ARM-type_fold [organisation]   C2_dom [organisation]   Kinase-like_dom [organisation]   PI3/4_kinase_cat_dom [organisation]   PI3/4_kinase_CS [organisation]   PI3K_adapt-bd_dom [organisation]   PI3K_C2_dom [organisation]   PI3K_Ras-bd_dom [organisation]   PI_Kinase [organisation]   PInositide-3_kin_accessory_dom [organisation]   Ubiquitin-rel_dom [organisation]  
Related proteins : CluSTrP42336
Domain families : Pfam (Sanger)PI3_PI4_kinase (PF00454)    PI3K_C2 (PF00792)    PI3K_p85B (PF02192)    PI3K_rbd (PF00794)    PI3Ka (PF00613)   
Domain families : Pfam (NCBI)pfam00454    pfam00792    pfam02192    pfam00794    pfam00613   
Domain families : Smart (EMBL)C2 (SM00239)  PI3K_C2 (SM00142)  PI3K_p85B (SM00143)  PI3K_rbd (SM00144)  PI3Ka (SM00145)  PI3Kc (SM00146)  
DMDM Disease mutations5290
Blocks (Seattle)P42336
PDB (SRS)2ENQ    2RD0    3HHM    3HIZ    3ZIM    4JPS    4L1B    4L23    4L2Y   
PDB (PDBSum)2ENQ    2RD0    3HHM    3HIZ    3ZIM    4JPS    4L1B    4L23    4L2Y   
PDB (IMB)2ENQ    2RD0    3HHM    3HIZ    3ZIM    4JPS    4L1B    4L23    4L2Y   
PDB (RSDB)2ENQ    2RD0    3HHM    3HIZ    3ZIM    4JPS    4L1B    4L23    4L2Y   
Peptide AtlasP42336
HPRD01382
IPIIPI00031386   IPI00784619   IPI00946104   IPI00946100   
Protein Interaction databases
DIP (DOE-UCLA)P42336
IntAct (EBI)P42336
BioGRIDPIK3CA
InParanoidP42336
Interologous Interaction database P42336
IntegromeDBPIK3CA
STRING (EMBL)PIK3CA
Ontologies - Pathways
Ontology : AmiGOangiogenesis  vasculature development  protein serine/threonine kinase activity  protein binding  ATP binding  cytosol  plasma membrane  phosphatidylinositol 3-kinase complex  1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex  glucose metabolic process  protein phosphorylation  phospholipid metabolic process  phosphatidylinositol biosynthetic process  epidermal growth factor receptor signaling pathway  blood coagulation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  kinase activity  1-phosphatidylinositol-3-kinase activity  lamellipodium  platelet activation  protein kinase activator activity  T cell costimulation  positive regulation of peptidyl-serine phosphorylation  phosphatidylinositol 3-kinase activity  phosphatidylinositol 3-kinase activity  1-phosphatidylinositol-4-phosphate 3-kinase activity  phosphatidylinositol-3-phosphate biosynthetic process  phosphatidylinositol-3-phosphate biosynthetic process  insulin receptor signaling pathway via phosphatidylinositol 3-kinase  Fc-epsilon receptor signaling pathway  Fc-gamma receptor signaling pathway involved in phagocytosis  regulation of multicellular organism growth  protein kinase B signaling  negative regulation of neuron apoptotic process  endothelial cell migration  insulin receptor substrate binding  hypomethylation of CpG island  small molecule metabolic process  innate immune response  positive regulation of protein kinase activity  phosphatidylinositol phosphorylation  phosphatidylinositol-4,5-bisphosphate 3-kinase activity  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  T cell receptor signaling pathway  leukocyte migration  cardiac muscle contraction  negative regulation of fibroblast apoptotic process  regulation of genetic imprinting  negative regulation of anoikis  
Ontology : EGO-EBIangiogenesis  vasculature development  protein serine/threonine kinase activity  protein binding  ATP binding  cytosol  plasma membrane  phosphatidylinositol 3-kinase complex  1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex  glucose metabolic process  protein phosphorylation  phospholipid metabolic process  phosphatidylinositol biosynthetic process  epidermal growth factor receptor signaling pathway  blood coagulation  insulin receptor signaling pathway  fibroblast growth factor receptor signaling pathway  kinase activity  1-phosphatidylinositol-3-kinase activity  lamellipodium  platelet activation  protein kinase activator activity  T cell costimulation  positive regulation of peptidyl-serine phosphorylation  phosphatidylinositol 3-kinase activity  phosphatidylinositol 3-kinase activity  1-phosphatidylinositol-4-phosphate 3-kinase activity  phosphatidylinositol-3-phosphate biosynthetic process  phosphatidylinositol-3-phosphate biosynthetic process  insulin receptor signaling pathway via phosphatidylinositol 3-kinase  Fc-epsilon receptor signaling pathway  Fc-gamma receptor signaling pathway involved in phagocytosis  regulation of multicellular organism growth  protein kinase B signaling  negative regulation of neuron apoptotic process  endothelial cell migration  insulin receptor substrate binding  hypomethylation of CpG island  small molecule metabolic process  innate immune response  positive regulation of protein kinase activity  phosphatidylinositol phosphorylation  phosphatidylinositol-4,5-bisphosphate 3-kinase activity  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  T cell receptor signaling pathway  leukocyte migration  cardiac muscle contraction  negative regulation of fibroblast apoptotic process  regulation of genetic imprinting  negative regulation of anoikis  
