Membrane Hsp70 — a novel target for the isolation of circulating tumor cells after epithelial-to-mesenchymal transition

The presence of circulating tumor cells (CTCs) in the peripheral blood is a pre-requisite for progression, invasion, and metastatic spread of cancer. Consequently, the enumeration and molecular characterization of CTCs from the peripheral blood of patients with solid tumors before, during and after treatment serves as a valuable tool for categorizing disease, evaluating prognosis and for predicting and monitoring therapeutic responsiveness. Many of the techniques for isolating CTCs are based on the expression of epithelial cell surface adhesion molecule (EpCAM, CD326) on tumor cells. However, the transition of adherent epithelial cells to migratory mesenchymal cells (epithelial-to-mesenchymal transition, EMT)—an essential element of the metastatic process—is frequently associated with a loss of expression of epithelial cell markers, including EpCAM. A highly relevant proportion of mesenchymal CTCs cannot therefore be isolated using techniques that are based on the “capture” of cells expressing EpCAM. Herein, we provide evidence that a monoclonal antibody (mAb) directed against a membrane-bound form of Hsp70 (mHsp70)—cmHsp70.1—can be used for the isolation of viable CTCs from peripheral blood of tumor patients of different entities in a more quantitative manner. In contrast to EpCAM, the expression of mHsp70 remains stably upregulated on migratory, mesenchymal CTCs, metastases and cells that have been triggered to undergo EMT. Therefore, we propose that approaches for isolating CTCs based on the capture of cells that express mHsp70 using the cmHsp70.1 mAb are superior to those based on EpCAM expression

Tensile Creep and Creep-Recovery Behavior of a SiC-Fiber Si 3 N 4 -Matrix Composite

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65802/1/j.1151-2916.1993.tb03753.x.pd

How moving home influences appliance ownership: a Passivhaus case study

Low carbon dwellings shift the focus to electricity consumption and appliances by significantly lowering space heating energy consumption. Using a UK Passivhaus (low carbon) case study, interviews and pre/post-move-in appliance audits were employed to investigate how moving home can change the appliance requirements of appliance-using practices. Changes in appliance ownership were due to differences in how appliance-using practices (e.g. cooking, laundering, homemaking) were being performed. Existing/new appliances complemented/conflicted with a new home on the basis of whether the social meanings of specific appliance-using practices (e.g. stylishness, convenience, thermal comfort, cleanliness) could be met. This was evident, when moving home more generally, by households buying new modern appliances and managing spatial constraints. More specifically, regarding Passivhaus, hosting and homemaking practices were performed in ways that met thermal comfort expectations, in addition to appliance purchasing also being influenced by a fear that the Passivhaus technologies could fail. Whilst skills and competences were needed to perform appliance-using practices, these were less prominent in influencing appliance ownership changes. Conclusions include reflections on how the elements of appliance-using practices change when moving home, as well as what adhering to building standards could mean for the standardisation of appliance-using practices and domestic life more generally

A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies