Daniel J Rader

Treatment Research Institute, Philadelphia PA, Philadelphia, Pennsylvania, United States

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Publications (630)5744.55 Total impact

  • Sumeet A Khetarpal, Daniel J Rader
    Arteriosclerosis Thrombosis and Vascular Biology 01/2015; · 6.34 Impact Factor
  • Alan Daugherty, Ira Tabas, Daniel J Rader
    Arteriosclerosis Thrombosis and Vascular Biology 01/2015; 35(1):11-2. · 5.53 Impact Factor
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    ABSTRACT: Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol16. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl−1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15, 17 and apolipoprotein C-III. Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
    Nature 12/2014; advance online publication. · 42.35 Impact Factor
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    ABSTRACT: Objectives: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by markedly elevated LDL-C levels, limited response to conventional lipid-lowering therapies, and high risk of premature CVD. Severe atherosclerosis, believed related to LDL-C levels, may be evident by the second decade of life. Clinicians have traditionally identified HoFH based upon LDL-C levels: untreated >500mg/dL or treated ≥300mg/dL. Recent studies suggest that the clinical presentation of HoFH may be more variable. We examined baseline treated LDL-C levels in a cohort of patients with genetically confirmed HoFH to assess the relevance of traditional identification. Methods: Baseline characteristics of 29 HoFH patients from a multinational Phase 3 study were collected. All subjects were ≥18 years and met the diagnosis of HoFH based on: untreated TC >500 mg/dL and both parents with documented untreated TC >250mg/dL; documented genetic mutations of genes known to affect LDLR functionality; or skin fibroblast LDLR activity <20% normal. Results: All patients had confirmed mutations in both alleles of LDLR (n=28) or LDLRAP1 (n=1) gene. Age ranged from 18-55 years; 93% of patients had a history of CVD, 35% had undergone CABG, and 10% each had undergone coronary angioplasty, aortic valve replacement, or mitral valve replacement/repair. Patients were receiving statins (93%; 76% with ezetimibe) and apheresis (62%). Treated LDL-C levels ranged from 152-564mg/dL; 38% had LDL-C <300mg/dL and 14% <200mg/dL (Table). There was no difference between levels of subjects receiving apheresis treatment or not. Conclusion: Contrary to conventional viewpoints, and consistent with recent studies, this cohort of patients provides further evidence of the heterogeneity of treated LDL-C values in genetically defined HoFH patients. Diagnosis of HoFH should not be excluded based on treated levels <300 mg/dL, but must also include other supportive clinical or genetic evidence.
    The 2nd World Congress of Clinical Lipidology, Vienna, Austria; 12/2014
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    ABSTRACT: Familial hypercholesterolemia (FH) is a genetic disease characterized by substantial elevations of low-density lipoprotein cholesterol, unrelated to diet or lifestyle. Untreated FH patients have 20 times the risk of developing coronary artery disease, compared with the general population. Estimates indicate that as many as 1 in 500 people of all ethnicities and 1 in 250 people of Northern European descent may have FH; nevertheless, the condition remains largely undiagnosed. In the United States alone, perhaps as little as 1% of FH patients have been diagnosed. Consequently, there are potentially millions of children and adults worldwide who are unaware that they have a life-threatening condition. In countries like the Netherlands, the United Kingdom, and Spain, cascade screening programs have led to dramatic improvements in FH case identification. Given that there are currently no systematic approaches in the United States to identify FH patients or affected relatives, the patient-centric nonprofit FH Foundation convened a national FH Summit in 2013, where participants issued a "call to action" to health care providers, professional organizations, public health programs, patient advocacy groups, and FH experts, in order to bring greater attention to this potentially deadly, but (with proper diagnosis) eminently treatable, condition. Copyright © 2014 Elsevier Inc. All rights reserved.
