Electrostatic interactions play a significant role in regulating biological systems and have received increasing attention due to their usefulness in designing advanced stimulus-responsive materials. Polypeptoids are highly tunable N-substituted peptidomimetic polymers that lack backbone hydrogen bonding and chirality. Therefore, polypeptoids are suitable systems to study the effect of noncovalent interactions of substituents without complications of backbone intramolecular and intermolecular hydrogen bonding. In this study, all-atom molecular dynamics (MD) simulations were performed on micelles formed by a series of sequence-defined ionic polypeptoid block copolymers consisting of a hydrophobic segment and a hydrophilic segment in an aqueous solution. By combining the results from MD simulations and experimental small-angle neutron scattering data, further insights were gained into the internal structure of the formed polypeptoid micelles, which is not always directly accessible from experiments. In addition, information was gained into the physics of the noncovalent interactions responsible for the self-assembly of weakly charged polypeptoids in an aqueous solution. While the aggregation number is governed by electrostatic repulsion of the negatively charged carboxylate (COO – ) substituents on the polypeptoid chain within the micelle, MD simulations indicate that the position of the charge on singly charged chains mediates the shape of the micelle through the charge–dipole interactions between the COO – substituent and the surrounding water. Therefore, the polypeptoid micelles formed from the single-charged series offer the possibility for tailorable micelle shapes. In contrast, the polypeptoid micelles formed from the triple-charged series are characterized by more pronounced electrostatic repulsion that competes with more significant charge–sodium interactions, making it difficult to predict the shape of the micelles. This work has helped further develop design principles for the shape and structure of self-assembled micelles by controlling the position of charged moieties on the backbone of polypeptoid block copolymers.
Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.
Background: Women at high risk for breast cancer due to genetics or risk factor profiles are counseled to adopt lifestyle, behavioral, and dietary changes to help reduce their risk. These recommendations are based on studies of women at average risk, so their effectiveness in high-risk women is unclear. Methods: We evaluated the impact of physical activity, smoking, alcohol consumption, and intake of folate and carotenoids on mammographic breast density—a proxy for breast cancer risk—among 387 high-risk women. Exposures were self-reported on questionnaires. Breast dense area, nondense area, and percent dense area were measured from screening mammograms with Library for Breast Radiodensity Assessment software. Cross-sectional associations were estimated with multivariable quantile regression models. Results: After adjusting for age, adiposity, reproductive history, and use of postmenopausal hormones, no breast density measure was associated with physical activity level, smoking status, alcohol consumption, or estimated intake of folate, alpha-carotene, beta-carotene, lutein/zeaxanthin, and beta-cryptoxanthin. Lycopene intake was associated with lower dense area when comparing the highest and lowest intake categories (adjusted difference in median = −14 cm2, 95% confidence interval: −29 to 1.3 cm2). This association may be explained by incomplete adjustment for adiposity. Conclusions: Recommended lifestyle, behavioral, and dietary changes to mitigate personal risk of breast cancer do not substantially impact mammographic breast density measures. Impact: Alternative strategies, such as increased uptake of chemoprevention, may better serve risk reduction efforts in women at high risk for breast cancer.
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