A Inbal

Tel Aviv University, Tell Afif, Tel Aviv, Israel

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Publications (83)391.01 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the study was to further investigate the role of fibrinogen-like protein 2 (FGL-2), a transmembrane prothrombinase that directly cleaves prothrombin to thrombin, in angiogenesis and tumor development and the mechanism(s) underlying these processes. To study angiogenesis HUVEC clones with decreased fgl-2 mRNA were generated by specific siRNA. To study tumorigenesis SCID mice were implanted with intact (wild type) and fgl-2-silenced PC-3 clones. IFN-γ treated HUVEC expressing increased fgl-2 mRNA exhibited significant capillary sprouting that was not inhibited by hirudin, whereas fgl-2 silencing completely inhibited blood-vessel formation. Tumors (poorly differentiated carcinoma) developed in all 12 mice injected with wild type PC-3 compared with 8/12 mice injected with the fgl-2-silenced PC-3 clone. The tumors developed by fgl-2-silenced PC-3 clones were smaller and less aggressive and contained significantly fewer blood vessels (p<0.05). All tumors' sections were negative for thrombin staining, indicating that FGL-2-induced tumorigenesis was not mediated by thrombin. In fgl-2-silenced tumors there was a decrease in fgl-2 mRNA (p=0.02) and ERK1/2 phosphorylation (p<0.05) by 80% and a 20%, respectively. The mechanism underlying these processes, studied in PC-3 clones, revealed that fgl-2 silencing was associated with a 65% decrease in FGF-2 mRNA (p<0.01) and a 30% down regulation of ERK1/2 phosphorylation (p<0.05). Together, these results suggest that FGL-2 mediates angiogenesis and tumorigenesis not by thrombin-mediated mechanism but rather through FGF-2/ERK signaling pathway. FGL-2 may serve as a valuable therapeutic target in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Thrombosis Research 12/2014; · 3.13 Impact Factor
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    ABSTRACT: A 75 year old patient presenting with mucocutaneous bleeding was diagnosed with acquired thrombasthenia. The diagnosis was based on lack of platelet aggregation with adenosine diphosphate (ADP), arachidonic acid and collagen, and normal aggregation induced by ristocetin.
    The Israel Medical Association journal: IMAJ 05/2014; 16(5):307-10. · 0.98 Impact Factor
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    ABSTRACT: Fibrinogen-like protein 2, FGL-2, was reported to be overexpressed in various cancer tissues, where it acts as a transmembrane prothrombinase. This study aims to determine the prothrombinase activity of FGL-2 in peripheral blood mononuclear cells (PBMC) of patients with B-cell lymphoma. FGL-2 activity was determined in patients with B-cell lymphoma (n = 53), and healthy controls (n = 145). FGL-2 activity in patients at diagnosis increased 3±0.3 fold (p<0.001). Sensitivity and specificity of the test was established at 73.6% and 80.7%, respectively, using a cutoff of 150% activity over control. Moreover, FGL-2 activity in 10 of 11 patients in remission decreased by 76%. In contrast, no significant difference was observed in expression levels of fgl-2 gene in patients and controls. Taken together, our study indicates that FGL-2 prothrombinase activity in PBMC of lymphoma patients is increased in active disease and normalizes during remission, thus being a potential marker for follow up of lymphoma patients.
