Tatiana V Byzova

Lerner Research Institute, Cleveland, Ohio, United States

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Publications (98)714.31 Total impact

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    ABSTRACT: Oxidative stress is an important contributing factor in a number of human pathologies ranging from atherosclerosis to cancer progression; however, the mechanisms underlying tissue protection from oxidation products are poorly understood. Oxidation of membrane phospholipids, containing the polyunsaturated fatty acid DHA, results in the accumulation of an end product, 2-(ω-carboxyethyl)pyrrole (CEP), which was shown to have pro-angiogenic and pro-inflammatory functions. While CEP is continuously accumulated during chronic processes such as tumor progression and atherosclerosis, its levels during wound healing return to normal when the wound is healed, suggesting the existence of a specific clearance mechanism. To identify the cellular and molecular mechanism for CEP clearance. Here we show that macrophages are able to bind, scavenge, and metabolize carboxyethylpyrrole derivatives of proteins but not structurally similar ethylpyrrole derivatives, demonstrating the high specificity of the process. F4/80(hi) and M2-skewed macrophages are much more efficient at CEP binding and scavenging compared to F4/80(lo) and M1-skewed macrophages. Depletion of macrophages leads to increased CEP accumulation in vivo. CEP binding and clearance are dependent on two receptors expressed by macrophages, CD36 and TLR2. While knockout of each individual receptor results in diminished CEP clearance, the lack of both receptors almost completely abrogates macrophages' ability to scavenge CEP derivatives of proteins. Our study demonstrates the mechanisms of recognition, scavenging, and clearance of pathophysiologically active products of lipid oxidation in vivo, thereby contributing to tissue protection against products of oxidative stress.
    Circulation Research 05/2015; 117(4). DOI:10.1161/CIRCRESAHA.117.305925 · 11.02 Impact Factor
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    Circulation Research 04/2015; 116(11). DOI:10.1161/RES.0000000000000054 · 11.02 Impact Factor
  • Katarzyna Bialkowska · Tatiana V Byzova · Edward F Plow
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    ABSTRACT: The contributions of integrins to cellular responses depend upon their activation, which is regulated by binding of proteins by their cytoplasmic tails. Kindlins are integrin cytoplasmic tail (CT) binding partners, are essential for optimal integrin activation, and kindlin-3 fulfills this role in hematopoietic cells. Here, we used human platelets and human erythroleukemia (HEL) cells, which express integrin αIIbβ3, to investigate whether phosphorylation of kindlin-3 regulate integrin activation. When HEL cells were stimulated with thrombopoietin (TPO) or phorbol 12-mirystate 13-acetate (PMA), αIIbβ3 became activated as evidenced by binding of an activation-specific monoclonal antibody and soluble fibrinogen, adherence and spreading on fibrinogen, colocalization of β3 integrin and kindlin-3 in focal adhesions, and enhanced β3 integrin-kindlin-3 association in immunoprecipitates. Kindlin-3 knockdown impaired adhesion and spreading on fibrinogen. Stimulation of HEL cells with agonists significantly increased kindlin-3 phosphorylation as detected by mass spectrometric sequencing. T482 or S484 was identified as a phosphorylation site, which resides in a sequence not conserved in kindlin-1 or kindlin-2. These same residues were phosphorylated in kindlin-3 when platelets were stimulated with thrombin. When expressed in HEL cells, T482S484/AA kindlin-3 decreased soluble ligand binding and cell spreading on fibrinogen compared to wild-type kindlin-3. A membrane-permeable peptide containing residues 476-485 of kindlin-3 was introduced into HEL cells and platelets, adhesion and spreading of both cell types was blunted compared to a scrambled control peptide. These data identify a role kindlin-3 phosphorylation in integrin β3 activation and provide a basis for functional differences between kindlin-3 and other two kindlin paralogs. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 01/2015; 290(10). DOI:10.1074/jbc.M114.634436 · 4.57 Impact Factor
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    ABSTRACT: Kindlins are integrin interacting proteins, essential for integrin mediated cell adhesiveness. In this study, we focused on the evolutionary origin and functional specialization of Kindlins as a part of evolutionary adaptation of cell adhesive machinery. The database searches revealed that many members of integrin machinery (including Talin and integrins) already existed prior to Kindlin emergence in evolution. Among the analyzed species, all metazoan lineages-but none of the premetazoans-had at least one Kindlin encoding gene, whereas Talin was present in several premetazoan lineages. Kindlin appears to originate from a duplication of the sequence encoding the N-terminal fragment of Talin (the Talin Head domain), with a subsequent insertion of the PH domain of a separate origin. Sequence analysis identified a member of the Actin Filament-associated Protein 1 (AFAP1) superfamily as the most likely origin of the Kindlin PH domain. The functional divergence between Kindlin paralogs was assessed using the sequence swap (chimera) approach. Comparison of Kindlin 2 (K2)/Kindlin 3 (K3) chimeras revealed that the F2 subdomain, in particular its C-terminal part, is crucial for the differential functional properties of K2 and K3. The presence of this segment enables K2 but not K3 to localize to focal adhesions. Sequence analysis of the C-terminal part of the F2 subdomain of K3 suggests that an insertion of a variable glycine-rich sequence in vertebrates contributed to the loss of constitutive K3 targeting to focal adhesions. Thus, emergence and subsequent functional specialization of Kindlins allowed multicellular organisms to develop additional tissue-specific adaptations of cell adhesiveness. © 2014 by The American Society for Cell Biology.