    American Heart Journal 12/2014; · 4.56 Impact Factor
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    ABSTRACT: BACKGROUND: Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS: We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS: With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS: Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
    New England Journal of Medicine 11/2014; 371(22):2072-82. · 54.42 Impact Factor
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    ABSTRACT: Recent trials demonstrated substantial improvement in lipid parameters with inhibition of proprotein convertase subtilisin-like/kexin type 9 (PCSK9). Although statins and fibrates have been reported to increase plasma PCSK9 levels, the effect of niacin on PCSK9 is unknown. We investigated the impact of niacin, atorvastatin, and fenofibrate on PCSK9 levels in 3 distinct studies. A statin-only study randomized 74 hypercholesterolemic patients to placebo, atorvastatin 10 mg/day, or atorvastatin 80 mg/day for 16 weeks. A dose-related increase in PCSK9 was noted such that atorvastatin 80 mg increased PCSK9 by a mean +27% (95% confidence interval [CI] +12 to +42), confirming the effect of statin therapy on raising PCSK9. A second study randomized 70 patients with carotid atherosclerosis to simvastatin 20 mg/day, simvastatin 80 mg/day, or simvastatin 20 mg/extended-release (ER) niacin 2 g/day. PCSK9 levels were increased with statin therapy, but decreased with the simvastatin 20 mg/ER niacin combination (mean -13%, CI -3 to -23). A final study involved 19 dyslipidemic participants on atorvastatin 10 mg with serial addition of fenofibric acid 150 mg followed by ER niacin 2 g/day. Fenofibric acid led to a +23% (CI +10 to +36, p = 0.001) increase in PCSK9; the addition of niacin resulted in a subsequent -17% decrease (CI -19 to -5, p = 0.004). A positive association was noted between change in PCSK9 and low-density lipoprotein cholesterol levels (r = 0.62, p = 0.006) with the addition of niacin. In conclusion, niacin therapy offsets the increase in PCSK9 levels noted with statin and fibrate therapy. A portion of the low-density lipoprotein cholesterol reduction seen with niacin therapy may be due to reduction in PCSK9. Copyright © 2014 Elsevier Inc. All rights reserved.
    The American Journal of Cardiology 10/2014; · 3.43 Impact Factor
  • Sony Tuteja, Daniel J Rader
    Nature Reviews Endocrinology 09/2014; · 11.03 Impact Factor
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    ABSTRACT: Endothelial lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration-dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at the sn-2 position, generating the corresponding PUFA-lyso PtdCho. This specificity for PUFA-PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.
    Lipids 08/2014; · 2.56 Impact Factor
  • Daniel J Rader, G Kees Hovingh
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    ABSTRACT: The cholesterol contained within HDL is inversely associated with risk of coronary heart disease and is a key component of predicting cardiovascular risk. However, despite its properties consistent with atheroprotection, the causal relation between HDL and atherosclerosis is uncertain. Human genetics and failed clinical trials have created scepticism about the HDL hypothesis. Nevertheless, drugs that raise HDL-C concentrations, cholesteryl ester transfer protein inhibitors, are in late-stage clinical development, and other approaches that promote HDL function, including reverse cholesterol transport, are in early-stage clinical development. The final chapters regarding the effect of HDL-targeted therapeutic interventions on coronary heart disease events remain to be written.
    The Lancet 08/2014; 384(9943):618–625. · 39.21 Impact Factor
  • Alanna Strong, Kevin Patel, Daniel J Rader
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    ABSTRACT: Genome-wide association studies have been used as an unbiased tool to identify novel genes that contribute to variations in LDL cholesterol levels in the hopes of uncovering new biology and new therapeutic targets for the treatment of atherosclerotic cardiovascular disease. The locus identified by genome-wide association studies with the strongest association with LDL cholesterol and atherosclerotic cardiovascular disease is the 1p13 sortilin-1 (SORT1) locus. Here, we review the identification and characterization of this locus, the initial physiological studies describing the role of SORT1 in lipoprotein metabolism, and recent work that has begun to sort out the complexity of this role.
