Paul W Noble

Cedars-Sinai Medical Center, Los Angeles, California, United States

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Publications (139)1113.74 Total impact

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    ABSTRACT: Peripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF).
    BMC genomics. 10/2014; 15(1):902.
  • New England Journal of Medicine 08/2014; 371(8):783-4. · 54.42 Impact Factor
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    ABSTRACT: Background and objectivePirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF.Methods All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug.ResultsA total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week–7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY.Conclusions This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated.
    Respirology 06/2014; · 2.78 Impact Factor
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    ABSTRACT: BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
    New England Journal of Medicine 05/2014; 370(22):2071-82. · 54.42 Impact Factor
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    ABSTRACT: BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
    New England Journal of Medicine 05/2014; 370(22):2071-82. · 54.42 Impact Factor
  • Christina E Barkauskas, Paul W Noble
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by severe and progressive scar formation in the gas-exchange regions of the lung. Despite years of research, therapeutic treatments remain elusive and there is a pressing need for deeper mechanistic insights into the pathogenesis of the disease. In this manuscript, we review our current knowledge of the triggers and/or perpetuators of pulmonary fibrosis with special emphasis on the alveolar epithelium and the underlying mesenchyme. In doing so, we raise a number of questions highlighting critical voids in our current understanding of how IPF develops and progresses.
    AJP Cell Physiology 04/2014; · 3.71 Impact Factor
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    ABSTRACT: A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive and disordered deposition of extracellular matrix. Although the lung extracellular matrix normally plays an essential role in development and maintenance of lung tissue through reciprocal interactions with resident cells, the disordered matrix in the diseased lung is increasingly recognized as an active and important contributor to IPF pathogenesis. This working group summary from a recently conducted National Heart, Lung, and Blood Institute strategic planning workshop for IPF research highlights recent advances, challenges, and opportunities in the study of matrix biology in IPF. Particular attention is given to the composition and mechanical properties of the matrix in normal and diseased lungs, and the biochemical and biomechanical influences exerted by pathological matrix. Recently developed model systems are also summarized as key tools for advancing our understanding of matrix biology in IPF. Emerging approaches to therapeutically target the matrix in preclinical and clinical settings are discussed, as are important concepts, such as alterations of the matrix with aging and the potential for the resolution of fibrosis. Specific recommendations for future studies in matrix biology of IPF are also proposed.
    American Journal Of Pathology 04/2014; · 4.60 Impact Factor
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    ABSTRACT: Rationale: FVC is a standard primary endpoint in clinical trials evaluating novel therapies for patients with IPF. However, all-cause mortality or a composite comprised of all-cause mortality and all-cause non-elective hospitalization has been proposed as the standard primary endpoint. Objectives: Conduct an evaluation of mortality in three Phase 3 clinical trials and evaluate the feasibility of mortality trials in IPF. Methods: Study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (N=347) or the INSPIRE study evaluating interferon-γ1b (N=275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided alpha of 0.05. Measurements and Main Results: Seventy-three deaths occurred during the period of observation (mean duration of follow-up, 80.1 weeks). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a 2-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2582 patients. Conclusion: The all-cause mortality rate is relatively low in IPF patients with mild-to-moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive.
    American Journal of Respiratory and Critical Care Medicine 01/2014; · 11.04 Impact Factor
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    ABSTRACT: RECAP is an open-label extension study evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) who completed the Phase 3 CAPACITY program.
    01/2014; 31(3):198-205.
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    ABSTRACT: 6-minute walk test distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with IPF; however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF.A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon gamma-1b (N=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD.Baseline 6MWD<250 m was associated with a 2-fold increase in the risk of mortality (HR 2.12; 95% CI 1.15-3.92) and a 24-week decline in 6MWD>50 m was associated with a nearly 3-fold increase in mortality risk (HR 2.73; 95% CI 1.60-4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic, 0.80 [95% CI 0.76-0.85] vs.0.75 [0.71-0.79]).Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model.
    European Respiratory Journal 12/2013; · 6.36 Impact Factor
