The Current Status of Bioartificial Pancreas Devices.

Type 1 diabetes mellitus is a common and highly morbid disease for which there is no cure. Treatment primarily involves exogenous insulin administration, and, under specific circumstances, islet or pancreas transplantation. However, insulin replacement alone fails to replicate the endocrine function of the pancreas and does not provide durable euglycemia. In addition, transplantation requires lifelong use of immunosuppressive medications, which has deleterious side effects, is expensive, and is inappropriate for use in adolescents. A bioartificial pancreas that provides total endocrine pancreatic function without immunosuppression is a potential therapy for treatment of type 1 diabetes. Numerous models are in development and take different approaches to cell source, encapsulation method, and device implantation location. We review current therapies for type 1 diabetes mellitus, the requirements for a bioartificial pancreas, and quantitatively compare device function.

High expression of polo-like kinase 1 is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive Her2 negative breast cancer.

Polo-like kinase 1 (PLK1), the most investigated member of the PLK family, plays a pivotal role both in the p53-mediated regulation of DNA damage repair and in mitosis, especially in the G2/M phase. However, the evidence on the clinical and prognostic relevance of PLK1 is limited to triple negative subtype among breast cancer (BC). We hypothesized that high expression of PLK1 is associated with TP53 inactivation, DNA repair deficiency, and worse prognosis in ER positive in BC in a large-scale cohort should clarify its clinical relevance for each BC subtype. Total of 3173 BC cases; 1025 from TCGA cohort, 1904 from METABRIC, and 244 from neoadjuvant chemotherapy (NAC) cohort from Gene Expression Omnibus dataset, GSE32603, were analyzed. PLK1 expressions were significantly higher in high Nottingham Grade and triple negative BC. High expression of PLK1 was significantly associated with TP53 mutation, high expression of TP53 mRNA as well as protein, and it significantly correlated with the homologous recombination deficiency score. High PLK1 expression significantly enriched cell cycle related gene sets (G2/M check point, E2F targets), MTORC1 signaling, and MYC target gene sets in the Gene Set Enrichment Analysis. High expression of PLK1 was significantly associated with tumor infiltrating lymphocytes and tumor associated macrophages (high levels of CD8+ T cells, M0 and M1 macrophage, and low levels of M2 macrophage), and high immune cytolytic activity. While high expression of PLK1 did not associate with pathological complete response after NAC, it was associated with poor prognosis in the whole cohort and in the ER-positive/HER2-negative subtype of TCGA. High expression of PLK1 is significantly associated with TP53 mutations, DNA repair deficiency and worse prognosis in BC particularly in HR+HER2- subtype. Using bioinformatics methods with large cohorts.

Synthesis and characterization of cyclic peptides that are ß-helical in trifluoroethanol.

We show that three designed cyclic d,l-peptides are ß-helical in TFE-a solvent in which the archetypal ß-helical peptide, gA, is unstructured. This result represents an advance in the field of ß-helical peptide foldamers and a step toward achieving ß-helical structure under a broad range of solvent conditions. We synthesized two of the three peptides examined using an improved variant of our original CBC strategy. Here, we began with a commercially available PEG-PS composite resin prefunctionalized with the alkanesulfonamide 'SCL' linker and preloaded with glycine. Our new conditions avoided C-terminal epimerization during the CBC step and simplified purification. In addition, we present results to define the scope and limitations of our CBC strategy. These methods and observations will prove useful in designing additional cyclic ß-helical peptides for applications ranging from transmembrane ion channels to ligands for macromolecular targets. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Circular dichroism analysis of cyclic ß-helical peptides adsorbed on planar fused quartz.

Conformational changes of three cyclic ß-helical peptides upon adsorption onto planar fused-quartz substrates were detected and analyzed by far-ultraviolet (UV) circular dichroism (CD) spectroscopy. In trifluoroethanol (TFE), hydrophobic peptides, Leu ß and Val ß, form left- and right-handed helices, respectively, and water-soluble peptide WS ß forms a left-handed helix. Upon adsorption, CD spectra showed a mixture of folded and unfolded conformations for Leu ß and Val ß and predominantly unfolded conformations for WS ß. X-ray photoelectron spectroscopy (XPS) provided insight about the molecular mechanisms governing the conformational changes, revealing that ca. 40% of backbone amides in Leu ß and Val ß were interacting with the hydrophilic substrate, while only ca. 15% of the amines/amides in WS ß showed similar interactions. In their folded ß-helical conformations, Leu ß and Val ß present only hydrophobic groups to their surroundings; hydrophilic surface groups can only interact with backbone amides if the peptides change their conformation. Conversely, as a ß helix, WS ß presents hydrophilic side chains to its surroundings that could, in principle, interact with hydrophilic surface groups, with the peptide retaining its folded structure. Instead, the observed unfolded surface conformation for WS ß and the relatively small percentage of surface-bound amides (15 versus 40% for Leu ß and Val ß) suggest that hydrophilic surface groups induce unfolding. Upon this surface-induced unfolding, WS ß interacts with the surface preferentially via hydrophilic side chains rather than backbone amides. In contrast, the unfolded ß-hairpin-like form of WS ß does not irreversibly adsorb on fused quartz from water, highlighting that solvation effects can be more important than initial conformation in governing peptide adsorption. Both label-free methods demonstrated in this work are, in general, applicable to structural analysis of a broad range of biomolecules adsorbed on transparent planar substrates, the surface properties of which could be customized.