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Tel Aviv, Israel

Barak S.,Aviv Sourasky Medical Center | Mimouni F.B.,Tel Aviv Sourasky Medial Center | Stern R.,Tel Aviv Sourasky Medial Center | Cohen N.,Tel Aviv Sourasky Medial Center | Marom R.,Tel Aviv Sourasky Medial Center
Journal of Perinatology | Year: 2015

Objective:To examine the hypothesis that maternal body mass index (BMI) (an index of maternal adiposity) correlates with cord blood concentrations of erythropoietin (EPO).Study design:Cross-sectional cohort study of consecutively born singleton term healthy infants born to mothers with various BMIs. Excluded were infants with major factors known to be associated with a potential increase in fetal erythropoiesis. Prepregnancy maternal BMI was calculated from maternal recollection.Result:There was a significant correlation between EPO concentrations and maternal BMI (R=0.427, P=0.007). This correlation remained significant in multiple stepwise regression analysis using the EPO concentration as the dependent variable, and maternal age, parity, gestational age and Apgar scores (1 or 5 min) as potential confounders.Conclusion:Cord blood concentrations of EPO correlate with maternal BMI. We speculate that increasing maternal BMI may represent a relative hypoxic burden on the fetus. © 2015 Nature America, Inc.

Ligumsky H.,Aviv Sourasky Medical Center | Ligumsky H.,Tel Aviv University | Rubinek T.,Aviv Sourasky Medical Center | Merenbakh-Lamin K.,Aviv Sourasky Medical Center | And 8 more authors.
Molecular Cancer Research | Year: 2015

Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Over-expression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities. Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer. © 2015 American Association for Cancer Research.

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