Pathways : BIOCARTARegulation of eIF4e and p70 S6 Kinase [Genes]    TPO Signaling Pathway [Genes]    Thrombin signaling and protease-activated receptors [Genes]    EGF Signaling Pathway [Genes]    Role of Erk5 in Neuronal Survival [Genes]    Growth Hormone Signaling Pathway [Genes]    Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK) [Genes]    AKT Signaling Pathway [Genes]    Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway [Genes]    mTOR Signaling Pathway [Genes]    PTEN dependent cell cycle arrest and apoptosis [Genes]    Role of nicotinic acetylcholine receptors in the regulation of apoptosis [Genes]    Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]    B Cell Survival Pathway [Genes]    Insulin Signaling Pathway [Genes]    Signaling of Hepatocyte Growth Factor Receptor [Genes]    Nerve growth factor pathway (NGF) [Genes]    T Cell Receptor Signaling Pathway [Genes]    VEGF, Hypoxia, and Angiogenesis [Genes]    Role of PI3K subunit p85 in regulation of Actin Organization and Cell Migration [Genes]    The Co-Stimulatory Signal During T-cell Activation [Genes]    CXCR4 Signaling Pathway [Genes]    Ras-Independent pathway in NK cell-mediated cytotoxicity [Genes]    CTCF: First Multivalent Nuclear Factor [Genes]    Role of ERBB2 in Signal Transduction and Oncology [Genes]    IGF-1 Signaling Pathway [Genes]    Phospholipase C Signaling Pathway [Genes]    Trefoil Factors Initiate Mucosal Healing [Genes]    Transcription factor CREB and its extracellular signals [Genes]    Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia [Genes]    IL-7 Signal Transduction [Genes]    Trka Receptor Signaling Pathway [Genes]    Fc Epsilon Receptor I Signaling in Mast Cells [Genes]    Human Cytomegalovirus and Map Kinase Pathways [Genes]    Rac 1 cell motility signaling pathway [Genes]    Phospholipids as signalling intermediaries [Genes]    Corticosteroids and cardioprotection [Genes]    Inhibition of Cellular Proliferation by Gleevec [Genes]    PDGF Signaling Pathway [Genes]    Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha) [Genes]    Ras Signaling Pathway [Genes]    Influence of Ras and Rho proteins on G1 to S Transition [Genes]    Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages [Genes]    Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD phosphorylation [Genes]    Regulation of BAD phosphorylation [Genes]    IL-2 Receptor Beta Chain in T cell Activation [Genes]    The IGF-1 Receptor and Longevity [Genes]    NFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes]   
Pathways : KEGGInositol phosphate metabolism    ErbB signaling pathway    Ras signaling pathway    Rap1 signaling pathway    Chemokine signaling pathway    HIF-1 signaling pathway    FoxO signaling pathway    Phosphatidylinositol signaling system    mTOR signaling pathway    PI3K-Akt signaling pathway    Apoptosis    Adrenergic signaling in cardiomyocytes    VEGF signaling pathway    Osteoclast differentiation    Focal adhesion    Toll-like receptor signaling pathway    Jak-STAT signaling pathway    Natural killer cell mediated cytotoxicity    T cell receptor signaling pathway    B cell receptor signaling pathway    Fc epsilon RI signaling pathway    Fc gamma R-mediated phagocytosis    TNF signaling pathway    Leukocyte transendothelial migration    Neurotrophin signaling pathway    Cholinergic synapse    Regulation of actin cytoskeleton    Insulin signaling pathway    Progesterone-mediated oocyte maturation    Estrogen signaling pathway    Prolactin signaling pathway    Thyroid hormone signaling pathway    Type II diabetes mellitus    Non-alcoholic fatty liver disease (NAFLD)    Aldosterone-regulated sodium reabsorption    Carbohydrate digestion and absorption    Bacterial invasion of epithelial cells    Chagas disease (American trypanosomiasis)    Toxoplasmosis    Amoebiasis    Hepatitis C    Hepatitis B    Measles    Influenza A    HTLV-I infection    Epstein-Barr virus infection    Pathways in cancer    Viral carcinogenesis    Proteoglycans in cancer    MicroRNAs in cancer    Colorectal cancer    Renal cell carcinoma    Pancreatic cancer    Endometrial cancer    Glioma    Prostate cancer    Melanoma    Chronic myeloid leukemia    Acute myeloid leukemia    Small cell lung cancer    Non-small cell lung cancer   
Protein Interaction DatabasePIK3CA
Wikipedia pathwaysPIK3CA
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PIK3CA
snp3D : Map Gene to Disease5290
SNP (GeneSNP Utah)PIK3CA
SNP : HGBasePIK3CA
Genetic variants : HAPMAPPIK3CA
Exome VariantPIK3CA
1000_GenomesPIK3CA 
Cancer Gene: CensusPIK3CA 
Somatic Mutations in Cancer : COSMICPIK3CA 
CONAN: Copy Number AnalysisPIK3CA 
Mutations and Diseases : HGMDPIK3CA
Mutations and Diseases : intOGenPIK3CA
Genomic VariantsPIK3CA  PIK3CA [DGVbeta]
dbVarPIK3CA
ClinVarPIK3CA
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM114480    114500    114550    162900    167000    171834    182000    211980    602501    603387    612918    613659    615108   
MedgenPIK3CA
GENETestsPIK3CA
Disease Genetic AssociationPIK3CA
Huge Navigator PIK3CA [HugePedia]  PIK3CA [HugeCancerGEM]
General knowledge
Homologs : HomoloGenePIK3CA
Homology/Alignments : Family Browser (UCSC)PIK3CA
Phylogenetic Trees/Animal Genes : TreeFamPIK3CA
Chemical/Protein Interactions : CTD5290
Chemical/Pharm GKB GenePA33308
Drug Sensitivity PIK3CA
Clinical trialPIK3CA
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=PIK3CA
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMinePIK3CA
iHOPPIK3CA
OncoSearchPIK3CA

