D LeRoith

Mount Sinai School of Medicine, Manhattan, New York, United States

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Publications (501)2284.5 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The trend toward personalized management of diabetes has focused attention on the differences among available pharmacological agents in terms of mechanisms of action, efficacy, and, most important, safety. Clinicians must select from these features to develop individualized therapy regimens. In June 2013, a nine-member Diabetes Care Editors' Expert Forum convened to review safety evidence for six major diabetes drug classes: insulin, sulfonylureas (SUs), thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter 2 inhibitors. This article, an outgrowth of the forum, summarizes well-delineated and theoretical safety concerns related to these drug classes, as well as the panelists' opinions regarding their best use in patients with type 2 diabetes. All of the options appear to have reasonably wide safety margins when used appropriately. Those about which we know the most-metformin, SUs, insulin, and perhaps now also TZDs-are efficacious in most patients and can be placed into a basic initial algorithm. However, these agents leave some clinical needs unmet. Selecting next steps is a more formidable process involving newer agents that are understood less well and for which there are unresolved questions regarding risk versus benefit in certain populations. Choosing a specific agent is not as important as implementing some form of early intervention and advancing rapidly to some form of combination therapy as needed. When all options are relatively safe given the benefits they confer, therapeutic decision making must rely on a personalized approach, taking into account patients' clinical circumstances, phenotype, pathophysiological defects, preferences, abilities, and costs.
    Diabetes care. 09/2014; 37(9):2647-59.
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    ABSTRACT: Triple-negative breast cancers (TNBC) are an aggressive disease subtype which unlike other subtypes lack an effective targeted therapy. Inhibitors of the insullin-like growth factor receptor (IGF-1R) have been considered for use in treating TNBC. Here we provide genetic evidence that IGF-1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt-1 and mutant IGF-1R, a reduction in IGF-1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamal cell phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacological inhibition of the IGF-1R in vitro was sufficient to increase the tumorsphere-forming efficiency of MMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor vs the IR-B isoform, which in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors an attenuation of IGF-1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes, with potential implications for understanding TNBC pathobiology and treatment.
    Cancer research. 08/2014;
  • Diabetes care. 07/2014; 37(7):1782-5.
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    ABSTRACT: Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes.
    Diabetes care. 06/2014; 37(6):1499-508.
  • Derek LeRoith
    Endocrinology and metabolism clinics of North America. 06/2014; 43(2):xiii-xvi.
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    ABSTRACT: A large body of research has contributed to our understanding of the pathophysiology of diabetic nephropathy. Yet, many questions remain regarding the progression of a disease that accounts for nearly half the patients entering dialysis yearly. Several murine models of diabetic nephropathy secondary to Type 2 Diabetes Mellitus (T2DM) do exist, and some are more representative than others, but all have limitations. In this study, we aimed to identify a new mouse model of diabetic nephropathy secondary to T2DM in a previously described T2DM model, MKR (MCK-KR-hIGF-IR) mouse. In this mouse model, T2DM develops as a result of functional inactivation of insulin-like growth factor-1 receptor (IGF-1R) in the skeletal muscle. These mice are lean, with marked insulin resistance, hyperinsulinemia, hyperglycemia, and dyslipidemia, and thus, are representative of non-obese human T2DM. We show that the MKR mice, when under stress (high fat diet or unilateral nephrectomy), develop progressive diabetic nephropathy with marked albuminuria and meet the histopathological criteria as defined by the Animal Models of Diabetic Complications Consortium. Finally, these MKR mice are fertile and are on a common background strain, making it a novel model to study the progression of diabetic nephropathy.
    AJP Renal Physiology 03/2014; · 4.42 Impact Factor
  • Haim Werner, Derek LeRoith
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    ABSTRACT: The involvement of insulin, the insulin-like growth factors (IGF1, IGF2) and their receptors in central nervous system development and function has been the focus of scientific interest for more than 30 years. The insulin-like peptides, both locally-produced proteins as well as those transported from the circulation into the brain via the blood brain barrier, are involved in a myriad of biological activities. These actions include, among others, neuronal survival, neurogenes, angiogenesis, excitatory and inhibitory neurotransmission, regulation of food intake, and cognition. In recent years, a linkage between brain insulin/IGF1 and certain neuropathologies has been identified. Epidemiological studies have demonstrated a correlation between diabetes (mainly type 2) and Alzheimer's disease. In addition, an aberrant decline in IGF1 values was suggested to play a role in the development of Alzheimer's disease. The present review focuses on the expression and function of insulin, IGFs and their receptors in the brain in physiological and pathological conditions.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 01/2014; · 3.68 Impact Factor
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    ABSTRACT: Objectives It is unclear why duration of type 2 diabetes (T2D) is associated with increased cognitive compromise. High hemoglobin A1c (HbA1c) has also been associated with dementia, and is the primary contributor to T2D complications. Here we investigated whether the association of duration of T2D with cognitive functioning is modulated by hemoglobin A1C levels. Methods This study examined non-demented community dwelling T2D elderly (n=897) participating in the Israel Diabetes and Cognitive Decline study, who were assessed with a broad neuropsychological battery. Subjects were all from the Maccabi Healthcare Services which has a Diabetes Registry with complete HbA1c measurements since 1998. Partial correlations were performed to examine the modulating effect of HbA1c on the relationship of duration of T2D with five cognitive measures, controlling for sociodemographic and cardiovascular risk factors. Results An interaction of duration of T2D with HbA1c was associated with executive functioning (p=.006), semantic categorization (p=.019), attention/working memory (p=.011), and overall cognition (p=.006), such that the associations between duration of T2D and cognitive impairment increased as HbA1c levels increased—but not for episodic memory (p=.984). Conclusions Since duration of T2D was associated with cognition in higher HbA1c levels and overall no associations were found in lower HbA1c levels, our results suggest that individuals with T2D may limit their risk of future cognitive decline by maintaining long-term good glycemic control.