    PLoS ONE 01/2014; 9(10):e109648. · 3.53 Impact Factor
  • The Israel Medical Association journal: IMAJ 01/2014; 16(1):61-2. · 0.98 Impact Factor
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    ABSTRACT: BACKGROUND: Factor XIII (FXIII), a plasma pro-transglutaminase, consists of two A subunits and two B subunits (FXIIIA2B2). Following activation by thrombin, it cross-links fibrin chains at the final step of coagulation. We previously reported that FXIII subunit A (FXIIIA) serves as a protein disulfide isomerase (PDI), and that PDI promotes platelet adhesion and aggregation. OBJECTIVE: This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. METHODS: Ex vivo experiments: Blood platelets derived from five patients with hereditary FXIIIA deficiency before and after treatment with Fibrogammin-P (FXIIIA2B2 concentrate) were washed and incubated on immobilized fibrinogen. Bound platelets were stained and counted by microscopy. In vitro experiments: Platelets derived from patients before treatment and five healthy controls were washed and analyzed for adhesion in the presence or absence of Fibrogammin-P or recombinant FXIII (FXIIIA2 concentrate). RESULTS: In ex vivo experiments, one hour after Fibrogammin-P treatment, mean (±SEM) platelet adhesion to fibrinogen increased by 27±2.32% (p<0.001). In in vitro experiments, treatment with Fibrogammin-P or recombinant FXIII (10IU/mL each) enhanced platelet adhesion to fibrinogen (in patients, by 29.95±6.7% and 29.05±5.3%, respectively; in controls, by 26.06±3.24% and 26.91±4.72, respectively; p<0.04 for all). Iodoacetamide-treated FXIII (I-FXIII), where transglutaminase activity is blocked, showed similar enhanced adhesion as untreated FXIII. By contrast, addition of an antibody that specifically blocks FXIIIA-PDI activity inhibited FXIII-mediated platelet adhesion to fibrinogen by 65%. CONCLUSION: These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.
    Thrombosis Research 12/2012; · 3.13 Impact Factor
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    ABSTRACT: The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) has been shown to synergize doxorubicin (Dox) anticancer activity while attenuating its cardiotoxicity. In this study we further explored the selectivity of AN-7's action in several cancer and normal cells treated with anticancer agents. The cells studied were murine mammary 4T1, human breast T47D and glioblastoma U251 cancer cell lines, neonatal rat cardiomyocytes, cardiofibroblasts and astrocytes, and immortalized cardiomyocyte H9C2 cells. Cell death, ROS production and changes in protein expression were measured and in vivo effects were evaluated in Balb-c mice. AN-7 synergized Dox and anti-HER2 cytotoxicity against mammary carcinoma cells with combination indices of 0.74 and 0.79, respectively, while it protected cardiomyocytes against their toxicity. Additionally AN-7 protected astrocytes from Dox-cytoxicity. Cell-type specific changes in the expression of proteins controlling survival, angiogenesis and inflammation by AN-7 or AN-7+Dox were observed. In mice, the protective effect of AN-7 against Dox cardiotoxicity was associated with a reduction in inflammatory factors. In summary, AN-7 augmented the anticancer activity of Dox and anti-HER2 and attenuated their toxicity against normal cells. AN-7 modulation of c-Myc, thrombospondin-1, lo-FGF-2 and other proteins were cell type specific. The effects of AN-7, Dox and their combination were preserved in vivo indicating the potential benefit of combining AN-7 and Dox for clinical use.
    Investigational New Drugs 02/2012; 30(1):130-43. · 3.50 Impact Factor
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    ABSTRACT: The histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) synergizes the cytotoxic effect of doxorubicin (Dox) and anti-HER2 on mammary carcinoma cells while protecting normal cells against their insults. This study investigated the concomitant changes occurring in heart tissue and tumors of mice bearing a subcutaneous 4T1 mammary tumor following treatment with AN-7, Dox, or their combination. Dox or AN-7 alone led to inhibition of both tumor growth and lung metastases, whereas their combination significantly increased their anticancer efficacy and attenuated Dox- toxicity. Molecular analysis revealed that treatment with Dox, AN-7, and to a greater degree, AN-7 together with Dox increased tumor levels of γH2AX, the marker for DNA double-strand breaks and decreased the expression of Rad51, a protein needed for DNA repair. These events culminated in increased apoptosis, manifested by the appearance of cytochrome-c in the cytosol. In the myocardium, Dox-induced cardiomyopathy was associated with an increase in γH2AX expression and a reduction in Rad51 and MRE11 expression and increased apoptosis. The addition of AN-7 to the Dox treatment protected the heart from Dox insults as was manifested by a decrease in γH2AX levels, an increase in Rad51 and MRE11 expression, and a diminution of cytochrome-c release. Tumor fibrosis was high in untreated mice but diminished in Dox- and AN-7-treated mice and was almost abrogated in AN-7+Dox-treated mice. By contrast, in the myocardium, Dox alone induced a dramatic increase in fibrosis, and AN7+Dox attenuated it. The high expression levels of c-Kit, Ki-67, c-Myc, lo-FGF, and VEGF in 4T1 tumors were significantly reduced by Dox or AN-7 and further attenuated by AN-7+Dox. In the myocardium, Dox suppressed these markers, whereas AN-7+Dox restored their expression. In conclusion, the combination of AN-7 and Dox results in two beneficial effects, improved anticancer efficacy and cardioprotection.
