Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.     

Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth‐factor‐like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy‐resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4‐tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4‐substituted benzylphosphonic acid and 6‐substituted naphthalen‐2‐ylmethylphosphonic acid analogues block ATX activity with K_i values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed‐mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b , the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose‐dependent manner. The average terminal half‐life for compound 22 is 10±5.4 h and it causes a long‐lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16‐F10 syngeneic mouse melanoma in a post‐inoculation treatment paradigm. The 4‐substituted benzylphosphonic acids and 6‐substituted naphthalen‐2‐ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX–LPA–LPAR axis both in vitro and in vivo.     

Effect of pH on the Binding of Sodium,Lysine, and Arginine Counterions to <Emphasis Type="SmallCaps">l</Emphasis>-Undecyl Leucinate Micelles

Micelle formation by the amino acid-based surfactant undecylenyl l-leucine was investigated as a function of solution pH with NMR, dynamic light scattering, and fluorescence spectroscopy. NMR and dynamic light scattering showed that 50 mM undecylenyl l-leucine and 50 mM NaHCO₃ solutions contained micelles approximately 20 Å in diameter and that micelle radius and the mole fraction of surfactant molecules associated with micelles changed very little with solution pH. The binding of the amino acids arginine and lysine to the anionic micelles was also investigated from pH 7.0 to 11.5. Below pH 9.0, the mole fraction of arginine cations bound to the micelles was approximately 0.4. Above pH 9.0, the arginine counterions became zwitterionic, and the mole fraction of bound arginine molecules decreased steadily to less than 0.1 at pH 11. When arginine dissociated from the micelles, their radii decreased from 14 to 10 Å. Similar behavior was observed with lysine; however, when lysine dissociated from the micelle surface, little change in micelle radius was observed. Two-dimensional NMR experiments suggested that below pH 9.0, l-arginine bound perpendicular to the micelle surface primarily though its side chain amine while l-lysine bound parallel to the surface through both of its amine functional groups. Finally, the rate at which the amide protons on the surfactant headgoup exchanged with solvent was investigated with NMR spectroscopy. The exchange reaction was faster in solutions containing only surfactant monomers and slower when the surfactants were in micellar form and the headgoup amide protons were less exposed to solvent.     

Nutritional properties of einkorn wheat (Triticum monococcum L.)

The hulled wheat einkorn (Triticum monococcum L. ssp. monococcum), a staple food of early farmers for many thousand years, today is cropped only in small areas of the Mediterranean region and continental Europe. Increasing attention to the nutritional quality of foods has fostered renewed interest in this low‐impact crop. The reappraisal of einkorn quality evidenced that this ancient wheat has some dietary advantages over polyploid wheats. Einkorn wholemeal is poor in dietary fibre but rich in proteins, lipids (mostly unsaturated fatty acids), fructans and trace elements (including zinc and iron). The good concentration of several antioxidant compounds (carotenoids, tocols, conjugated polyphenols, alkylresorcinols and phytosterols) and low β‐amylase and lipoxygenase activities (which limit antioxidant degradation during food processing) contribute to the excellent nutritional properties of its flour, superior to those of other wheats. Conversely, einkorn has relatively low bound polyphenol content and high polyphenol oxidase activity. In spite of eliciting weaker toxic reactions than other Triticum species, einkorn is not suitable for coeliacs. Current trends towards the consumption of functional foods suggest that this cereal may still play a significant role in human consumption, especially in the development of new or special foods with superior nutritional quality. © 2013 Society of Chemical Industry     

Modifications of spider silk sequences in an attempt to control the mechanical properties of the synthetic fibers

Bacteria were genetically engineered to produce two spider silk protein variants composed of basic repeat units combining a flagelliform elastic motif ([GPGGX]₄) and a major ampullate silk strength motif ([linker/poly-alanine]. The secondary structures of the pure recombinant proteins in solution were determined by circular dichroism. The data presented suggest that the nature of the 5th and 10th amino acid (X) in the [GPGGX]₂ elastic motif and temperature have an impact on the amount of β-sheet structures present in the proteins. More specifically, increasing temperatures seem to be positively correlated with β-sheet formation for both proteins and this state is irreversible or reversible when both X (5th and 10th) in the elastic motif are hydrophilic or hydrophobic respectively. Moreover, each pure silk-like protein was able to spontaneously self-assemble into films from aqueous solutions. Two kinds of synthetic fibers were made by pulling fibers from these preassembled films as well as spinning fibers from each protein resolubilized in HFIP. The mechanical data show that the pulled fibers are far tougher than the spun fibers suggesting a better fiber organization. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Exploring the within-person coupling of sleep and cognition in older African Americans.

This study examined the within-person relationship between sleep and cognitive functioning. Fifty community-dwelling African Americans (age range = 50–80 years) were asked to report their sleep duration and quality the previous evening and to complete cognitive measures over 8 occasions within a 2–3 week period. A within-person daily change in sleep duration was significantly associated with worse global cognitive performance. The greater an individual deviated away from his or her average sleep duration on a particular day, the more likely his or her performance would decline. These results demonstrate that the sleep-cognition relationship can be observed at a within-person level of analysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Carotenoids evolution during pasta,bread and water biscuit preparation from wheat flours

The loss of carotenoids content during food processing was investigated during the production of bread, water biscuits and pasta from refined flours of einkorn, bread and, for pasta only, durum wheat semolina.