Nikhil C Munshi

Harvard Medical School, Boston, Massachusetts, United States

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Publications (373)2824.6 Total impact

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  • Leukemia. 10/2014;
  • Jooeun Bae, Nikhil C. Munshi, Kenneth C. Anderson
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    ABSTRACT: Multiple myeloma (MM) is a B-cell malignancy characterized by the clonal proliferation of malignant plasma cells in the bone marrow and the development of osteolytic bone lesions. MM has emerged as a paradigm within the cancers for the success of drug discovery and translational medicine. This article discusses immunotherapy as an encouraging option for the goal of inducing effective and long-lasting therapeutic outcome. Divided into two distinct approaches, passive or active, immunotherapy, which targets tumor-associated antigens has shown promising results in multiple preclinical and clinical studies.
    Hematology/Oncology Clinics of North America 10/2014; 28(5):927–943. · 2.08 Impact Factor
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    ABSTRACT: Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors. We identified 1,907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. Numbers of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.
    eLife Sciences 10/2014; · 8.52 Impact Factor
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    ABSTRACT: Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient as well as a set of commonly mutated genes across multiple patients. Here we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27% (range 11-47%) of mutated alleles are found to be expressed and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications.
    Blood 09/2014; · 9.78 Impact Factor
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    ABSTRACT: Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared to healthy individuals. By using loss-of-function approaches we defined that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cell cycle progression and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/β-catenin signaling by destabilizing β-catenin, leading to down-regulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718, effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM.
    Blood 09/2014; · 9.78 Impact Factor
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    ABSTRACT: Introduction: Multiple myeloma patients who are refractory to lenalidomide and bortezomib have a dismal prognosis. Pomalidomide is a new immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma (RRMM) that is unique in that it demonstrates promising activity but appears to be associated with lower toxicity than thalidomide or lenalidomide.Areas covered: We review the mechanisms of action of pomalidomide, evaluate preclinical data, summarize the results of dose-finding Phase I studies and describe Phase II/III studies of this drug in combination with dexamethasone and other agents. Data presented were gathered from multiple sources, including articles from PubMed, published abstracts from the annual meetings of the American Society of Hematology and American Society of Clinical Oncology and websites such as http://clinicaltrials.gov/.Expert opinion: The regulatory approval of pomalidomide represents an important addition to a hematologist’s armamentarium for the treatment of RRMM. Pomalidomide is well tolerated and demonstrates a high level of anti-myeloma activity. Pomalidomide combined with dexamethasone should be considered as standard-of-care therapy for advanced RRMM following progression on both lenalidomide and bortezomib. Ongoing and future studies will characterize the activity of different combinations intended to improve treatment responses, and the potential role of pomalidomide as maintenance therapy.
    Expert Opinion on Orphan Drugs. 09/2014;
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    ABSTRACT: Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.
    British Journal of Haematology 08/2014; · 4.94 Impact Factor
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    ABSTRACT: Waldenström's macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications (hyperviscosity, neuropathy). Mature studies show that rituximab combinations with cyclophosphamide/dexamethasone (DRC), or bendamustine (BR) or bortezomib/dexamethasone (BDR) provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second generation proteasome inhibitors (carfilzomib), mTOR inhibitors and BTK inhibitors, are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long lasting remission re-use of a prior effective regimen may be appropriate. AutoSCT may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.
    Blood 07/2014; · 9.78 Impact Factor
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    ABSTRACT: Here we report that targeting casein kinase 1 (CSNK1α1) is a potential novel treatment strategy in multiple myeloma (MM) therapy distinct from proteasome inhibition. CSNK1α1 is expressed in all the tested MM cell lines and patient MM cells, and is not altered during bortezomib-triggered cytotoxicity. Inhibition of CSNK1α1 kinase activity in MM cells with targeted therapy D4476 or shRNAs triggers cell G0/G1 phase arrest, prolonged G2/M phase, and apoptosis. D4476 also induced cytotoxicity in bortezomib-resistant MM cells and enhances bortezomib-triggered cytotoxicity. CSNK1α1 signaling pathways include CDKN1B, P53 and FADD; gene signatures involved included interferon alpha (IFNα), tumor necrosis factor alpha (TNFα), and LIN9. Additionally, reduction of Csnk1α1 prevents cMYC/KRAS12V transformation of BaF3 cells independent of IL3. Impartially, reducing Csnk1α1 prevented development of cMYC/KRAS12V-induced plasmacytomas (PCTs) in mice, suggesting that CSNK1α1 may be involved in MM initiation and progression. Our data suggest that targeting CSNK1α1, alone or combined with bortezomib, is a potential novel therapeutic strategy in MM. Moreover, inhibition of CSNK1α1 may prevent the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM.Leukemia accepted article preview online, 25 June 2014; doi:10.1038/leu.2014.202.
    Leukemia 06/2014; · 10.16 Impact Factor
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    ABSTRACT: BACKGROUND Multiple myeloma (MM) patients may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether NTX or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. METHODS We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 MM patients in remission who previously received 8-12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. RESULTS All patients had continued suppression of NTX levels, except one patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, while bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. CONCLUSION Our data show that NTX levels continue to be suppressed after aBP therapy and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. This data provide the basis for less frequent dosing of aBPs.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2014;
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    ABSTRACT: We evaluated a cocktail of HLA-A2-specific peptides including heteroclitic XBP1 US184-192 (YISPWILAV), heteroclitic XBP1 SP367-375 (YLFPQLISV), native CD138260-268 (GLVGLIFAV) and native CS1239-247 (SLFVLGLFL), for their ability to elicit multipeptide-specific cytotoxic T lymphocytes (MP-CTLs) using T cells from smoldering multiple myeloma (SMM) patients. Our results demonstrate that MP-CTLs generated from SMM patients' T cells show effective anti-MM responses including CD137 (4-1BB) upregulation, CTL proliferation, interferon-γ production and degranulation (CD107a) in an HLA-A2-restricted and peptide-specific manner. Phenotypically, we observed increased total CD3(+)CD8(+) T cells (>80%) and cellular activation (CD69(+)) within the memory SMM MP-CTL (CD45RO(+)/CD3(+)CD8(+)) subset after repeated multipeptide stimulation. Importantly, SMM patients could be categorized into distinct groups by their level of MP-CTL expansion and antitumor activity. In high responders, the effector memory (CCR7(-)CD45RO(+)/CD3(+)CD8(+)) T-cell subset was enriched, whereas the remaining responders' CTL contained a higher frequency of the terminal effector (CCR7(-)CD45RO(-)/CD3(+)CD8(+)) subset. These results suggest that this multipeptide cocktail has the potential to induce effective and durable memory MP-CTL in SMM patients. Therefore, our findings provide the rationale for clinical evaluation of a therapeutic vaccine to prevent or delay progression of SMM to active disease.Leukemia advance online publication, 17 June 2014;doi:10.1038/leu.2014.159.
    Leukemia. 05/2014;
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    ABSTRACT: With advent of several treatment options in multiple myeloma, a selection of effective regimen has become an important issue. Use of GEP is considered an important tool in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated ability of GEP to predict complete response in MM. GEP from pre-treatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional datasets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four datasets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56% to 78% in test datasets and no significant difference with regard to GEP platforms, treatment regimens or in newly-diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.Leukemia accepted article peview online, 15 April 2014. doi:10.1038/leu.2014.140.
    Leukemia 04/2014; · 10.16 Impact Factor
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    ABSTRACT: With advent of several treatment options in multiple myeloma, a selection of effective regimen has become an important issue. Use of GEP is considered an important tool in predicting outcome; however, it is unclear whether such genomic analysis alone can adequately predict therapeutic response. We evaluated ability of GEP to predict complete response in MM. GEP from pre-treatment MM cells from 136 uniformly treated MM patients with response data on an IFM, France led study were analyzed. To evaluate variability in predictive power due to microarray platform or treatment types, additional datasets from three different studies (n=511) were analyzed using same methods. We used several machine learning methods to derive a prediction model using training and test subsets of the original four datasets. Among all methods employed for GEP-based CR predictive capability, we got accuracy range of 56% to 78% in test datasets and no significant difference with regard to GEP platforms, treatment regimens or in newly-diagnosed or relapsed patients. Importantly, permuted P-value showed no statistically significant CR predictive information in GEP data. This analysis suggests that GEP-based signature has limited power to predict CR in MM, highlighting the need to develop comprehensive predictive model using integrated genomics approach.Leukemia accepted article peview online, 15 April 2014. doi:10.1038/leu.2014.140.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2014; · 10.16 Impact Factor
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    ABSTRACT: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5 0 truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
    Nature Communications 04/2014; · 10.74 Impact Factor
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    ABSTRACT: OBJECTIVE. The purpose of this study was to describe the MRI features of extramedullary myeloma and to evaluate the role of MRI in extramedullary myeloma. MATERIALS AND METHODS. The cases of 28 patients (15 men, 13 women; mean age, 57.53 years; range, 34-83 years) with extramedullary myeloma who underwent MRI at one institution from January 2004 through December 2012 were retrospectively identified through an electronic search of an institutional radiology database. Two radiologists reviewed images from 44 MRI examinations in consensus to document the morphologic, signal-intensity, and enhancement characteristics of extramedullary myeloma. Electronic medical records were reviewed to document the indication for MRI and subsequent management of extramedullary myeloma. RESULTS. A total of 72 sites of extramedullary myeloma were noted, most commonly the paraspinal-epidural location (28/72, 39%). Two radiologic patterns were identified: lesions contiguous with bone (n = 44) and lesions noncontiguous with bone (n = 28). Lesions contiguous with bone were larger (p = 0.001; Student t test). Of 28 paraspinal-epidural lesions, 13 compressed the cord. Compared with skeletal muscle, most of the lesions were hypointense to isointense on T1-weighted images (67/72, 93.1%) and isointense to hyperintense on T2-weighted images (62/72, 86.1%). Lesions noncontiguous with bone were more often hypointense on T2-weighted images (8/28 vs 2/44; p = 0.006; Fisher exact test). Neurologic symptoms prompted MRI in most cases (n = 32/44). MRI was helpful in management by radiotherapy and surgery (19/28). CONCLUSION. Extramedullary myeloma can be contiguous or noncontiguous with bone. Lesions contiguous with bone are larger, often occur in a paraspinal or epidural location, and can cause cord compression. Lesions noncontiguous with bone can be T2 hypointense. MRI helps in treatment planning.
    American Journal of Roentgenology 04/2014; 202(4):803-10. · 2.90 Impact Factor
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    ABSTRACT: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM.
    British Journal of Haematology 04/2014; · 4.94 Impact Factor
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    ABSTRACT: Sp1 transcription factor controls a pleiotropic group of genes and its aberrant activation has been reported in number of malignancies including multiple myeloma. Here we investigated and report its aberrant activation in Waldenstrom's macroglobulinemia (WM). Both loss of - and gain of Sp1 function studies have highlighted a potential oncogenic role of Sp1 in WM. We have further investigated effect of a small molecule inhibitor (Terameprocol-TMP) targeting Sp1 activity in WM. Treatment with TMP inhibited growth and survival and impaired NF-κB and STAT3 activity in WM cells. We next investigated and observed that TMP treatment induced further inhibition of WM cells in MYD88 knock-down WM cells. Moreover, we observed that BTK, a downstream target of MYD88 signaling pathway, is transcriptionally regulated by Sp1 in WM cells. Combined use of TMP with BTK or IRAK1/4 inhibitors resulted in significant and synergistic dose-dependent antiproliferative effect in MYD88 L265P-expressing WM cells. In summary, these results demonstrate Sp1 as an important transcription factor that regulates proliferation and survival of WM cells independent of MYD88 pathway activation and provide preclinical rationale for clinical development of TMP in WM alone or in combination with inhibitors of MYD88 pathway.
    Blood 03/2014; · 9.78 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. Cancer Res; 74(6); 1-13. ©2014 AACR.
    Cancer Research 03/2014; · 9.28 Impact Factor