    PLoS ONE 01/2012; 7(2):e31393. · 3.53 Impact Factor
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    ABSTRACT: Acquired thrombotic thrombocytopenic purpura (TTP) is an uncommon disease in adults, characterized by fever, neurological manifestations, microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, and the presence of antibodies against the enzyme ADAMTS13. Treatment with plasmapheresis has increased the survival from 10% to more than 90%. Still, there is a subset of patients with resistant TTP who fail to respond to plasmapheresis or remain dependent on this procedure. There is mounting evidence that rituximab may play an important role in remission induction of resistant/relapsing TTP, but the extent of the remission is unknown. We present here four patients with chronic-relapsing TTP who responded favorably to rituximab. All four patients achieved prolonged remission of 23 to 82 months after the treatment. One patient relapsed 6 years afterthe initial treatment with rituximab and re-entered remission following retreatment.
    The Israel Medical Association journal: IMAJ 07/2011; 13(7):398-401. · 0.98 Impact Factor
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    ABSTRACT: Tissue transglutaminase was reported to act as protein disulfide isomerase (PDI). We studied whether plasma transglutaminase - coagulation factor XIII (FXIII) - has PDI activity as well. PDI activity was measured by determining the ability to renature reduced-denatured RNase (rdRNase). We found that FXIII can renature rdRNase, with efficiency comparable to commercial PDI. This PDI activity was inhibited by bacitracin. Like tissue transglutaminase, FXIII-mediated PDI activity is independent of its transglutaminase activity and is located on the A subunit. Surface-associated PDI has been previously shown to catalyse two distinct functions: transnitrosation with subsequent release of intracellular nitric oxide and disulfide bond rearrangement during platelet integrin ligation. Our results imply that FXIII-PDI activity may have a role in platelet function.
    Thrombosis and Haemostasis 06/2009; 101(5):840-4. · 5.76 Impact Factor
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    ABSTRACT: During the haemostatic response, the formation of a primary platelet plug limits bleeding and provides a surface for clotting factors to assemble and become activated. The initial platelet plug is stabilized by fibrin monomers, covalently cross-linked by FXIII, forming a platelets-fibrin thrombus. Defects in platelets as well as inherited deficiencies of coagulation factors including fibrinogen, FII, FV, FV + FVIII, FVII, FX, FXI and FXIII deficiencies, generally lead to lifelong bleeding disorders, whose severity of bleeding symptoms is heterogeneous in platelets abnormalities but generally inversely proportional to the degree of the factor deficiency in rare bleeding disorders (RBDs). The prevalence of platelet defects among the general population has not been established, whereas for RBDs it ranges from approximately 1 in 2 million to 1 in 500,000, being higher in countries where consanguineous marriages are diffused. As a consequence of the rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects, and the actual management of bleeding episodes are not well established. In this review the main features, diagnosis, available treatment options and treatment complications of the platelet disorders, caused by abnormalities in platelet receptors for adhesive proteins, platelet receptors for soluble agonists, platelet granules, signal transduction pathways, or procoagulant phospholipids will be discussed by Dr Cattaneo, whereas fibrinogen deficiency and FXIII deficiency will be described by Dr Inbal and Dr de Moerloose, respectively. Finally, the update of the Rare Bleeding Disorders Database will be presented by Dr Spreafico.
