H C Lane

National Institute of Allergy and Infectious Diseases, 베서스다, Maryland, United States

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Publications (327)3224.74 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite successfully suppressed viremia by treatment, patients with high levels of biomarkers of coagulation/inflammation are at an increased risk of developing non-AIDS defining serious illnesses such as cardiovascular diseases. Thus, there is a relationship between persistent immune activation and coagulation and inflammation, although the mechanisms are poorly understood. Platelets play an important role in this process. Although interactions between platelets and elements of the innate immune system, such as monocytes, are well described, little is known about the interaction between platelets and the adaptive immune system. We investigated the interaction of a component of the coagulation system, platelets, and the adaptive immune system, T cells. Healthy controls and combination antiretroviral therapy (cART) treated HIV infected patients with viral loads of less than 40 copies/ml for more than 15 months were analysed for platelet-T cell conjugate formation. Platelets can form conjugates with T cells and were preferentially seen in CD4 and CD8 T cell subsets with more differentiated phenotypes [memory, memory/effector and terminal effector memory (TEM)]. Compared with healthy controls, these conjugates in patients with HIV infection were more frequent and more often composed of activated platelets (CD42bCD62P) and were significantly associated with the D-dimer serum levels. These data support a model in which platelet-T cell conjugates may play a critical role in the fast recruitment of antigen-experienced T cells to the place of injury. This mechanism can contribute in maintaining a state of coagulation/inflammation observed in these patients contributing to the pathology of the disease.
    AIDS (London, England) 05/2015; DOI:10.1097/QAD.0000000000000701 · 6.56 Impact Factor
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    ABSTRACT: More than 26 000 cases of Ebola virus disease (EVD) have been reported in western Africa, with high mortality. Several patients have been medically evacuated to hospitals in the United States and Europe. Detailed clinical data are limited on the clinical course and management of patients with EVD outside western Africa. To describe the clinical characteristics and management of a cluster of patients with EVD, including the first cases of Ebola virus (EBOV) infection acquired in the United States. Retrospective clinical case series. Three U.S. hospitals in September and October 2014. First imported EVD case identified in the United States and 2 secondary EVD cases acquired in the United States in critical care nurses who cared for the index case patient. Clinical recovery, EBOV RNA level, resolution of Ebola viremia, survival with discharge from hospital, or death. The index patient had high EBOV RNA levels, developed respiratory and renal failure requiring critical care support, and died. Both patients with secondary EBOV infection had nonspecific signs and symptoms and developed moderate illness; EBOV RNA levels were moderate, and both patients recovered. Both surviving patients received uncontrolled treatment with multiple investigational agents, including convalescent plasma, which limits generalizability of the results. Early diagnosis, prompt initiation of supportive medical care, and moderate clinical illness likely contributed to successful outcomes in both survivors. The inability to determine the potential benefit of investigational therapies and the effect of patient-specific factors that may have contributed to less severe illness highlight the need for controlled clinical studies of these interventions, especially in the setting of a high level of supportive medical care. None.
