S B Liggett

Florida Metropolitan University/Tampa Campus, Tampa, Florida, United States

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Publications (260)1768.07 Total impact

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    ABSTRACT: Because of its comparatively recent evolution, Homo sapiens exhibit relatively little within-species genomic diversity. However, because of genome size, a proportionately small amount of variation creates ample opportunities for both rare mutations that may cause disease as well as more common genetic variations that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry. Those population effects extend to differences in frequency of common gene variants that may be important in heart failure natural history or therapy. For cell-signaling mechanisms important in heart failure, we review and present new data for genetic variation between AA and EA populations. Data indicate that: 1) neurohormonal signaling mechanisms frequently (16 of the 19 investigated polymorphisms) exhibit racial differences in the allele frequencies of variants comprising key constituents; 2) some of these differences in allele frequency may differentially affect the natural history of heart failure in AA compared with EA individuals; and 3) in many cases, these differences likely play a role in observed racial differences in drug or device response.
    JACC: Heart Failure. 12/2014;
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    ABSTRACT: G-protein coupled receptors (GPCRs) are the most pervasive signaling superfamily in the body and act as receptors to endogenous agonists and drugs. For β-agonist mediated bronchodilation, the receptor: G-protein: effector network is the β2-adrenergic receptor (β2AR), Gs, and adenylyl cyclase, expressed on airway smooth muscle (ASM). Using ASM-targeted transgenesis, we have previously explored which of these three early signaling elements represents a limiting factor, or bottleneck, in transmission of the signal from agonist binding to ASM relaxation. Here we overexpressed Gαs in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of Gαs expression. Contraction of ASM from acetylcholine was not affected in Gαs transgenics, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in Gαs-transgenic mouse ASM cells was enhanced compared to ASM from nontransgenic littermates. Agonist-promoted inhibition of platelet derived growth factor-stimulated ASM proliferation was also enhanced in Gαs mouse ASM. The enhanced maximal β-agonist response for relaxation, cAMP production, and growth inhibition were all of similar magnitude. Taken together, it appears that a limiting factor in β-agonist responsiveness in ASM is the expression level of Gαs. Gene therapy or pharmacological means of increasing Gαs (or its coupling efficiency to β2AR) thus represent an interface for development of novel therapeutic agents for improvement of β-agonist therapy.
    American journal of physiology. Lung cellular and molecular physiology. 09/2014;
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    ABSTRACT: Nearly full-length RNA genome sequences for 39 rhinovirus B isolates (RV-B), representing 13 different genotypes, were resolved as part of ongoing studies at the University of Wisconsin that attempt to link rhinovirus (RV) diversity and respiratory disease in infants.
    Genome announcements. 01/2014; 2(2).
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    ABSTRACT: Human rhinovirus (RV) isolates from the RV-C species are recently discovered infectious agents that are closely linked to asthma and wheezing etiologies in infants. Clinical study samples collected at the University of Wisconsin-Madison describe 41 nearly complete genome sequences representing 21 RV-C genotypes.
    Genome announcements. 01/2014; 2(2).
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    ABSTRACT: Full-length or nearly full-length RNA genome sequences for 98 rhinovirus (RV) A isolates (from the Enterovirus genus of the Picornaviridae family), representing 43 different genotypes, were resolved as part of ongoing studies to define RV genetic diversity and its potential link to respiratory disease.
    Genome announcements. 01/2014; 2(2).
  • Stephen B Liggett
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    ABSTRACT: There is a need to expand the classes of drugs used to treat obstructive lung diseases to achieve better outcomes. With only one class of direct bronchodilators (β-agonists), we sought to find receptors on human airway smooth muscle (ASM) that act via a unique mechanism to relax the muscle, have a diverse agonist binding profile to enhance the probability of finding new therapeutics, and relax ASM with equal or greater efficacy than β-agonists. We have found that human and mouse ASM express six bitter taste receptor (TAS2R) subtypes, previously thought only to exist in taste buds of the tongue. Agonists acting at TAS2Rs evoke profound bronchodilation via a Ca(2+)-dependent mechanism. TAS2R function is not altered in asthma models, undergoes minimal tachyphylaxis upon repetitive dosing, and relaxes even under extreme desensitization of relaxation by β-agonists. Taken together, TAS2Rs on ASM represent a novel pathway to consider for development of agonists in the treatment of asthma and chronic obstructive lung disease.
    Transactions of the American Clinical and Climatological Association 01/2014; 125:64-75.
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    ABSTRACT: Bitter taste receptors (TAS2Rs) have recently been found to be expressed on human airway smooth muscle (HASM) and their activation results in marked relaxation. These agents have been proposed as a new class of bronchodilators in the treatment of obstructive lung diseases since they act via a different mechanism than -agonists. The TAS2R signal transduction pathway in HASM has multiple elements that are potentially subject to regulation by inflammatory, genetic, and epigenetic mechanisms associated with asthma. To address this, expression, signaling and physiologic functions of the three major TAS2Rs (subtypes 10, 14, 31) on HASM were studied. Transcript expression of these TAS2Rs was not decreased in HASM derived from asthmatic donors compared to nonasthmatics (n=6 from each group). In addition, [Ca2+]i signaling using TAS2R subtype specific agonists (diphenhydramine, chloroquine, saccharin, and flufenamic acid) was not impaired in the asthmatic-derived cells, nor was the response to quinine which activates all three subtypes. HASM cell mechanics measured by magnetic twisting cytometry revealed equivalent TAS2R-mediated relaxation of methacholine treated cells between the two groups. Human precision cut lung slices (PCLS) treated with IL-13 caused a decrease in -agonist (formoterol) mediated relaxation of carbachol contracted airways compared to control slices. In contrast, TAS2R-mediated relaxation was unaffected by IL-13. Taken together, we conclude that TAS2R expression or function is unaffected in HASM derived from asthmatics or the IL-13 inflammatory environment.
    American Journal of Respiratory Cell and Molecular Biology 11/2013; · 4.15 Impact Factor
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    ABSTRACT: This study assessed the impact of bucindolol, a beta-blocker/sympatholytic agent, on the development of atrial fibrillation (AF) in advanced chronic heart failure with reduced left ventricular ejection fraction (HFREF) patients enrolled in the BEST (Beta-Blocker Evaluation of Survival Trial). β-Blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by β1- and α2c-adrenergic receptor (AR) polymorphisms that can be used to subdivide HFREF populations into those with bucindolol effectiveness levels that are enhanced, unchanged, or lost. BEST enrolled 2,708 New York Heart Association (NYHA) class III to IV HFREF patients. A substudy in which 1,040 patients' DNA was genotyped for the β1-AR position 389 Arg/Gly and the α2c322-325 wild type (Wt)/deletion (Del) polymorphisms, and new-onset AF was assessed from adverse event case report forms or electrocardiograms at baseline and at 3 and 12 months. In the entire cohort, bucindolol reduced the rate of new-onset AF compared to placebo by 41% (hazard ratio [HR]: 0.59 [95% confidence interval (CI): 0.44 to 0.79], p = 0.0004). In the 493 β1389 arginine homozygotes (Arg/Arg) in the DNA substudy, bucindolol reduced new-onset AF by 74% (HR: 0.26 [95% CI: 0.12 to 0.57]), with no effect in β1389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test = 0.008). When β1389 Gly carriers were subdivided by α2c Wt homozygotes (n = 413, HR: 0.94 [95% CI: 0.48 to 1.82], p = 0.84) or Del variant carriers (n = 134, HR: 1.33 [95% CI: 0.32 to 5.64], p = 0.70), there was a positive interaction test (p = 0.016) when analyzed with β1389 Arg homozygotes. Bucindolol prevented new-onset AF; β1 and α2c polymorphisms predicted therapeutic response; and the 47% of patients who were β1389 Arg homozygotes had an enhanced effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; NCT00000560).
    JACC. Heart failure. 08/2013; 1(4):338-344.