    Haemophilia 08/2008; 14 Suppl 3:202-10. · 3.17 Impact Factor
  • Haemophilia 06/2008; 14(3):621-4. · 3.17 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitory prodrugs that are metabolized to butyric acid and formaldehyde possess antineoplastic properties and low toxicity. We sought to characterize the antiangiogenic and antimetastatic activities of two lead prodrugs, pivaloyloxymethyl butyrate (AN-9) and butyroyloxymethyl-diethyl phosphate (AN-7) in murine cancer models. In the sc implanted human colon carcinoma HT-29 xenograft model AN-7, exhibited superior anticancer activity compared to AN-9, as was evident by the significantly greater inhibition of tumor growth and reduction of serum CEA. AN-7 was also more effective in reducing mean vessel density (MVD) by 7-fold, bFGF, Ki-67 (7-fold) and HIF-1alpha in immunohistochemically stained tumor sections. Semi-quantitative evaluation of the levels of bFGF, HDAC1 and HIF-1alpha by Western blot analysis showed a decrease in expression only in the tumors of mice treated with AN-7. The level of bFGF was reduced 3-fold in the tumor and that of TIMP1 was elevated (by 3-fold) in the serum of AN-7 treated mice. In a 4T1 metastatic breast carcinoma model, AN-7 inhibited the formation of lung lesions by 76% and AN-9 by 47%, further demonstrating the greater efficacy of AN-7 compared to AN-9 (P<0.02). Both AN-7 and AN-9 exhibited antimetastatic and antiangiogenic activities by reducing vascularization, bFGF expression and HIF-1alpha. Yet, AN-7 was more potent than AN-9.
    Clinical and Experimental Metastasis 05/2008; 25(7):703-16. · 3.46 Impact Factor
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    ABSTRACT: Factor XIII is a plasma transglutaminase that participates in the final stage of the coagulation cascade. Thrombin-activated FXIII (FXIIIa) catalyzes the formation of covalent crosslinks between gamma-glutamyl and epsilon-lysyl residues on fibrin molecules to yield the mature clot. In addition to its role in hemostasis, FXIIIa was previously shown by us to stimulate endothelial cells to exhibit pro-angiogenic activity. In this work, we studied the effect of FXIIIa on other cells that participate in angiogenesis and tissue repair, such as monocytes and fibroblasts. FXIIIa significantly enhanced migration and proliferation, and inhibited apoptosis of monocytes and fibroblasts. Similar to our previous observations with endothelial cells, the stimulating effect of FXIIIa on monocytes and fibroblasts was elicited via its binding to alpha (v)beta (3) integrin leading to cJun upregulation and TSP-1 downregulation. Since monocytes and fibroblasts are essential components of the tissue repair process, the results of this study, together with the proangiogenic activity of FXIIIa, further substantiate a significant role of FXIII in tissue repair.
    Cellular Physiology and Biochemistry 02/2007; 19(1-4):113-20. · 3.42 Impact Factor
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    ABSTRACT: Hereditary thrombocythaemia (HT) is an inherited autosomal dominant disorder. Recent studies reported six different mutations, four within the thrombopoietin (TPO) gene and two within c-Mpl (TPO receptor) gene in six unrelated families with HT. This study investigated the molecular basis of hereditary thrombocythaemia in an Israeli-Jewish family. We screened the genes for TPO and c-Mpl by amplification and sequencing of all the corresponding exons including exon/intron boundaries and promoters. In addition, plasma levels of TPO and erythropoietin (EPO) were measured. No abnormality in the TPO/c-Mpl genes has been identified in affected HT family members. Plasma TPO and EPO levels were found to be normal/low or normal respectively in the individuals affected. In conclusion, lack of a molecular lesion within either TPO or cMpl genes indicate that HT may be caused by factors other than TPO-cMpl axis in this family.
    British Journal of Haematology 12/2006; 135(3):348-51. · 4.94 Impact Factor
  • Rima Dardik, Aida Inbal
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    ABSTRACT: We have recently demonstrated that thrombin-activated FXIII (FXIIIA-subunit), a plasma transglutaminase, activates VEGFR-2 by crosslinking it with the alpha(v)beta(3) integrin on the surface of endothelial cells (EC), thereby stimulating angiogenesis. Tissue transglutaminase (tTG), which is functionally and structurally related to FXIIIA, is expressed by numerous cell types, among them EC. However, its role in EC function has not been fully characterized. In the present study, we investigated the potential involvement of tTG in angiogenesis. Using co-immunoprecipitation and immunofluorescent staining experiments, we observed that tTG forms a complex with VEGFR-2 on the cell surface and within the cytoplasm of EC. Stimulation of EC with VEGF resulted in translocation of the tTG-VEGFR-2 complex from the cytoplasm to the nucleus. In VEGF-treated cells, tTG-VEGFR-2 interaction resulted in incorporation of VEGFR-2 into high molecular weight crosslinked complex (es), as revealed by an antibody against gamma-glutamyl-epsilon-lysine isopeptide bond. tTG -VEGFR-2 association was inhibited by a specific VEGFR-2 protein tyrosine kinase inhibitor (PTKI ), as well as by cystamine, inhibitor of the transglutaminase activity of tTG, but not by bacitracin which inhibits the protein-disulfide isomerase (PDI) activity of tTG. Furthermore, cystamine completely abolished the VEGF-induced nuclear translocation of the tTG-VEGFR-2 complex. Blockade of the crosslinking activity of tTG by cystamine enhanced VEGF-induced migration of EC in Boyden chamber by 31% (P < 0.02), and prolonged VEGF-induced signaling response, as demonstrated by sustained activation of the MAP kinase ERK. Taken together, our findings suggest that endothelial cell tTG might be involved in modulation of the cellular response to VEGF by forming an intracellular complex with VEGFR-2, and mediating its translocation into the nucleus upon VEGF stimulation.
    Experimental Cell Research 10/2006; 312(16):2973-82. · 3.56 Impact Factor
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    ABSTRACT: To compare the effect of aspirin and enoxaparin on live births in women with unexplained recurrent miscarriages, as well as secondary outcomes including birth weight, uterine and umbilical blood flows, and congenital malformations. Multicenter randomized comparative cohort study. Four centers including two university hospitals, a peripheral general hospital, and a community health clinic. One hundred seven patients were randomized, 104 were available for analysis; 54 were randomized to enoxaparin and 50 to aspirin. Treatment with enoxaparin or aspirin in subsequent pregnancy. Subsequent live births or miscarriage, and the incidence of obstetric complications. Both groups had a similar live birth rate (relative risk = 0.92, 95% confidence interval: 0.58-1.46). In primary aborters, live births occurred in 17 of 18 (94%) enoxaparin-treated pregnancies compared to 18 of 22 (81%) aspirin-treated pregnancies. In the aspirin group, two pregnancies were terminated: for tricuspid insufficiency and for hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome. One enoxaparin-treated infant was growth restricted (2,020 g) at 36 weeks. Preeclampsia was found in three aspirin-treated patients. Preterm delivery, placental Doppler blood flow, apgar scores, and mean birth weights were similar in both groups. In the aspirin group, one infant underwent orchidectomy after testicular torsion in utero, and one infant had hypoglycemia and convulsions. Both regimens were associated with a high live birth rate and few late pregnancy complications.
    Fertility and sterility 09/2006; 86(2):362-6. · 3.97 Impact Factor
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    ABSTRACT: Thrombin-activated Factor XIII (FXIIIa), a plasma transglutaminase, stabilizes fibrin clots by crosslinking fibrin chains. FXIIIa was previously shown by us to exhibit proangiogenic activity associated with downregulation of thrombospondin-1, phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2), and upregulation of c-Jun. In the current study, we evaluated the proangiogenic effect of FXIIIa in two murine models: a neonatal heterotopic cardiac allograft model in normal mice, and a Matrigel plug model in FXIII-deficient mice. In the neonatal cardiac allograft model, the number of new vessels as well as graft viability (contractile performance) was significantly higher in FXIIIa-injected animals than in controls. A significant increase in the level of c-Jun mRNA and a significant decrease in the level of TSP-1 mRNA were observed in heart allografts treated with FXIIIa. A marked decrease in TSP-1 protein expression was observed within the endothelial cells of hearts treated with FXIIIa. In the Matrigel plug model, FXIII-deficient mice showed a significantly decreased number of new vessels compared to that of the control mice, and the number of vessels almost reached normal levels following addition of FXIIIa. The results of this study provide substantial in vivo evidence for the proangiogenic activity of FXIIIa.