Publication Stats

18k Citations
2,824.60 Total Impact Points

Institutions

  • 2002–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • Dana-Farber Cancer Institute
      • • Department of Medical Oncology
      • • Bing Center for Waldenstrom's Macroglobulinemia
      Boston, Massachusetts, United States
  • 2013
    • Tongji University
      Shanghai, Shanghai Shi, China
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 2012
    • Thomas Jefferson University
      • Division of Internal Medicine
      Philadelphia, PA, United States
  • 2004–2012
    • University of Leeds
      • School of Medicine
      Leeds, England, United Kingdom
  • 2011
    • Athens State University
      Athens, Alabama, United States
    • Novartis Institutes for BioMedical Research
      Cambridge, Massachusetts, United States
  • 2008–2010
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • University of Rochester
      • James P. Wilmot Cancer Center
      Rochester, NY, United States
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      Catanzaro, Calabria, Italy
  • 2009
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • National Institutes of Health
      Maryland, United States
  • 2005–2008
    • Harvard University
      • Department of Stem Cell and Regenerative Biology
      Cambridge, Massachusetts, United States
  • 2007
    • Hospital of the University of Pennsylvania
      • Division of Hematology/Oncology
      Philadelphia, Pennsylvania, United States
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
  • 2006
    • Mayo Foundation for Medical Education and Research
      • Division of Hematology
      Scottsdale, AZ, United States
  • 1996–2005
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2003
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 1997–2002
    • University of Arkansas for Medical Sciences
      • Department of Internal Medicine
      Little Rock, Arkansas, United States
  • 2001
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1999
    • University of South Carolina
      Columbia, South Carolina, United States