A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales

Investigating Crack Initiation and Propagation of Concrete in Restrained Shrinkage Circular/Elliptical Ring Test

The restrained ring test, which is recommended by AASHTO and ASTM, has been used for assessing the potential of early-age cracking of concrete and other cement-based materials. Recently, a novel elliptical ring test method has been proposed to replace the circular ring test method for the purpose of shortening ring test duration and observing crack initiation and propagation more conveniently. In order to explore the mechanism of this novel test method, a numerical model is developed to analyze crack initiation and propagation process in restrained concrete rings, in which the effect of concrete shrinkage is simulated by a fictitious temperature drop applied on concrete causing the same strain as that induced by shrinkage. First, an elastic analysis is conducted to obtain the circumferential stress contour of a concrete ring subject to restrained shrinkage. Combined with the fictitious crack model, a fracture mechanics method is introduced to determine crack initiation and propagation, in which crack resistance caused by cohesive force acting on fracture process zone is considered. Finite element analysis is carried out to simulate the evolution of stress intensity factor in restrained concrete rings subject to circumferential drying. Cracking age and position of a series of circular/elliptical concrete rings are obtained from numerical analyses which agree reasonably well with experimental results. It is found that the sudden drop of steel strain observed in the restrained ring test represents the onset of unstable crack propagation rather than crack initiation. The results given by the AASHTO/ASTM restrained ring test actually reflects the response of a concrete ring as a structure to external stimulation, in this case restrained concrete shrinkage.The financial support from the National Natural Science Foundation of China under the grants of NSFC 51478083 & 51421064, Engineering and Physical Sciences Research Council under the grant of EP/I031952/1, and the National Basic Research Program of China (973 Program, Grant No. 2015CB057703) is gratefully acknowledged