Publications (55)454.95 Total impact
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Article: Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function.
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ABSTRACT: Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110α in lymphocyte responses in vitro and in vivo. p110α inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110δ inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110α inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110δ inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that while acute p110α inhibition partially diminishes AKT activation, selective p110α inhibitors are likely to be less immunosuppressive in vivo compared to p110δ or pan-class I inhibitors.Journal of Biological Chemistry 12/2012; · 4.77 Impact Factor -
Article: Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment.
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ABSTRACT: The interactions between the bone marrow (BM) microenvironment and acute myeloid leukemia (AML) is known to promote survival of AML cells. In this study, we used reverse phase-protein array (RPPA) technology to measure changes in multiple proteins induced by stroma in leukemic cells. We then investigated the potential of an mTOR kinase inhibitor, PP242, to disrupt leukemia/stroma interactions, and examined the effects of PP242 in vivo using a mouse model. Using RPPA, we confirmed that multiple survival signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), were up-regulated in primary AML cells cocultured with stroma. PP242 effectively induced apoptosis in primary samples cultured with or without stroma. Mechanistically, PP242 attenuated the activities of mTORC1 and mTORC2, sequentially inhibited phosphorylated AKT, S6K, and 4EBP1, and concurrently suppressed chemokine receptor CXCR4 expression in primary leukemic cells and in stromal cells cultured alone or cocultured with leukemic cells. In the in vivo leukemia mouse model, PP242 inhibited mTOR signaling in leukemic cells and demonstrated a greater antileukemia effect than rapamycin. Our findings indicate that disrupting mTOR/AKT signaling with a selective mTOR kinase inhibitor can effectively target leukemic cells within the BM microenvironment.Blood 07/2012; 120(13):2679-89. · 9.90 Impact Factor -
Article: PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances.
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ABSTRACT: Activation of PI3K (phosphoinositide 3-kinase) is a shared response to engagement of diverse types of transmembrane receptors. Depending on the cell type and stimulus, PI3K activation can promote different fates including proliferation, survival, migration and differentiation. The diverse roles of PI3K signalling are well illustrated by studies of lymphocytes, the cells that mediate adaptive immunity. Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B- and T-cells. These findings have prompted the development of PI3K inhibitors for the treatment of autoimmunity and inflammatory diseases. PI3K activation, however, has both positive and negative roles in immune system activation. Consequently, although PI3K suppression can attenuate immune responses it can also enhance inflammation, disrupt peripheral tolerance and promote autoimmunity. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B-cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukaemia and lymphoma cells from their protective niche. These encouraging findings have given further momentum to PI3K drug development efforts in both cancer and immune diseases.Biochemical Journal 03/2012; 442(3):465-81. · 4.90 Impact Factor -
Article: The in vivo evaluation of active-site TOR inhibitors in models of BCR-ABL+ leukemia.
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ABSTRACT: Preclinical evaluation of candidate anticancer compounds requires appropriate animal models. Most commonly, solid tumor xenograft systems are employed in which immunocompromised mice are implanted with human cancer cell lines. Genetically engineered mouse models of solid tumors are also frequently employed. Both of these approaches can also be applied to studies of hematological malignancies. In this chapter, we describe three types of mouse models of leukemia driven by the human BCR-ABL oncogene. We also discuss the application of these models to preclinical testing of active-site TOR inhibitors, a novel class of compounds that selectively target the ATP-binding pocket of the target of rapamycin (TOR) kinase.Methods in molecular biology (Clifton, N.J.) 01/2012; 821:251-65. -
Article: Akt and mTOR in B Cell Activation and Differentiation.