    Annals of internal medicine 05/2015; DOI:10.7326/M15-0530 · 16.10 Impact Factor
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    ABSTRACT: The ongoing outbreak of Ebola in West Africa has raised a general awareness that at present there are no Ebola-specific medical countermeasures (MCMs) with proven effectiveness. This paper recapitulates discussions held at the 6th International Filovirus Symposium in March 2014 as well as the subsequent design of a randomized clinical trial design for treating Ebola virus-infected patients evacuated from West Africa to the United States. A number of different drugs or biologics were critically reviewed and 3 different postexposure strategies were identified as being farthest along in development; passive immunotherapy with monoclonal antibodies, postexposure vaccination with constructs involving viral vectors (such as vesicular stomatitis virus), and antisense compounds directly targeting the viral genome such as modified phosphorodiamidate morpholino oligomer-based compounds and small interfering RNA products. At the time of the meetings, there were no investigational new drugs (INDs) in place for the candidate MCMs. Developers and sponsors of these candidate products were strongly encouraged to prepare pre-IND packets and submit pre-IND meeting requests to the Food and Drug Administration. Some of these investigational products have already been used under emergency authorizations to treat patients in Africa as well as patients evacuated to the United States or Western Europe. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    The Journal of Infectious Diseases 05/2015; DOI:10.1093/infdis/jiv115 · 5.78 Impact Factor
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    ABSTRACT: Characterizing perturbations in the immune response to tuberculosis in HIV can develop insights into the pathogenesis of coinfection. HIV+TB+ and TB monoinfected (TB+) subjects recruited from clinics in Bamako prior to initiation of TB treatment were evaluated at time-points following initiation of therapy. Flow cytometry assessed CD4+/CD8+Tcell subsets and activation markers CD38/HLA-DR. Antigen specific responses to TB proteins were assessed by intracellular cytokine detection and proliferation. HIV+TB+ subjects had significantly higher markers of immune activation in the CD4+ and CD8+Tcells compared to TB+ subjects. HIV+TB+ had lower numbers of TB-specific CD4+Tcells at baseline. Plasma IFNγ levels were similar between HIV+TB+ and TB+ subjects. No differences were observed in in-vitro proliferative capacity to TB antigens between HIV+TB+ and TB+ subjects. Subjects with HIV+TB+ coinfection demonstrate in vivo expansion of TB-specific CD4+Tcells. Immunodeficiency associated with CD4+Tcell depletion may be less significant compared to immunosuppression associated with HIV viremia or untreated TB infection. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 04/2015; 159(1). DOI:10.1016/j.clim.2015.04.002 · 3.99 Impact Factor
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    ABSTRACT: Background The current Ebola virus disease (EVD) outbreak has resulted in more than 24,000 cases and 10,000 deaths. We present a preliminary report from two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate to prevent EVD. Methods We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 26 adults at each site (52 participants in all) were consecutively enrolled into groups of 13 each. Three volunteers in each group received an intramuscular injection of placebo, and 10 received an intramuscular injection of the rVSV-ZEBOV vaccine at a dose of either 3 million plaque-forming units (PFU) or 20 million PFU. Safety and immunogenicity were assessed for the 28 days after vaccination. Results The most common adverse events were injection-site pain, myalgia, and fatigue; no events resulted in withdrawal from the study. Transient VSV viremia was noted in all the vaccine recipients. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the group receiving 20 million PFU than in the group receiving 3 million PFU, as assessed by ELISA (geometric mean antibody titer, 4079 vs. 1300; P<0.001) and by pseudovirion neutralization assay (geometric mean antibody titer, 441 vs. 223; P=0.07). Conclusions No safety concerns were identified after a single administration of the rVSV-ZEBOV vaccine candidate, and anti-Ebola immune responses were identified in all the volunteers. VSV viremia was detected but was of limited duration. These preliminary results support the further development of the vaccine dose of 20 million PFU. (Funded by the National Institutes of Health and others; rVSVΔG-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).
    New England Journal of Medicine 04/2015; DOI:10.1056/NEJMoa1414216 · 54.42 Impact Factor
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    ABSTRACT: Safe and effective vaccines and drugs are needed for the prevention and treatment of Ebola virus disease, including following a potentially high-risk exposure such as a needlestick. To assess response to postexposure vaccination in a health care worker who was exposed to the Ebola virus. Case report of a physician who experienced a needlestick while working in an Ebola treatment unit in Sierra Leone on September 26, 2014. Medical evacuation to the United States was rapidly initiated. Given the concern about potentially lethal Ebola virus disease, the patient was offered, and provided his consent for, postexposure vaccination with an experimental vaccine available through an emergency Investigational New Drug application. He was vaccinated on September 28, 2014. The vaccine used was VSVΔG-ZEBOV, a replicating, attenuated, recombinant vesicular stomatitis virus (serotype Indiana) whose surface glycoprotein gene was replaced by the Zaire Ebola virus glycoprotein gene. This vaccine has entered a clinical trial for the prevention of Ebola in West Africa. The vaccine was administered 43 hours after the needlestick occurred. Fever and moderate to severe symptoms developed 12 hours after vaccination and diminished over 3 to 4 days. The real-time reverse transcription polymerase chain reaction results were transiently positive for vesicular stomatitis virus nucleoprotein gene and Ebola virus glycoprotein gene (both included in the vaccine) but consistently negative for Ebola virus nucleoprotein gene (not in the vaccine). Early postvaccination cytokine secretion and T lymphocyte and plasmablast activation were detected. Subsequently, Ebola virus glycoprotein-specific antibodies and T cells became detectable, but antibodies against Ebola viral matrix protein 40 (not in the vaccine) were not detected. It is unknown if VSVΔG-ZEBOV is safe or effective for postexposure vaccination in humans who have experienced a high-risk occupational exposure to the Ebola virus, such as a needlestick. In this patient, postexposure vaccination with VSVΔG-ZEBOV induced a self-limited febrile syndrome that was associated with transient detection of the recombinant vesicular stomatitis vaccine virus in blood. Strong innate and Ebola-specific adaptive immune responses were detected after vaccination. The clinical syndrome and laboratory evidence were consistent with vaccination response, and no evidence of Ebola virus infection was detected.
    JAMA The Journal of the American Medical Association 03/2015; 313(12). DOI:10.1001/jama.2015.1995 · 30.39 Impact Factor
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    ABSTRACT: Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 11/2014; 33(1). DOI:10.1200/JCO.2014.57.3329 · 17.88 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2575-2575. DOI:10.1158/1538-7445.AM2014-2575 · 9.28 Impact Factor
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    ABSTRACT: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients.
    PLoS ONE 07/2014; 9(7):e101785. DOI:10.1371/journal.pone.0101785 · 3.53 Impact Factor
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    ABSTRACT: Objectives: After DNA or RNA virus infection, cytosolic foreign DNA or RNA derived from the infecting viruses is recognized by intracellular pathogen recognition receptors (PRRs) and induces activation of the innate immune system. Transfection of DNA has been used as an experimental model for DNA virus-mediated innate responses. We have previously reported that DNA transfection preferentially induces Type-III IFN (IFN-λ1) rather than Type-I IFN (IFN-β). In this study, we compared the DNA-mediated immune response between healthy controls and HIV-1 infected patients with undetectable viral loads and assessed potential innate immune responses in these patients. Methods: The study consisted of 50 HIV-1 negative healthy donors, 46 patients on combination antiretroviral therapy with HIV-1 viral loads <50 copies/ml and 7 long term non-progressors (LTNPs). PBMCs were isolated from whole blood using Ficoll-Paque. DNA transfection was performed using Lipofectamine 2000. After 22 hours incubation, total cellular RNA was extracted and real time RT-PCR was performed to determine gene expression level of IFN-λ1, IFN-β and RANTES. Gene induction was compared by fold change. Results: Baseline levels of endogenous gene expression of IFN-λ1, IFN-β and RANTES in HIV-1 patients were higher than in controls. Following DNA transfection, both HIV infected patients and healthy controls induced gene induction, however, the induction in HIV-1 patients was at a significantly lower level compared to uninfected controls. Conclusion: HIV-1 treated patients with undetectable viral loads have lower levels of innate immune responses via cytosolic DNA sensing systems. This may be caused by persistent immune activation.
    Journal of AIDS & Clinical Research 06/2014; 5(6):315. DOI:10.4172/2155-6113.1000315 · 6.83 Impact Factor
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    ABSTRACT: Objective IL-27 is an immunomodulatory cytokine with potent anti-HIV properties in PBMCs, CD4+ T cells, macrophages and immature dendritic cells. Previous smaller studies have suggested that HIV-1 infection may alter IL-27 and influence HIV-1 pathogenesis. The aim of this study was to examine the relationship between plasma IL-27 levels in a well-characterised cohort of HIV-1 infected patients. Methods Patients were stratified into four groups based on HIV-1 viral load and matched according to age, gender and those receiving antiretroviral treatment. IL-27 levels and C-reactive protein (CRP) were measured using electrochemiluminescence assays. D-dimer and CD4+ T cell counts were measured using an Enzyme Linked Fluorescence Assay and FACS, respectively. sCD14 and sCD163 were measured using ELISA. HIV-1 viral load was measured by bDNA or qRT-PCR assays. Results Plasma IL-27 levels were measured in 505 patients (462 HIV+, 43 controls). The mean level (±SEM) of IL-27 in controls was 2990.7±682.1 pg/ml, in the <50 copies/ml group it was 2008.0±274.8 pg/ml, in the 51–10,000 copies group it was 1468.7±172.3 pg/ml, in the 10,001–100,000 copies/ml group it was 1237.9±127.3 pg/ml and in the >100,000 copies/ml group it was 1590.1±223.7 pg/ml. No statistically significant difference in IL-27 levels between groups were seen. There were no correlations noted between IL-27 and HIV-1 viral load or CD4+ T cell counts. There was a small correlation noted between D-dimer and IL-27 (Spearman r = 0.09, p = 0.03) and sCD163 and IL-27 (Spearman r = 0.12, p = 0.005). No correlation was observed between IL-27 and CRP or sCD14 levels. Conclusions This is the largest study examining the levels of plasma IL-27 in HIV-1 infection. While IL-27 levels are not significantly altered in HIV-1 infection compared to uninfected controls there may be a small association between IL-27 and D-dimer levels and IL-27 and sCD163 levels.