    The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 01/2014; · 3.35 Impact Factor
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    ABSTRACT: Background Type 2 diabetes (T2D) is associated with increased risk of dementia. The prospective longitudinal Israel Diabetes and Cognitive Decline study aims at identifying T2D-related characteristics associated with cognitive decline. Methods Subjects are population-based T2D 65+, initially cognitively intact. Medical conditions, blood examinations, and medication use data are since 1998; cognitive, functional, demographic, psychiatric, DNA, and inflammatory marker study assessments were conducted every 18 months. Because the duration of T2D reflects its chronicity and implications, we compared short (0–4.99 years), moderate (5–9.99), and long (10+) duration for the first 897 subjects. Results The long duration group used more T2D medications, had higher glucose, lower glomerular filtration rate, slower walking speed, and poorer cognitive functioning. Duration was not associated with most medical, blood, urine, and vital characteristics. Conclusions Tracking cognition, with face-to-face evaluations, exploiting 15 years of historical detailed computerized, easily accessible, and validated T2D-related characteristics may provide novel insights into T2D-related dementia.
    Alzheimer's & Dementia. 01/2014;
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    ABSTRACT: Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective.
    PLoS ONE 01/2014; 9(7):e102319. · 3.53 Impact Factor
  • Derek LeRoith
    Endocrinology and Metabolism Clinics of North America. 01/2014;
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    ABSTRACT: To study the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (T2D).
    PLoS ONE 01/2014; 9(6):e97384. · 3.53 Impact Factor
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    ABSTRACT: Obesity and the Metabolic Syndrome are associated with multiple factors that may cause an increased risk for cancer and cancer-related mortality. Factors involved include hyperinsulinemia, hyperglycemia, hyperlipidemia and IGFs. Insulin resistance is also associated with alterations in the levels of proinflammatory cytokines, chemokines, adipokines (leptin, adiponectin) that may also be contributing factors. The insulin family of proteins is ubiquitously expressed and has pleiotropic effects on metabolism and growth. However insulin, IGF-1 and particularly IGF-2 have been identified as tumor promoters in multiple studies. Mouse models have focused on insulin and IGF-1 and their receptors as being involved in tumor progression and metastases. The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen. Its role has been supported by preclinical studies and the importance of insulin resistance and hyperinsulinemia in obesity and early diabetes. Since the focus of this review is the insulin-family we will focus on insulin, IGF-1 and IGF-2.
    Journal of Mammary Gland Biology and Neoplasia 10/2013; · 7.52 Impact Factor
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    ABSTRACT: Individuals with type 2 diabetes (T2D) are at greater risk of bone fractures than those without diabetes. Certain oral diabetic medications may further increase the risk of fracture. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are incretin-based therapies and are being increasingly used for the management of T2D. It has been hypothesized that these agents may reduce fracture risk in those with T2D. In this study we used a mouse model of T2D to examine the effects of the DPP-IV inhibitor, MK-0626, on bone. Male wild type (WT) and diabetic (MKR) mice were treated with MK-0626, pioglitazone, alendronate or vehicle. The effects of treatment with MK-0626 on bone microarchitecture and turnover were compared to treatment with pioglitazone, alendronate and vehicle. Osteoblast differentiation was determined by alkaline phosphatase staining of bone marrow cells from WT and MKR mice after treatment with pioglitazone, MK-0626 or PBS. We found that MK-0626 had neutral effects on cortical and trabecular bone in diabetic mice. Pioglitazone had detrimental effects on the trabecular bone of WT but not diabetic mice. Alendronate caused improvements in cortical and trabecular bone architecture in diabetic and WT mice. MK-0626 did not alter osteoblast differentiation but pioglitazone impaired osteoblast differentiation in vitro. Overall, the DPP-IV inhibitor, MK-0626, had no adverse effects on bone in an animal model of T2D, or directly on osteoblasts in culture. These findings are reassuring as DPP-IV inhibitors are being widely used to treat patients with T2D who are already at an increased risk of fractures. This article is protected by copyright. All rights reserved.
