Governments at all levels are increasingly motivating the private sector to participate in infrastructure development using alternative project delivery methods to relieve financial burden. When designing contracts, g...Governments at all levels are increasingly motivating the private sector to participate in infrastructure development using alternative project delivery methods to relieve financial burden. When designing contracts, governments usually offer incentives while requiring cost or time guarantee to balance project attractiveness to the private sector and fair protection of public interest. However, a practical and critical problem is how to properly design these provisions. Although previous studies have investigated the value of these provisions, a knowledge gap still exists with respect to methods of fairly and effectively designing such provisions. This study fills this gap by developing a methodology that analyzes the appropriateness of guarantee or warranty provisions for contracts. In this study, a contract reliability index is constructed, and a process of evaluating contract reliability is proposed. The New Mexico Highway 44 project, in which three warranty provision arrangements are investigated, is used as a case study to illustrate the analysis process. Results show that although a ceiling clause can effectively motivate the private sector to participate in the project, it sacrifices a significant amount of public benefits. By contrast, although a warranty option can protect public benefits, it cannot effectively incentivize the private sector. A combination of the ceiling clause and the warranty option will therefore result in improved contract provision design. The proposed methodology in this study is especially useful for governments in properly determining contract clauses in infrastructure development.展开更多
Background:Overexpression of ATP-binding cassette(ABC)transporter is a major contributor to multidrug resistance(MDR),in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic drugs.In this work,...Background:Overexpression of ATP-binding cassette(ABC)transporter is a major contributor to multidrug resistance(MDR),in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic drugs.In this work,we evaluated the sensitizing effect of sitravatinib,a broad-spectrum tyrosine kinase inhibitor(TKI),on ATP-binding cassette subfamily B member 1(ABCB1)-and ATP-binding cassette subfamily C member 10(ABCC10)-mediated MDR.Methods:MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non-toxic concentrations.Tritium-labeled paclitaxel transportation,Western blotting,immunofluorescence analysis,and ATPase assay were carried out to elucidate the mechanism of sitravatinib-induced chemosensitization.The in vitro findings were translated into preclinical evaluation with the establishment of xenograft models.Results:Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10-mediated MDR.Our in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human-mouse chimeric model.Furthermore,sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ABCB1.Thus,sitravatinib could considerably enhance the intracellular concentration of anticancer drugs.Interestingly,no significant alterations of both expression level and localization of ABCB1 were observed.More importantly,sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1-mediated xenograft model without observable toxic effect.Conclusions:The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1.展开更多
文摘Governments at all levels are increasingly motivating the private sector to participate in infrastructure development using alternative project delivery methods to relieve financial burden. When designing contracts, governments usually offer incentives while requiring cost or time guarantee to balance project attractiveness to the private sector and fair protection of public interest. However, a practical and critical problem is how to properly design these provisions. Although previous studies have investigated the value of these provisions, a knowledge gap still exists with respect to methods of fairly and effectively designing such provisions. This study fills this gap by developing a methodology that analyzes the appropriateness of guarantee or warranty provisions for contracts. In this study, a contract reliability index is constructed, and a process of evaluating contract reliability is proposed. The New Mexico Highway 44 project, in which three warranty provision arrangements are investigated, is used as a case study to illustrate the analysis process. Results show that although a ceiling clause can effectively motivate the private sector to participate in the project, it sacrifices a significant amount of public benefits. By contrast, although a warranty option can protect public benefits, it cannot effectively incentivize the private sector. A combination of the ceiling clause and the warranty option will therefore result in improved contract provision design. The proposed methodology in this study is especially useful for governments in properly determining contract clauses in infrastructure development.
基金supported by NIH(No.1R15GM116043-01)National Natural Science Foundation of China(No.81872901)as well as some supports from Department of Pharmaceutical Sciences,St.John’s University.
文摘Background:Overexpression of ATP-binding cassette(ABC)transporter is a major contributor to multidrug resistance(MDR),in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic drugs.In this work,we evaluated the sensitizing effect of sitravatinib,a broad-spectrum tyrosine kinase inhibitor(TKI),on ATP-binding cassette subfamily B member 1(ABCB1)-and ATP-binding cassette subfamily C member 10(ABCC10)-mediated MDR.Methods:MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non-toxic concentrations.Tritium-labeled paclitaxel transportation,Western blotting,immunofluorescence analysis,and ATPase assay were carried out to elucidate the mechanism of sitravatinib-induced chemosensitization.The in vitro findings were translated into preclinical evaluation with the establishment of xenograft models.Results:Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10-mediated MDR.Our in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human-mouse chimeric model.Furthermore,sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ABCB1.Thus,sitravatinib could considerably enhance the intracellular concentration of anticancer drugs.Interestingly,no significant alterations of both expression level and localization of ABCB1 were observed.More importantly,sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1-mediated xenograft model without observable toxic effect.Conclusions:The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1.
