Engineering topics

Wells, Alan

Publications and source records attributed to Wells, Alan.

4 records

DOE OSTI2018

A Systems Perspective of Heterocellular Signaling

Signal exchange between different cell types is essential for development and function of multicellular organisms, and its dysregulation is causal in many diseases. Unfortunately, most cell-signaling work has employed single cell types grown under conditions unrelated to their native context. Recent technical developments have started to provide the tools needed to follow signaling between multiple cell types, but gaps in the information they provide have limited their usefulness in building realistic models of heterocellular signaling. Currently, only targeted assays have the necessary sensitivity, selectivity and spatial resolution to usefully probe heterocellular signaling processes, but these are best used to test specific, mechanistic models. Decades of systems biology research with monocultures has provided a solid foundation for building models of heterocellular signaling, but current models lack a realistic description of regulated proteolysis and the feedback processes triggered within and between cells. Identification and understanding of key regulatory processes in the extracellular environment and of recursive signaling patterns between cells will be essential to building predictive models of heterocellular systems.

systems biology, EGFR, heterocellular, Wound heali↗

DOE OSTI2018

Liver ‘organ on a chip’

Highlights: • Ex vivo hepatic culture systems vary in complexity, from 2D to perfusion. • Cells can be sourced from humans (cell lines, stem cells, or primary) for species fidelity. • Including non-parenchymal cells is important to hepatocyte functionality. • Perfusion culture systems best mimic the complex physiology of the liver. • Scaling is important to reproduce paracrine signaling of the liver. The liver plays critical roles in both homeostasis and pathology. It is the major site of drug metabolism in the body and, as such, a common target for drug-induced toxicity and is susceptible to a wide range of diseases. In contrast to other solid organs, the liver possesses the unique ability to regenerate. The physiological importance and plasticity of this organ make it a crucial system of study to better understand human physiology, disease, and response to exogenous compounds. These aspects have impelled many to develop liver tissue systems for study in isolation outside the body. Herein, we discuss these biologically engineered organoids and microphysiological systems.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2018

Biomarker identification for statin sensitivity of cancer cell lines

Highlights: • Graphical modeling is used to find a biomarker signature for statin sensitivity. • Predictions from the model were experimentally validated in four human cell lines. • Enrichment analysis and predicted combination therapies show relevance of signature. Statins are potent cholesterol reducing drugs that have been shown to reduce tumor cell proliferation in vitro and tumor growth in animal models. Moreover, retrospective human cohort studies demonstrated decreased cancer-specific mortality in patients taking statins. We previously implicated membrane E-cadherin expression as both a marker and mechanism for resistance to atorvastatin-mediated growth suppression of cancer cells; however, a transcriptome-profile-based biomarker signature for statin sensitivity has not yet been reported. Here, we utilized transcriptome data from fourteen NCI-60 cancer cell lines and their statin dose-response data to produce gene expression signatures that identify statin sensitive and resistant cell lines. We experimentally confirmed the validity of the identified biomarker signature in an independent set of cell lines and extended this signature to generate a proposed statin-sensitive subset of tumors listed in the TCGA database. Finally, we predicted drugs that would synergize with statins and found several predicted combination therapies to be experimentally confirmed. The combined bioinformatics-experimental approach described here can be used to generate an initial biomarker signature for anticancer drug therapy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

Groundwork for Universal Canister System Development

The mission of the United States Department of Energy’s Office of Environmental Management is to complete the safe cleanup of the environmental legacy brought about from five decades of nuclear weapons development and government-sponsored nuclear energy research. Some of the wastes that that must be managed have been identified as good candidates for disposal in a deep borehole in crystalline rock (SNL 2014a). In particular, wastes that can be disposed of in a small package are good candidates for this disposal concept. A canister-based system that can be used for handling these wastes during the disposition process (i.e., storage, transfers, transportation, and disposal) could facilitate the eventual disposal of these wastes. This report provides information for a program plan for developing specifications regarding a canister-based system that facilitates small waste form packaging and disposal and that is integrated with the overall efforts of the DOE’s Office of Nuclear Energy Used Fuel Disposition Campaign's Deep Borehole Field Test. Wastes to be considered as candidates for the universal canister system include capsules containing cesium and strontium currently stored in pools at the Hanford Site, cesium to be processed using elutable or nonelutable resins at the Hanford Site, and calcine waste from Idaho National Laboratory. The initial emphasis will be on disposal of the cesium and strontium capsules in a deep borehole that has been drilled into crystalline rock. Specifications for a universal canister system are derived from operational, performance, and regulatory requirements for storage, transfers, transportation, and disposal of radioactive waste. Agreements between the Department of Energy and the States of Washington and Idaho, as well as the Deep Borehole Field Test plan provide schedule requirements for development of the universal canister system. Future work includes collaboration with the Hanford Site to move the cesium and strontium capsules into dry storage, collaboration with the Deep Borehole Field Test to develop surface handling and emplacement techniques and to develop the waste package design requirements, developing universal canister system design options and concepts of operations, and developing system analysis tools. Areas in which further research and development are needed include material properties and structural integrity, in-package sorbents and fillers, waste form tolerance to heat and postweld stress relief, waste package impact limiters, sensors, cesium mobility under downhole conditions, and the impact of high pressure and high temperature environment on seals design.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