We present a simple method of fabricating highly potent dual action antibacterial composites consisting of a cationic polymer matrix and embedded silver bromide nanoparticles. A simple and novel technique of on-site precipitation of AgBr was used to synthesize the polymer/nanoparticle composites. The synthesized composites have potent antibacterial activity toward both gram-positive and gram-negative bacteria. The materials form good coatings on surfaces and kill both airborne and waterborne bacteria. Surfaces coated with these composites resist biofilm formation. These composites are different from other silver-containing antibacterial materials both in the ease of synthesis and in the use of a silver salt nanoparticle instead of elemental silver or complex silver compounds. We also demonstrate the ability to tune the release of biocidal Ag(+) ions from these composites by controlling the size of the embedded AgBr nanoparticles. These composites are potentially useful as antimicrobial coatings in a wide variety of biomedical and general use applications.

Estrogens have been demonstrated to rapidly modulate calcium levels in a variety of cell types. However, the significance of estrogen-mediated calcium flux in neuronal cells is largely unknown. The relative importance of intra- and extracellular sources of calcium in estrogenic effects on neurons is also not well understood. Previously, we have demonstrated that membrane-limited estrogens, such as E-BSA given before an administration of a 2-hour pulse of 17β-estradiol (E₂), can potentiate the transcription mediated by E₂ from a consensus estrogen response element (ERE)-driven reporter gene. Inhibitors to signal transduction cascades given along with E-BSA or E₂ demonstrated that calcium flux is important for E-BSA-mediated potentiation of transcription in a transiently transfected neuroblastoma cell line. In this report, we have used inhibitors to different voltage-gated calcium channels (VGCCs) and to intracellular store receptors along with E-BSA in the first pulse or with E₂ in the second pulse to investigate the relative importance of these channels to estrogen-mediated transcription. Neither L- nor P-type VGCCs seem to play a role in estrogen action in these cells; while N-type VGCCs are important in both the non-genomic and genomic modes of estrogen action. Specific inhibitors also showed that the ryanodine receptor and the inositol trisphosphate receptor are important to E-BSA-mediated transcriptional potentiation. This report provides evidence that while intracellular stores of calcium are required to couple non-genomic actions of estrogen initiated at the membrane to transcription in the nucleus, extracellular sources of calcium are also important in both non-genomic and genomic actions of estrogens.

A recently reported deletion of about 40 Mb in length between 6.12/6.57 and 46.73/47.31 Mb on the Y chromosome long arm of the C57BL/6JBomTac inbred strain made us closely examine the strain’s breeding history and reproductive characteristics. We verified that the two copies of Rbm31y that are present inside the putative deletion were indeed deleted. This inbred strain presents an expected litter size for a C57BL/6 substrain. In vitro fertilization (IVF) efficiency and breeding efficiencies are comparable to those of the C57BL/6NTac substrain; however, the male/female sex ratio in the C57BL/6JBomTac is mildly skewed towards females. There is an increase in the percentage of sperm shape abnormalities found in C57BL/6JBomTac (35%) versus C57BL/6NTac (11%). The most frequent type of sperm abnormality observed is bent heads (19%). Additionally, there is deregulation of several transcripts expressed in the testes. We determined that this mutation arose in the C57BL/6JBomTac Foundation Colony in 2008, and it was completely fixed in the colony by 2009.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-017-9680-0) contains supplementary material, which is available to authorized users.

We report the synthesis of novel steroidal androgen receptor ligands comprising 11beta-alkyl-Delta(9)-derivatives of 19-nortestosterone. These compounds are structurally related to the antiprogestin, antiglucocorticoid, and antiandrogen drug mifepristone (RU486). Nortestosterone analogues bearing 11beta-octyl and 11beta-decyl side-chains bind tightly to recombinant AR protein (IC(50) = 6.6 nM and IC(50) = 0.8 nM), block AR dimerization, exhibit activity against LNCaP prostate cancer cells, and comprise partial AR agonists with low antiglucocorticoid activity.

Humanized immune system mice are critical immuno-oncology tools, and next gen models using human cytokine-expressing mice, such as the NOG-EXL expressing hGM-CSF and hIL-3, drive differentiation of specific cell types. The huNOG-EXL (engrafted with human CD34+ hematopoietic stem cells) is widely used as it develops both myeloid and lymphoid lineages. Our goal was to determine the degree of variance between stem cell donors, tumor types, and immune cell reconstitution (tissue, phenotype and/or kinetics) within a huNOG-EXL lung cancer model. We studied tumor growth kinetics, human immune reconstitution, and tumor infiltrating leukocytes (TIL) in a human cell-derived model of non-small cell lung cancer (NSCLC; A549) and a patient-derived model of small cell lung cancer (SCLC; LU5173). Method: huNOG-EXL were inoculated (n=5 x 2 donors x tumor) with A549 (expanded in vitro to 5x106 cells per inoculum) or LU5173 (P5, warm tumors 600-1000 mm3 total size derived 3 mm3 per inoculum) in the flank subcutaneously (SQ). Tumor growth and body weight were measured for 80+ days. The main study used n=20 huNOG-EXL per donor across three different donors and both tumors for a total n=120. Mice were randomized at a tumor volume of 80-120 mm3 (A549) or 150-250 mm3 (LU5173) into a vehicle (human IgG4) or test article group (Pembrolizumab; humanized anti-PD1 antibody). 24 h later, mice were given (BIW x 7) drug or vehicle (10 mg/kg; 5 ml/kg; IP). 24 h after final dose, animals were sacrificed and blood, spleen, and tumor collected for a 2-panel 16 color FACS analysis. Results: Notable differences were seen between tumor types in slope and late-stage impact on body weight. A549 had accelerated growth but at late time points (day 70) tumor volume and body weight declined for both donors. LU5173 had delayed growth but larger sustained volume sizes, with no adverse effects on animal health or tumor volume reduction in both donors. In the main study, aAcross all three donors, huNOG-EXL reconstituted human lymphoid and myeloid lineages in blood, spleen, and tumor at ~23 wks post engraftment. Donor differences were seen in the overall reconstitution and distribution across the 16 cell types measured. There was a significant difference in the extent of human immune cell infiltration between tumor types. A549 tumors had significantly more hCD45+ cells than LU5173 tumors. The tumor growth inhibition did not significantly differ between treatment groups. Conclusion: Our study provides a comprehensive look at a HIS mouse that reconstitutes multiple human lineages in the context of a human lung cancer model. The significant power and large-scale FACS analysis in multiple tissues demonstrates the impact that tumor type, mouse strain, timeline, and donor can impart on an in vivo efficacy study. Proper power analysis accounting for these is required for successful immuno-oncology studies. Citation Format: Janell R. Richardson, Megan MacBride, Esther Andino, Marla Wilwol, SueEllen Bethmann, Taylor Knapp, Emily Shako, Paul Volden. Defining variation within a next gen humanized immune system mouse model of human lung cancer in the context of a checkpoint inhibitor efficacy study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2935.