A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies

Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probe H5 with an optimal fit into granzyme B. We demonstrate that probe H5 enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probe H5 may enable the monitoring of early responses to anticancer treatments using tissue biopsies

New models for cold rolling: generalized slab theory and slip lines for fast predictions without finite elements

In this work, a new mathematical model for cold rolling processes is presented. Starting from the governing equations and assuming only a narrow roll gap aspect ratio (in effect, large rolls on a thin strip), we find a solution by introducing two length scales inherent to the problem. The solution consists of a large scale, along with small (next order) correction at a small scale. The leading-order solution depends on the large length scale and matches with slab theory. The next-order correction depends on both the large and small length scales, and reveals rapid stress and strain oscillation. These oscillations are also seen in preliminary FE simulations. The oscillations resemble the slip-line fields, and the FE simulations suggest a strong connection between these oscillations and the residual stress in the resulting strip. The modelling approach used here has potential applications for modelling many metal forming processes, just as the slip-line theory itself did, but with the distinct advantage of simplicity and quick computation.</p

New discoveries in cold rolling: understanding stress distribution and parameter dependence for faster, more accurate models

The finite element (FE) method is a powerful tool for simulating industrial metal forming processes such as metal rolling. FE allows users to estimate the stress distribution in the metal sheet during the rolling process. However, FE simulations do not allow for real-time online process control due to model complexity and computational time. This paper forms part of a largescale research project aimed at designing a simple-but-accurate mathematical model that provides sufficiently precise results (compared to FE simulations) with faster computational timescales allowing for real-time process control. To validate the asympotics-based mathematical model, an accurate FE model is required. In this paper, we give a detailed description of a quasi-static Abaqus/Explicit FE model and show how this is optimised to represent the rolling process. We report new insights gained from the FE simulations which can guide the development of simpler, faster mathematical models.</p