Speech Communication

Contains research objectives and summary of research.National Institutes of Health (Grant 2 RO1 NS04332-11)National Institutes of Health (Grant 5 RO1 NS04332-11)U. S. Navy Office of Naval Research (Contract ONR N00014-67-A-0204-0069

Management of diarrhea in patients with HER2-positive breast cancer treated with neratinib: A case series and summary of the literature

INTRODUCTION: Neratinib and neratinib-based combinations have demonstrated efficacy for treatment of human epidermal growth factor receptor 2-positive (HER2+) early-stage and metastatic breast cancers. However, diarrhea has been reported as a common adverse event leading to neratinib discontinuation. Results from the CONTROL trial suggest that proactive diarrhea management with antidiarrheal prophylaxis or dose escalation of neratinib from a lower starting dose to the full FDA-approved dose of 240 mg/day can reduce the incidence, duration, and severity of neratinib-associated diarrhea in patients with early-stage breast cancer. Dose escalation has been included in the FDA-approved label for both early-stage and metastatic HER2+ breast cancer since June 2021. CASE SERIES: This series of five cases details real-world clinical implementation of strategies for management of neratinib-induced diarrhea in patients with early-stage and metastatic HER2+ breast cancer, including a patient with a pre-existing gastrointestinal disorder. MANAGEMENT AND OUTCOME: In four of five cases, diarrhea was managed with neratinib dose escalation, and antidiarrheal prophylaxis with loperamide plus colestipol was used in the remaining case. Management of diarrhea allowed all patients to remain on therapy. DISCUSSION: This case series shows that neratinib-associated diarrhea can be managed effectively with neratinib dose escalation from a lower initial starting dose and/or prophylactic antidiarrheal medications in a real-world clinical setting. The findings highlight the importance of patient-provider communication in proactive management of adverse events. Widespread implementation of the strategies described here may improve adherence and thereby clinical outcomes for patients with HER2+ breast cancer treated with neratinib

Water Dynamics at Protein Interfaces: Ultrafast Optical Kerr Effect Study

The behavior of water molecules surrounding a protein can have an important bearing on its structure and function. Consequently, a great deal of attention has been focused on changes in the relaxation dynamics of water when it is located at the protein surface. Here we use the ultrafast optical Kerr effect to study the H-bond structure and dynamics of aqueous solutions of proteins. Measurements are made for three proteins as a function of concentration. We find that the water dynamics in the first solvation layer of the proteins are slowed by up to a factor of 8 in comparison to those in bulk water. The most marked slowdown was observed for the most hydrophilic protein studied, bovine serum albumin, whereas the most hydrophobic protein, trypsin, had a slightly smaller effect. The terahertz Raman spectra of these protein solutions resemble those of pure water up to 5 wt % of protein, above which a new feature appears at 80 cm–1, which is assigned to a bending of the protein amide chain

Speech Communication

Contains research objectives and summary of research on six research projects and reports on three research projects.National Institutes of Health (Grant 5 RO1 NS04332-13)National Institutes of Health (Fellowship 1 F22 MH5825-01)National Institutes of Health (Grant 1 T32 NS07040-01)National Institutes of Health (Fellowship 1 F22 NS007960)National Institutes of Health (Fellowship 1 F22 HD019120)National Institutes of Health (Fellowship 1 F22 HD01919-01)U. S. Army (Contract DAAB03-75-C-0489)National Institutes of Health (Grant 5 RO1 NS04332-12

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Communication Research

Contains reports on seven research projects.Carnegie Foundatio

Speech Communication

Contains reports on three research projects.National Institutes of Health (Grant 2 ROI NS04332)National Institutes of Health (Training Grant 5 T32 NS07040)C. J. LeBel FellowshipsNational Institutes of Health (Grant 5 RO1 NS13028)National Science Foundation (Grant BNS76-80278)National Science Foundation (Grant BNS77-26871

Communication Research

Contains reports on nine research projects.Bell Telephone Laboratories, Incorporate

Speech Communication

Contains reports on two research projects.National Institutes of Health (Grant 2 ROl1 NS04332)National Institutes of Health (Training Grant 5 T32 NS07040)C.J. LeBel FellowshipsNational Science Foundation (Grant BNS77-26871

Three Stages of Lysozyme Thermal Stabilization by High and Medium Charge Density Anions

Addition of high and medium charge density anions (phosphate, sulfate, and chloride) to lysozyme in pure water demonstrates three stages for stabilization of the protein structure. The first two stages have a minor impact on lysozyme stability and are probably associated with direct interaction of the ions with charged and partial charges on the protein’s surface. There is a clear transition between the second and third stages; in the case of sodium chloride, disodium sulfate and disodium hydrogen phosphate this is at 550, 210, and 120 mM, respectively. Stabilization of lysozyme can be explained by the free energy required to hydrate the protein as it unfolds. At low ion concentrations, the protein’s hydration layer is at equilibrium with the bulk water. After the transition, bulk water is depleted and the protein is competing for water with the ions. With competition for water between the protein and the ions at higher salt concentrations, the free energy required to hydrate the interior of the protein rises and it is this that stabilizes the protein structure