OBJECTIVE
To investigate whether cell adhesion to fibronectin induces drug resistance in human bladder cancer cells, and to study the survival signalling pathway in cell adhesion to fibronectin‐mediated chemotherapy resistance in vitro.
MATERIALS AND METHODS
T24 cells (human bladder cancer cell lines) were pre‐coated with fibronectin, and treated with mitomycin C (MMC) and the specific phosphoinositide‐3 kinase (PI3‐K) inhibitor LY294002. The apoptosis and cell cycles were analysed. The activity of the caspase‐8, ‐9 and apoptosis‐inducing factor (AIF) apoptosis pathways were assessed using colorimetric assay, immunofluorescence, Western blot and flow cytometry. The expression of glycogen synthase kinase‐3β (GSK‐3β) and cyclin D1, as the key regulator of G1/S phase transition, were determined by Western blot. The expression of PI3‐K, Akt, phospho‐Akt and β1‐integrin were also examined by Western blot.
RESULTS
Apoptosis induced by MMC was significantly resisted by fibronectin adhesion in T24 cells, and this effect was through inhibition of the caspase‐9 and AIF apoptosis pathways, but not the caspase‐8 pathway. Fibronectin antagonized MMC‐induced G0/G1‐phase arrest by inactivating GSK‐3β to stabilize cyclin D1 expression in T24 cells. Furthermore, fibronectin‐mediated protection of T24 cells was dependent on the activity of the PI3‐K/Akt signalling pathway, and the protection could be abolished by the PI3‐K inhibitor LY294002.
CONCLUSIONS
Fibronectin‐mediated PI3‐K/Akt activation protects T24 cells from MMC‐induced cell death through inhibition of both caspase‐9 and AIF‐mediated apoptosis and GSK‐3β/cyclin D1 involved G0/G1‐phase arrest.
Breeding blankets are designed to ensure tritium self-sufficiency in deuterium–tritium fusion power plants. In addition to this, breeder blankets play a vital role in shielding key components of the reactor, and provide the main source of heat which will ultimately be used to generate electricity. Blanket design is critical to the success of fusion reactors and integral to the design process. Neutronic simulations of breeder blankets are regularly performed to ascertain the performance of a particular design. An iterative process of design improvements and parametric studies are required to optimize the design and meet performance targets. Within the EU DEMO program the breeding blanket design cycle is repeated for each new baseline design. One of the key steps is to create three-dimensional models suitable primarily for use in neutronics, but could be used in other computer-aided design (CAD)-based physics and engineering analyses. This article presents a novel blanket design tool which automates the process of producing heterogeneous 3D CAD-based geometries of the helium-cooled pebble bed, water-cooled lithium lead, helium-cooled lithium lead and dual-coolant lithium lead blanket types. The paper shows a method of integrating neutronics, thermal analysis and mechanical analysis with parametric CAD to facilitate the design process. The blanket design tool described in this paper provides parametric geometry for use in neutronics and engineering simulations. This paper explains the methodology of the design tool and demonstrates use of the design tool by generating all four EU blanket designs using the EU DEMO baseline. Neutronics and heat transfer simulations using the models have been carried out. The approach described has the potential to considerably speed up the design cycle and greatly facilitate the integration of multiphysics studies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations –citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.