Long‐term daily oral administration of intestinal permeation enhancers is safe and effective in mice

Abstract Although protein drugs are powerful biologic therapeutics, they cannot be delivered orally because their large size and hydrophilicity limit their absorption across the intestinal epithelium. One potential solution is the incorporation of permeation enhancers into oral protein formulations; however, few have advanced clinically due to toxicity concerns surrounding chronic use. To better understand these concerns, we conducted a 30‐day longitudinal study of daily oral permeation enhancer use in mice and resultant effects on intestinal health. Specifically, we investigated three permeation enhancers: sodium caprate (C10), an industry standard, as well as 1‐phenylpiperazine (PPZ) and sodium deoxycholate (SDC). Over 30 days of treatment, all mice gained weight, and none required removal from the study due to poor health. Furthermore, intestinal permeability did not increase following chronic use. We also quantified the gene expression of four tight junction proteins (claudin 2, claudin 3, ZO‐1, and JAM‐A). Significant differences in gene expression between untreated and permeation enhancer‐treated mice were found, but these varied between treatment groups, with most differences resolving after a 1‐week washout period. Immunofluorescence microscopy revealed no observable differences in protein localization or villus architecture between treated and untreated mice. Overall, PPZ and SDC performed comparably to C10, one of the most clinically advanced enhancers, and results suggest that the chronic use of some permeation enhancers may be therapeutically viable from a safety standpoint

Pro-environmental actions, climate change, and defensiveness: do self-affirmations make a difference to people's motives and beliefs about making a difference?

Social concerns with the imperative of environmentally sustainable life-styles sit rather awkwardly with ideas about the widespread denial of global environmental problems. Given the very obvious threat and denial dimensions to these issues, we conducted two studies assessing the impact of self-affirmation manipulations on people's beliefs and motives regarding pro-environmental actions. In Study 1, participants (N =125) completed a self-affirmation task and read information on the threat of climate change. Results showed that the self-affirmation manipulation resulted in lower levels of denial and greater perceptions of personal involvement in relation to climate change. In Study 2, participants (N =90) completed a self-affirmation task and read some information on recycling. Findings showed a beneficial effect of a self-affirmation manipulation on intentions to increase recycling behaviour (among lower recyclers). The results are discussed in relation to the potential benefits of self-affirmation manipulations for promoting pro-environmental action

A rare TP53 mutation predominant in ashkenazi jews confers risk of multiple cancers

Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G\u3eC;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G\u3eC probands and one c.1000G\u3eA proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G\u3eC allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G\u3eC;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS