Optimization of eIF4E-Binding Peptide Pep8 to Disrupt the RBM38-eIF4E Complex for Induction of p53 and Tumor Suppression.

Interaction of RNA-binding protein RBM38 with eIF4E on p53 mRNA is known to suppress p53 mRNA translation, which can be disrupted by an 8-amino acid peptide (Pep8-YPYAASPA) derived from RBM38, leading to induction of p53 and tumor suppression. Here, we rationally designed multiple Pep8 derivatives and screened for their binding affinities towards eIF4E in silico. We showed that several key residues within Pep8 are necessary for its structure and function. We identified a shortened 7-amino acid peptide (Pep7-PSAASPV) that has the highest affinity towards eIF4E and is the most potent inducer of p53 expression. We found that iRGD is an effective vehicle to deliver Pep7 inside of cells for induction of p53 expression and growth suppression as compared to other cell penetrating peptides (Penetratin and Pep-1). We found that peptide cyclization enhances Pep8 affinity for eIF4E, induction of p53 and tumor cell growth suppression. We also found that the ability of Pep7 to induce p53 expression and growth suppression is conserved in cells derived from canine osteosarcoma, a spontaneous tumor model frequently used for testing the feasibility of a therapeutic agent for human cancer. Moreover, we showed that both human and canine osteosarcoma cells, which are notoriously resistant to radiation therapy, were sensitized by Pep7 to radiation-induced growth suppression and cell death. Together, our data suggest that Pep7 may be explored to sensitize tumors to radiation therapy.

Formula supplementation in hospital and subsequent feeding at discharge among women who intended to exclusively breastfeed: An administrative data retrospective cohort study.

BACKGROUND: Among women who intend to exclusively breastfeed, it is important to identify mothers and their infants who have a greater risk of formula supplementation in hospital, and are unlikely to recover exclusive breastfeeding at discharge. We investigated factors associated with in-hospital formula feeding among healthy term infants born to women who intended to exclusively breastfeed, and among this group, predictors of infant feeding at discharge. METHODS: Retrospective cohort study utilizing routinely collected clinical data for women who intended to exclusively breastfeed and gave birth to healthy term infants in five hospitals in New South Wales, Australia, 2010-2013. Robust Poisson regression was used to obtain adjusted relative risks (aRR) for the associations between formula feeding in hospital, feeding at discharge, and associated factors. RESULTS: Of 24 713 mother-infant dyads in the study population, 16.5% received formula in hospital. After adjustment, the strongest predictors of formula supplementation were breastfeeding difficulties (aRR 2.90 [95% confidence interval {CI} 2.74-3.07]), Asian born mother (aRR 2.07 [95% CI 1.92-2.23]), and neonatal conditions (aRR 2.00 [95% CI 1.89-2.13]). Among infants who received formula (n=3998), 49.3% were fully breastfeeding at discharge, 33.1% partially breastfeeding, and 17.5% formula-only feeding. Compared with formula-only feeding, special care nursery admission (aRR 1.23 [95% CI 1.17-1.30]) and ≥1 neonatal conditions (compared with none) were most strongly associated with fully breastfeeding at discharge (aRR 1.21 [95% CI 1.16-2.16]). CONCLUSION: Women and their infants who receive formula in hospital need additional support to attain exclusive breastfeeding by hospital discharge. Such support is especially needed for younger women, smokers, and women with breastfeeding difficulties.

Factors Associated with Recurrent Infant Feeding Practices in Subsequent Births.

BACKGROUND: Previous breastfeeding experience has been associated with subsequent infant feeding practices. However, few longitudinal studies have investigated formula-only feeding patterns or the full range of potentially associated characteristics. OBJECTIVE: This study aimed to determine the recurrence of infant feeding practices and maternal, birthing, and infant characteristics associated with recurrent formula-only feeding and changes between exclusive breastfeeding and formula-only feeding across subsequent births. METHODS: We conducted a population-based record-linkage study of 317 027 mothers, with a term singleton live-birth in 2007-2011, New South Wales, Australia. Infant feeding patterns were described using sequential birth pairs. For mothers with a first and second birth, robust Poisson regression was used to investigate the association between maternal, birthing, and infant characteristics and infant feeding patterns. Combined relative risks (RRs) were calculated for selected maternal characteristics. RESULTS: Across 69 994 sequential birth pairs, the recurrence rate of formula-only feeding was 71%, and 92% for exclusive breastfeeding. Maternal characteristics < 25 years old, being Australian born or single, smoking during pregnancy, and living in lower socioeconomic areas were most strongly associated with repeat formula-only feeding (RR, 22.1; 95% confidence interval [CI], 18.6-26.3), changing from exclusive breastfeeding to formula-only feeding (RR, 9.0; 95% CI, 7.4-10.7), and being less likely to change from formula-only feeding to exclusive breastfeeding (RR, 0.47; 95% CI, 0.38-0.59). CONCLUSION: Infant feeding practices were strongly recurrent, highlighting the importance of successful breastfeeding for first-time mothers. Additional support for young mothers from disadvantaged backgrounds accounting for infant feeding history, experiences, and common barriers could improve recurrent exclusive breastfeeding and positively affect infant and maternal health.