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ABSTRACT: Activation of phosphoinositide 3-kinase (PI3K) is required for B cell proliferation and survival. PI3K signaling also controls key aspects of B cell differentiation. Upon engagement of the B cell receptor (BCR), PI3K activation promotes Ca(2+) mobilization and activation of NFκB-dependent transcription, events which are essential for B cell proliferation. PI3K also initiates a distinct signaling pathway involving the Akt and mTOR serine/threonine kinases. It has been generally assumed that activation of Akt and mTOR downstream of PI3K is essential for B cell function. However, Akt and mTOR have complex roles in B cell fate decisions and suppression of this pathway can enhance certain B cell responses while repressing others. In this review we will discuss genetic and pharmacological studies of Akt and mTOR function in normal B cells, and in malignancies of B cell origin.Frontiers in immunology. 01/2012; 3:228. -
Article: PI3Kδ inhibitors in cancer: rationale and serendipity merge in the clinic.
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ABSTRACT: Several phosphoinositide 3-kinase (PI3K) inhibitors are in the clinic and many more are in preclinical development. CAL-101, a selective inhibitor of the PI3Kδ isoform, has shown remarkable success in certain hematologic malignancies. Although PI3Kδ signaling plays a central role in lymphocyte biology, the degree of single-agent therapeutic activity of CAL-101 during early-phase development has been somewhat unexpected. CAL-101 works in part by blocking signals from the microenvironment that normally sustain leukemia and lymphoma cells in a protective niche. As PI3Ks enter the arena of molecular-targeted therapies, CAL-101 provides proof of principle that isoform-selective compounds can be effective in selected cancer types and patient populations. Significance: A key question is whether compounds targeting a single PI3K catalytic isoform can provide meaningful single agent efficacy in cancer cells that express multiple isoforms. Clinical studies of the drug CAL-101 have provided a significant advance by showing that selective targeting of PI3Kδ achieves efficacy in chronic lymphocytic leukemia, in part through targeting the tumor microenvironment.Cancer discovery. 12/2011; 1(7):562-72. -
Article: Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins.
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ABSTRACT: Cancer cells are hypersensitive to nutrient limitation because oncogenes constitutively drive glycolytic and TCA (tricarboxylic acid) cycle intermediates into biosynthetic pathways. As the anaplerotic reactions that replace these intermediates are fueled by imported nutrients, the cancer cell's ability to generate ATP becomes compromised under nutrient-limiting conditions. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from internal sources when external nutrients are unavailable. Normal cells, in contrast, can adapt to the nutrient stress that kills cancer cells by becoming quiescent and catabolic. In the present study we show that FTY720, a water-soluble sphingolipid drug that is effective in many animal cancer models, selectively starves cancer cells to death by down-regulating nutrient transporter proteins. Consistent with a bioenergetic mechanism of action, FTY720 induced homoeostatic autophagy. Cells were protected from FTY720 by cell-permeant nutrients or by reducing nutrient demand, but blocking apoptosis was ineffective. Importantly, AAL-149, a FTY720 analogue that lacks FTY720's dose-limiting toxicity, also triggered transporter loss and killed patient-derived leukaemias while sparing cells isolated from normal donors. As they target the metabolic profile of cancer cells rather than specific oncogenic mutations, FTY720 analogues such as AAL-149 should be effective against many different tumour types, particularly in combination with drugs that inhibit autophagy.Biochemical Journal 07/2011; 439(2):299-311. · 4.90 Impact Factor -
Article: A lipid kinase cousin cooperates to promote cancer.
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ABSTRACT: Phosphoinositide 3-kinases (PI3Ks) are considered promising drug targets in oncology. In this issue of Cancer Cell, Schmid et al. demonstrate that the PI3Kγ isoform is required for inflammatory myeloid cells to traffic to tumors. Though tumor cells do not express PI3Kγ, selective inhibition of this isoform suppresses tumor growth and angiogenesis.Cancer cell 06/2011; 19(6):693-5. · 25.29 Impact Factor -
Article: B-1 cell lymphoma in mice lacking the steroid and xenobiotic receptor, SXR.