    PLoS ONE 06/2014; 9(6):e98989. DOI:10.1371/journal.pone.0098989 · 3.53 Impact Factor
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    ABSTRACT: Background Optimising the selection of antiretroviral drugs for patients experiencing virological failure remains a challenge, particularly in resource-limited settings where the latest drugs may not be accessible and genotyping may not be affordable to guide drug selection. The RDI was set up in 2002 to develop computational models that predict virological response to different combinations of drugs, and to make those models freely available to assist optimal drug selection. Materials and methods In order to collect sufficient data to develop such models, HIV cohorts and clinics around the world were approached for a range of longitudinal clinical, virological and treatment data for their patients. These data have been used to train a range of neural network, support vector machine, linear regression and random forest models to predict virological response to combination therapy. The models re tested with independent validation sets and their accuracy compared with that of genotyping with rules-based interpretation. Results Data from approximately 110,000 patients have been collected. The best performing models (random forests) routinely predict virological response/failure to a change of therapy with an accuracy of 80% or more, even without the use of a genotype. Moreover, they are significantly more accurate than genotyping itself. They are able to identify simple, less costly, alternative drug combinations that are predicted to be effective for the majority of cases that failed following a treatment change in the clinic. The models are used to power the free online HIV Treatment Response Prediction System HIV-TRePS. Conclusions HIV-TRePS, in essence, makes the distilled experience of hundreds of physicians treating tens of thousands of patients available to all. Use of the system to help guide antiretroviral treatment selection following virological failure has significant potential to improve patient outcomes and save costs following a switch to antiretroviral drug therapy, particularly in resource-limited settings.
    HIV Drug Therapy in the Americas, Rio de Janeiro, Brazil; 05/2014
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    ABSTRACT: Author Summary While the acute CD4 depletion observed in the initial phase of HIV infection is likely due to direct cytopathic effects of the virus, the mechanism/s underlying the steady decline of the CD4 T cell pool during the chronic phase of infection are unclear and are felt to be associated with “immune activation.” We hypothesized that the combination of two distinct forces: homeostatic (CD4 T cell depletion) and inflammatory (HIV-driven IFN-α), lead to a form of T cell activation that results in a decline in the CD4 T cell pool and an increase in the CD8 T cells. IL-7 and lymphopenia enhanced CD4 T cell responsiveness to IFN-α by modulating expression of the Signal Transducers and Activators of Transcription 1, 2 and 3. In a murine model, CD4 T cell depletion and CD8 T cell expansion were observed in a lymphopenic host chronically treated with IFN-α. These findings suggest that a synergistic interaction between lymphopenia and IFN-α may play a role in the pathogenesis of HIV infection. The analysis of this pathway may contribute to the development of new strategies to reverse the dysregulation of the T cell pools seen in patients with HIV infection.
