Clifford J Rosen

Maine Medical Center Research Institute, Скарбороу, Maine, United States

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Publications (396)2993.26 Total impact

  • Dennis M Black · Clifford J Rosen
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    ABSTRACT: Key Clinical Points Postmenopausal Osteoporosis Fractures and osteoporosis are common, particularly among older women, and hip fractures can be devastating. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk. Bisphosphonates (generic) and denosumab reduce the risk of hip, nonvertebral, and vertebral fractures; bisphosphonates are commonly used as first-line treatment in women who do not have contraindications. Teriparatide reduces the risk of nonvertebral and vertebral fractures. Osteonecrosis of the jaw and atypical femur fractures have been reported with treatment but are rare. The benefit-to-risk ratio for osteoporosis treatment is strongly positive for most women with osteoporosis. Because benefits are retained after discontinuation of alendronate or zoledronic acid, drug holidays after 5 years of alendronate therapy or 3 years of zoledronic acid therapy may be considered for patients at lower risk for fracture.
    No preview · Article · Jan 2016 · New England Journal of Medicine
  • Gang Xi · Xinchun Shen · Clifford J. Rosen · David R. Clemmons
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    ABSTRACT: Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to RPTPβ stimulates polymerization and inactivation of phosphatase activity. Since PTEN is the primary target of RPTPβ this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPβ inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPβ function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPβ and this was required for RPTPβ polymerization. Vimentin serine phosphorylation mediated its binding to RPTPβ and PKCζ was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCζ-mediated vimentin phosphorylation, we focused on insulin receptor substrate -1(IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCζ and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCζ and vimentin were used to confirm that activated PKCζ directly phosphorylated vimentin. PKCζ does not contain a SH-2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCζ recruitment we analyzed the role of p62 (a PKCζ binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCζ/p 62 association. Subsequent analysis showed the p62/ PKCζ complex was co-recruited to IRS-1. Peptides that disrupted p62/ PKCζ or p 62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCζ activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative interaction between RPTPβ and the IGF-I receptor leading to a coordinated series of signaling events that are required for osteoblast differentiation. Our findings emphasize the important role IRS-1 plays in modulating these signaling events and confirm its essential role in facilitating osteoblast differentiation. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Cheryl L Ackert-Bicknell · Clifford J Rosen
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    ABSTRACT: When moving a mutant allele (i.e. a knockout, or floxed allele) from one genetic background to another, often genes around the mutant allele are also transferred. These extra genes are referred to as Passenger Genes. While the existence of passenger genes has long been recognized, the possible impact of these genes on the phenotype of the resulting mice is largely ignored. In this Commentary was discuss a paper by Vanden Berghe et al which highlights the problems passenger genes might cause and provides a resource for finding putative deleterious passenger genes in transgenic congenic mice. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
  • Michaela R Reagan · Clifford J Rosen
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    ABSTRACT: The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights that the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two tissues - bone and blood - by providing a unique environment for stem and stromal cells to flourish while simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism's lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable.
    No preview · Article · Nov 2015 · Nature Reviews Rheumatology
  • Pierre Hardouin · Pierre J Marie · Clifford J Rosen