Bibliography

High frequency of mutations of the PIK3CA gene in human cancers.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE.
Science. 2004 Apr 23;304(5670):554. Epub 2004 Mar 11.
PMID 15016963
 
Oncogenic PI3K deregulates transcription and translation.
Bader AG, Kang S, Zhao L, Vogt PK.
Nat Rev Cancer. 2005 Dec;5(12):921-9.(REVIEW)
PMID 16341083
 
Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic.
Kang S, Bader AG, Vogt PK.
Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):802-7. Epub 2005 Jan 12.
PMID 15647370
 
PIK3CA mutations in head and neck squamous cell carcinoma.
Qiu W, Schonleben F, Li X, Ho DJ, Close LG, Manolidis S, Bennett BP, Su GH.
Clin Cancer Res. 2006 Mar 1;12(5):1441-6.
PMID 16533766
 
PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas.
Schonleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, Remotti HE, Su GH.
Clin Cancer Res. 2006 Jun 15;12(12):3851-5.
PMID 16778113
 
A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.
Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R.
Cancer Cell. 2007 Oct;12(4):395-402.
PMID 17936563
 
Biochemistry. PI3K charges ahead.
Lee JY, Engelman JA, Cantley LC.
Science. 2007 Jul 13;317(5835):206-7.
PMID 17626872
 
Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene.
Muller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT, Koeffler HP.
Leuk Res. 2007 Jan;31(1):27-32. Epub 2006 Jun 9.
PMID 16764926
 
Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective PIK3CA overexpression by gene amplification.
Angulo B, Suarez-Gauthier A, Lopez-Rios F, Medina PP, Conde E, Tang M, Soler G, Lopez-Encuentra A, Cigudosa JC, Sanchez-Cespedes M.
J Pathol. 2008 Feb;214(3):347-56.
PMID 17992665
 
Drug discovery approaches targeting the PI3K/Akt pathway in cancer.
Garcia-Echeverria C, Sellers WR.
Oncogene. 2008 Sep 18;27(41):5511-26.
PMID 18794885
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2009Montserrat Sanchez-Cespedes
Programa d'Epigenetica i Biologia del Cancer-PEBC, Institut d'Investigacions Biomediques Bellvitge (IDIBELL), Hospital Durant i Reynals, Avinguda Gran Via de l'Hospitalet, 199-203 08907-L'Hospitalet de Llobregat-Barcelona, Spain

Citation

This paper should be referenced as such :
Sanchez-Cespedes, M
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(3):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PIK3CAID415ch3q26.html

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indexed on : Tue Aug 26 15:26:09 CEST 2014

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