ArticleNature2021
PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism.
Registry-linked trialOpen access · greenAbstract read
In one paragraph
Article in Nature, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06091332 (Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus), which is not on this map. Cited by 132 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
132citing papers in PubMed, 2 pooled it
15.8field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Randomized, Placebo-controlled Pilot Trial
Who cites it
132 citing papers in PubMed, 2 syntheses or guidelines pooled it, 185 citations in OpenAlex.
- Rho-associated kinase inhibitors in cerebral cavernous malformations: a preclinical systematic review.Neurosurgical review · 2026Pooled it
- Molecular Pathways and Circulating Biomarkers in Cerebral Cavernous Malformations-A Systematic Review.International journal of molecular sciences · 2026Pooled it
- Trial
- Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.Molecular biomedicine · 2026Review
- Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MicroRNA-21-3p regulation of NADPH oxidase 4 and vascular endothelial growth factor A contributes to hemorrhage in cerebral cavernous malformations.Non-coding RNA research · 2026Article
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- Aspirin Use and the Risk of Symptomatic Hemorrhage in Patients With Cerebral Cavernous Malformations and Ischemic Cerebrovascular Disease.Stroke (Hoboken, N.J.) · 2026Article
- A targeted vector for brain endothelial cell gene delivery and cerebrovascular malformation modelling.Nature biomedical engineering · 2026Article
- Endothelial dysfunction: A central mechanism linking autosomal dominant polycystic kidney disease and intracranial aneurysms (Review).International journal of molecular medicine · 2026Review
- Article
- Review
- Intramedullary Spinal Cord Cavernous Angiomas in Familial Cerebral Cavernous Malformations.Genes · 2026Review
- CXCL13⁺ CD4⁺ T cells are associated with B-cell recruitment and lesion progression in cerebral cavernous malformations.Journal of neuroinflammation · 2026Article
- Rapamycin Partially Reverts Cavernoma Endothelial Cell Phenotype and, When Combined With Lapatinib, Ameliorates Chronic Lesions.Journal of cellular and molecular medicine · 2026Article
- Human stem cell models in cerebral cavernous malformations.Stem cell research & therapy · 2026Review
- Identification of the adhesion GPCR ADGRL4/ELTD1 as a novel potential prognostic biomarker for cerebral cavernous malformation disease.Molecular medicine (Cambridge, Mass.) · 2026Article
- TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation.The Journal of experimental medicine · 2026Article
- Knockin expression of human ADAMTS5 impairs cardiovascular development and aggravates cerebral cavernous malformations in mice.Disease models & mechanisms · 2026Article
- Tumor-like proliferation of CCM3 knockout endothelial cells: insights from semaxinib treatment and transcriptome profiling of co-cultures.Acta neuropathologica communications · 2026Article
72 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
28 authors at 9 institutions in 2 countries.
Aileen A Ren *Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-1116-900X
Daniel A Snellings *Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.ORCID http://orcid.org/0000-0003-0615-9111
Yourong S SuDepartment of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
Courtney C HongDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-0515-6816
Marco CastroAngiogenesis and Metabolism Laboratory, Max Planck institute for Heart and Lung Research, Bad Nauheim, Germany.ORCID http://orcid.org/0000-0001-7851-7446
Alan T TangDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-1422-0349
Matthew R DetterDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.ORCID http://orcid.org/0000-0003-1207-2565
Nicholas HobsonNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
Romuald GirardNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-5893-9315
Sharbel RomanosNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
Rhonda LightleNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
Thomas MooreNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
Robert ShenkarNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-1300-6845
Christian BenavidesDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
M Makenzie BeamanDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.ORCID http://orcid.org/0000-0003-4066-2060
Helge Müller-FielitzInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.ORCID http://orcid.org/0000-0003-2815-4426
Mei ChenDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
Patricia MerickoDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
Jisheng YangDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
Derek C SungDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-6966-2596
Michael T LawtonDepartment of Neurosurgery, The Barrow Neurological Institute, Phoenix, AZ, USA.
J Michael RuppertCancer Institute, West Virginia University, Morgantown, WV, USA.