    No preview · Article · Nov 2015 · Bone
  • Julie R Ingelfinger · Clifford J Rosen
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    ABSTRACT: Patients with type 2 diabetes mellitus are at increased risk for incident cardiovascular and renal disease, conditions that increase the risk of death at a young age.(1) Although intensive glycemic control has improved surrogate markers of cardiovascular risk in such patients, there has been no significant reduction in the risk of major adverse cardiovascular events (MACE), including nonfatal stroke or myocardial infarction and death from cardiovascular causes.(2) Now, in the results of the EMPA-REG OUTCOME trial published in this issue of the Journal, Zinman et al. report a decreased risk of death from all causes and cardiovascular causes among . . .
    No preview · Article · Nov 2015 · New England Journal of Medicine
  • Gang Xi · Clifford J Rosen · David R Clemmons
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    ABSTRACT: IGF-I / IGF BP-2 coordinately stimulate osteoblast differentiation but the mechanisms by which they function have not been determined. AMP-activated protein kinase (AMPK) is induced during differentiation and AMPK knockout mice have reduced bone mass. IGF-I modulates AMPK in other cell types therefore these studies determined whether IGF-I/ IGFBP-2 stimulate AMPK activation and the mechanism by which AMPK modulates differentiation. Calvarial osteoblasts and MC-3T3 cells expressed activated AMPK early in differentiation and AMPK inhibitors attenuated differentiation. However expression of constitutively activated AMPK inhibited differentiation. To resolve this discrepancy we analyzed the time course of AMPK induction. AMPK activation was required early in differentiation (days 3-6) but downregulation of AMPK after day 9 was also necessary. IGF-I/ IGFBP-2 induced AMPK through their respective receptors and blocking receptor activation blocked AMPK induction. To determine the mechanism by which AMPK functioned we analyzed components of the autophagosome. Activated AMPK stimulated ULK-1 S555 phosphorylation as well as beclin-1 and LC3II induction. Inhibition of AMPK attenuated these changes and direct inhibition of autophagy inhibited differentiation. Conversely expression of activated AMPK was associated with persistence of these changes beyond day 9 and inhibited differentiation. Blocking AMPK activation after day 9 downregulated these autophagosome components and rescued differentiation. This allowed induction of mTOR and AKT which suppressed autophagy. The results show that early induction of AMPK in response to IGF-I/IGFBP-2 followed by suppression is required for osteoblast differentiation. AMPK functions through stimulation of autophagy. The findings suggest that these early catabolic changes are important for determining the energy source for osteoblast respiration and downregulation of these components may be required for induction of glycolysis which is required for the final anabolic stages of differentiation.
    No preview · Article · Nov 2015 · Endocrinology