    Thrombosis and Haemostasis 04/2006; 95(3):546-50. · 5.76 Impact Factor
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    ABSTRACT: Four missense mutations in the factor XIII A-subunit gene, Arg260Leu, Ala318Val, Thr398Asn and Gly210Arg, were previously reported by us in patients with severe factor XIII deficiency. The objective of our study was to discern the effect of all four mutations on the stability and intracellular localization of the factor XIII A-subunit by their expression in COS cells. In-vitro mutagenesis, transient expression of the mutants in COS cells and subsequent pulse-chase analyses were carried out. Intracellular localization of wild-type and mutant proteins was analyzed by immunohistochemistry using a monoclonal antibody against factor XIII A-subunit. Pulse-chase analyses of metabolically labeled proteins demonstrated rapid intracellular degradation of each mutant protein as compared with wild type. Immunocytochemical and immunofluorescence analyses disclosed that wild-type and all four mutant factor XIII A-subunit proteins were diffusely distributed within the cytoplasm but not in the endoplasmic reticulum of the COS-7 cells. The Arg260Leu, Ala318Val, Thr398Asn and Gly210Arg mutations in FXIII A-subunit cause rapid intracellular degradation of the corresponding mutated protein.
    Blood Coagulation and Fibrinolysis 04/2006; 17(2):125-30. · 1.25 Impact Factor
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    R Dardik, J Loscalzo, A Inbal
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    ABSTRACT: Factor XIII is a plasma transglutaminase that participates in the final stage of the coagulation cascade. Thrombin-activated FXIII (FXIIIa) catalyzes the formation of covalent cross-links between gamma-glutamyl and epsilon-lysyl residues on adjacent fibrin chains in polymerized fibrin to yield the mature clot. In addition to its role in hemostasis, FXIII is known to participate in wound healing and embryo implantation, which are processes involving angiogenesis. In this review, we discuss the role of FXIII in angiogenesis and the molecular mechanisms underlying its proangiogenic effects. The FXIII role in tissue repair and remodeling may at least in part be attributed to its pro-angiogenic activity.
    Journal of Thrombosis and Haemostasis 02/2006; 4(1):19-25. · 6.08 Impact Factor
  • Aida Inbal, Rima Dardik
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    ABSTRACT: Factor FXIII (FXIII) is a plasma transglutaminase that catalyzes the cross link formation between fibrin chains to stabilize the clot. Beside it s function in hemostasis FXIII has a role in wound healing and embryo implantation--processes that involve angiogenesis. In this review we discuss the role of FXIII in angiogenesis and the molecular mechanisms underlying its pro-angiogenic effect. In addition, FXIII role in wound repair is discussed.
    Pathophysiology of Haemostasis and Thrombosis 02/2006; 35(1-2):162-5. · 2.23 Impact Factor

Publication Stats

1k Citations
391.01 Total Impact Points


  • 1993–2014
    • Tel Aviv University
      • • Felsenstein Medical Research Center
      • • Goldschleger Eye Research Institute
      Tell Afif, Tel Aviv, Israel
  • 2001–2009
    • Rabin Medical Center
      Tell Afif, Tel Aviv, Israel
  • 1994–2007
    • Sheba Medical Center
      • Department of Pathology
      Gan, Tel Aviv, Israel
  • 2004
    • Ministry of Health (Israel)
      Yerushalayim, Jerusalem District, Israel
  • 1989–1990
    • Brigham and Women's Hospital
      • Division of Hematology
      Boston, MA, United States
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States