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ABSTRACT: The steroid and xenobiotic receptor (SXR) is a broad-specificity nuclear hormone receptor that is highly expressed in the liver and intestine, where its primary function is to regulate drug and xenobiotic metabolism. SXR is expressed at lower levels in other tissues, where little is known about its physiological functions. We previously linked SXR with immunity and inflammation by showing that SXR antagonizes the activity of nuclear factor (NF)-κB in vitro and in vivo. SXR(-/-) mice demonstrate aberrantly high NF-κB activity and overexpression of NF-κB target genes. Here we show that SXR(-/-) mice develop B cell lymphoma in an age-dependent manner. SXR(-/-) mice develop multiple hyperplastic lymphoid foci composed of B-1a cells in the intestine, spleen, lymph nodes, peritoneal cavity, and blood. In all circumstances, these lymphocytes possess cell surface and molecular characteristics of either chronic lymphocytic leukemia or non-Hodgkin's lymphoma originating from B-1 lymphocytes. These results demonstrate a novel and unsuspected role for SXR signaling in the B-1 cell compartment, establish SXR as a tumor suppressor in B-1 cells, and may provide a link between metabolism of xenobiotic compounds and lymphomagenesis.Molecular Endocrinology 03/2011; 25(6):933-43. · 4.54 Impact Factor -
Article: Target of rapamycin signaling in leukemia and lymphoma.
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ABSTRACT: Growth factors and many oncogenes activate the lipid kinase phosphoinositide 3-kinase (PI3K), initiating a signaling cascade that includes the protein kinases AKT and target of rapamycin (TOR). The PI3K/AKT/TOR signaling pathway is a significant contributor to disease in various human cancers, including hematologic malignancies. Here we discuss different strategies to inhibit TOR for the treatment of leukemia, lymphoma, and myeloma. The TOR enzyme exists in two complexes in cells, TORC1 and TORC2. The majority of preclinical and clinical efforts to target TOR have involved using rapamycin and its analogs (rapalogs), which suppress TORC1 only partially and do not acutely inhibit TORC2. A new class of small molecules targeting the ATP-binding site of the TOR kinase, termed active-site TOR inhibitors (asTORi), achieves greater inhibition of both TOR complexes, resulting in broader suppression of the PI3K/AKT/TOR signaling network. Preclinical evidence suggests that asTORi have greater efficacy than rapalogs in Philadelphia chromosome-positive acute lymphoblastic leukemia and in T-cell lymphoma. These agents also show greater tolerability in animal models relative to rapalogs or inhibitors of PI3K. These findings encourage broader evaluation of asTORi efficacy in acute myeloid leukemia, B-cell lymphoma, myeloma, and other blood cancers.Clinical Cancer Research 11/2010; 16(22):5374-80. · 7.74 Impact Factor -
Article: Targeting TOR dependence in cancer.
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ABSTRACT: A challenge in cancer therapy has been to identify targets whose function is essential for survival of malignant cells but not normal cells. This Perspective discusses recent evidence that novel inhibitors of the kinase TOR can provide an unprecedented balance of anti-cancer efficacy and tolerability.Oncotarget 05/2010; 1(1):69-76. · 4.78 Impact Factor -
Article: Foxo1 regulates marginal zone B-cell development.
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ABSTRACT: A fundamental component of signaling initiated by the BCR and CD19 is the activation of phosphoinositide 3-kinase. Downstream of phosphoinositide 3-kinase, the protein kinase AKT phosphorylates several substrates, including members of the forkhead box subgroup O (Foxo) transcription factor family. Among the Foxo proteins, Foxo1 has unique functions in bone marrow B-cell development and peripheral B-cell function. Here, we report a previously unrecognized role for Foxo1 in controlling the ratio of mature B-cell subsets in the spleen. Conditional deletion of Foxo1 in B cells resulted in an increased percentage of marginal zone B cells and a decrease in follicular (FO) B cells. In addition, Foxo1 deficiency corrected the absence of marginal zone B cells that occurs in CD19-deficient mice. These findings show that Foxo1 regulates the balance of mature B-cell subsets and is required for the marginal zone B-cell deficiency phenotype of mice lacking CD19.European Journal of Immunology 05/2010; 40(7):1890-6. · 5.10 Impact Factor -
Article: Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor.
