Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.
Identifieur interne : 002173 ( PubMed/Corpus ); précédent : 002172; suivant : 002174Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.
Auteurs : Sandra D. Castillo ; Elena Tzouanacou ; May Zaw-Thin ; Inma M. Berenjeno ; Victoria E R. Parker ; I Igo Chivite ; Maria Milà-Guasch ; Wayne Pearce ; Isabelle Solomon ; Ana Angulo-Urarte ; Ana M. Figueiredo ; Robert E. Dewhurst ; Rachel G. Knox ; Graeme R. Clark ; Cheryl L. Scudamore ; Adam Badar ; Tammy L. Kalber ; Julie Foster ; Daniel J. Stuckey ; Anna L. David ; Wayne A. Phillips ; Mark F. Lythgoe ; Valerie Wilson ; Robert K. Semple ; Neil J. Sebire ; Veronica A. Kinsler ; Mariona Graupera ; Bart VanhaesebroeckSource :
- Science translational medicine [ 1946-6242 ] ; 2016.
English descriptors
- KwdEn :
- Animals, Cell Proliferation (drug effects), Endothelial Cells (drug effects), Endothelial Cells (pathology), Humans, Mesoderm (drug effects), Mesoderm (embryology), Mesoderm (pathology), Mice, Inbred C57BL, Mosaicism (drug effects), Mutation (genetics), Pericytes (drug effects), Pericytes (pathology), Phosphatidylinositol 3-Kinases (genetics), Receptor, TIE-2 (metabolism), Sirolimus (pharmacology), Vascular Malformations (enzymology), Vascular Malformations (genetics).
- MESH :
- chemical , genetics : Phosphatidylinositol 3-Kinases.
- drug effects : Cell Proliferation, Endothelial Cells, Mesoderm, Mosaicism, Pericytes.
- embryology : Mesoderm.
- enzymology : Vascular Malformations.
- genetics : Mutation, Vascular Malformations.
- chemical , metabolism : Receptor, TIE-2.
- pathology : Endothelial Cells, Mesoderm, Pericytes.
- chemical , pharmacology : Sirolimus.
- Animals, Humans, Mice, Inbred C57BL.
Abstract
Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.
DOI: 10.1126/scitranslmed.aad9982
PubMed: 27030595
Links to Exploration step
pubmed:27030595Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.</title>
<author><name sortKey="Castillo, Sandra D" sort="Castillo, Sandra D" uniqKey="Castillo S" first="Sandra D" last="Castillo">Sandra D. Castillo</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Tzouanacou, Elena" sort="Tzouanacou, Elena" uniqKey="Tzouanacou E" first="Elena" last="Tzouanacou">Elena Tzouanacou</name>
<affiliation><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK. Institut Pasteur, Département de Biologie du Développement, CNRS URA 2578, 75724 Paris cedex 15, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Zaw Thin, May" sort="Zaw Thin, May" uniqKey="Zaw Thin M" first="May" last="Zaw-Thin">May Zaw-Thin</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Berenjeno, Inma M" sort="Berenjeno, Inma M" uniqKey="Berenjeno I" first="Inma M" last="Berenjeno">Inma M. Berenjeno</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Parker, Victoria E R" sort="Parker, Victoria E R" uniqKey="Parker V" first="Victoria E R" last="Parker">Victoria E R. Parker</name>
<affiliation><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Chivite, I Igo" sort="Chivite, I Igo" uniqKey="Chivite I" first="I Igo" last="Chivite">I Igo Chivite</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Mila Guasch, Maria" sort="Mila Guasch, Maria" uniqKey="Mila Guasch M" first="Maria" last="Milà-Guasch">Maria Milà-Guasch</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pearce, Wayne" sort="Pearce, Wayne" uniqKey="Pearce W" first="Wayne" last="Pearce">Wayne Pearce</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Solomon, Isabelle" sort="Solomon, Isabelle" uniqKey="Solomon I" first="Isabelle" last="Solomon">Isabelle Solomon</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Angulo Urarte, Ana" sort="Angulo Urarte, Ana" uniqKey="Angulo Urarte A" first="Ana" last="Angulo-Urarte">Ana Angulo-Urarte</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Figueiredo, Ana M" sort="Figueiredo, Ana M" uniqKey="Figueiredo A" first="Ana M" last="Figueiredo">Ana M. Figueiredo</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Dewhurst, Robert E" sort="Dewhurst, Robert E" uniqKey="Dewhurst R" first="Robert E" last="Dewhurst">Robert E. Dewhurst</name>
<affiliation><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Knox, Rachel G" sort="Knox, Rachel G" uniqKey="Knox R" first="Rachel G" last="Knox">Rachel G. Knox</name>
<affiliation><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Clark, Graeme R" sort="Clark, Graeme R" uniqKey="Clark G" first="Graeme R" last="Clark">Graeme R. Clark</name>
<affiliation><nlm:affiliation>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Scudamore, Cheryl L" sort="Scudamore, Cheryl L" uniqKey="Scudamore C" first="Cheryl L" last="Scudamore">Cheryl L. Scudamore</name>