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    ABSTRACT: The median survival of patients with idiopathic pulmonary fibrosis continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the National Heart, Lung and Blood Institute held a workshop aimed at coordinating research efforts and accelerating the development of idiopathic pulmonary fibrosis therapies. Basic, translational and clinical researchers gathered with representatives from the National Heart Lung and Blood Institute, patient advocacy groups, pharmaceutical companies and the Food and Drug Administration to review the current state of idiopathic pulmonary fibrosis research and identify priority areas, opportunities for collaborations and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: 1) biology of alveolar epithelial injury and aberrant repair, 2) role of extracellular matrix, 3) preclinical modeling, 4) the role of inflammation and immunity, 5) genetic, epigenetic and environmental determinants, 6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional and patient communities and the National Heart Lung and Blood Institute.
    American Journal of Respiratory and Critical Care Medicine 10/2013; · 11.04 Impact Factor
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    ABSTRACT: Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα+ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.
    The Journal of clinical investigation 06/2013; · 15.39 Impact Factor
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    ABSTRACT: Background: The role and mechanism of action of MIF in hyperoxia-induced acute lung injury (HALI) in the newborn lung are not known. We hypothesized that MIF is a critical regulatory molecule in HALI in the developing lung.
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    ABSTRACT: The role and mechanism of action of MIF in hyperoxia-induced acute lung injury (HALI) in the newborn lung are not known. We hypothesized that MIF is a critical regulatory molecule in HALI in the developing lung. We studied newborn wild type (WT), MIF knockout (MIFKO), and MIF lung transgenic (MIFTG) mice in room air and hyperoxia exposure for 7 postnatal (PN) days. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed. MIF mRNA and protein expression were significantly increased in WT lungs at PN7 of hyperoxia exposure. The pattern of expression of Angiopoietin 2 protein (in MIFKO>WT>MIFTG) was similar to the mortality pattern (MIFKO>WT>MIFTG) in hyperoxia at PN7. In room air, MIFKO and MIFTG had modest but significant increases in chord length, compared to WT. This was associated with decreased expression of Angiopoietin 1 and Tie 2 proteins in the MIFKO and MIFTG, as compared to the WT control lungs in room air. However, on hyperoxia exposure, while the chord length was increased from their respective room air controls, there were no differences between the 3 genotypes. These data point to the potential roles of Angiopoietins 1, 2 and their receptor Tie2 in the MIF-regulated response in room air and upon hyperoxia exposure in the neonatal lung.
    PLoS ONE 04/2013; 8(4):e60560. · 3.53 Impact Factor
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    ABSTRACT: β-Arrestins regulate G protein-coupled receptors through receptor desensitization while also acting as signaling scaffolds to facilitate numerous effector pathways. Recent studies have provided evidence that β-arrestins play a key role in inflammatory responses. Here, we summarize these advances on the roles of β-arrestins in immune regulation and inflammatory responses under physiological and pathological conditions, with an emphasis on translational implications of β-arrestins on human diseases.
    Progress in molecular biology and translational science 01/2013; 118:359-93. · 2.32 Impact Factor
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    ABSTRACT: SESSION TYPE: ILD PostersPRESENTED ON: Wednesday, October 24, 2012 at 01:30 PM - 02:30 PMPURPOSE: Among the various interstitial lung diseases, idiopathic pulmonary fibrosis (IPF) is the most common, devastating, and fatal. A progressive condition of unknown etiology with a clear predilection for the elderly, IPF almost invariably ends in respiratory failure within five years of diagnosis. The limited understanding of IPF pathogenesis precludes the ability to provide effective treatment options. Evidence suggests that endoplasmic reticulum (ER) stress, protein misfolding, and the subsequent unfolded protein response (UPR) may represent a mechanism in the development of pulmonary fibrosis, as part of a dysfunctional repair process following lung injury. We therefore investigate whether the aging epithelium is more susceptible to ER stress and activation of the UPR.METHODS: Using a murine model of pulmonary fibrosis and ER stress, we conduct in vivo and in vitro studies in young and aged C57Bl6 mice. Intrapulmonary tunicamycin is administered to induce ER stress. Protein expression of key components of the ER stress/UPR system is examined. Hydroxyproline assay and histology evaluate for the development of fibrosis.RESULTS: In mouse whole lung and primary type 2 alveolar epithelial cells, tunicamycin reliably induces ER stress. Basal levels of protein chaperones are lower in naïve aged mice as compared to naïve young mice. Aged mice also display less BiP increase following ER stress. Basal levels of pro-apoptotic factors are higher in naïve aged mice and increase further following ER stress. Aged mice develop significantly more fibrosis in response to bleomycin as compared to their younger counterparts.CONCLUSIONS: In mouse lung, aging alters the unfolded protein response to ER stress. Augmented lung fibrosis is seen in aging, which may be in part due to an altered ER stress/UPR pathway.CLINICAL IMPLICATIONS: With enhanced understanding of the molecular and cellular aspects of pulmonary aging, and in particular the interaction between aging, pulmonary fibrosis, and ER stress, the ultimate goal is to develop effective therapies for, and thereby reduce mortality from, IPF.DISCLOSURE: The following authors have nothing to disclose: Jessica Chia, Kenneth Schmader, Paul NobleNo Product/Research Disclosure InformationDuke University Medical Center, Durham, NC.
    Chest 10/2012; 142(4_MeetingAbstracts):444A. · 7.13 Impact Factor