    Current opinion in lipidology. 08/2014;
  • Journal of Cardiac Failure 08/2014; 20(8S):S81. · 3.07 Impact Factor
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    ABSTRACT: Rationale: Familial hypercholesterolemia (FH) is a genetic disorder that arises due to loss-of-function mutations in the low-density lipoprotein receptor (LDLR) and homozygous FH (hoFH) is a candidate for gene therapy using adeno-associated viral (AAV) vectors. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL) negatively regulate LDLR protein and could dampen AAV encoded LDLR expression. Objective: We sought to create vectors expressing gain-of-function human LDLR variants that are resistant to degradation by human PCSK9 and IDOL and thereby enhance hepatic LDLR protein abundance and plasma LDL cholesterol reduction. Methods and Results: Amino acid substitutions were introduced into the coding sequence of human LDLR cDNA to reduce interaction with hPCSK9 and hIDOL. A panel of mutant hLDLRs was initially screened in vitro for escape from PCSK9. The variant hLDLR-L318D was further evaluated using a mouse model of hoFH lacking endogenous LDLR and apolipoprotein B mRNA editing enzyme, APOBEC-1 (DKO). Administration of wild type hLDLR to DKO mice, expressing hPCSK9, led to diminished LDLR activity. However, LDLR-L318D was resistant to hPCSK9 mediated degradation and effectively reduced cholesterol levels. Similarly, the LDLR-K809R\C818A construct avoided hIDOL regulation and achieved stable reductions in serum cholesterol. An AAV8.LDLR-L318D\K809R\C818A vector that carried all three amino acid substitutions conferred partial resistance to both hPCSK9 and hIDOL mediated degradation. Conclusions: Amino acid substitutions in the human LDLR confer partial resistance to PCSK9 and IDOL regulatory pathways with improved reduction in cholesterol levels and improve upon a potential gene therapeutic approach to treat homozygous FH subjects.
    Circulation Research 07/2014; · 11.09 Impact Factor
  • Daniel J Rader
    Cardiovascular Research 07/2014; · 5.81 Impact Factor
  • Sumeet A Khetarpal, Daniel J Rader
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    ABSTRACT: A wealth of novel lipid loci have been identified through a variety of approaches focused on common and low-frequency variation and collaborative metaanalyses in multiethnic populations. Despite progress in identification of loci, the task of determining causal variants remains challenging. This work will undoubtedly be enhanced by improved understanding of regulatory DNA at a genomewide level as well as new methodologies for interrogating the relationships between noncoding SNPs and regulatory regions. Equally challenging is the identification of causal genes at novel loci. Some progress has been made for a handful of genes and comprehensive testing of candidate genes using multiple model systems is underway. Additional insights will be gleaned from focusing on lowfrequency and rare coding variation at candidate loci in large populations. This article is part of a Special Issue entitled: From Genome to Function.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 06/2014; · 5.09 Impact Factor
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    ABSTRACT: Background Obesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear. Methods We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure. Results Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone. Conclusions In adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT0371293 .).
    New England Journal of Medicine 06/2014; 370(24):2265-2275. · 54.42 Impact Factor
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    ABSTRACT: Rationale: Individuals with naturally occurring loss-of-function PCSK9 mutations experience reduced blood low-density lipoprotein cholesterol (LDL-C) levels and protection against cardiovascular disease. Objective: The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system can efficiently introduce loss-of-function mutations into the endogenous PCSK9 gene in vivo. Methods and Results: We used adenovirus to express Cas9 and a CRISPR guide RNA targeting Pcsk9 in mouse liver, where the gene is specifically expressed. We found that within three to four days of administration of the virus, the mutagenesis rate of Pcsk9 in the liver was as high as >50%. This resulted in decreased plasma PCSK9 levels, increased hepatic LDL receptor levels, and decreased plasma cholesterol levels (by 35%-40%) in the blood. No off-target mutagenesis was detected in 10 selected sites. Conclusions: Genome editing with the CRISPR-Cas9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice. This approach may have therapeutic potential for the prevention of cardiovascular disease in humans.
    Circulation Research 06/2014; · 11.09 Impact Factor
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    ABSTRACT: The period following an acute coronary syndrome (ACS) represents a critical time frame with a high risk for recurrent events and death. The pathogenesis of this increase in clinical cardiovascular disease events after ACS is complex, with molecular mechanisms including increased thrombosis and inflammation. Dyslipoproteinemia is common in patients with ACS and predictive of recurrent cardiovascular disease events after presentation with an ACS event. Although randomized clinical trials have provided fairly convincing evidence that high-dose statins reduce the risk of recurrent cardiovascular events after ACS, there remain questions about how aggressively to reduce low-density lipoprotein cholesterol levels in ACS. Furthermore, no other lipid-related interventions have yet been proven to be effective in reducing major cardiovascular events after ACS. Here, we review the relationship of lipoproteins as biomarkers to cardiovascular risk after ACS, the evidence for lipid-targeted interventions, and the potential for novel therapeutic approaches in this arena.