<affiliation><nlm:affiliation>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Badar, Adam" sort="Badar, Adam" uniqKey="Badar A" first="Adam" last="Badar">Adam Badar</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Kalber, Tammy L" sort="Kalber, Tammy L" uniqKey="Kalber T" first="Tammy L" last="Kalber">Tammy L. Kalber</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Foster, Julie" sort="Foster, Julie" uniqKey="Foster J" first="Julie" last="Foster">Julie Foster</name>
<affiliation><nlm:affiliation>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Stuckey, Daniel J" sort="Stuckey, Daniel J" uniqKey="Stuckey D" first="Daniel J" last="Stuckey">Daniel J. Stuckey</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="David, Anna L" sort="David, Anna L" uniqKey="David A" first="Anna L" last="David">Anna L. David</name>
<affiliation><nlm:affiliation>UCL Institute for Women's Health, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Phillips, Wayne A" sort="Phillips, Wayne A" uniqKey="Phillips W" first="Wayne A" last="Phillips">Wayne A. Phillips</name>
<affiliation><nlm:affiliation>Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lythgoe, Mark F" sort="Lythgoe, Mark F" uniqKey="Lythgoe M" first="Mark F" last="Lythgoe">Mark F. Lythgoe</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Wilson, Valerie" sort="Wilson, Valerie" uniqKey="Wilson V" first="Valerie" last="Wilson">Valerie Wilson</name>
<affiliation><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Semple, Robert K" sort="Semple, Robert K" uniqKey="Semple R" first="Robert K" last="Semple">Robert K. Semple</name>
<affiliation><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sebire, Neil J" sort="Sebire, Neil J" uniqKey="Sebire N" first="Neil J" last="Sebire">Neil J. Sebire</name>
<affiliation><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Kinsler, Veronica A" sort="Kinsler, Veronica A" uniqKey="Kinsler V" first="Veronica A" last="Kinsler">Veronica A. Kinsler</name>
<affiliation><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Graupera, Mariona" sort="Graupera, Mariona" uniqKey="Graupera M" first="Mariona" last="Graupera">Mariona Graupera</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Vanhaesebroeck, Bart" sort="Vanhaesebroeck, Bart" uniqKey="Vanhaesebroeck B" first="Bart" last="Vanhaesebroeck">Bart Vanhaesebroeck</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation>
</affiliation>
</author>
</titleStmt>
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<idno type="doi">10.1126/scitranslmed.aad9982</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.</title>
<author><name sortKey="Castillo, Sandra D" sort="Castillo, Sandra D" uniqKey="Castillo S" first="Sandra D" last="Castillo">Sandra D. Castillo</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Tzouanacou, Elena" sort="Tzouanacou, Elena" uniqKey="Tzouanacou E" first="Elena" last="Tzouanacou">Elena Tzouanacou</name>
<affiliation><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK. Institut Pasteur, Département de Biologie du Développement, CNRS URA 2578, 75724 Paris cedex 15, France.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Zaw Thin, May" sort="Zaw Thin, May" uniqKey="Zaw Thin M" first="May" last="Zaw-Thin">May Zaw-Thin</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Berenjeno, Inma M" sort="Berenjeno, Inma M" uniqKey="Berenjeno I" first="Inma M" last="Berenjeno">Inma M. Berenjeno</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Parker, Victoria E R" sort="Parker, Victoria E R" uniqKey="Parker V" first="Victoria E R" last="Parker">Victoria E R. Parker</name>
<affiliation><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Chivite, I Igo" sort="Chivite, I Igo" uniqKey="Chivite I" first="I Igo" last="Chivite">I Igo Chivite</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Mila Guasch, Maria" sort="Mila Guasch, Maria" uniqKey="Mila Guasch M" first="Maria" last="Milà-Guasch">Maria Milà-Guasch</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Pearce, Wayne" sort="Pearce, Wayne" uniqKey="Pearce W" first="Wayne" last="Pearce">Wayne Pearce</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Solomon, Isabelle" sort="Solomon, Isabelle" uniqKey="Solomon I" first="Isabelle" last="Solomon">Isabelle Solomon</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Angulo Urarte, Ana" sort="Angulo Urarte, Ana" uniqKey="Angulo Urarte A" first="Ana" last="Angulo-Urarte">Ana Angulo-Urarte</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Figueiredo, Ana M" sort="Figueiredo, Ana M" uniqKey="Figueiredo A" first="Ana M" last="Figueiredo">Ana M. Figueiredo</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Dewhurst, Robert E" sort="Dewhurst, Robert E" uniqKey="Dewhurst R" first="Robert E" last="Dewhurst">Robert E. Dewhurst</name>
