Yuval Shaked

Technion - Israel Institute of Technology, H̱efa, Haifa, Israel

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Publications (96)727.05 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pressure overload induces adaptive remodeling processes in the heart. However, when pressure overload persists, adaptive changes turn into maladaptive alterations leading to cardiac hypertrophy and heart failure. ATF3 is a stress inducible transcription factor that is transiently expressed following neuroendocrine stimulation. However, its role in chronic pressure overload dependent cardiac hypertrophy is currently unknown. The objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes. Pressure overload was induced by phenylephrine (PE) mini-osmotic pumps in various mice models of whole body, cardiac specific, bone marrow (BM) specific and macrophage specific ATF3 ablations. We show that ATF3-KO mice exhibit a significantly reduced expression of cardiac remodeling markers following chronic pressure overload. Consistently, the lack of ATF3 specifically in either cardiomyocytes or BM derived cells blunts the hypertrophic response to PE infusion. A unique cross-talk between cardiomyocytes and macrophages was identified. Cardiomyocytes induce an ATF3 dependent induction of an inflammatory response leading to macrophage recruitment to the heart. Adoptive transfer of wild type macrophages, but not ATF3-KO derived macrophages, into wild type mice potentiates maladaptive response to PE infusion. Collectively, this study places ATF3 as a key regulator in promoting pressure overload induced cardiac hypertrophy through a cross-talk between cardiomyocytes and macrophages. Inhibiting this cross-talk may serve as a useful approach to blunt maladaptive remodeling processes in the heart. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 07/2015; 198:232-240. DOI:10.1016/j.ijcard.2015.06.099 · 6.18 Impact Factor
  • 05/2015; 02(999):1-1. DOI:10.2174/2212697X02666150511203657
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    ABSTRACT: Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here we show that the pro-inflammatory cytokine, IL-1β, is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL-1β, or its receptor, using either genetic or pharmacologic approach, results in slightly retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL-1 receptor antagonist, Anakinra, exhibit increased number of M2 macrophages and vessel leakiness when compared to paclitaxel monotherapy treated mice, indicating a pro-metastatic role of M2 macrophages in the IL-1β-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL-1 pathway on tumor growth. Accordingly, treatments using 'add-on' drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 04/2015; 14(6). DOI:10.1158/1535-7163.MCT-14-0969 · 6.11 Impact Factor
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    ABSTRACT: Unbiased proteomic analysis of plasma samples holds the promise to reveal clinically invaluable disease biomarkers. However the tremendous dynamic range of the plasma proteome has so far hampered the identification of such low abundant markers. To overcome this challenge we analyzed the plasma microparticle proteome, and reached an unprecedented depth of over 3,000 plasma proteins in single runs. To add a quantitative dimension, we developed PROMIS-Quan PROteomics of MIcroparticles with Super-SILAC Quantification, a novel mass spectrometry-based technology for plasma microparticle proteome quantification. PROMIS-Quan enables a two step relative and absolute SILAC quantification. First, plasma microparticle proteomes are quantified relative to a super-SILAC mix composed of cell lines from distinct origins. Next, the absolute amounts of selected proteins of interest are quantified relative to the super-SILAC mix. We applied PROMIS-Quan to prostate cancer and compared plasma microparticle samples of healthy individuals and prostate cancer patients. We identified in total 5,374 plasma-microparticle proteins, and revealed a predictive signature of 3 proteins that were elevated in the patient-derived plasma microparticles. Finally, PROMIS-Quan enabled determination of the absolute quantitative changes in prostate specific antigen (PSA) upon treatment. We propose PROMIS-Quan as an innovative platform for biomarker discovery, validation and quantification in both the biomedical and in the clinical worlds. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Molecular &amp Cellular Proteomics 01/2015; 14(4). DOI:10.1074/mcp.M114.043364 · 7.25 Impact Factor
  • Ofrat Beyar Katz · Yuval Shaked
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    ABSTRACT: There are several approaches for the management of malignant disease. However, tumor resistance to therapy is still a major challenge in the clinic. Efflux transporters, genetic responses and enzyme activity in tumor cells are examples of the main modalities that account for resistance to therapy. In addition, emerging evidence suggests that the host also plays a significant role in promoting therapy resistance. Recruitment of different host cell types to the treated tumor site occurs in response to a range of therapies, including chemotherapy, radiation, surgery and even targeted drugs. This host response may have a protective effect on the tumor cells, not only negating anti-tumor activity, but also promoting a resistant tumor. In this review we focus on host-tumor interactions leading to therapy resistance with special emphasis on different host cells and secreted factors within the tumor microenvironment. The development of novel inhibitors that block the host response to therapy could be used as a treatment strategy to enhance therapy outcomes and survival.
    Drug Resistance Updates 12/2014; 19. DOI:10.1016/j.drup.2014.12.002 · 8.82 Impact Factor
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    ABSTRACT: The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.
    ecancermedicalscience 09/2014; 8:463. DOI:10.3332/ecancer.2014.463 · 1.20 Impact Factor
