Lymphocytes of BRCA1 and BRCA2 germ-line mutation carriers, with or without breast cancer, are not abnormally sensitive to the chromosome damaging effect of moderate folate deficiency

Mutations in BRCA1 and BRCA2 genes may cause defective DNA repair and increase risk for breast cancer. Folate deficiency is associated with increased breast cancer risk and induces chromosome abnormalities. We hypothesised that BRCA1 and BRCA2 germ-line mutation carriers are more sensitive to the genome damaging effect of folate deficiency compared to healthy non-carrier controls and that this sensitivity is further increased in those carriers who develop breast cancer. We tested these hypotheses in lymphocytes cultured in medium containing 12 nM or 120 nM folic acid (FA) for 9 days and measured proliferative capacity and chromosomal instability using the cytokinesis-block micronucleus (CBMN) assay. BRCA1 and BRCA2 mutation carriers with or without breast cancer were not abnormally sensitive to FA deficiency-induced chromosome instability however BRCA2 mutation carriers had significantly reduced cell proliferation. FA deficiency reduced cell proliferation and increased micronucleus formation significantly accounting for 45-59% and 70-75% of the variance in these parameters compared to 0.3-8.5% and 0.2-0.3% contributed by BRCA1 or BRCA2 mutation carrier status respectively. The results of this study suggest that moderate folate deficiency has a stronger effect on chromosomal instability than BRCA1 or BRCA2 mutations found in breast cancer families.Sasja Beetstra, Carolyn Salisbury, Julie Turner, Meryl Altree, Ross McKinnon, Graeme Suthers and Michael Fenec

The scent of love is in the air(way): a potential drug target for sleep apnea?

Fundamentally, obstructive sleep apnea (OSA) is characterized by the interaction between impaired pharyngeal anatomy and inadequate dilator muscle function during sleep [1]. Accordingly, strategies to reactivate upper airway dilator muscle activity during sleep are a key target for emerging pharmacotherapy for OSA [1–7]. Indeed, several preclinical, e.g. [8–12] and translational clinical proof of concept findings e.g. [2, 5, 6, 13–18] show considerable promise for the development of OSA pharmacotherapy.Amal M. Osman, Thomas J. Altree, and Danny J. Ecker

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics : an UNGAP review

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area