    Diabetes/Metabolism Research and Reviews 09/2013; · 2.97 Impact Factor
  • Article: Foreword.
    Derek Leroith
    Endocrinology and metabolism clinics of North America 09/2013; 42(3):xiii-xv. · 3.56 Impact Factor
  • Emily J Gallagher, Derek Leroith
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    ABSTRACT: The aim of this review article is to discuss the epidemiological links between diabetes and cancer; the potential biological mechanisms linking diabetes, obesity and cancer; the risk of cancer associated with antidiabetic medications. The data discussed in this review were obtained from the American Association of Clinical Endocrinologists Consensus Conference on Diabetes and Cancer, held in New York, NY, USA, September 2012. The results of these studies demonstrate a significant association between diabetes and the risk of multiple cancers, including hepatocellular, pancreatic, endometrial, colorectal, breast, kidney, bladder, gastric, and ovarian cancer, non-Hodgkin lymphoma, T cell lymphoma and leukemia. There are multiple potential biological mechanisms that may link type 2 diabetes, obesity and cancer. Insulin resistance and hyperinsulinemia may lead to direct activation of the insulin receptors on tumor cells and promote tumor growth. Other potential mechanisms include increased circulating, local or bioavailable insulin-like growth factor 1, hyperglycemia, dyslipidemia, increased circulating or local estrogen, adipokines and direct and indirect effects of inflammatory cytokines. Epidemiological studies have had conflicting results regarding the associations between various classes of antidiabetic medication and cancer development. Animal studies have demonstrated increased tumor growth with certain medications, but their relevance to humans is uncertain. Metformin may, however, have protective effects on cancer development and may improve survival in patients with cancer. We describe the current understanding of the links among diabetes, antidiabetic medication and cancer risk. We highlight some of the issues that should be addressed in the future to prevent cancer development and death in those with diabetes.
    Current opinion in endocrinology, diabetes, and obesity 08/2013; · 3.77 Impact Factor
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    ABSTRACT: In this study, we investigated whether loss of growth hormone receptor (GHR) signaling in post-natal skeletal muscle alters muscle mass and regenerative ability in adult mice, and if this was dependent on insulin-like growth factor-1 receptor (IGF-1R) signaling. In order to do so, we employed mouse models with skeletal muscle-specific loss of GHR signaling (mGHRKO), IGF-1R and insulin receptor (IGF-1R/IR) signaling (MKR), or both GHR and IGF-1R/IR signaling (mGHRKO/MKR). We did not find a reduction in muscle cross sectional area, fiber type composition, or response to pathological muscle injury in male mGHRKO and mGHRKO/MKR mice when compared to control and MKR mice, respectively. This could potentially be explained by unchanged skeletal muscle Igf-1 expression in mGHRKO and mGHRKO/MKR mice relative to control and MKR mice respectively. Furthermore, MKR and mGHRKO/MKR mice, but not mGHRKO mice, demonstrated reduced fiber fusion after cardiotoxin injection, suggesting that IGF-1, and not GH, promotes fiber fusion in adult mice. In summary, our data suggest that GHR signaling in the post-natal skeletal muscle does not play a significant role in regulating muscle mass or muscle regeneration. Additionally, in our model, muscle Igf-1 expression is not dependent on GHR signaling in the post-natal skeletal muscle.
    Endocrinology 07/2013; · 4.72 Impact Factor
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    ABSTRACT: Endogenous hyperinsulinemia and insulin receptor (IR)/ insulin-like growth factor-1 receptor (IGF-1R) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. In vitro, insulin stimulation of the IR increases proliferation of breast cancer cells. However, in vivo studies demonstrating that IR activation increases tumor growth, independent of IGF-1R activation are lacking. We hypothesized that endogenous hyperinsulinemia increases mammary tumor growth by directly activating the IR rather than the IGF-1R or hybrid receptors. We aimed to determine whether stimulating the IR with the insulin analog AspB10 could increase tumor growth independent of IGF-1R signaling. We induced orthotopic mammary tumors in control FVB/n and hyperinsulinemic MKR mice and treated them with the insulin analog AspB10, rhIGF-1 or vehicle. Tumors from mice with endogenous hyperinsulinemia were larger and had greater IR phosphorylation, but not IGF-1R phosphorylation than those from control mice. Chronic AspB10 administration also increased tumor growth and IR (but not IGF-1R) phosphorylation in tumors. IGF-1 led to activation of both the IGF-1R and IR and probably hybrid receptors. Our results demonstrate that IR phosphorylation increases tumor growth, independently of IGF-1R / hybrid receptor phosphorylation and warrant consideration when developing therapeutics targeting the IGF-1R, but not the IR.
