A Critical Role of Ser26 Hydrogen Bonding in Aß42 Assembly and Toxicity.

Amyloid ß-protein (Aß) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Computational studies of the most pathologic form of Aß, the 42-residue Aß42 peptide, have suggested that hydrogen bonding involving Ser26 may be particularly important in organizing a monomer folding nucleus and in subsequent peptide assembly. To study this question, we experimentally determined structure-activity relationships among Aß42 peptides in which Ser26 was replaced with Gly, Ala, α-aminobutryic acid (Abu), or Cys. We observed that aliphatic substitutions (Ala and Abu) produced substantially increased rates of formation of ß-sheet, hydrophobic surface, and fibrils, and higher levels of cellular toxicity. Replacement of the Ser hydroxyl group with a sulfhydryl moiety (Cys) did not have these effects. Instead, this peptide behaved like native Aß42, even though the hydropathy of Cys was similar to that of Abu and very different from that of Ser. We conclude that H bonding of Ser26 is the factor most important in its contribution to Aß42 conformation, assembly, and subsequent toxicity.

No Acute Changes in LVEF Observed With Concurrent Trastuzumab and Breast Radiation With Low Heart Doses.

INTRODUCTION/BACKGROUND: Treatment for HER2-postitive breast cancer often includes trastuzumab, breast/chest wall (CW) radiation (RT), and anthracyclines, all of which have cardiac toxicity. We aimed to evaluate the relationship between heart dose and acute left ventricular ejection fraction (LVEF) changes in patients who received concurrent trastuzumab and breast/CW RT with and without anthracycline use. PATIENTS AND METHODS: We retrospectively reviewed all nonmetastatic breast cancer patients from 2008 to 2015 who received concurrent trastuzumab and breast/CW RT. Baseline LVEF was compared with the LVEF closest to treatment completion as well as with the lowest post-treatment LVEF. LVEF changes were correlated with laterality, heart dosimetric parameters, and doxorubicin use. RESULTS: Eighty-eight patients were included in our analysis. The median follow-up was 45 months. Forty-one patients were right-sided and 47 left-sided. Thirty-one patients received doxorubicin, 16 right-sided and 15 left-sided. Mean heart dose was 1.10 Gy and 3.63 Gy for right- and left-sided patients, respectively (P < .001). In the entire cohort, a significant LVEF decrease of 3.0% was observed pre- and post-treatment. There was a significant effect of doxorubicin (P = .013) and a nonsignificant effect of RT laterality (P = .088) on LVEF change. The test of interaction between doxorubicin and laterality was not significant (P = .90). No significant association was found between LVEF change and heart dosimetric parameters, including percent volume of heart receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), and 45 Gy (V45), and maximum dose. Similar results were found when baseline LVEF was compared with the lowest post-treatment LVEF. CONCLUSION: With cardiac doses < 4 Gy, declines in LVEF were not related to tumor laterality or heart dosimetric parameters. Statistically significant LVEF decreases were mainly attributed to doxorubicin.