    Molecular Biology of the Cell 12/2014; 26(4). DOI:10.1091/mbc.E14-08-1294 · 4.47 Impact Factor
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    ABSTRACT: The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion.
    Nature Communications 12/2014; 5:5880. DOI:10.1038/ncomms6880 · 11.47 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) are associated with cancer progression, aggressiveness and metastasis. However, the frequency and predictive value of CTCs in patients remains unknown. If circulating cells are involved in tumor aggressiveness and metastasis, then cell levels should decline upon tumor removal in localized cancer patients, but remain high in metastatic patients. Accordingly, proposed biomarkers CD117/c-kit, CD133, CXCR4/CD184, and CD34-positive cell percentages in the blood of patients undergoing radical prostatectomy for localized cancer were assessed by flow cytometry prior to intervention and 1-3 months postoperatively. Only circulating CD117+ cell percentages decreased after radical prostatectomy, increased with cancer progression and correlated with high PSA values. Notably, postoperative CD117+ levels did not decrease in patients experiencing biochemical recurrence. In a xenograft model, CD117-enriched tumors were more vascularized and aggressive. Thus, CD117 expression on CTCs promotes tumor progression and could be a biomarker for prostate cancer diagnosis, prognosis, and/or response to therapy.
    Oncotarget 12/2014; 6(3). DOI:10.18632/oncotarget.2796 · 6.36 Impact Factor
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    ABSTRACT: A specific role for Akt1 in events following myocardial infarction (MI) and ischemia/reperfusion (I/R) injury is not known. We aimed to determine whether Akt1 deletion in in vivo mouse models of MI and after ischemia I/R injury would alter myocyte survival, cardiac function, and fibrosis. Akt1(+/+) and Akt1(-/-) mice were subjected to MI and I/R, followed by assessment of downstream signaling events and functional consequences. Although no difference in infarct size following short-term MI was observed between Akt1(+/+) and Akt1(-/-) mice, I/R caused substantially more cardiomyocyte apoptosis and tissue damage in Akt1(-/-) mice compared with Akt1(+/+). Importantly, these effects were reversed upon pretreatment with GSK-3 inhibitor SB415286. Counterintuitively, Akt1(-/-) hearts exhibited improved cardiac function following long-term MI compared with Akt1(+/+) and were associated with reduced fibrosis in the left ventricle (LV). Our results demonstrate that Akt1-mediated inhibition of GSK-3 activity is critical for cardioprotection following I/R. However, in the long term, Akt1 contributes to fibrosis in post-MI hearts and might exacerbate cardiac dysfunction showing dichotomous role for Akt1 in cardiac remodeling after MI. Our data suggest that better understanding of the Akt1/GSK-3 pathway may provide insights for better therapeutic strategies in post-MI tissues.Laboratory Investigation advance online publication, 21 July 2014; doi:10.1038/labinvest.2014.95.