    Diabetes 07/2013; · 7.90 Impact Factor
  • Emily J Gallagher, Derek Leroith
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    ABSTRACT: A polymorphism in the fibroblast growth factor receptor 4 gene has been associated with cancer progression and treatment resistance and is now reported to increase insulin secretion, providing a possible genetic link between hyperinsulinemia and cancer (Ezzat et al., 2013).
    Cell metabolism 06/2013; 17(6):808-9. · 17.35 Impact Factor
  • Article: Foreword.
    Derek Leroith
    Endocrinology and metabolism clinics of North America 06/2013; 42(2):xiii-xv. · 3.56 Impact Factor

Publication Stats

17k Citations
2,284.50 Total Impact Points

Institutions

  • 2005–2014
    • Mount Sinai School of Medicine
      • • Department of Psychiatry
      • • Department of Medicine
      • • Division of Endocrinology, Diabetes and Bone Disease
      Manhattan, New York, United States
    • University of Washington Seattle
      • Division of Metabolism, Endocrinology and Nutrition
      Seattle, WA, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 2013
    • Università di Pisa
      Pisa, Tuscany, Italy
  • 2011
    • Albert Einstein College of Medicine
      New York City, New York, United States
    • Rutgers New Jersey Medical School
      • Department of Neurology and Neurosciences
      Newark, NJ, United States
  • 1985–2010
    • National Institutes of Health
      • • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      • • Section on Molecular and Cell Biology
      Maryland, United States
    • University of Cincinnati
      • Division of Endocrinology, Diabetes & Metabolism
      Cincinnati, Ohio, United States
  • 2008
    • Sinai Hospital
      • Department of Medicine
      New York City, New York, United States
    • National Cancer Institute
      • Grupo de Investigación de Biología del Cáncer
      Μπογκοτά, Bogota D.C., Colombia
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 2003–2008
    • Cajal Institute
      Madrid, Madrid, Spain
    • Tel Aviv University
      • Department of Human Molecular Genetics and Biochemistry
      Tel Aviv, Tel Aviv, Israel
    • University of Vermont
      Burlington, Vermont, United States
    • French National Institute for Agricultural Research
      • Physiologie de la Reproduction et des Comportements (PRC)
      Paris, Ile-de-France, France
  • 1982–2008
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
  • 2007
    • McGill University
      • Department of Medicine
      Montréal, Quebec, Canada
  • 2006
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • Pennsylvania State University
      • Department of Neural and Behavioral Sciences
      University Park, MD, United States
  • 1991–2005
    • Georgetown University
      • Department of Physiology and Biophysics
      Washington, Washington, D.C., United States
    • University of Florida
      • College of Medicine
      Gainesville, FL, United States
  • 2004
    • George Washington University
      Washington, Washington, D.C., United States
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
    • Charles University in Prague
      Praha, Praha, Czech Republic
    • NCI-Frederick
      Maryland, United States
    • University of Nevada School of Medicine
      Reno, Nevada, United States
  • 1988–2004
    • National Eye Institute
      Maryland, United States
  • 2002
    • Universidad de Cundinamarca
      Μπογκοτά, Bogota D.C., Colombia
  • 2001–2002
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 1992–2001
    • Weizmann Institute of Science
      • Department of Molecular Cell Biology
      Israel
  • 2000
    • University of Virginia
      • Department of Pediatrics
      Charlottesville, VA, United States
    • The University of Tokyo
      • Department of Applied Biological Chemistry
      Tokyo, Tokyo-to, Japan
  • 1998
    • National Cancer Institute (USA)
      Maryland, United States
  • 1997
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1993–1997
    • Ben-Gurion University of the Negev
      • • Faculty of Health Sciences
      • • Division of Pediatrics
      Beersheba, Southern District, Israel
    • Ukrainian Academy of Agrarian Sciences
      Kievo, Kyiv City, Ukraine
    • University of Texas Health Science Center at San Antonio
      • Department of Biochemistry
      San Antonio, TX, United States
  • 1996
    • Molecular and Cellular Biology Program
      • Laboratory of Cellular and Molecular Biology
      Seattle, Washington, United States
  • 1995
    • Sheba Medical Center
      Gan, Tel Aviv, Israel
  • 1992–1995
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
  • 1993–1994
    • Institute Of Molecular Biology And Genetics
      Kievo, Kyiv City, Ukraine
  • 1989–1994
    • University of Maryland, Baltimore
      • • Department of Medicine
      • • Department of Obstetrics, Gynecology and Reproductive Sciences
      Baltimore, MD, United States
  • 1990
    • University of South Carolina School of Medicine - Greenville
      Greenville, South Carolina, United States