Efrat Assa-Kunik

Laniado Hospital, Natanya, Central District, Israel

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Publications (7)30.94 Total impact

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    ABSTRACT: Vascular diseases are a major cause of morbidity and mortality, particularly in diabetic patients. Stem/progenitor cell (SPCs) treatments with bone-marrow (BM)-derived cells show safety and promising outcomes, albeit not without some pre-procedural adverse events related to cell collection and mobilization. We describe a novel technology for generating a therapeutic population (BGC101) of enriched endothelial progenitor cells (EPCs) from unmobilized blood, using dendritic cells (DCs) to specifically direct SPC activity in vitro. Selected immature plasmacytoid and myeloid DCs from 24 healthy and 2 diabetic donors were activated with anti-inflammatory and pro-angiogenic molecules to induce specific activation signals. Co-culturing of activated DCs with SPCs for 12-66 hours generated 83.7 ± 7.4 × 10(6) BGC101 cells with 97% viability from 250 ml of blood. BGC101, comprising 52.4 ± 2.5% EPCs (expressing Ulex-lectin, AcLDL uptake, Tie2, vascular endothelial growth factor (VEGF) receptor 1 and 2, and CD31), 16.1 ± 1.9% SPCs (expressing CD34 and CD184), and residual B and T helper cells, demonstrated angiogenic and stemness potential and secretion of IL-8, IL-10, VEGF, and osteopontin. When administered to immunodeficient mice with limb ischemia (n = 40), BGC101 yielded a high safety profile and significantly increased blood perfusion, capillary density, and leg function after 21 days. Cell tracking and biodistribution showed that engraftment was restricted to the ischemic leg. These observations provide preliminary evidence that alternatively-activated DCs can promote the generation of EPC-enriched SPCs within a one-day culture. The resulting product BGC101 has the potential for treatment of various vascular conditions such as coronary heart disease, stroke and peripheral ischemia. This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2014 · Diabetes/Metabolism Research and Reviews
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    ABSTRACT: Selective degeneration of neuronal projections and neurite pruning are critical for establishment and maintenance of functional neural circuits in both insects and mammals. However, the molecular mechanisms that govern developmental neurite pruning versus injury-induced neurite degeneration are still mostly unclear. Here, we show that the effector caspases 6 and 3 are both expressed within axons and that, on trophic deprivation, they exhibit distinct modes of activation. Surprisingly, inhibition of caspases is not sufficient for axonal protection and a parallel modulation of a NAD(+)-sensitive pathway is required. The proapoptotic protein BAX is a key element in both pathways as its genetic ablation protected sensory axons against developmental degeneration both in vitro and in vivo. Last, we demonstrate that both pathways are also involved in developmental dendritic pruning in Drosophila. More specifically, the mouse Wld(S) (Wallerian degeneration slow) protein, which is mainly composed of the full-length sequence of the NAD(+) biosynthetic Nmnat1 enzyme, can suppress dendritic pruning in C4da (class IV dendritic arborization) sensory neurons in parallel to the fly effector caspases. These findings indicate that two distinct autodestruction pathways act separately or in concert to regulate developmental neurite pruning.
    Preview · Article · May 2010 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: The specification of polar, main-body and stalk follicle cells in the germarium of the Drosophila ovary plays a key role in the formation of the egg chamber and polarisation of its anterior-posterior axis. High levels of Notch pathway activation, resulting from a germline Delta ligand signal, induce polar cells. Here we show that low Notch activation levels, originating from Delta expressed in the polar follicle cells, are required for stalk formation. The metalloprotease Kuzbanian-like, which cleaves and inactivates Delta, reduces the level of Delta signaling between follicle cells, thereby limiting the size of the stalk. We find that Notch activation is required in a continuous fashion to maintain the polar and stalk cell fates. We further demonstrate that mutual antagonism between the Notch and JAK/STAT signaling pathways provides a crucial facet of follicle cell patterning. Notch signaling in polar and main-body follicle cells inhibits JAK/STAT signaling by preventing STAT nuclear translocation, thereby restricting the influence of this pathway to stalk cells. Conversely, signaling by JAK/STAT reduces Notch signaling in the stalk. Thus, variations in the levels of Notch pathway activation, coupled with a continuous balance between the Notch and JAK/STAT pathways, specify the identity of the different follicle cell types and help establish the polarity of the egg chamber.