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ABSTRACT: Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. Unexpectedly, PP242 has much weaker effects than rapamycin on the proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase (PI3K), is more immunosuppressive than PP242. These findings establish that Ph(+) transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.Nature medicine 02/2010; 16(2):205-13. · 27.14 Impact Factor -
Article: B cell receptor signaling: picky about PI3Ks.
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ABSTRACT: The B cell receptor (BCR) and the pre-BCR control cell fate at many stages of B cell development, survival, and antigen response. Most of these processes require the activation of phosphatidylinositol 3-kinase (PI3K). Previous work has pointed to p110delta as the key catalytic isoform of PI3K for many B cell responses. A study of mice with different combinations of PI3K mutations confirms the central role of p110delta in agonist-mediated signaling, while identifying an unexpected function for the p110alpha isoform in tonic signaling by the pre-BCR and mature BCR.Science Signaling 01/2010; 3(134):pe25. · 7.50 Impact Factor -
Article: Regulatory subunits of class IA PI3K.
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ABSTRACT: All class I PI3K enzymes are obligate heterodimers, consisting of a catalytic subunit tightly bound to a regulatory subunit. The regulatory subunit influences the subcellular location, binding partners, and activity of the catalytic subunit. Regulatory subunits also possess adaptor functions in cellular signaling, which are largely independent of their role in regulating PI3K activity. This chapter reviews the structure and function of PI3K regulatory subunits, focusing on the class IA subgroup.Current topics in microbiology and immunology 01/2010; 346:225-44. · 4.93 Impact Factor -
Article: The p85beta regulatory subunit of phosphoinositide 3-kinase has unique and redundant functions in B cells.
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ABSTRACT: Phosphoinositide kinase (PI3K) is activated by various receptors on lymphocytes and regulates development, activation, and tolerance. Genetic ablation of PI3K function in T cells leads to the appearance of autoimmune disorders. In B cells, loss of the class IA regulatory subunit p85alpha causes a partial defect in B cell development and proliferation, whereas loss of p85beta alone causes no apparent changes in B cell function. Here we investigate further the consequences of p85beta deletion in B cells, in the presence or absence of p85alpha. We demonstrate that p85beta partially compensates for loss of p85alpha in B cell development and peripheral survival, with greater defects observed when both isoforms are absent. BCR-mediated AKT phosphorylation is partially reduced in p85alpha-deficient B cells and further diminished with concomitant loss of p85beta. Unexpectedly, loss of p85beta results in increased BCR-mediated proliferation and ERK phosphorylation. These results indicate that the p85beta regulatory isoform has partially overlapping functions with p85alpha in B cells as well as a unique role in opposing BCR responses.Autoimmunity 08/2009; 42(5):447-58. · 2.47 Impact Factor -
Article: Fine tuning the immune response with PI3K.
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ABSTRACT: The phosphoinositide 3-kinase (PI3K) family of lipid kinases regulates diverse aspects of lymphocyte behavior. This review discusses how genetic and pharmacological tools have yielded an increasingly detailed understanding of how PI3K enzymes function at different stages of lymphocyte development and activation. Following antigen receptor engagement, activated PI3K generates 3-phosphorylated inositol lipid products that serve as membrane targeting signals for numerous proteins involved in the assembly of multiprotein complexes, termed signalosomes, and immune synapse formation. In B cells, class IA PI3K is the dominant subgroup whose loss causes profound defects in development and antigen responsiveness. In T cells, both class IA and IB PI3K contribute to development and immune function. PI3K also regulates both chemokine responsiveness and antigen-driven changes in lymphocyte trafficking. PI3K modulates the function not only of effector T cells, but also regulatory T cells; these disparate functions culminate in unexpected autoimmune phenotypes in mice with PI3K-deficient T cells. Thus, PI3K signaling is not a simple switch to promote cellular activation, but rather an intricate web of interactions that must be properly balanced to ensure appropriate cellular responses and maintain immune homeostasis. Defining these complexities remains a challenge for pharmaceutical development of PI3K inhibitors to combat inflammation and autoimmunity.Immunological Reviews 04/2009; 228(1):253-72. · 11.15 Impact Factor -
Article: Immune regulation by rapamycin: moving beyond T cells.