<affiliation><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Knox, Rachel G" sort="Knox, Rachel G" uniqKey="Knox R" first="Rachel G" last="Knox">Rachel G. Knox</name>
<affiliation><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Clark, Graeme R" sort="Clark, Graeme R" uniqKey="Clark G" first="Graeme R" last="Clark">Graeme R. Clark</name>
<affiliation><nlm:affiliation>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Scudamore, Cheryl L" sort="Scudamore, Cheryl L" uniqKey="Scudamore C" first="Cheryl L" last="Scudamore">Cheryl L. Scudamore</name>
<affiliation><nlm:affiliation>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Badar, Adam" sort="Badar, Adam" uniqKey="Badar A" first="Adam" last="Badar">Adam Badar</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Kalber, Tammy L" sort="Kalber, Tammy L" uniqKey="Kalber T" first="Tammy L" last="Kalber">Tammy L. Kalber</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Foster, Julie" sort="Foster, Julie" uniqKey="Foster J" first="Julie" last="Foster">Julie Foster</name>
<affiliation><nlm:affiliation>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Stuckey, Daniel J" sort="Stuckey, Daniel J" uniqKey="Stuckey D" first="Daniel J" last="Stuckey">Daniel J. Stuckey</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="David, Anna L" sort="David, Anna L" uniqKey="David A" first="Anna L" last="David">Anna L. David</name>
<affiliation><nlm:affiliation>UCL Institute for Women's Health, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Phillips, Wayne A" sort="Phillips, Wayne A" uniqKey="Phillips W" first="Wayne A" last="Phillips">Wayne A. Phillips</name>
<affiliation><nlm:affiliation>Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Parkville, Victoria 3010, Australia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lythgoe, Mark F" sort="Lythgoe, Mark F" uniqKey="Lythgoe M" first="Mark F" last="Lythgoe">Mark F. Lythgoe</name>
<affiliation><nlm:affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Wilson, Valerie" sort="Wilson, Valerie" uniqKey="Wilson V" first="Valerie" last="Wilson">Valerie Wilson</name>
<affiliation><nlm:affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Semple, Robert K" sort="Semple, Robert K" uniqKey="Semple R" first="Robert K" last="Semple">Robert K. Semple</name>
<affiliation><nlm:affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sebire, Neil J" sort="Sebire, Neil J" uniqKey="Sebire N" first="Neil J" last="Sebire">Neil J. Sebire</name>
<affiliation><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Kinsler, Veronica A" sort="Kinsler, Veronica A" uniqKey="Kinsler V" first="Veronica A" last="Kinsler">Veronica A. Kinsler</name>
<affiliation><nlm:affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Graupera, Mariona" sort="Graupera, Mariona" uniqKey="Graupera M" first="Mariona" last="Graupera">Mariona Graupera</name>
<affiliation><nlm:affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Vanhaesebroeck, Bart" sort="Vanhaesebroeck, Bart" uniqKey="Vanhaesebroeck B" first="Bart" last="Vanhaesebroeck">Bart Vanhaesebroeck</name>
<affiliation><nlm:affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</nlm:affiliation>
</affiliation>
</author>
</analytic>
<series><title level="j">Science translational medicine</title>
<idno type="eISSN">1946-6242</idno>
<imprint><date when="2016" type="published">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Cell Proliferation (drug effects)</term>
<term>Endothelial Cells (drug effects)</term>
<term>Endothelial Cells (pathology)</term>
<term>Humans</term>
<term>Mesoderm (drug effects)</term>
<term>Mesoderm (embryology)</term>
<term>Mesoderm (pathology)</term>
<term>Mice, Inbred C57BL</term>
<term>Mosaicism (drug effects)</term>
<term>Mutation (genetics)</term>
<term>Pericytes (drug effects)</term>
<term>Pericytes (pathology)</term>
<term>Phosphatidylinositol 3-Kinases (genetics)</term>
<term>Receptor, TIE-2 (metabolism)</term>
<term>Sirolimus (pharmacology)</term>
<term>Vascular Malformations (enzymology)</term>
<term>Vascular Malformations (genetics)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Phosphatidylinositol 3-Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Proliferation</term>
<term>Endothelial Cells</term>
<term>Mesoderm</term>
<term>Mosaicism</term>
<term>Pericytes</term>
</keywords>
<keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Mesoderm</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Vascular Malformations</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term>
<term>Vascular Malformations</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptor, TIE-2</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Endothelial Cells</term>
<term>Mesoderm</term>
<term>Pericytes</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Sirolimus</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Humans</term>
<term>Mice, Inbred C57BL</term>
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<front><div type="abstract" xml:lang="en">Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27030595</PMID>
<DateCreated><Year>2016</Year>
<Month>03</Month>
<Day>31</Day>
</DateCreated>
<DateCompleted><Year>2016</Year>
<Month>12</Month>
<Day>19</Day>
</DateCompleted>
<DateRevised><Year>2017</Year>
<Month>11</Month>
<Day>16</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1946-6242</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>8</Volume>
<Issue>332</Issue>
<PubDate><Year>2016</Year>
<Month>Mar</Month>
<Day>30</Day>
</PubDate>
</JournalIssue>
<Title>Science translational medicine</Title>
<ISOAbbreviation>Sci Transl Med</ISOAbbreviation>
</Journal>
<ArticleTitle>Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.</ArticleTitle>
<Pagination><MedlinePgn>332ra43</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1126/scitranslmed.aad9982</ELocationID>
<Abstract><AbstractText>Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.</AbstractText>
<CopyrightInformation>Copyright © 2016, American Association for the Advancement of Science.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Castillo</LastName>
<ForeName>Sandra D</ForeName>
<Initials>SD</Initials>
<AffiliationInfo><Affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tzouanacou</LastName>
<ForeName>Elena</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK. Institut Pasteur, Département de Biologie du Développement, CNRS URA 2578, 75724 Paris cedex 15, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zaw-Thin</LastName>
<ForeName>May</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Berenjeno</LastName>
<ForeName>Inma M</ForeName>
<Initials>IM</Initials>
<AffiliationInfo><Affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Parker</LastName>
<ForeName>Victoria E R</ForeName>
<Initials>VE</Initials>
<AffiliationInfo><Affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chivite</LastName>
<ForeName>Iñigo</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Milà-Guasch</LastName>
<ForeName>Maria</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pearce</LastName>
<ForeName>Wayne</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Solomon</LastName>
<ForeName>Isabelle</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Angulo-Urarte</LastName>
<ForeName>Ana</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Figueiredo</LastName>
<ForeName>Ana M</ForeName>
<Initials>AM</Initials>
<AffiliationInfo><Affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dewhurst</LastName>
<ForeName>Robert E</ForeName>
<Initials>RE</Initials>
<AffiliationInfo><Affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Knox</LastName>
<ForeName>Rachel G</ForeName>
<Initials>RG</Initials>
<AffiliationInfo><Affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Clark</LastName>
<ForeName>Graeme R</ForeName>
<Initials>GR</Initials>
<AffiliationInfo><Affiliation>Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Scudamore</LastName>
<ForeName>Cheryl L</ForeName>
<Initials>CL</Initials>
<AffiliationInfo><Affiliation>Mary Lyon Centre, MRC Harwell, Harwell OX11 0RD, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Badar</LastName>
<ForeName>Adam</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kalber</LastName>
<ForeName>Tammy L</ForeName>
<Initials>TL</Initials>
<AffiliationInfo><Affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Foster</LastName>
<ForeName>Julie</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Stuckey</LastName>
<ForeName>Daniel J</ForeName>
<Initials>DJ</Initials>
<AffiliationInfo><Affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>David</LastName>
<ForeName>Anna L</ForeName>
<Initials>AL</Initials>
<AffiliationInfo><Affiliation>UCL Institute for Women's Health, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Phillips</LastName>
<ForeName>Wayne A</ForeName>
<Initials>WA</Initials>
<AffiliationInfo><Affiliation>Cancer Biology and Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia. Department of Surgery (St. Vincent's Hospital), University of Melbourne, Parkville, Victoria 3010, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lythgoe</LastName>