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    ABSTRACT: Pulmonary fibrosis occurs in a variety of clinical settings, constitutes a major cause of morbidity and mortality, and represents an enormous unmet medical need. However, the disease is heterogeneous, and the failure to accurately discern between forms of fibrosing lung diseases leads to inaccurate treatments. Pulmonary fibrosis occurring in the context of connective tissue diseases is often characterized by a distinct pattern of tissue pathology and may be amenable to immunosuppressive therapies. In contrast, idiopathic pulmonary fibrosis (IPF) is a progressive and lethal form of fibrosing lung disease that is recalcitrant to therapies that target the immune system. Although animal models of fibrosis imperfectly recapitulate IPF, they have yielded numerous targets for therapeutic intervention. Understanding the heterogeneity of these diseases and elucidating the final common pathways of fibrogenesis are critical for the development of efficacious therapies for severe fibrosing lung diseases.
    The Journal of clinical investigation 08/2012; 122(8):2756-62. · 15.39 Impact Factor
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    Paul W Noble
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    ABSTRACT: The lung is a complex organ with multiple functions; in addition to facilitating gas exchange, it also serves as the first line of defense against inhaled environmental pathogens and toxins. Given these critical roles, disruption of normal cell function or cell-cell interactions can have devastating health consequences. The articles of this Review Series highlight recent progress in understanding the pathophysiology of several pulmonary diseases and suggest how these insights are leading to the development of new therapeutic strategies.
    The Journal of clinical investigation 08/2012; 122(8):2722-3. · 15.39 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis causes progressive morbidity and has a worldwide incidence that is increasing. There are a number of promising therapies, one of which has been approved in Europe, parts of Asia, and India, and others that are at various stages of development. Despite this, there continues to be debate about the most appropriate clinical endpoint that should be used in future randomized controlled clinical trials of novel therapies in idiopathic pulmonary fibrosis. In a recent Pulmonary Perspective in this journal, the case for the use of a variety of clinical endpoints was analyzed, and the article concluded that FVC, the endpoint most commonly used recently and in ongoing studies, was not an appropriate option. In this Pulmonary Perspective we present a counterpoint in which we explore the basis on which this conclusion is drawn and present data that strongly and logically support the use of FVC as a valid and robust measure that fulfils the criteria for an ideal clinical endpoint and that is meaningful to patient and clinician alike.
    American Journal of Respiratory and Critical Care Medicine 07/2012; 186(8):712-5. · 11.04 Impact Factor
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    ABSTRACT: Mechanisms that regulate regional epithelial cell diversity and pathologic remodeling in airways are poorly understood. We hypothesized that regional differences in cell composition and injury-related tissue remodeling result from the type and composition of local progenitors. We used surface markers and the spatial expression pattern of an SFTPC-GFP transgene to subset epithelial progenitors by airway region. Green fluorescent protein (GFP) expression ranged from undetectable to high in a proximal-to-distal gradient. GFP(hi) cells were subdivided by CD24 staining into alveolar (CD24(neg)) and conducting airway (CD24(low)) populations. This allowed for the segregation of three types of progenitors displaying distinct clonal behavior in vitro. GFP(neg) and GFP(low) progenitors both yielded lumen containing colonies but displayed transcriptomes reflective of pseudostratified and distal conducting airways, respectively. CD24(low)GFP(hi) progenitors were present in an overlapping distribution with GFP(low) progenitors in distal airways, yet expressed lower levels of Sox2 and expanded in culture to yield undifferentiated self-renewing progeny. Colony-forming ability was reduced for each progenitor cell type after in vivo bleomycin exposure, but only CD24(low) GFP(hi) progenitors showed robust expansion during tissue remodeling. These data reveal intrinsic differences in the properties of regional progenitors and suggest that their unique responses to tissue damage drive local tissue remodeling.
    Stem Cells 06/2012; 30(9):1948-60. · 7.70 Impact Factor

Publication Stats

7k Citations
1,113.74 Total Impact Points

Institutions

  • 2013–2014
    • Cedars-Sinai Medical Center
      Los Angeles, California, United States
  • 2009–2014
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
    • National Institutes of Health
      Maryland, United States
  • 2007–2013
    • Duke University Medical Center
      • • Division of Pulmonary, Allergy, and Critical Care Medicine
      • • Department of Medicine
      Durham, NC, United States
  • 2012
    • Beijing University of Chinese Medicine and Pharmacology
      Peping, Beijing, China
  • 2010–2012
    • Imperial College London
      Londinium, England, United Kingdom
  • 2011
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
  • 1998–2009
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, CA, United States
  • 2004–2006
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
    • University of Washington Seattle
      • Division of Pulmonary and Critical Care Medicine
      Seattle, WA, United States
  • 2000–2005
    • Yale University
      • Section of Pulmonary and Critical Care Medicine
      New Haven, CT, United States
  • 1999
    • Johns Hopkins Medicine
      • Division of Pulmonary and Critical Care Medicine
      Baltimore, MD, United States
  • 1996–1999
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, MD, United States