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ABSTRACT: The mammalian target of rapamycin (mTOR) is a multifunctional kinase that promotes cell growth and division in response to growth factor and nutrient signals. Rapamycin exerts its potent immunosuppressive effects in part through direct effects on antigen-specific lymphocytes; however, rapamycin also modulates adaptive immunity through its effects on innate immune cells, including dendritic cells and macrophages. Studies have established rapamycin-sensitive functions of mTOR, downstream of Toll-like receptors, in shaping the cytokine response of myeloid cells and driving the production of interferon by plasmacytoid dendritic cells. These findings point to new strategies for boosting or suppressing specific immune responses.Science Signaling 02/2009; 2(67):pe25. · 7.50 Impact Factor -
Article: Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells.
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ABSTRACT: Some cases of pre-B cell acute lymphoblastic leukemia (pre-B-ALL) are caused by the Philadelphia (Ph) chromosome-encoded BCR-ABL oncogene, and these tend to have a poor prognosis. Inhibitors of the PI3K/AKT pathway reduce BCR-ABL-mediated transformation in vitro; however, the specific PI3K isoforms involved are poorly defined. Using a murine model of Ph+ pre-B-ALL, we found that deletion of both Pik3r1 and Pik3r2, genes encoding class IA PI3K regulatory isoforms, severely impaired transformation. BCR-ABL-dependent pre/pro-B cell lines could be established at low frequency from progenitors that lacked these genes, but the cells were smaller, proliferated more slowly, and failed to cause leukemia in vivo. These cell lines displayed nearly undetectable PI3K signaling function and were resistant to the PI3K inhibitor wortmannin. However, they maintained activation of mammalian target of rapamycin (mTOR) and were more sensitive to rapamycin. Treatment with rapamycin caused feedback activation of AKT in WT cell lines but not PI3K-deficient lines. A dual inhibitor of PI3K and mTOR, PI-103, was more effective than rapamycin at suppressing proliferation of mouse pre-B-ALL and human CD19+CD34+)Ph+ ALL leukemia cells treated with the ABL kinase inhibitor imatinib. Our findings provide mechanistic insights into PI3K dependency in oncogenic networks and provide a rationale for targeting class IA PI3K, alone or together with mTOR, in the treatment of Ph+ ALL.Journal of Clinical Investigation 10/2008; 118(9):3038-50. · 15.39 Impact Factor -
Article: FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase.
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ABSTRACT: In T cells, the PI3K pathway promotes proliferation and survival induced by Ag or growth factors, in part by inactivating the FOXO transcription factor 1. We now report that FOXO1 controls the expression of L-selectin, an essential homing molecule, in human T lymphocytes. This control is already operational in unprimed T cells and involves a transcriptional regulation process that requires the FOXO1 DNA-binding domain. Using transcriptional profiling, we demonstrate that FOXO1 also increases transcripts of EDG1 and EDG6, two sphingosine-1-phosphate receptors that regulate lymphocyte trafficking. Additionally, FOXO1 binds the promoter of the cell quiescence and homing regulator Krüppel-like factor 2 and regulates its expression. Together, these results reveal a new function of FOXO1 in the immune system and suggest that PI3K controls a coordinated network of transcription factors regulating both cell quiescence and homing of human T lymphocytes.The Journal of Immunology 10/2008; 181(5):2980-9. · 5.79 Impact Factor
Top co-authors
Top Journals
Institutions
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2002–2012
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University of California, Irvine
- Department of Molecular Biology and Biochemistry
Irvine, CA, USA
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2005
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Beth Israel Medical Center
New York City, NY, USA
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2002–2003
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Beth Israel Deaconess Medical Center
Boston, MA, USA -
Harvard University
- Joslin Diabetes Center
Boston, MA, USA
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