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    ABSTRACT: Acute chemotherapy can induce rapid bone-marrow derived pro-angiogenic cell (BMDC) mobilization and tumor homing, contributing to tumor regrowth. In order to study the contribution of tumor cells to tumor regrowth following therapy, we focused on tumor-derived microparticles (TMPs). EMT/6 murine-mammary carcinoma cells exposed to paclitaxel chemotherapy exhibited an increased number of TMPs and significantly altered their angiogenic properties. Similarly, breast cancer patients had increased levels of plasma MUC-1+TMPs following chemotherapy. In addition, TMPs from cells exposed to paclitaxel induced higher BMDC mobilization and colonization but had no increased effect on angiogenesis in Matrigel plugs and tumors than TMPs from untreated cells. Since TMPs abundantly express osteopontin, a protein known to participate in BMDC trafficking, the impact of osteopontin-depleted TMPs on BMDC mobilization, colonization, and tumor angiogenesis was examined. While EMT/6 tumors grown in mice inoculated with osteopontin-depleted TMPs had lower numbers of BMDC infiltration and microvessel density compared with EMT/6 tumors grown in mice inoculated with wild-type TMPs, no significant difference in tumor growth was seen between the two groups. However, when BMDCs from paclitaxel-treated mice were injected into wild-type EMT/6-bearing mice, a substantial increase in tumor growth and BMDC infiltration was detected compared to osteopontin-depleted EMT/6-bearing mice injected with BMDCs from paclitaxel-treated mice. Collectively, our results suggest that osteopontin expressed by TMPs play an important role in BMDC mobilization and colonization of tumors, but is not sufficient to enhance the angiogenic activity of BMDCs in tumors. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 07/2014; 135(2). DOI:10.1002/ijc.28678 · 5.01 Impact Factor
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    ABSTRACT: Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2 mg and lenalidomide 10 mg for 21 days/28 in CMML (n = 12) and higher risk MDS (n = 8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays occurred were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. Conclusions: Lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.
    Leukemia research 07/2014; 38(7). DOI:10.1016/j.leukres.2014.03.022 · 2.69 Impact Factor
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    ABSTRACT: Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses - called metronomic chemotherapy (MC) - has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.
    Neoplasia (New York, N.Y.) 06/2014; 16(6). DOI:10.1016/j.neo.2014.05.011 · 5.40 Impact Factor
  • Cancer Research 05/2014; 73(3 Supplement):B59-B59. DOI:10.1158/1538-7445.TIM2013-B59 · 9.28 Impact Factor
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    ABSTRACT: Tumor derived microparticles (TMPs) have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs). Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.
    PLoS ONE 04/2014; 9(4):e95983. DOI:10.1371/journal.pone.0095983 · 3.23 Impact Factor
  • Tali Voloshin · Ella Fremder · Yuval Shaked
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    ABSTRACT: A wide spectrum of both normal and diseased cell types shed extracellular vesicles that facilitate intercellular communication without direct cell-to-cell contact. Microparticles (MPs) are a subtype of extracellular vesicles that participate in multiple biological processes. They carry abundant bioactive molecules including different forms of nucleic acids and proteins that can markedly modulate cellular behavior. MPs are involved in several hallmarks of cancer such as drug resistance, thrombosis, immune evasion, angiogenesis, tumor invasion and metastasis. Such MPs originate from either cancer or other host cells. As MPs are secreted and can be detected in various body fluids, they can be used as potential diagnostic and prognostic biomarkers as well as vehicles for delivery of cytotoxic drugs. This review summarizes accumulating evidence on the biological properties of MPs in cancer, with reference to their potential usage in clinical settings.
    Cancer Microenvironment 04/2014; 7(1-2). DOI:10.1007/s12307-014-0144-8
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    ABSTRACT: Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses – called metronomic chemotherapy (MC) – has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.
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    ABSTRACT: We previously reported that the host response to certain chemotherapies can induce primary tumor regrowth, angiogenesis, and even metastases in mice, but the possible impact of anti-vascular endothelial growth factor-A (VEGF-A) therapy in this context has not been fully explored. We therefore used combinations of anti-VEGF-A with chemotherapy on various tumor models in mice including primary tumors, experimental lung metastases, and spontaneous lung metastases of 4T1-breast and CT26-colon murine cancer cell lines. Our results show that a combined treatment with anti-VEGF-A and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX) but not with anti-VEGF-A and gemcitabine/cisplatinum (Gem/CDDP) enhances the treatment outcome partly due to reduced angiogenesis, in both primary tumors and in experimental lung metastases models. However, neither treatment group exhibited an improved treatment outcome in the spontaneous lung metastases model nor were changes in endothelial cell numbers found at metastatic sites. Since chemotherapy has recently been shown to induce tumor cell invasion, we tested the invasion properties of tumor cells when exposed to plasma from FOLFOX-treated mice or cancer patients. While plasma from FOLFOX-treated mice or patients induced invasion properties of tumor cells, the combination of anti-VEGF-A and FOLFOX abrogated these effects, despite the reduced plasma VEGF-A levels detected in FOLFOX-treated mice. These results suggest that the therapeutic impact of antiangiogenic drugs varies in different tumor models, and that anti-VEGF-A therapy can block the invasion properties of tumor cells in response to chemotherapy. These results may implicate an additional therapeutic role for anti-VEGF-A when combined with chemotherapy.
    Molecular Cancer Therapeutics 10/2013; 13(1). DOI:10.1158/1535-7163.MCT-13-0356 · 6.11 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):LB-343-LB-343. DOI:10.1158/1538-7445.AM2013-LB-343 · 9.28 Impact Factor
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    ABSTRACT: Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2 neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. ShRNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network forming ability of endothelial cells suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours, but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultra-sonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents was previously found to improve the delivery of chemotherapeutic agents into tumours, and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.
    Carcinogenesis 07/2013; 34(10). DOI:10.1093/carcin/bgt241 · 5.27 Impact Factor
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    ABSTRACT: In addition to its direct effects on tumor cells, chemotherapy can rapidly activate various host processes that contribute to therapy resistance and tumor regrowth. The host response to chemotherapy consists of changes in numerous cell types and cytokines. Examples include the acute mobilization and tumor homing of pro-angiogenic bone marrow-derived cells, activation of cells in the tumor microenvironment to produce systemic or paracrine factors, and tissue-specific responses that provide a protective niche for tumor cells. All of these factors reduce chemotherapy efficacy, and blocking the host response at various levels may therefore significantly improve treatment outcome. However, before the combination of conventional chemotherapy with agents blocking specific aspects of the host response can be implemented into clinical practice, a better understanding of the molecular mechanisms behind the host response is required.Oncogene advance online publication, 25 March 2013; doi:10.1038/onc.2013.94.
    Oncogene 03/2013; DOI:10.1038/onc.2013.94 · 8.56 Impact Factor
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    Tali Voloshin · Emile E Voest · Yuval Shaked
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    ABSTRACT: Almost any type of anti-cancer treatment including chemotherapy, radiation, surgery and targeted drugs can induce host molecular and cellular immunological effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome. Tumor relapse due to host immunological effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. This short review will describe the types of host cells that participate in this process, the types of factors secreted from the host following therapy that can promote tumor re-growth, and the possible implications of this unique and yet only partially-known process. It is postulated that blocking these specific immunological effects in the reactive host in response to cancer therapy may aid in identifying new host-dependent targets for cancer, which in combination with conventional treatments can prolong therapy efficacy and extend survival. Additional studies investigating this specific research direction - both in preclinical models and in the clinical setting - are essential in order to advance our understanding of how tumors relapse and evade therapy.
    Experimental Cell Research 03/2013; 319(11). DOI:10.1016/j.yexcr.2013.03.007 · 3.37 Impact Factor
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    ABSTRACT: Paclitaxel (PTX) and alendronate (ALN) are effective drugs used for the treatment of breast cancer bone metastases. Growing evidence suggests that low-dose taxanes and bisphosphonates possess anti-angiogenic properties. However, PTX is water-insoluble and toxic, even if administered at anti-angiogenic dosing schedule. Polymer conjugation of PTX will increase water-solubility and improve its pharmacokinetic profile directing it to the tumor site. We further propose to combine it with ALN for active bone targeting. We conjugated ALN and PTX with poly(ethylene glycol) (PEG) forming self-assembled micelles where PTX molecules are located at the inner core and the water-soluble ALN molecules at the outer shell. PTX-PEG-ALN micelles exhibited similar in vitro cytotoxic and anti-angiogenic activity as the free drugs. Biodistribution analysis demonstrated preferential tumor accumulation of FITC-labeled PTX-PEG-ALN micelles. Pharmacokinetic studies revealed longer t(1/2) of the conjugate than free PTX. PTX-PEG-ALN micelles achieved improved efficacy and safety profiles over free PTX in syngeneic and xenogeneic mouse models of mCherry-infected mammary adenocarcinoma in the tibia, as monitored intravitally non-invasively by a fluorescence imaging system. The described data warrants the potential use of PTX-PEG-ALN as bone-targeted anticancer and anti-angiogenic therapy for breast cancer bone metastases.
    Biomaterials 02/2013; 34(15). DOI:10.1016/j.biomaterials.2013.01.052 · 8.31 Impact Factor
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    F Bertolini · Y Shaked · P Mancuso
    British Journal of Cancer 02/2013; 108(6). DOI:10.1038/bjc.2012.528 · 4.82 Impact Factor

Publication Stats

4k Citations
727.05 Total Impact Points

Institutions

  • 2009–2015
    • Technion - Israel Institute of Technology
      H̱efa, Haifa, Israel
  • 2012
    • IEO - Istituto Europeo di Oncologia
      Milano, Lombardy, Italy
  • 2003–2011
    • University of Toronto
      • • Department of Medical Biophysics
      • • Department of Medicine
      • • Sunnybrook Health Sciences Centre
      Toronto, Ontario, Canada
  • 2010
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands
  • 2008
    • Memorial Sloan-Kettering Cancer Center
      • Department of Pediatrics
      New York, New York, United States
  • 2005–2008
    • Sunnybrook Health Sciences Centre
      • Division of Molecular and Cell Biology
      Toronto, Ontario, Canada