  • Stephen B Liggett
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    ABSTRACT: Introduction: There is an unmet need for a new class of direct bronchodilators for the treatment of asthma and chronic obstructive lung disease. Unexpectedly, bitter taste receptors (TAS2Rs) have been localized on airway smooth muscle and when activated cause marked smooth muscle relaxation through a mechanism that is distinct from β2-adrenegic receptors. Thus TAS2R agonists have emerged as a novel class of bronchodilator. Areas covered: A synopsis of the TAS2R family and its biology for bitter taste perception on the tongue is provided, followed by a review of the identification and molecular and physiological characterization of TAS2R subtypes on human and mouse airway smooth muscle. The proposed molecular mechanisms leading to the relaxation response are provided, along with gaps in our understanding at certain points in the signaling cascade. Unresolved issues that may need to be considered for drug development are discussed. Expert opinion: TAS2R agonists show promise as a new class of highly efficacious bronchodilators for treatment of obstructive lung disease. With tens of thousands of known natural and synthetic bitter compounds, there is substantial diversity within the known agonists, and, a ready source of agents for screening and further development of an inhaled TAS2R agonist for therapeutic purposes.
    Expert Opinion on Therapeutic Targets 04/2013; · 4.90 Impact Factor
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    ABSTRACT: BACKGROUND: -In patients with chronic heart failure and reduced left ventricular ejection fraction (HFREF) β-blockers prevent cardiac arrhythmias, including ventricular tachycardia/fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β-blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors (ARs). METHODS AND RESULTS: -From a substudy of the β-Blocker Evaluation of Survival Trial (BEST, n = 1040), we identified those with the high functioning 389Arg vs. the lower function 389Gly β(1) adrenergic receptor (AR) variant, and the loss of function (α2C)322-325 AR deletion vs. the 322-325 wild type (Wt)/deletion (Del) variant. VT/VF was recorded on case report forms as an adverse event. There were 493 Arg 389 β(1) receptor homozygotes (β(1)389 Arg/Arg) vs. 547 Gly389 carriers and 207 (α2C)322-325 Del carriers vs. 833 homozygous Wts ((α2C)322-325 Wt/Wt). In all genotypes bucindolol was associated with a lower incidence of VT/VF (subhazard ratio (SHR) 0.42 (0.27, 0.64), P=0.00006). Bucindolol reduced VT/VF in β(1)389 Arg homozygotes (SHR 0.26 (0.14, 0.50), P=0.00005) but not in β(1)389 Gly carriers (SHR 0.60 (0.34, 1.07), P=0.09). For genotype combinations, the (α2C)322-325 polymorphism altered the VT/VF bucindolol response in β(1)389 Gly carriers, with (α2C) Del genotypes associated with complete efficacy loss. A test of interaction was statistically significant (P=0.028) for treatment group and a β(1)389/(α2C)322-325 three genotype construct, effectively identifying patients who exhibited enhanced response, no substantial response modification and loss of response. CONCLUSIONS: -Bucindolol prevents VT/VF in HFREF subjects, and this effect is modulated by β(1)389 Arg/Gly and (α2C)322-325 Wt/Del AR polymorphisms.
    Circulation Arrhythmia and Electrophysiology 12/2012; · 5.95 Impact Factor
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    ABSTRACT: Background Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322–325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. Methodology In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322–325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles. Principal Findings The combination of β1389 Arg+α2C322–325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β1389 Arg homozygotes+α2C322–325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit. Conclusions On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322–325 Wt homozygotes), and no (β1389 Gly carriers+α2C322–325 Del carriers) efficacy.
    PLoS ONE 10/2012; 7(10). · 3.53 Impact Factor
  • Adam A Clark, Stephen B Liggett, Steven D Munger
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    ABSTRACT: We present a novel hypothesis that could explain many off-target effects of diverse pharmaceuticals. Specifically, we propose that any drug with a bitter taste could have unintended actions in the body through stimulation of extraoral type 2 taste receptors (T2Rs). T2Rs were first identified in the oral cavity, where they function as bitter taste receptors. However, recent findings indicate that they are also expressed outside the gustatory system, including in the gastrointestinal and respiratory systems. T2R ligands include a diverse array of natural and synthetic compounds, many of which are toxins. Notably, many pharmaceuticals taste bitter, with compounds such as chloroquine, haloperidol, erythromycin, procainamide, and ofloxacin known to activate T2Rs. Bitter-tasting compounds can have specific physiological effects in T2R-expressing cells. For example, T2Rs are found in some gastrointestinal endocrine cells, including those that secrete the peptide hormones (e.g., ghrelin and glucagon-like peptide-1) in response to stimulation by bitter-tasting compounds. In the respiratory system, stimulation of T2Rs expressed in respiratory epithelia and smooth muscle has been implicated in protective airway reflexes, ciliary beating, and bronchodilation. If our hypothesis is confirmed, it would offer a new paradigm for understanding the off-target actions of diverse drugs and could reveal potential new therapeutic targets.-Clark, A. A., Liggett, S. B., Munger, S. D. Extraoral bitter taste receptors as mediators of off-target drug effects.