    Laboratory Investigation 07/2014; 94(10). DOI:10.1038/labinvest.2014.95 · 3.68 Impact Factor
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    ABSTRACT: Objective: Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbβ3-mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbβ3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin αIIbβ3 in platelets in supporting integrin αIIbβ3-mediated platelet functions. Approach and results: We generated a strain of kindlin-3 knockin (K3KI) mice that express a kindlin-3 mutant that carries an integrin-interaction defective substitution. K3KI mice could survive normally and express integrin αIIbβ3 on platelets similar to their wild-type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbβ3 activation, suppressed platelet spreading and platelet aggregation, prolonged tail bleeding time, and absence of platelet-mediated clot retraction. In addition, whole blood drawn from K3KI mice showed resistance to in vitro thrombus formation and, as a consequence, K3KI mice were protected from in vivo arterial thrombosis. Conclusions: These observations demonstrate that the direct binding of kindlin-3 to integrin αIIbβ3 is involved in supporting integrin αIIbβ3 activation and integrin αIIbβ3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2014; 34(9). DOI:10.1161/ATVBAHA.114.303851 · 6.00 Impact Factor
  • Edward F Plow · Julia Meller · Tatiana V Byzova
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    ABSTRACT: This review considers recent developments concerning the role of integrins in vascular biology with a specific emphasis on integrin activation, and the crosstalk between integrins and growth factor receptors. Recent studies have shown leukocytes can mediate direct transfer of molecules into endothelial cells, how specific integrins can be used to transduce signaling events, in particular in vascular beds, and how endothelial cell integrins can be targeted with specific ligands for the delivery of therapeutics. Kindlin and talin are both essential for integrin activation based on in-vivo studies of mice and humans in which the genes encoding for these proteins have been inactivated. Recent studies have attempted to translate these in-vivo realities into in-vitro models with mixed results. Mechanisms and consequences of integrin-ligand interactions on blood and vascular cells remain a major topic of hematological research. Crucial to the ligand binding function of integrins are two intracellular binding partners, talin and kindlin. In seeking to define the molecular basis for 'integrin activation', a mechanism must be envisioned in which both proteins talin and kindlin are required to produce a productive functional response, be it platelet aggregation or leukocyte extravasation. On endothelial cells, integrins and vascular endothelial growth factor receptor 2 influence the activation of one another by virtue of their direct physical interaction. It has been shown that this bidirectional communication is subject to regulation during angiogenesis.
    Current opinion in hematology 03/2014; 21(3). DOI:10.1097/MOH.0000000000000042 · 3.97 Impact Factor
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    ABSTRACT: The intricacy of multiple feedback loops in the pathways downstream of Akt allows this kinase to control multiple cellular processes in the cardiovascular system and precludes inferring consequences of its activation in specific pathological conditions. Akt1, the major Akt isoform in the heart and vasculature, has a protective role in the endothelium during atherosclerosis. However, Akt1 activation may also have detrimental consequences in the cardiovascular system. Mice lacking both the high-density lipoprotein receptor SR-BI (scavenger receptor class B type I) and ApoE (apolipoprotein E), which promotes clearance of remnant lipoproteins, are a model of severe dyslipidemia and spontaneous myocardial infarction. We found that Akt1 was activated in these mice, and this activation correlated with cardiac dysfunction, hypertrophy, and fibrosis; increased infarct area; cholesterol accumulation in macrophages and atherosclerosis; and reduced life span. Akt1 activation was associated with inflammation, oxidative stress, accumulation of oxidized lipids, and increased abundance of CD36, a major sensor of oxidative stress, and these events created a positive feedback loop that exacerbated the consequences of oxidative stress. Genetic deletion of Akt1 in this mouse model resulted in decreased mortality, alleviation of multiple complications of heart disease, and reduced occurrence of spontaneous myocardial infarction. Thus, interference with Akt1 signaling in vivo could be protective and improve survival under dyslipidemic conditions by reducing oxidative stress and responses to oxidized lipids.
    Science Signaling 08/2013; 6(287):ra67. DOI:10.1126/scisignal.2003948 · 6.28 Impact Factor
  • A. Goc · J. Liu · T. Byzova · S. Shenoy
    Cancer Research 05/2013; 72(4 Supplement):A47-A47. DOI:10.1158/1538-7445.PRCA2012-A47 · 9.33 Impact Factor
  • Young-Woong Kim · Xiaoxia Z West · Tatiana V Byzova
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    ABSTRACT: Recent evidence suggests that processes of inflammation and angiogenesis are interconnected, especially in human pathologies. Newly formed blood vessels enable the continuous recruitment of inflammatory cells, which release a variety of proangiogenic cytokines, chemokines, and growth factors and further promote angiogenesis. These series of positive feedback loops ultimately create a vicious cycle that exacerbates inflammation, transforming it into the chronic process. Recently, this concept of reciprocity of angiogenesis and inflammation has been expanded to include oxidative stress as a novel mechanistic connection between inflammation-driven oxidation and neovascularization. Production of reactive oxygen species results from activation of immune cells by proinflammatory stimuli. As oxidative stress can lead to chronic inflammation by activating a variety of transcription factors including NF-κB, AP-1, and PPAR-γ, inflammation itself has a reciprocal relationship with oxidative stress. This review discusses the recent findings in the area bridging neovascularization and oxidation and highlights novel mechanisms of inflammation- and oxidative stress-driven angiogenesis.
