Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

ABSTRACT This paper is based on a practical project jointly conducted by a major trucking company and a renowned operations research consulting firm. It studies a large-scale, real-time truckload pickup and delivery problem. A number of cost factors are carefully measured such as loaded/empty travel distance, travel time, crew labor, equipment rental or operational cost, and revenue for completing the movements. This paper proposes a generalized decomposition algorithm that is capable of considering sophisticated business rules. The goal is to recommend executable and efficient truck routing decisions to minimize operating costs. Numerical tests are conducted with operational data from J.B.HUNT. A fleet of 5,000 trucks is considered in this experiment. The test result not only shows significant cost savings but also demonstrates computational efficiency for real-time application.

ABSTRACT This paper presents a case study of table reservation practice for restaurant business within Walt Disney World. A unique feature here is to consider table combination to capture revenue potentials from different party sizes and at different time periods. For example, a party of large size can be served by combining two or more small tables. A mixed integer programming (MIP) model is developed to make the reservation recommendation. We propose a rolling horizon reservation policy such that the value of a particular table is periodically evaluated and updated. This is a typical revenue management method in the airlines and other industries, the essence of which is to compare the future expected revenue with a currently offered price. Using historical data, numerical test shows a significant revenue improvement potential from our proposed model.

Background and aims: Statins are reported to have a beneficial effect on portal hypertension (PTH); however, the exact mechanism remains unknown. Hepatic stellate cells (HSCs) can be activated by transforming growth factor beta (TGFβ) and play an important role in angiogenesis leading to PTH. Statins potently stimulate the transcription factor, Kruppel-like factor 2 (KLF2), which can negatively regulate angiogenesis. Our present study aimed to investigate the anti-angiogenic potential of statins in HSCs through the KLF2 pathway. Method: TGFβ-induced human HSCs were exposed to simvastatin. Cell viability and proliferation were determined by MTT and BrdU-proliferation assays, respectively. Cell migration was investigated using a transwell and wound-healing assays. Gene quantification was measured by real-time polymerase chain reaction. Protein expression was detected by western blot analysis and immunohistochemistry. Inflammatory factors were measured using enzyme-linked immunosorbent assays. Result: Simvastatin was found to reduced cell migration and proliferation and inhibit expression of alpha smooth muscle actin in TGFβ-induced HSCs. Furthermore, simvastatin promoted already increased mRNA and protein levels of KLF2 in TGFβ-induced HSCs. In accordance with KLF2 overexpression, simvastatin increased production of endothelial nitric oxide synthesis (eNOS) and downregulated expression of some proangiogenic proteins, such as vascular endothelial growth factor, hypoxia inducible factor-1a and nuclear factor-kappa B in TGFβ-induced HSCs. At the same time, secretion of interferon-gamma increased in TGFβ induced HSCs, which was decreased by simultaneous addition of simvastatin. Conclusion: Simvastatin suppressed the proangiogenic environment of HSCs activated by TGFβ, and KLF2 pathway is involved in the course.