  • No preview · Article · Nov 2015 · International journal of radiation oncology, biology, physics
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    ABSTRACT: Bone minerals are acquired during growth and are key determinants of adult skeletal health. During puberty, the serum levels of growth hormone (GH) and its downstream effector IGF-1 increase and play critical roles in bone acquisition. The goal of the current study was to determine how bone cells integrate signals from the GH/IGF-1 to enhance skeletal mineralization and strength during pubertal growth. Osteocytes, the most abundant bone cells, were shown to orchestrate bone modeling during growth. We used dentin matrix protein (Dmp)-1-mediated Ghr gene deletion in mice (DMP-GHRKO) to address the role of the GH/IGF axis in osteocytes. We found that DMP-GHRKO did not affect linear growth but compromised overall bone accrual. DMP-GHRKO mice exhibited reduced serum inorganic phosphate (Pi) and parathyroid hormone (PTH) levels and decreased bone formation indices and were associated with an impaired response to intermittent PTH treatment. Using an osteocyte-like cell line along with in vivo studies, we found that PTH sensitized the response of bone to GH by increasing Janus kinase-2 and IGF-1R protein levels. We concluded that endogenously secreted PTH and GHR signaling in bone are necessary to establish radial bone growth and optimize mineral acquisition during growth.-Liu, Z., Kennedy, O. D., Cardoso, L., Basta-Pljakic, J., Partridge, N. C., Schaffler, M. B., Rosen, C. J., Yakar, S. DMP-1-mediated Ghr gene recombination compromises skeletal development and impairs skeletal response to intermittent PTH.
    No preview · Article · Oct 2015 · The FASEB Journal
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    ABSTRACT: Heterochromatin protein 1 binding protein 3 (HP1BP3) is a recently described histone H1-related protein with roles in chromatin structure and transcriptional regulation. To explore the potential physiological role of HP1BP3 we have previously described an Hp1bp3(-/-) mouse model with reduced postnatal viability and growth. We now find that these mice are proportionate dwarfs, with reduction in body weight, body length and organ weight. In addition to their small size, micro-CT analysis showed that Hp1bp3(-/-) mice present a dramatic impairment of their bone development and structure. By three weeks of age, mice of both sexes have severely impaired cortical and trabecular bone, and these defects persist into adulthood and beyond. Primary cultures of both osteoblasts and osteoclasts from Hp1bp3(-/-) bone marrow and splenocytes respectively showed normal differentiation and function, strongly suggesting that the impaired bone accrual is due to non-cell autonomous systemic cues in-vivo. One major endocrine pathway regulating both body growth and bone acquisition is the IGF regulatory system, composed of insulin like growth factor 1 (IGF-1), the IGF receptors (IGFR) and the IGF binding proteins (IGFBPs). At 3 weeks of age Hp1bp3(-/-) mice exhibited a 60 reduction in circulating IGF-1 and a four-fold increase in the levels of IGFBP-1 and IGFBP-2. These alterations were reflected in similar changes in the hepatic transcripts of the Igf1, Igfbp1 and Igfbp2 genes. Collectively, these results suggest that HP1BP3 plays a key role in normal growth and bone development by regulating transcription of endocrine IGF-1 components.
    No preview · Article · Sep 2015 · Endocrinology
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    ABSTRACT: Substantial evidence shows that skeletal fragility should be considered among the complications associated with type 2 diabetes. Individuals with type 2 diabetes have increased fracture risk, despite normal bone mineral density (BMD) and high BMI-factors that are generally protective against fractures. The mechanisms underlying skeletal fragility in diabetes are not completely understood, but are multifactorial and likely include effects of obesity, hyperglycaemia, oxidative stress, and accumulation of advanced glycation end products, leading to altered bone metabolism, structure, and strength. Clinicians should be aware that BMD measurements underestimate fracture risk in people with type 2 diabetes, and that new treatments for diabetes, with neutral or positive effects on skeletal health, might play a part in the management of diabetes in those at high risk of fracture. Data for the optimum management of osteoporosis in patients with type 2 diabetes are scarce, but in the absence of evidence to the contrary, physicians should follow guidelines established for postmenopausal osteoporosis.
    No preview · Article · Sep 2015
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    ABSTRACT: Since the publication of the first issue of this journal in November 2005, our understanding of the endocrine system has evolved, with the identification of novel hormones and novel endocrine roles for previously identified molecules. Here, we have asked six of our Advisory Board Members to comment on how these insights have led to the recognition that many organs and tissues that were not widely considered part of the classic endocrine system in the past have important endocrine functions.
    No preview · Article · Sep 2015 · Nature Reviews Endocrinology
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    Clifford J Rosen · Julie R Ingelfinger
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    ABSTRACT: Body-mass index (BMI), which represents a complex trait with high heritability, is a clinically relevant surrogate for obesity.(1) Genomewide association studies have identified nearly 10,000 genetic polymorphisms in single-nucleotide variants (SNVs) associated with various human disorders and traits. However, approximately 90% of these variants are in genomic regions that do not map to coding regions and, therefore, do not directly affect protein synthesis or translation.(2) However, risk-associated loci containing noncoding variants can alter gene expression by modulating the activity of neighboring cis-regulatory elements - that is, noncoding DNA sequences in or near a gene that can modify the expression . . .
    Preview · Article · Aug 2015 · New England Journal of Medicine
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    ABSTRACT: Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal 'regulated' MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal 'constitutive' MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism.
    Full-text · Article · Aug 2015 · Nature Communications
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    ABSTRACT: Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2(-)(/-) mice (-/-), where male mice exhibited decreased bone and increased fat mass, while female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGFBP-2 and estrogen, we subjected Igfbp2 -/- and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests prior to sacrifice. At harvest, femurs were collected for μ CT, serum for protein levels, brown (BAT) and inguinal (IWAT) adipose depots for histology, gene expression, and XF24 mitochondrial analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30 with OVX. In the absence of IGFBP-2, OVX had no effect on pre-formed BAT; however, there was significant 'browning' of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intra-abdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure (EE), physical activity and BAT mitochondrial respiration were decreased less in the OVX -/- compared to OVX +/+. Mitochondrial respiration of IWAT was reduced in OVX +/+ yet remained unchanged in OVX -/- mice. These changes were associated with significant increases in Fgf21 and Foxc2 expression, two proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in FGF-21.