Markus SchwaningerInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.ORCID http://orcid.org/0000-0002-4510-9718
Jakob KörbelinUniversity Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and Bone Marrow Transplantation, Hamburg, Germany.ORCID http://orcid.org/0000-0002-5435-7182
Michael PotenteAngiogenesis and Metabolism Laboratory, Max Planck institute for Heart and Lung Research, Bad Nauheim, Germany.ORCID http://orcid.org/0000-0002-5689-0036
Issam A AwadNeurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
Douglas A MarchukDepartment of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. douglas.marchuk@duke.edu.ORCID http://orcid.org/0000-0002-3110-6671
Mark L KahnDepartment of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA. markkahn@pennmedicine.upenn.edu.ORCID http://orcid.org/0000-0002-6489-7086
University of Pennsylvania · USUniversity of Chicago · USDuke University · USUniversity of Lübeck · DEBarrow Neurological Institute · USMax Delbrück Center · DEMax Planck Institute for Heart and Lung Research · DEUniversität Hamburg · DEWest Virginia University · US
Funding
Women's Cancer Research ProgramP30CA014236 · NCI · DUKE UNIVERSITY · PI JOHN N. NORTON · 1985 to 2026
$174.8MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007171 · NIGMS · DUKE UNIVERSITY · PI KONTOS, CHRISTOPHER D · 1985 to 2021
$31.2MHEMATOLOGY CLINICAL RESEARCH TRAINING PROGRAMT32HL007439 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI LAWRENCE F BRASS, PETER S KLEIN · 1985 to 2026
$17.1MSomatic mutation(s) and cellular changes in CCM pathogenesisP01NS092521 · NINDS · DUKE UNIVERSITY · PI MARCHUK, DOUGLAS A. · 2015 to 2024
$12.9MRED CELL HEMOGLOBIN RESEARCH TRAINING PROGRAMT32HL007150 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI STELLA T CHOU, Mortimer Poncz · 1985 to 2026
$7.4MMedical Scientist Training Program Training GrantT32GM145449 · NIGMS · DUKE UNIVERSITY · PI Christopher D Kontos · 2022 to 2026
$6.6MHeg-CCM Signaling in Cardiovascular Development and DiseaseR01HL094326 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI KAHN, MARK L · 2009 to 2018
$3.5MTLR4 and the microbiome in CCM diseaseR01NS100949 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI KAHN, MARK L · 2017 to 2021
$2.8MMolecular mechanisms of CCM signalingR01HL102138 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI KAHN, MARK L · 2010 to 2014
$2.6MThe molecular pathogenesis of cerebral cavernous malformationsF30NS100252 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI TANG, ALAN TIEN · 2017 to 2018
$80kInvestigating the Role of Somatic Mutations in Arteriovenous MalformationsF31HL152738 · NHLBI · DUKE UNIVERSITY · PI SNELLINGS, DANIEL · 2020 to 2021
$71kInvestigating the molecular determinants of cerebral cavernous malformations downstream of MEKK3-KLF2/4 signalingF31NS115256 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI HONG, COURTNEY · 2019 to 2021
$56kEuropean Research CouncilNCI NIH HHS P30 CA014236NHLBI NIH HHS F31 HL152738NHLBI NIH HHS R01 HL094326NHLBI NIH HHS R01 HL102138NHLBI NIH HHS T32 HL007150NHLBI NIH HHS T32 HL007439NIGMS NIH HHS T32 GM007171NIGMS NIH HHS T32 GM145449NINDS NIH HHS F30 NS100252NINDS NIH HHS F31 NS115256NINDS NIH HHS P01 NS092521NINDS NIH HHS R01 NS100949
Abstract
Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK3
Indexed as
MutationAnimalsAnimals, NewbornClass I Phosphatidylinositol 3-KinasesDisease Models, AnimalEndothelial CellsGain of Function MutationHemangioma, Cavernous, Central Nervous SystemHumansKruppel-Like Factor 4Kruppel-Like Transcription FactorsLoss of Function MutationMaleMAP Kinase Kinase Kinase 3Mechanistic Target of Rapamycin Complex 1MiceClass I Phosphatidylinositol 3-KinasesKLF4 protein, humanKlf4 protein, mouseKruppel-Like Factor 4Kruppel-Like Transcription FactorsMAP Kinase Kinase Kinase 3Mechanistic Target of Rapamycin Complex 1PIK3CA protein, humanPik3ca protein, mouseSirolimusTOR Serine-Threonine Kinases
Identifiers
What OpenQuestion holds
Textmetadata
LicenceTDM
Read underepoch 390
Registered trials
NCT06091332ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.