    PLoS Pathogens 03/2014; 10(3):e1003976. DOI:10.1371/journal.ppat.1003976 · 8.06 Impact Factor
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    ABSTRACT: Determining the precise lifespan of human T-cell is challenging due to inability of standard techniques to distinguish between dividing and dying cells. Here, we measured the duration of in vivo persistence by following a pool of T-cells that were "naturally" labeled with a single integrated clone of a replication-incompetent HIV-1 provirus. Utilizing a combination of techniques we were able to sequence/map an integration site of a unique provirus with a stop codon at position 42 of the HIV-1 protease. In-vitro reconstruction of this provirus into an infectious clone confirmed its inability to replicate. By combing cell separation and integration site-specific PCR we were able to follow the fate of this single provirus in multiple T-cell subsets over a 20-year period. As controls, a number of additional integrated proviruses were also sequenced. The replication-incompetent HIV-1 provirus was solely contained in the pool of effector memory (EM) CD4 T-cell for 17 years. The percentage of the total EM CD4 T-cells containing the replication-incompetent provirus peaked at 1% with a functional half-life of 11.1 months. In the process of sequencing multiple proviruses, we also observed high levels of lethal mutations in the peripheral blood pool of proviruses. These data indicate that human EM CD4 T-cells are able to persist in vivo for >17 years without detectably reverting to a central memory phenotype. A secondary observation is that the fraction of the pool of integrated HIV-1 proviruses capable of replicating may be considerably less than the 12% currently noted in the literature.
    AIDS (London, England) 01/2014; 28(8). DOI:10.1097/QAD.0000000000000223 · 6.56 Impact Factor
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    ABSTRACT: The optimal individualized selection of antiretroviral drugs in resource-limited settings is challenging because of the limited availability of drugs and genotyping. Here we describe the development of the latest computational models to predict the response to combination antiretroviral therapy without a genotype, for potential use in such settings. Random forest models were trained to predict the probability of a virological response to therapy (<50 copies HIV RNA/mL) following virological failure using the following data from 22 567 treatment-change episodes including 1090 from southern Africa: baseline viral load and CD4 cell count, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. The models were assessed during cross-validation and with an independent global test set of 1000 cases including 100 from southern Africa. The models' accuracy [area under the receiver-operating characteristic curve (AUC)] was evaluated and compared with genotyping using rules-based interpretation systems for those cases with genotypes available. The models achieved AUCs of 0.79-0.84 (mean 0.82) during cross-validation, 0.80 with the global test set and 0.78 with the southern African subset. The AUCs were significantly lower (0.56-0.57) for genotyping. The models predicted virological response to HIV therapy without a genotype as accurately as previous models that included a genotype. They were accurate for cases from southern Africa and significantly more accurate than genotyping. These models will be accessible via the online treatment support tool HIV-TRePS and have the potential to help optimize antiretroviral therapy in resource-limited settings where genotyping is not generally available.
    Journal of Antimicrobial Chemotherapy 11/2013; 69(4). DOI:10.1093/jac/dkt447 · 5.44 Impact Factor

Publication Stats

24k Citations
3,224.74 Total Impact Points


  • 1985–2015
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      베서스다, Maryland, United States
  • 1985–2012
    • National Institutes of Health
      • • Branch of Bio-statistics
      • • Laboratory of Virology (LV)
      • • Critical Care Medicine Department
      • • Section on Molecular and Cell Biology
      • • National Institute of Allergy and Infectious Diseases (NIAID)
      • • Laboratory of Immunoregulation
      Maryland, United States
  • 2010
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 2001–2008
    • Leidos Biomedical Research
      Maryland, United States
  • 1989–2007
    • National Institute of Allergy and Infectious Disease
      베서스다, Maryland, United States
  • 2000–2005
    • National Human Genome Research Institute
      Maryland, United States
    • State of Maryland
      Maryland City, Maryland, United States
    • Hospital Ramos Mejia
      Buenos Aires, Buenos Aires F.D., Argentina
    • University of New South Wales
      • Kirby Institute
      Kensington, New South Wales, Australia
    • University of Washington Seattle
      • Department of Pediatrics
      Seattle, Washington, United States
  • 2004
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 1989–2002
    • Georgetown University
      • • Division of Infectious Diseases
      • • Department of Microbiology and Immunology
      Washington, D. C., DC, United States
  • 1999
    • Brigham Young University - Provo Main Campus
      Provo, Utah, United States
  • 1997
    • National Cancer Institute (USA)
      Maryland, United States
  • 1996
    • Department of Health and Human Services
      Patersonia, Tasmania, Australia
  • 1992
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 1988
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1984
    • NCI-Frederick
      Фредерик, Maryland, United States