    No preview · Article · Jul 2015 · Endocrinology
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    Beata Lecka-Czernik · Clifford J Rosen
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    ABSTRACT: New evidence has recently emerged defining a close relationship between fat and bone metabolism. Adipose tissue is one of the largest organs in the body but its functions vary by location and origin. Adipocytes can act in an autocrine manner to regulate energy balance by sequestering triglycerides and then, depending on demand, releasing fatty acids through lipolysis for energy utilization, and in some cases through uncoupling protein 1 for generating heat. Adipose tissue can also act in an endocrine or paracrine manner by releasing adipokines that modulate the function of other organs. Bone is one of those target tissues, although recent evidence has emerged that the skeleton reciprocates by releasing its own factors that modulate adipose tissue and beta cells in the pancreas. Therefore, it is not surprising that these energy- modulating tissues are controlled by a central regulatory mechanism, primarily the sympathetic nervous system. Disruption in this complex regulatory circuit and its downstream tissues is manifested in a wide range of metabolic disorders, for which the most prevalent is type 2 diabetes mellitus. The aim of this review is to summarize our knowledge of common determinants in bone and adipose function and the translational implications of recent work in this emerging field. Copyright © 2015. Published by Elsevier Inc.
    Preview · Article · Jul 2015 · Bone
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    ABSTRACT: The formation of brown, white and beige adipocytes have been a subject of intense scientific interest in recent years due to the growing obesity epidemic in the United States and around the world. This interest has led to the identification and characterization of specific tissue resident progenitor cells that give rise to each adipocyte population in vivo. However, much still remains to be discovered about each progenitor population in terms of their "niche" within each tissue and how they are regulated at the cellular and molecular level during healthy and diseased states. While our knowledge of brown, white and beige adipose tissue is rapidly increasing, little is still known about marrow adipose tissue and its progenitor despite recent studies demonstrating possible roles for marrow adipose tissue in regulating the hematopoietic space and systemic metabolism at large. This chapter focuses on our current knowledge of brown, white, beige and marrow adipose tissue with a specific focus on the formation of each tissue from tissue resident progenitor cells.
    Full-text · Article · Jul 2015
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    ABSTRACT: This study investigated the effects of loss of Cthrc1 on adipogenesis, body composition, metabolism, physical activity, and muscle physiology. Complete metabolic and activity monitoring as well as grip strength measurements and muscle myography was performed in Cthrc1 null and wildtype mice. Compared to wildtypes, Cthrc1 null mice had similar body weights but significantly reduced energy expenditure, decreased lean mass, and increased fat mass, especially visceral fat. In vitro studies demonstrated that Cthrc1 inhibited adipocyte differentiation as well as PPAR and CREB reporter activity, while preadipocytes isolated from Cthrc1 null mice exhibited enhanced adipogenic differentiation. Voluntary physical activity in Cthrc1 null mice as assessed by wheel running was reduced to approximately half the distance covered by wildtypes. Reduced grip strength was observed in Cthrc1 null mice at the age of 15 weeks or older with reduced performance and mass of hyphenate muscle. In the brain, Cthrc1 expression was most prominent in neurons of thalamic and hypothalamic nuclei with evidence for secretion into the circulation in the median eminence. Our data indicate that Cthrc1 regulates body composition through inhibition of adipogenesis. In addition, central Cthrc1 may be a mediator of muscle function and physical activity. © 2015 The Obesity Society.
    Full-text · Article · Jul 2015 · Obesity
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    ABSTRACT: There is considerable consumer and physician interest in vitamin D as a possible therapeutic agent for a range of clinical conditions, and despite mixed evidence the interest does not appear to lessen. Some clinicians believe that consumption of vitamin D is inadequate and, in turn, advocate vitamin D supplementation to increase serum levels of the nutrient. However, evidence concerning the role of vitamin D in health and disease is conflicting, and primary care physicians have little time to sort through the data and may find it difficult to advise their patients. To better understand the challenges that primary care physicians face regarding vitamin D, and to help inform those who provide guidance for clinical decision-making, the Office of Dietary Supplements at the National Institutes of Health, with co-sponsorship from other federal health agencies, held a conference titled Vitamin D: Moving Toward Evidence-based Decision Making in Primary Care in December 2014.(1) More than 20 invited presenters and panelists considered laboratory methods for measuring vitamin D status, discussed how clinical studies of vitamin D should be evaluated and used in developing recommendations, noted the role of values and preferences in clinical decision making, debated the current science related to at-risk groups, and described emerging data about health risks of excessive intakes of vitamin D. Eight questions about vitamin D stem from the Conference presentations as well as other expert sources. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · The American journal of medicine
  • Beata Lecka-Czernik · Clifford J Rosen
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    ABSTRACT: Skeletal complications have recently been recognized as another of the several co-morbidities associated with diabetes. Clinical studies suggest that disordered glucose and lipid metabolism have a profound effect on bone. Diabetes-related changes in skeletal homeostasis result in a significant increased risk of fractures, although the pathophysiology may differ from postmenopausal osteoporosis. Efforts to understand the underlying mechanisms of diabetic bone disease have focused on the direct interaction of adipose tissue with skeletal remodeling and the potential influence of glucose utilization and energy uptake on these processes. One aspect that has emerged recently is the major role of the central nervous system in whole body metabolism, bone turnover, adipose tissue remodeling and beta cell secretion of insulin. Importantly the skeleton contributes to the metabolic balance inherent in physiologic states. New animal models have provided the insights necessary to begin to dissect the effects of obesity and insulin resistance on the acquisition and maintenance of bone mass. In this Perspective, we will focus on potential mechanisms that underlie the complex interactions between adipose tissue and skeletal turnover by focusing on the clinical evidence and on pre-clinical studies indicating that glucose intolerance may have a significant impact on the skeleton. In addition, we will raise fundamental questions that need to be addressed in future studies to resolve the conundrum associated with glucose intolerance, obesity, and osteoporosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research