    Journal of Molecular Medicine 03/2013; 91(3):323-8. DOI:10.1007/s00109-013-1007-3 · 5.11 Impact Factor
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    ABSTRACT: Rationale: A prothrombotic state and increased platelet reactivity are common in pathophysiological conditions associated with oxidative stress and infections. Such conditions are associated with an appearance of altered-self ligands in circulation that can be recognized by Toll-like receptors (TLRs). Platelets express a number of TLRs, including TLR9; however, the role of TLR in platelet function and thrombosis is poorly understood. Objective: To investigate the biological activities of carboxy(alkylpyrrole) protein adducts, an altered-self ligand generated in oxidative stress, on platelet function and thrombosis. Methods and results: In this study we show that carboxy(alkylpyrrole) protein adducts represent novel unconventional ligands for TLR9. Furthermore, using human and murine platelets, we demonstrate that carboxy(alkylpyrrole) protein adducts promote platelet activation, granule secretion, and aggregation in vitro and thrombosis in vivo via the TLR9/MyD88 pathway. Platelet activation by TLR9 ligands induces IRAK1 and AKT phosphorylation, and it is Src kinase-dependent. Physiological platelet agonists act synergistically with TLR9 ligands by inducing TLR9 expression on the platelet surface. Conclusions: Our study demonstrates that platelet TLR9 is a functional platelet receptor that links oxidative stress, innate immunity, and thrombosis.
    Circulation Research 10/2012; 112(1). DOI:10.1161/CIRCRESAHA.112.274241 · 11.02 Impact Factor
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    B A Kerr · N P McCabe · W Feng · T V Byzova
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    ABSTRACT: Although the survival rate for early detected cancers is high, once a cancer metastasizes to bone, it is incurable. Interestingly, patients without visible metastases display abnormal bone formation and resorption, suggesting a link between primary cancers and the bone microenvironment prior to metastasis, and this link likely facilitates preparation of the pre-metastatic niche. We hypothesized that communication with the primary tumor would result in bone remodeling alterations, and that platelets could facilitate this communication. By using three tumor models, we demonstrate that primary tumor growth stimulates bone formation measured by microcomputed tomography. Further, platelet depletion prevented tumor-induced bone formation, highlighting the importance of platelets in the communication between tumors and the bone microenvironment. Finally, we determine that platelets sequester a variety of tumor-derived proteins, TGF-β1 and MMP-1 in particular, which regulate bone formation. Thus, our data reveal that platelets function as mediators of tumor-bone communication prior to metastasis.Oncogene advance online publication, 15 October 2012; doi:10.1038/onc.2012.447.
    Oncogene 10/2012; 32(36). DOI:10.1038/onc.2012.447 · 8.46 Impact Factor
  • Heart (British Cardiac Society) 10/2012; 98(Suppl 2):E7-E8. DOI:10.1136/heartjnl-2012-302920a.15 · 5.60 Impact Factor
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    ABSTRACT: Integrin activation on hematopoietic cells is essential for platelet aggregation, leukocyte adhesion, transmigration through endothelium and extracellular matrix into inflamed tissues. In order to migrate through matrix, leukocyte integrin adhesion complexes undergo dynamic changes. Here we show that Kindlin-3, a main activator and binding partner of integrins in hematopoietic cells, can be cleaved by calpain in an activation-dependent manner. This calpain-mediated cleavage occurs in platelets and leukocytes as well as in endothelial cells. We determined the calpain I cleavage site in Kindlin-3 at tyrosine Y373 in the N-terminal part of Kindlin-3 PH domain. Expression of calpain-resistant Y373N mutant of Kindlin-3 promotes stronger cell adhesion to extracellular matrix under flow as well as to activated endothelium. In contrast, Y373N mutation in Kindlin-3 hinders cell migration. Mechanistically, calpain-resistant Y373N mutant of Kindlin-3 exhibited an activation-independent association with β integrin cytoplasm domain. Thus, cleavage of Kindlin-3 by calpain controls the dynamics of integrin- Kindlin-3 interaction and as a result, integrin-dependent adhesion and migration of hematopoietic cells. This represents a novel mechanism regulating reversibility of integrin adhesion complexes in leukocytes, which, in turn, is critical for their successful transmigration through the extracellular matrix.