    Full-text · Article · Apr 2007 · Development
  • Amir Sapir · Efrat Assa-Kunik · Rachel Tsruya · Eyal Schejter · Ben-Zion Shilo
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    ABSTRACT: Unidirectional signaling from cells expressing Delta (Dl) to cells expressing Notch is a key feature of many developmental processes. We demonstrate that the Drosophila ADAM metalloprotease Kuzbanian-like (Kul) plays a key role in promoting this asymmetry. Kul cleaves Dl efficiently both in cell culture and in flies, and has previously been shown not to be necessary for Notch processing during signaling. In the absence of Kul in the developing wing, the level of Dl in cells that normally receive the signal is elevated, and subsequent alterations in the directionality of Notch signaling lead to prominent phenotypic defects. Proteolytic cleavage of Dl by Kul represents a general mechanism for refining and maintaining the asymmetric distribution of Dl, in cases where transcriptional repression of Dl expression does not suffice to eliminate Dl protein.
    No preview · Article · Feb 2005 · Development
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    S Elhyany · E Assa-Kunik · S Tsory · T Muller · S Fedida · S Segal · D Fishman
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    ABSTRACT: A deregulated activity of PKB/Akt (where PKB stands for protein kinase B) renders tumour cells resistant to a variety of apoptosis-inducing stimuli. Elucidation of the mechanisms responsible for this deregulation is of prime importance for the development of novel anti-cancer drugs. Results of the present study demonstrate that the constitutive activity of PKB/Akt in B16BL6 melanoma cells depends on the integrity of cholesterol-enriched membrane microdomains, since the exposure of cells to cholesterol-depleting agents decreases the phosphorylation of this enzyme, with no change in its total protein level. Inhibitors of Hsp90 (heat-shock protein 90) decreased phosphorylation of PKB/Akt with a similar pattern. Dephosphorylation of the enzyme, as a consequence of raft disintegration, could be precluded by inhibition of serine/threonine (but not tyrosine) phosphatases. Our results imply that destabilization of lipid rafts seemingly affects the association of Hsp90 with the respective serine/threonine phosphatases, thereby increasing the accessibility to PKB/Akt to deactivating phosphatases. We have found recently that reconstituted expression of H-2K class I glycoproteins in class I-deficient B16BL6 cells also decreases the phosphorylation of PKB/Akt. Therefore it is possible that raft-associated regulation of this important enzyme involves both H-2K glycoproteins and Hsp90.
    Preview · Article · Dec 2004 · Biochemical Society Transactions
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    ABSTRACT: In a variety of malignancies, the immune-escape phenotype is associated, in part, with the inability of tumor cells to properly present their Ags to CTLs due to a deranged expression of MHC class I glycoproteins. However, these molecules were found to possess broader nonimmune functions, including participation in signal transduction and regulation of proliferation, differentiation, and sensitivity to apoptosis-inducing factors; processes, which are characteristically impaired during malignant transformation. We investigated whether the deranged expression of MHC class I expression by tumor cells could affect proper receptor-mediated signal transduction and accentuate their malignant phenotype. The malignant and H-2K murine MHC class I-deficient B16BL6 melanoma cells were characterized by an attenuated capacity to bind insulin due to the retention of corresponding receptor in intracellular stores. The restoration of H-2K expression in these cells, which abrogated their capacity to form tumors in mice, enhanced membrane translocation of the receptor, presumably, by modulating its glycosylation. The addition of insulin to H-2K-expressing melanoma cells cultured in serum-free conditions precluded apoptotic death by up-regulating the activity of protein kinase B (PKB)/Akt. In contrast, the deficiency for H-2K characteristic to the malignant clones was associated with a constitutive high activity of PKB/Akt, which rendered them resistant to apoptosis, induced by deprivation of serum-derived growth factors. The possibility to correct the regulation of PKB/Akt activity by restoration of H-2K expression in B16BL6 melanoma cells may be considered as an attractive approach for cancer therapy, since an aberrant activation of this enzyme is characteristic to resistant malignancies.
    Full-text · Article · Oct 2003 · The Journal of Immunology

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