    The FASEB Journal 09/2012; · 5.70 Impact Factor
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    ABSTRACT: G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (-9.1±6.8 versus -6.8±7.1 versus -5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P=0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48-3.55]; P=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.
    Hypertension 09/2012; 60(4):957-64. · 6.87 Impact Factor
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    ABSTRACT: Recently, bitter taste receptors (TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca(2+) concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic β-agonists. The β(2)-adrenergic receptor (β(2)AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of β(2)AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed >90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of β(2)AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca(2+) concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by >90%. In mouse trachea, β(2)AR desensitization by β-agonist amounted to 92 ± 6.0% (P < 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 ± 3.5%). In human lung slices, chronic β-agonist exposure culminated in 64 ± 5.7% (P < 0.001) desensitization of β(2)AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic β-agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.
    AJP Lung Cellular and Molecular Physiology 06/2012; 303(4):L304-11. · 3.52 Impact Factor
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • Wayne C.H. Wang, Susan G. Dorsey, Stephen B. Liggett
    American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
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    ABSTRACT: A pro-asthmatic culture milieu and β(2)-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single-nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing P-values <0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5' of the thyroid hormone receptor-β gene was associated with BDR in the childhood population and two adult populations (P-value=0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.The Pharmacogenomics Journal advance online publication, 3 January 2012; doi:10.1038/tpj.2011.56.
    The Pharmacogenomics Journal 01/2012; · 5.13 Impact Factor

Publication Stats

12k Citations
1,768.07 Total Impact Points


  • 2014
    • Florida Metropolitan University/Tampa Campus
      Tampa, Florida, United States
  • 2009–2014
    • University of Wisconsin–Madison
      • Institute for Molecular Virology
      Madison, Wisconsin, United States
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
  • 2012–2013
    • University of South Florida
      Tampa, Florida, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Environmental Health Sciences
      Baltimore, MD, United States
    • University of Maryland, Baltimore County
      Baltimore, Maryland, United States
  • 2009–2013
    • University of Colorado
      • Division of Cardiology
      Denver, Colorado, United States
  • 2006–2013
    • University of Maryland, Baltimore
      • • Division of Pulmonary and Critical Care Medicine
      • • Department of Medicine
      Baltimore, Maryland, United States
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1989–2012
    • Duke University Medical Center
      • • Department of Anesthesiology
      • • Department of Medicine
      Durham, North Carolina, United States
  • 2011
    • University of Florida
      • Department of Pharmacotherapy and Translational Research
      Gainesville, FL, United States
  • 2005–2011
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1989–2011
    • Washington University in St. Louis
      • • Department of Anesthesiology
      • • Center for Pharmacogenomics
      • • Department of Medicine
      Saint Louis, MO, United States
  • 2007–2010
    • Loyola University Maryland
      Baltimore, Maryland, United States
  • 1995–2010
    • University of Cincinnati
      • • Department of Molecular Genetics, Biochemistry, and Microbiology
      • • Department of Internal Medicine
      • • Division of Pulmonary, Critical Care & Sleep Medicine
      • • College of Medicine
      Cincinnati, OH, United States
    • University of Nottingham
      • School of Medicine
      Nottigham, England, United Kingdom
  • 2008
    • University of Michigan
      • Department of Epidemiology
      Ann Arbor, MI, United States
  • 2000–2006
    • The Ohio State University
      • • Department of Surgery
      • • Division of Pharmacology
      Columbus, OH, United States
  • 1998
    • University of California, San Diego
      • Department of Pharmacology
      San Diego, CA, United States
  • 1989–1995
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1993
    • Cincinnati Children's Hospital Medical Center
      • Division of Pulmonary Medicine
      Cincinnati, OH, United States
  • 1988–1992
    • University of Washington Seattle
      • • Department of Pathology
      • • Department of Medicine
      Seattle, WA, United States