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Besser M.J.,Ella Institute of Melanoma | Besser M.J.,Tel Aviv University | Shoham T.,GreenOnyx | Harari-Steinberg O.,Ella Institute of Melanoma | And 12 more authors.

Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy. © 2013 Besser et al. Source

Pode-Shakked B.,Metabolic Disease Unit | Reish O.,Genetics Institute | Aktuglu-Zeybek C.,Istanbul University | Kesselman D.,University of Maryland University College | And 3 more authors.
Journal of Pediatric Gastroenterology and Nutrition

Glucose galactose malabsorption (GGM) is a rare autosomal recessive disorder characterized by life-threatening osmotic diarrhea at infancy. When the intake of the offending sugars (namely, glucose, galactose and lactose) is ceased, the diarrhea promptly stops. Mutations in the SLC5A1 gene, encoding the sodium-glucose co-transporter located in the brush border of enterocytes, have been shown to cause the disease. More than 300 subjects of diverse origin have been reported worldwide, most of whom are a result of a consanguineous union. We examined 6 patients from 4 families presenting with complaints consistent with GGM and responsive to the appropriate fructose-based diet. Genomic DNA of the patients was polymerase chain reaction amplified for each of the 15 exons of the SLC5A1 gene and analyzed by nucleotide sequencing. The analysis lead to the identification of 2 novel mutations: a 1915 del C mutation, a frameshift mutation leading to a premature stop at codon 645; and a substitution missense mutation of T to C on nucleotide 947 (exon 9) causing a L316P substitution. In addition, G426R and C255W mutations previously described were identified; in both cases, the patients were shown to be homozygous and their parents heterozygous for the mutation. Of note, additional patients who underwent a similar evaluation at our center for suspected GGM did not show mutations in the SLC5A1 gene. Because the latter did not previously undergo a diagnostic algorithm in full, for instance, one that may consist of a glucose breath hydrogen test and an empiric attempt of a dietary switch to galactomin, we suggest that molecular genotyping of such patients should only follow such appropriate clinical evaluation. © 2013 by European Society for Pediatric Gastroenterology,Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Source

Shukrun R.,Pediatric Stem Cell Research Institute | Shukrun R.,Sheba Centers for Regenerative Medicine and Cancer Research | Shukrun R.,Tel Aviv University | Pode Shakked N.,Pediatric Stem Cell Research Institute | And 6 more authors.
Pediatric Nephrology

Wilms' tumor (WT), a common renal pediatric solid tumor, serves as a model for a malignancy formed by renal precursor cells that have failed to differentiate properly. Here we review recent evidence showing that the tumors' heterogeneous cell population contains a small fraction of cancer stem cells (CSC) identified by two markers: Neural Cell Adhesion Molecule 1 (NCAM1) expression and Aldehyde dehydrogenase 1 (ALDH1) enzymatic activity. In vivo studies show these CSCs to both self-renew and differentiate to give rise to all tumor components. Similar to other malignancies, the identification of a specific CSC fraction has allowed the examination of a novel targeted therapy, aimed at eradicating the CSC population. The loss of CSCs abolishes the tumor's ability to sustain and propagate, hence, causing tumor degradation with minimal damage to normal tissue. © 2013 IPNA. Source

Pleniceanu O.,Pediatric Stem Cell Research Institute | Pleniceanu O.,Sheba Center for Regenerative Medicine | Pleniceanu O.,Tel Aviv University | Harari-Steinberg O.,Pediatric Stem Cell Research Institute | And 5 more authors.
Stem Cells

End-stage renal disease (ESRD) is defined as the inability of the kidneys to remove waste products and excess fluid from the blood. ESRD progresses from earlier stages of chronic kidney disease (CKD) and occurs when the glomerular filtration rate (GFR) is below 15 ml/minute/1.73 m2. CKD and ESRD are dramatically rising due to increasing aging population, population demographics, and the growing rate of diabetes and hypertension. Identification of multipotential stem/progenitor populations in mammalian tissues is important for therapeutic applications and for understanding developmental processes and tissue homeostasis. Progenitor populations are ideal targets for gene therapy, cell transplantation, and tissue engineering. The demand for kidney progenitors is increasing due to severe shortage of donor organs. Because dialysis and transplantation are currently the only successful therapies for ESRD, cell therapy offers an alternative approach for kidney diseases. However, this approach may be relevant only in earlier stages of CKD, when kidney function and histology are still preserved, allowing for the integration of cells and/or for their paracrine effects, but not when small and fibrotic end-stage kidneys develop. Although blood- and bone marrow-derived stem cells hold a therapeutic promise, they are devoid of nephrogenic potential, emphasizing the need to seek kidney stem cells beyond known extrarenal sources. Moreover, controversies regarding the existence of a true adult kidney stem cell highlight the importance of studying cell-based therapies using pluripotent cells, progenitor cells from fetal kidney, or dedifferentiated/reprogrammed adult kidney cells. © AlphaMed Press. Source

Pode-Shakked N.,Pediatric Stem Cell Research Institute | Pode-Shakked N.,Sheba Centers for Regenerative Medicine and Cancer Research | Pode-Shakked N.,Tel Aviv University | Shukrun R.,Pediatric Stem Cell Research Institute | And 27 more authors.
EMBO Molecular Medicine

There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated - NCAM1 expressing - "blastema" phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets. © 2012 The Authors. Source

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