    Journal of Biological Chemistry 09/2012; 287(47). DOI:10.1074/jbc.M112.380469 · 4.57 Impact Factor
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    Bethany A Kerr · Tatiana V Byzova
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    ABSTRACT: A new mechanism regulating pathological angiogenesis has been identified that involves the activation of ataxia-telangiectasia mutated (Atm) kinase in response to reactive oxygen species. Importantly, this Atm-dependent pathway is specifically activated in pathological, but not in normal, angiogenesis, suggesting that it could be therapeutically targeted in diseases associated with pathological angiogenesis (pages 1208-1216).
    Nature medicine 08/2012; 18(8):1184-5. DOI:10.1038/nm.2881 · 27.36 Impact Factor
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    A Goc · J Liu · T V Byzova · P R Somanath
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    ABSTRACT: Activation of Akt and increased expression of integrin β(3) are the two most important changes that have been linked to the attainment of metastatic potential by prostate cancer cells. However, a direct link between Akt activity and inside-out activation of integrin β(3) in mediating prostate cancer cell metastatic properties is not established. Using functional and biochemical approaches, we examined the role of Akt1 in the affinity modulation of integrin β(3) in prostate cancer cells. Although expression of murine TRAMP and human PC3 cells with constitutively active Akt1 (CA-Akt1) enhanced their affinity for integrin α(v)β(3) specific ligands and motility on various extracellular matrix proteins, the reverse was observed with the expression of dominant-negative Akt1 (DN-Akt1). Although enhanced motility and transendothelial migration of CA-Akt1-expressing cells were blunted by co-expression with DN-integrin β(3) or upon pre-treatment with integrin β(3)-blocking antibodies (LM 609), impaired motility and transendothelial migration of DN-Akt1-expressing cells were rescued by pre-treatment of prostate cancer cells with integrin β(3)-activating antibodies, AP7.4. Our data is the first to demonstrate a link between Akt1 activity and affinity modulation of integrin β(3) in the regulation of prostate cancer cell motility, transendothelial migration and chemotaxis to metastatic stimuli.
    British Journal of Cancer 07/2012; 107(4):713-23. DOI:10.1038/bjc.2012.295 · 4.84 Impact Factor
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    ABSTRACT: Akt, a serine-threonine protein kinase, exists as three isoforms. The Akt signaling pathway controls multiple cellular functions in the cardiovascular system, and the atheroprotective endothelial cell-dependent role of Akt1 has been recently demonstrated. The role of Akt3 isoform in cardiovascular pathophysiology is not known. We explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Using hyperlipidemic ApoE(-/-) mice, we demonstrated a macrophage-dependent, atheroprotective role for Akt3. In vitro experiments demonstrated differential subcellular localization of Akt1 and Akt3 in macrophages and showed that Akt3 specifically inhibits macrophage cholesteryl ester accumulation and foam cell formation, a critical early event in atherogenesis. Mechanistically, Akt3 suppresses foam cell formation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway. These studies demonstrate the nonredundant atheroprotective role for Akt3 exerted via the previously unknown link between the Akt signaling pathway and cholesterol metabolism.
    Cell metabolism 05/2012; 15(6):861-72. DOI:10.1016/j.cmet.2012.04.020 · 17.57 Impact Factor

Publication Stats

4k Citations
714.31 Total Impact Points


  • 2004–2015
    • Lerner Research Institute
      Cleveland, Ohio, United States
  • 2012
    • University of Georgia
      Атина, Georgia, United States
  • 2005–2012
    • Cleveland Clinic
      • Department of Molecular Cardiology
      Cleveland, Ohio, United States
  • 2004–2007
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 2003
    • Kemerovo Cardiology Centre
      Shcheglovsk, Kemerovo, Russia
    • Texas Heart Institute
      Houston, Texas, United States
  • 2002
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia