Peter Carmeliet

Harvard Medical School, Boston, Massachusetts, United States

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Publications (584)5721.97 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. Ten SNPs were associated with bevacizumab-induced hypertension (P ≤ 0.05), but none surpassed the threshold adjusted for multiple testing (P < 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). The genes described in this large genetic analysis using pooled datasets warrant further functional investigation regarding their role in mediating bevacizumab-induced hypertension.
    Angiogenesis 02/2014; · 3.97 Impact Factor
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    ABSTRACT: We studied whether plasma levels of angiogenic factors VEGF and placental growth factor (PlGF) in coronary artery disease patients or undergoing cardiac surgery are modified, and whether those factors modulate endothelial progenitor's angiogenic potential. A total of 143 patients' plasmas from two different studies were analyzed (30 coronary artery disease patients, 30 patients with stable angina, coupled with 30 age and sex-matched controls; 53 patients underwent cardiac surgery). Among factors screened, only PlGF was found significantly increased in these pathological populations. PlGF-1 and PlGF-2 were then tested on human endothelial-colony-forming cells (ECFCs). We found that PlGF-1 and PlGF-2 induce VEGFR1 phosphorylation and potentiate ECFCs tubulogenesis in vitro. ECFCs VEGFR1 was further inhibited using a specific small interfering RNA (siRNA) and the chemical compound 4321. We then observed that the VEGFR1-siRNA and the compound 4321 decrease ECFCs tubulogenesis potential in vitro. Finally, we tested the compound 4321 in the preclinical Matrigel(®)-plug model with C57Bl/6J mice as well as in the murine hindlimb ischemia model. We found that 4321 inhibited the plug vascularization, attested by the hemoglobin content and the VE-Cadherin expression level and that 4321 inhibited the post-ischemic revascularization. PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.
    Angiogenesis 01/2014; · 3.97 Impact Factor
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    ABSTRACT: Various tumors metastasize via lymph vessels and lymph nodes to distant organs. Even though tumors are hypoxic, the mechanisms of how hypoxia regulates lymphangiogenesis remain poorly characterized. Here, we show that hypoxia reduced vascular endothelial growth factor C (VEGF-C) transcription and cap-dependent translation via the upregulation of hypophosphorylated 4E-binding protein 1 (4E-BP1). However, initiation of VEGF-C translation was induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. IRES-dependent VEGF-C translation was independent of hypoxia-inducible factor 1α (HIF-1α) signaling. Notably, the VEGF-C IRES activity was higher in metastasizing tumor cells in lymph nodes than in primary tumors, most likely because lymph vessels in these lymph nodes were severely hypoxic. Overall, this transcription-independent but translation-dependent upregulation of VEGF-C in hypoxia stimulates lymphangiogenesis in tumors and lymph nodes and may contribute to lymphatic metastasis.
    Cell reports. 12/2013;
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    ABSTRACT: During vessel sprouting, a migratory endothelial tip cell guides the sprout, while proliferating stalk cells elongate the branch. Tip and stalk cell phenotypes are not genetically predetermined fates, but are dynamically interchangeable to ensure that the fittest endothelial cell (EC) leads the vessel sprout. ECs increase glycolysis when forming new blood vessels. Genetic deficiency of the glycolytic activator PFKFB3 in ECs reduces vascular sprouting by impairing migration of tip cells and proliferation of stalk cells. PFKFB3-driven glycolysis promotes the tip cell phenotype during vessel sprouting, since PFKFB3 overexpression overrules the pro-stalk activity of Notch signaling. Furthermore, PFKFB3-deficient ECs cannot compete with wild-type neighbors to form new blood vessels in chimeric mosaic mice. In addition, pharmacological PFKFB3 blockade reduces pathological angiogenesis with modest systemic effects, likely because it decreases glycolysis only partially and transiently.
    Cell cycle (Georgetown, Tex.) 12/2013; 13(1). · 5.24 Impact Factor
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    ABSTRACT: Strategies targeting pathological angiogenesis have focused primarily on blocking vascular endothelial growth factor (VEGF), but resistance and insufficient efficacy limit their success, mandating alternative antiangiogenic strategies. We recently provided genetic evidence that the glycolytic activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) promotes vessel formation but did not explore the antiangiogenic therapeutic potential of PFKFB3 blockade. Here, we show that blockade of PFKFB3 by the small molecule 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. 3PO also suppressed vascular hyperbranching induced by inhibition of Notch or VEGF receptor 1 (VEGFR1) and amplified the antiangiogenic effect of VEGF blockade. Although 3PO reduced glycolysis only partially and transiently in vivo, this sufficed to decrease pathological neovascularization in ocular and inflammatory models. These insights may offer therapeutic antiangiogenic opportunities.
    Cell metabolism 12/2013; · 17.35 Impact Factor
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    ABSTRACT: Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand due to a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11bhiF4/80hiLy6Clo TAM subsets, designated as MHC-II(lo) and MHC-II(hi) TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-II(lo) TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II(lo) TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II(hi) counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in PHD2-haplodeficient mice, resulting in better oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowers hypoxia-sensitive gene expression and angiogenic activity in the MHC-II(lo) TAM subset. The same observation in PHD2(+/+) → PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-II(lo) TAM.
    Cancer Research 11/2013; · 8.65 Impact Factor
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    ABSTRACT: Edema represents a key feature of nasal polyp (NP) disease. Members of the vascular endothelial growth factor (VEGF) family may be involved, but the precise role of VEGF-A, VEGF-B, placental growth factor (PlGF), and their receptors VEGFR1 and VEGFR2 in NP edema formation remains elusive. Exploring the expression of VEGF family members and their receptors and their correlation with clinical, radiological, and edema markers in NP. The expression of VEGF-A, VEGF-B, PlGF, VEGFR1, and VEGFR2 was measured in NP (n = 23) and control tissue (n = 22) at mRNA and protein level. Edema was evaluated by measuring albumin levels and wet/dry ratios. Computed tomography (CT) scans were scored using the Lund-Mackay scoring system. IL-5 mRNA expression was determined by real-time RT-PCR. Cell suspensions from NP (n = 10) and control tissue (n = 12) were stimulated in vitro with IL-1β or TNFα. mRNA expression of VEGFR1 and VEGF-B was significantly higher in NP compared with control tissue. Expression levels of VEGF-B and VEGFR1 significantly correlated with NP albumin content (VEGF-B: P = 0.0208; VEGFR1: P = 0.0293), CT scan scores (VEGF-B: P = 0.0075; VEGFR1: P = 0.0068), and IL-5 mRNA (VEGF-B: P = 0.0027; VEGFR1: P = 0.0001). In vitro stimulation of control and NP tissue cell suspensions with IL-1β or TNFα significantly reduced the expression of VEGFR2 in control tissue, without altering VEGFR1 and VEGF-B expression. hVEGF-B induced nitric oxide production in NP macrophages (P < 0.05). Expression levels of VEGFR1 and VEGF-B correlate with edema and clinical markers of NP disease and therefore represent potential therapeutic targets.
    Allergy 10/2013; · 5.88 Impact Factor
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    ABSTRACT: The progressive deposition of amyloid-β (Aβ) in the brain is a pathologic feature of Alzheimer's disease (AD). This study was aimed to determine whether endogenous tissue plasminogen activator (tPA) modulates the pathogenic process of AD. tPA expression and activity developed around amyloid plaques in the brains of human amyloid precursor protein-overexpressing Tg2576 mice, which were weakened by the genetic ablation of tPA. Although the complete loss of tPA was developmentally fatal to Tg2576 mice, tPA-heterozygous Tg2576 mice expressed the more severe degenerative phenotypes than tPA wild-type Tg2576 mice, including abnormal and unhealthy growth, shorter life spans, significantly enhanced Aβ levels, and the deposition of more and larger amyloid plaques in the brain. In addition, the expression of synaptic function-associated proteins was significantly reduced, which in turn caused a more severe impairment in learning and memory performance in Tg2576 mice. Thus, endogenous tPA, preferentially its aggregate form, could degrade Aβ molecules and maintain low levels of brain Aβ, resulting in the delay of AD pathogenesis.
    Neurobiology of aging 10/2013; · 5.94 Impact Factor
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    ABSTRACT: The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression.
    EMBO Molecular Medicine 10/2013; 5(10):1523-1536. · 7.80 Impact Factor
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    ABSTRACT: The use of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with standard therapeutic approaches, has offered clinical benefit for patients with advanced colorectal, breast, ovarian, renal, non small-cell lung cancer and glioblastoma. However, the strategy of administering bevacizumab until disease progression has been challenged by certain preclinical evidence, suggesting that prolonged exposure to anti-VEGF treatment may elicit an adaptive-evasive response, resulting in a more aggressive tumor phenotype. Moreover, the use of bevacizumab in adjuvant chemotherapeutic regimens has led to less promising results than expected. Despite our poor understanding of how bevacizumab acts in micrometastatic disease, numerous clinical trials (involving >20,000 cancer patients) are ongoing or are planned to test the therapeutic benefit in the adjuvant setting. The discrepancy of bevacizumab's efficiency in the two settings calls into question the validity of current strategies that use similar treatment regimens for early and advanced disease. Herein, we review the mechanisms of bevacizumab activity in the macro- as compared to the micrometastatic environment and discuss possible alternative strategies in the adjuvant setting that might spur attention for future clinical trials. Rather than providing an encyclopedic survey of the literature, we highlight exemplary principles.
    Pharmacology [?] Therapeutics 09/2013; · 7.79 Impact Factor
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    ABSTRACT: Vessel sprouting by endothelial cells (ECs) during angiogenesis relies on a navigating tip cell and on proliferating stalk cells that elongate the shaft. To date, only genetic signals have been shown to regulate vessel sprouting. However, emerging evidence indicates that the angiogenic switch also requires a metabolic switch. Indeed, angiogenic signals not only induce a change in EC metabolism but this metabolic adaptation also co-determines vessel sprouting. The glycolytic activator PFKFB3 regulates stalk cell proliferation and renders ECs more competitive to reach the tip. We discuss the emerging link between angiogenesis and EC metabolism during the various stages of vessel sprouting, focusing only on genetic signals for which an effect on EC metabolism has been documented.
    Trends in Endocrinology and Metabolism 09/2013; · 8.90 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal and differentiation(1). Although 40-45% of patients younger than 65 years can be cured with current therapies, only 10% of older patients reach long-term survival(1). As only very few novel AML drugs were approved in the last two decades there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We here report that Axl, a member of the Tyro3, Axl, Mer receptor (TAMR) tyrosine kinase family(2-4), represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche, which can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and -wt AML, improves clinically relevant endpoints and depends on presence of Gas6 and Axl. Axl-inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.
    Blood 08/2013; · 9.06 Impact Factor
  • Katrien De Bock, Maria Georgiadou, Peter Carmeliet
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    ABSTRACT: Endothelial cells (ECs) are quiescent for years but can plastically switch to angiogenesis. Vascular sprouting relies on the coordinated activity of migrating tip cells at the forefront and proliferating stalk cells that elongate the sprout. Past studies have identified genetic signals that control vascular branching. Prominent are VEGF, activating tip cells, and Notch, which stimulates stalk cells. After the branch is formed and perfused, ECs become quiescent phalanx cells. Now, emerging evidence has accumulated indicating that ECs not only adapt their metabolism when switching from quiescence to sprouting but also that metabolism regulates vascular sprouting in parallel to the control by genetic signals.
    Cell metabolism 08/2013; · 17.35 Impact Factor
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    ABSTRACT: To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Bα regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Bα in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Bα in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Bα controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Bα, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Bα/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion.
    The EMBO Journal 08/2013; · 9.82 Impact Factor
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    ABSTRACT: We hypothesized that VEGF-containing hydrogels that gelify in situ following injection into a traumatized spinal cord, could stimulate spinal cord regeneration. Injectable hydrogels composed of 0.5% MVG alginate, supplemented or not with fibrinogen, were used. The addition of fibrinogen to alginate had no effect on cell proliferation in vitro but supported neurite growth ex vivo. When injected into a rat spinal cord in a hemisection model, alginate supplemented with fibrinogen was well tolerated. The release of VEGF that was incorporated into the hydrogel was influenced by the VEGF formulation (encapsulated in microspheres or in nanoparticles or in solution (free)). A combination of free VEGF and VEGF-loaded nanoparticles was mixed with alginate:fibrinogen and injected into the lesion of the spinal cord. Four weeks post-injection injection, angiogenesis and neurite growth were increased compared to hydrogel alone. The local delivery of VEGF by injectable alginate:fibrinogen-based hydrogel induced some plasticity in the injured spinal cord involving fiber growth into the lesion site.
    Journal of Biomedical Materials Research Part A 08/2013; · 2.83 Impact Factor
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    ABSTRACT: Vessel sprouting by migrating tip and proliferating stalk endothelial cells (ECs) is controlled by genetic signals (such as Notch), but it is unknown whether metabolism also regulates this process. Here, we show that ECs relied on glycolysis rather than on oxidative phosphorylation for ATP production and that loss of the glycolytic activator PFKFB3 in ECs impaired vessel formation. Mechanistically, PFKFB3 not only regulated EC proliferation but also controlled the formation of filopodia/lamellipodia and directional migration, in part by compartmentalizing with F-actin in motile protrusions. Mosaic in vitro and in vivo sprouting assays further revealed that PFKFB3 overexpression overruled the pro-stalk activity of Notch, whereas PFKFB3 deficiency impaired tip cell formation upon Notch blockade, implying that glycolysis regulates vessel branching.
    Cell 08/2013; 154(3):651-63. · 31.96 Impact Factor
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    ABSTRACT: Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.
    The Journal of clinical investigation 08/2013; 123(8):3190-200. · 15.39 Impact Factor
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    ABSTRACT: The phagocyte NADPH oxidase Nox2 generates superoxide ions implicated in the elimination of microorganisms and the redox control of inflammatory signaling. However, the role of Nox2 in phagocyte functions unrelated to immunity or pathologies is unknown. During development, oriented cell migrations insure the timely recruitment and function of phagocytes in developing tissues. Here, we have addressed the role of Nox2 in the directional migration of microglial cells during development. We show that microglial Nox2 regulates the chemotaxis of purified microglia mediated by the colony stimulating factor-1 receptor (CSF-1R) and the vascular endothelial growth factor receptor-1 (VEGFR1). Stimulation of these receptors triggers activation of Nox2 at the leading edge of polarized cells. In the early postnatal stages of mouse brain development, Nox2 is activated in macrophages / microglial cells in the lateral ventricle or the adjacent subventricular zone (SVZ). Fluorescent microglia injected into the lateral ventricle infiltrate the dorso-caudal SVZ through a mechanism that is blocked by pretreatment of the injected cells with an irreversible Nox inhibitor. Infiltration of endogenous microglia into the caudal SVZ of the cerebral cortex is prevented by (1) Nox2 gene deficiency, (2) treatment with a Nox2 inhibitor (apocynin), and (3) invalidation of the VEGFR1 kinase. We conclude that phagocytes move out of the lateral ventricle soon after birth and infiltrate the cortical SVZ through a mechanism requiring microglial Nox2 and VEGFR1 activation. Nox2 therefore modulates the migration of microglia and their development.GLIA 2013;
    Glia 07/2013; · 5.07 Impact Factor
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    ABSTRACT: Abstract BACKGROUND & AIMS: Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitors are protective in mouse models of inflammatory bowel disease (IBD). Here, we investigated the therapeutic target(s) and mechanism(s) involved. METHODS: The effect of genetic deletion of individual HIF-prolyl hydroxylase (PHD) enzymes on the development of dextran sulphate sodium (DSS)-induced colitis was examined in mice. RESULTS: PHD1(-/-), but not PHD2(+/-) or PHD3(-/-), mice were less susceptible to the development of colitis than wild-type controls as determined by weight loss, disease activity, colon histology, neutrophil infiltration, and cytokine expression. Reduced susceptibility of PHD1(-/-) mice to colitis was associated with increased density of colonic epithelial cells relative to wild-type controls, which was because of decreased levels of apoptosis that resulted in enhanced epithelial barrier function. Furthermore, with the use of cultured epithelial cells it was confirmed that hydroxylase inhibition reversed DSS-induced apoptosis and barrier dysfunction. Finally, PHD1 levels were increased with disease severity in intestinal tissue from patients with IBD and in colonic tissues from DSS-treated mice. CONCLUSIONS: These results imply a role for PHD1 as a positive regulator of intestinal epithelial cell apoptosis in the inflamed colon. Genetic loss of PHD1 is protective against colitis through decreased epithelial cell apoptosis and consequent enhancement of intestinal epithelial barrier function. Thus, targeted PHD1 inhibition may represent a new therapeutic approach in IBD.
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    ABSTRACT: Although peroxisome biogenesis and β-oxidation disorders are well known for their neurodevelopmental defects, patients with these disorders are increasingly diagnosed with neurodegenerative pathologies. In order to investigate the cellular mechanisms of neurodegeneration in these patients, we developed a mouse model lacking multifunctional protein 2 (MFP2, also called D-bifunctional protein), a central enzyme of peroxisomal β-oxidation, in all neural cells (Nestin-Mfp2(-/-)) or in oligodendrocytes (Cnp-Mfp2(-/-)) and compared these models with an already established general Mfp2 knockout. Nestin-Mfp2 but not Cnp-Mfp2 knockout mice develop motor disabilities and ataxia, similar to the general mutant. Deterioration of motor performance correlates with the demise of Purkinje cell axons in the cerebellum, which precedes loss of Purkinje cells and cerebellar atrophy. This closely mimics spinocerebellar ataxias of patients affected with mild peroxisome β-oxidation disorders. However, general knockouts have a much shorter life span than Nestin-Mfp2 knockouts which is paralleled by a disparity in activation of the innate immune system. Whereas in general mutants a strong and chronic proinflammatory reaction proceeds throughout the brain, elimination of MFP2 from neural cells results in minor neuroinflammation. Neither the extent of the inflammatory reaction nor the cerebellar degeneration could be correlated with levels of very long chain fatty acids, substrates of peroxisomal β-oxidation. In conclusion, MFP2 has multiple tasks in the adult brain, including the maintenance of Purkinje cells and the prevention of neuroinflammation but this is not mediated by its activity in oligodendrocytes nor by its role in very long chain fatty acid degradation.
    Neurobiology of Disease 06/2013; · 5.62 Impact Factor

Publication Stats

41k Citations
5,721.97 Total Impact Points


  • 2013
    • Harvard Medical School
      • Department of Radiation Oncology
      Boston, Massachusetts, United States
    • National and Kapodistrian University of Athens
      • Division of Clinical Therapeutics
      Athens, Attiki, Greece
  • 2007–2012
    • University of Liège
      • Laboratory of Tumor and Development Biology
      Liège, WAL, Belgium
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
    • CRG Centre for Genomic Regulation
      Barcino, Catalonia, Spain
  • 2004–2012
    • Université de Rouen
      • Microbiology Signals and Microenvironment Lab (LMSM) (EA 4312)
      Mont-Saint-Aignan, Upper Normandy, France
  • 2000–2012
    • Maastricht University
      • • Cardiologie
      • • Farmacologie
      Maastricht, Provincie Limburg, Netherlands
    • Massachusetts General Hospital
      • Department of Radiation Oncology
      Boston, MA, United States
  • 1995–2012
    • Vlaams Instituut voor Biotechnologie
      • Molecular Cell Biology
      Gand, Flanders, Belgium
  • 1994–2012
    • Leuven University College
      Louvain, Flanders, Belgium
    • Princeton University
      Princeton, New Jersey, United States
    • Whitehead Institute for Biomedical Research
      Cambridge, Massachusetts, United States
  • 1988–2012
    • Universitair Ziekenhuis Leuven
      • • Department of Cardiovascular diseases
      • • Department of General internal medicine
      Leuven, VLG, Belgium
  • 2011
    • Max Planck Institute for Molecular Biomedicine
      • Molecular Neurogenetics Laboratory
      Muenster, North Rhine-Westphalia, Germany
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University of Colorado
      • Department of Anesthesiology
      Denver, CO, United States
    • Uppsala University
      • The Rudbeck Laboratory
      Uppsala, Uppsala, Sweden
  • 2009–2011
    • Universität Heidelberg
      • Department of General, Visceral and Transplantation Surgery
      Heidelberg, Baden-Wuerttemberg, Germany
    • Charité Universitätsmedizin Berlin
      • Medical Department, Division of Hepatology and Gastroenterology
      Berlin, Land Berlin, Germany
  • 2008–2011
    • Vesalius Research Center
      Louvain, Flanders, Belgium
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
    • University Pompeu Fabra
      • Center for Genomic Regulation (CRG)
      Barcelona, Catalonia, Spain
  • 2005–2011
    • Goethe-Universität Frankfurt am Main
      • Zentrum für Molekulare Medizin
      Frankfurt am Main, Hesse, Germany
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
    • University of Geneva
      • Division of Angiology and Hemostasis
      Genève, GE, Switzerland
  • 1989–2011
    • KU Leuven
      • • Vesalius Research Center
      • • Laboratory of Neurobiology and Gene Therapy
      • • Center for Molecular and Vascular Biology
      • • Department of Reproduction, Development and Regeneration
      • • Faculty of Pharmaceutical Sciences
      Leuven, VLG, Belgium
  • 2010
    • Yale University
      • Section of Cardiovascular Medicine
      New Haven, CT, United States
  • 2002–2010
    • University of Helsinki
      • Molecular/Cancer Biology Laboratory
      Helsinki, Southern Finland Province, Finland
    • University of Virginia
      Charlottesville, Virginia, United States
  • 2007–2008
    • Leiden University Medical Centre
      • Department of Anatomy and Embryology
      Leiden, South Holland, Netherlands
  • 2006–2008
    • Dartmouth Medical School
      • Department of Medicine
      Hanover, New Hampshire, United States
    • CSU Mentor
      Long Beach, California, United States
  • 2002–2007
    • University of Amsterdam
      • • Department of Pathology
      • • Faculty of Medicine AMC
      Amsterdam, North Holland, Netherlands
  • 2003
    • Monash University (Malaysia)
      Labuan, Labuan, Malaysia
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
    • Università Vita-Salute San Raffaele
      Milano, Lombardy, Italy
  • 1998–2002
    • The Scripps Research Institute
      La Jolla, California, United States
  • 2001
    • Hebrew University of Jerusalem
      • Department of Biochemistry and Molecular Biology
      Jerusalem, Jerusalem District, Israel
  • 1999–2001
    • Kinki University
      • Department of Neurosurgery
      Ōsaka, Ōsaka, Japan
    • Flanders Mechatronics Technology Centre
      Louvain, Flanders, Belgium
  • 1996–1999
    • Umeå University
      • • Department of Medical Biosciences
      • • Department of Medical Biochemistry and Biophysics
      Umeå, Vaesterbotten, Sweden
    • Howard Hughes Medical Institute
      Maryland, United States
  • 1996–1997
    • University of Notre Dame
      • Department of Chemistry and Biochemistry
      United States