<ForeName>Mark F</ForeName>
<Initials>MF</Initials>
<AffiliationInfo><Affiliation>Centre for Advanced Biomedical Imaging, University College London, London WC1E 6BT, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wilson</LastName>
<ForeName>Valerie</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Semple</LastName>
<ForeName>Robert K</ForeName>
<Initials>RK</Initials>
<AffiliationInfo><Affiliation>Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sebire</LastName>
<ForeName>Neil J</ForeName>
<Initials>NJ</Initials>
<AffiliationInfo><Affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kinsler</LastName>
<ForeName>Veronica A</ForeName>
<Initials>VA</Initials>
<AffiliationInfo><Affiliation>UCL Institute of Child Health, London WC1N 1EH, UK. Great Ormond Street Hospital for Children, NHS Foundation Trust, London WC1N 3JH, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Graupera</LastName>
<ForeName>Mariona</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Vascular Signaling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Vanhaesebroeck</LastName>
<ForeName>Bart</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>UCL Cancer Institute, University College London, London WC1E 6BT, UK. sandra.castillo@ucl.ac.uk bart.vanh@ucl.ac.uk.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>G0901338</GrantID>
<Agency>Medical Research Council</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>FS/15/33/31608</GrantID>
<Agency>British Heart Foundation</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>MC_UU_12012/5</GrantID>
<Agency>Medical Research Council</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>WT098498</GrantID>
<Agency>Wellcome Trust</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>MRC_MC_UU_12012/5</GrantID>
<Agency>Medical Research Council</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>WT104076MA</GrantID>
<Agency>Wellcome Trust</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>BBS/B/15481</GrantID>
<Agency>Biotechnology and Biological Sciences Research Council</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>C23338/A15965</GrantID>
<Agency>Cancer Research UK</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>097721/Z/11/Z</GrantID>
<Agency>Wellcome Trust</Agency>
<Country>United Kingdom</Country>
</Grant>
</GrantList>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
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<NlmUniqueID>101505086</NlmUniqueID>
<ISSNLinking>1946-6234</ISSNLinking>
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<ChemicalList><Chemical><RegistryNumber>EC 2.7.1.-</RegistryNumber>
<NameOfSubstance UI="D019869">Phosphatidylinositol 3-Kinases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.1.137</RegistryNumber>
<NameOfSubstance UI="C484760">PIK3CA protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.1.137</RegistryNumber>
<NameOfSubstance UI="C546639">Pik3ca protein, mouse</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber>
<NameOfSubstance UI="D042787">Receptor, TIE-2</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber>
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</Chemical>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D042783" MajorTopicYN="N">Endothelial Cells</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008648" MajorTopicYN="N">Mesoderm</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000196" MajorTopicYN="N">embryology</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009030" MajorTopicYN="N">Mosaicism</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D020286" MajorTopicYN="N">Pericytes</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D042787" MajorTopicYN="N">Receptor, TIE-2</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D020123" MajorTopicYN="N">Sirolimus</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D054079" MajorTopicYN="N">Vascular Malformations</DescriptorName>
<QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName>
</MeshHeading>
</MeshHeadingList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year>
<Month>10</Month>
<Day>29</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2016</Year>
<Month>02</Month>
<Day>04</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2016</Year>
<Month>4</Month>
<Day>1</Day>
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<Hour>6</Hour>
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<PubMedPubDate PubStatus="medline"><Year>2016</Year>
<Month>12</Month>
<Day>20</Day>
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