PyMT-Maclow: A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development

CD68+ tumor-associated macrophages (TAMs) are pro-tumorigenic, pro-angiogenic and are associated with decreased survival rates in patients with cancer, including breast cancer. Non-specific models of macrophage ablation reduce the number of TAMs and limit the development of mammary tumors. However, the lack of specificity and side effects associated with these models compromise their reliability. We hypothesized that specific and controlled macrophage depletion would provide precise data on the effects of reducing TAM numbers on tumor development. In this study, the MacLow mouse model of doxycycline-inducible and selective CD68+ macrophage depletion was crossed with the murine mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) mouse model of spontaneous ductal breast adenocarcinoma to generate the PyMT-MacLow line. In doxycycline-treated PyMT-MacLow mice, macrophage numbers were decreased in areas surrounding tumors by 43%. Reducing the number of macrophages by this level delayed tumor progression, generated less proliferative tumors, decreased the vascularization of carcinomas and down-regulated the expression of many pro-angiogenic genes. These results demonstrate that depleting CD68+ macrophages in an inducible and selective manner delays the development of mammary tumors and that the PyMT-MacLow model is a useful and unique tool for studying the role of TAMs in breast cancer

Induction of Prdx1 and Prdx6 in liver cells by serum and TPA

Peroxiredoxins are thiol-specific antioxidants that protect cells from oxidative damage and have proliferative and anti-apoptotic activity. We investigated the effect of serum and phorbol ester treatment on expression of Prdx1 and Prdx6 in H2.35 cells, and the possible role of Sp1 on Prdx6 induction. Serum stimulation induced a 30% increase in Prdx1 mRNA and a three-fold increase in Prdx6 mRNA. We showed a similar effect of phorbol ester treatment, which led to a 30% increase in Prdx1 mRNA, and over a two-fold increase in Prdx6 expression. Analysis of the Prdx6 proximal promoter sequence revealed four consensus Sp1 sites. Inhibition of Sp1 with mithramycin A blocked Prdx6 induction by TPA and inhibited the serum-induced transcriptional activity of the Prdx6 proximal promoter. These data suggest an important role for Prdx6 in the cellular response to serum and TPA, and implicate Sp1 as a possible mediator of Prdx6 regulation

A Structural Approach to Market Definition With an Application to the Hospital Industry

Market definition is essential to merger analysis. Because no standard approach to market definition exists, opposing parties in antitrust cases often disagree about the extent of the market. These differences have been particularly relevant in the hospital industry, where the courts have denied seven of eight merger challenges since 1994, due largely to disagreements over geographic market definition. We compare geographic markets produced using common ad hoc methodologies to a method that directly applies the “SSNIP test” to hospitals in California using a structural model. Our results suggest that previously employed methods overstate hospital demand elasticities by a factor of 2.4 to 3.4 and define larger markets than would be implied by the merger guidelines’s hypothetical monopolist test. The use of these methods in differentiated product industries may lead to mistaken geographic market delineation, and was likely a contributing factor to the permissive legal environment for hospital mergers.

Multiple-Material Topology Optimization of Compliant Mechanisms Created via Polyjet 3D Printing

Compliant mechanisms are able to transfer motion, force, and energy using a monolithic structure without discrete hinge elements. The geometric design freedoms and multi-material capability offered by the PolyJet 3D printing process enables the fabrication of compliant mechanisms with optimized topology. The inclusion of multiple materials in the topology optimization process has the potential to eliminate the narrow, weak, hinge-like sections that are often present in single-material compliant mechanisms. In this paper, the authors propose a design and fabrication process for the realization of 3-phase, multiple-material compliant mechanisms. The process is tested on a 2D compliant force inverter. Experimental and theoretical performance of the resulting 3-phase inverter is compared against a standard 2-phase design.Mechanical Engineerin