Publication Stats

18k Citations
2,993.26 Total Impact Points

Institutions

  • 2009-2016
    • Maine Medical Center Research Institute
      Скарбороу, Maine, United States
    • Icahn School of Medicine at Mount Sinai
      • Department of Medicine
      Borough of Manhattan, New York, United States
    • Oregon State University
      • Department of Nutrition and Exercise Sciences (NES)
      Corvallis, Oregon, United States
  • 2013-2015
    • Tufts University
      Бостон, Georgia, United States
  • 2012-2015
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 2008-2015
    • Maine Medical Center
      Portland, Maine, United States
  • 1994-2015
    • University of Maine
      • Department of Food Science and Human Nutrition
      Orono, Minnesota, United States
  • 2000-2011
    • The Jackson Laboratory
      Bar Harbor, Maine, United States
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1999-2011
    • Creighton University
      • Department of Medicine
      Omaha, Nebraska, United States
  • 1996-2011
    • St. Joseph's Hospital
      Savannah, Georgia, United States
    • Society for Clinical Trials
      Society Hill, New Jersey, United States
  • 2006
    • Cornell University
      • Department of Animal Science
      Итак, New York, United States
    • University of Texas Health Science Center at San Antonio
      • Department of Biochemistry
      San Antonio, Texas, United States
  • 2002-2006
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
    • Loma Linda University
      • Department of Medicine
      لوما ليندا، كاليفورنيا, California, United States
  • 2005
    • University of California, San Francisco
      • Department of Epidemiology and Biostatistics
      San Francisco, CA, United States
  • 2003
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • National Eye Institute
      Maryland, United States
    • National Institutes of Health
      베서스다, Maryland, United States
  • 1997-2002
    • Columbia University
      • • Department of Genetics and Development
      • • Department of Medicine
      New York, New York, United States
  • 1998
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
    • Beth Israel Medical Center
      • Division of Rheumatology
      New York City, New York, United States
  • 1996-1997
    • Husson College
      Saint Joseph, Missouri, United States
  • 1995
    • Boston University
      Boston, Massachusetts, United States