    Circulation Research 06/2014; 114(12):1880-9. · 11.09 Impact Factor

Publication Stats

32k Citations
5,744.55 Total Impact Points


  • 2011–2014
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
    • Universität zu Lübeck
      Lübeck Hansestadt, Schleswig-Holstein, Germany
    • The University of Western Ontario
      London, Ontario, Canada
    • University of Utah
      Salt Lake City, Utah, United States
  • 1998–2014
    • University of Pennsylvania
      • • Perelman School of Medicine
      • • Division of Translational Medicine and Human Genetics
      • • Cardiovascular Institute
      • • Institute for Translational Medicine and Therapeutics
      • • Department of Medicine
      • • Department of Pharmacology
      • • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
  • 1993–2014
    • Hospital of the University of Pennsylvania
      • • Division of Cardiovascular Medicine
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2013
    • Vanderbilt University
      • Department of Medicine
      Nashville, MI, United States
    • CGH Medical Center
      Sterling, Illinois, United States
  • 2008–2013
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Wistar Institute
      Philadelphia, Pennsylvania, United States
    • Stanford University
      • Division of Pediatric Cardiology
      Stanford, CA, United States
    • Temple University
      • Section of Hospital Medicine
      Philadelphia, PA, United States
  • 2003–2013
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
    • Hanson Institute
      Tarndarnya, South Australia, Australia
    • University of Adelaide
      • Discipline of Medicine
      Adelaide, South Australia, Australia
  • 1990–2013
    • National Heart, Lung, and Blood Institute
      • Hematology Branch
      Maryland, United States
  • 2012
    • Columbia University
      • Department of Medicine
      New York City, NY, United States
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
  • 2010–2012
    • University of Groningen
      • Department of Pediatrics
      Groningen, Province of Groningen, Netherlands
    • Massachusetts General Hospital
      • • Center for Human Genetic Research
      • • Cardiovascular Research Center
      Boston, MA, United States
    • Emory University
      Atlanta, Georgia, United States
    • The Rockefeller University
      • Laboratory of Biochemical Genetics and Metabolism
      New York City, NY, United States
    • University of Michigan
      • Department of Biostatistics
      Ann Arbor, MI, United States
  • 2004–2012
    • The Children's Hospital of Philadelphia
      • • Division of Endocrinology and Diabetes
      • • Division of Gastroenterology, Hepatology and Nutrition
      • • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2009
    • Chestnut Hill College
      Philadelphia, Pennsylvania, United States
  • 2007–2009
    • Thomas Jefferson University Hospitals
      • Division of Cardiology
      Philadelphia, Pennsylvania, United States
  • 2004–2009
    • Tufts University
      • • Cardiovascular Nutrition Research Laboratory
      • • Lipid Metabolism Research Laboratory
      • • Division of Endocrinology, Diabetes and Metabolism
      Boston, GA, United States
  • 2006–2008
    • deCODE genetics, Inc.
      Reikiavik, Capital Region, Iceland
    • University of Delaware
      • Department of Biological Sciences
      Newark, DE, United States
  • 2004–2007
    • Heart Research Institute
      Newtown, New South Wales, Australia
  • 2005
    • Ludwig-Maximilian-University of Munich
      • Department of Internal Medicine II
      München, Bavaria, Germany
    • University of Toronto
      • Department of Medicine
      Toronto, Ontario, Canada
    • University of Massachusetts Amherst
      • Department of Public Health
      Amherst Center, MA, United States
  • 2002
    • The Jikei University School of Medicine
      • Department of Cardiology
      Tokyo, Tokyo-to, Japan
  • 2000
    • Universität Heidelberg
      • Department of Internal Medicine I, Endocrinology and Metabolism
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1997
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 1993–1995
    • Bristol-Myers Squibb
      • Department of Metabolic Diseases
      New York City, NY, United States
  • 1992
    • University of Hamburg
      • Department of Internal Medicine II and Clinic (Oncology Center)
      Hamburg, Hamburg, Germany