Modeling Three-dimensional Invasive Solid Tumor Growth in Heterogeneous Microenvironment under Chemotherapy

A systematic understanding of the evolution and growth dynamics of invasive solid tumors in response to different chemotherapy strategies is crucial for the development of individually optimized oncotherapy. Here, we develop a hybrid three-dimensional (3D) computational model that integrates pharmacokinetic model, continuum diffusion-reaction model and discrete cell automaton model to investigate 3D invasive solid tumor growth in heterogeneous microenvironment under chemotherapy. Specifically, we consider the effects of heterogeneous environment on drug diffusion, tumor growth, invasion and the drug-tumor interaction on individual cell level. We employ the hybrid model to investigate the evolution and growth dynamics of avascular invasive solid tumors under different chemotherapy strategies. Our simulations reproduce the well-established observation that constant dosing is generally more effective in suppressing primary tumor growth than periodic dosing, due to the resulting continuous high drug concentration. In highly heterogeneous microenvironment, the malignancy of the tumor is significantly enhanced, leading to inefficiency of chemotherapies. The effects of geometrically-confined microenvironment and non-uniform drug dosing are also investigated. Our computational model, when supplemented with sufficient clinical data, could eventually lead to the development of efficient in silico tools for prognosis and treatment strategy optimization.Comment: 41 pages, 8 figure

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

The aim of this study is to investigate the effects of CYP3A4 genetic polymorphisms on the metabolism of cyclosporine (CsA) in vitro and identify drugs that interact with CsA. An enzymatic incubation system was developed to evaluate the kinetic parameters of CYP3A4 on CsA catalysis. A total of 132 drugs were screened to identify potential drug–drug interactions. Sprague–Dawley rats were used to determine the interaction between CsA and nimodipine and nisoldipine. The metabolite AM1 was measured by ultra-performance liquid chromatography–tandem mass spectrometry. The results demonstrate that 16 CYP3A4 variants (CYP3A4.7, 8, 9, 12, 13, 14, 16, 18, 19, 23, 24, 28, 31, 32, 33, and 34) have a lower metabolic capacity for CsA, ranging from 7.19% to 72.10%, than CYP3A4.1. In contrast, the relative clearance rate of CYP3A4.5 is significantly higher than that of CYP3A4.1. Moreover, CYP3A4.20 loses its catalytic ability, and five other variants have no significant difference. A total of 12 drugs, especially calcium channel blockers, were found to remarkably inhibit the metabolism of CsA with an inhibitory rate of over 80%. Nimodipine inhibits the activity of CsA in rat liver microsomes with an IC50 of 20.54 ± 0.93 μM, while nisoldipine has an IC50 of 16.16 ± 0.78 μM. In in vivo, three groups of Sprague–Dawley rats were administered CsA with or without nimodipine or nisoldipine; the AUC(0-t) and AUC(0-∞) of CsA were significantly increased in the nimodipine group but not obviously in the nisoldipine group. Mechanistically, the inhibition mode of nimodipine on cyclosporine metabolism is a mixed inhibition. Our data show that gene polymorphisms of CYP3A4 and nimodipine remarkably affect the metabolism of CsA, thus providing a reference for the precise administration of CsA

Realization of high-dynamic-range broadband magnetic-field sensing with ensemble nitrogen-vacancy centers in diamond

We present a new magnetometry method integrating an ensemble of nitrogen-vacancy (NV) centers in a single-crystal diamond with an extended dynamic range for monitoring the fast changing magnetic-field. The NV-center spin resonance frequency is tracked using a closed-loop frequency locked technique with fast frequency hopping to achieve a 10 kHz measurement bandwidth, thus, allowing for the detection of fast changing magnetic signals up to 0.723 T/s.This technique exhibits an extended dynamic range subjected to the working bandwidth of the microwave source. This extended dynamic range can reach up to 4.3 mT, which is 86 times broader than the intrinsic dynamic range. The essential components for NV spin control and signal processing such as signal generation, microwave frequency control, data processing and readout are integrated in a board-level system. With this platform, we demonstrate broadband magnetometry with an optimized sensitivity of 4.2 nT-Hz-1/2. This magnetometry method has the potential to be implemented in a multichannel frequency locked vector magnetometer suitable for a wide range of practical applications such as magnetocardiography and high-precision current sensors.Comment: 18 pages, 9 figure

Effects of Chronic Disease Diagnoses on Alcohol Consumption among Elderly Individuals—Longitudinal Evidence from China

OBJECTIVES: This study estimates the effect of chronic disease diagnoses (CDDs) on elderly Chinese individuals’ alcohol consumption behaviour. SUBJECTS AND PARTICIPANTS: Our analysis was applied to a publicly available dataset that covers 5724 individuals aged 50 or above and spans 15 years (2000–2015: six waves) from the China Health and Nutrition Survey. DESIGN: The outcome variables are elderly individuals’ weekly consumption of alcoholic beverages: beer, red wine, Chinese spirits and total alcohol intake. The explanatory variable of primary interest is the number of chronic diseases diagnosed (including hypertension, diabetes, stroke and myocardial infarction). Other covariates concern sample individuals’ sociodemographic and health-related characteristics. A Chamberlain-Mundlak correlated random-effect Tobit model is adopted to simultaneously account for the clustering of ‘zeros’ in the outcome variable and endogeneity issues such as omitted variables and reverse causality. RESULTS: Our estimation suggests that, on average, an additional chronic disease diagnosed by medical doctors reduced an elderly Chinese individual’s weekly consumption of beer, red wine and Chinese spirits, respectively, by 1.49 (95% CI −2.85 to –0.13), 0.93 (95% CI −1.63 to –0.23) and 0.89 (95% CI −1.23 to –0.54) ounces. These effects translate into a reduction of 0.95 (95% CI −1.29 to –0.60) ounces in total weekly alcohol consumption and a reduction of 24% (95% CI −0.35 to –0.14) in the incidence of excessive drinking. Further explorations suggest that elderly Chinese individuals’ alcohol consumption is most responsive to diabetes and stroke diagnoses, but the effects vary across different beverages. Moreover, males, rural residents, smokers and those living with non-drinkers respond to CDDs more strongly than their respective counterparts. CONCLUSION: While CDDs reduced alcohol consumption among elderly Chinese individuals, they failed to stop all heavy drinkers from excessive drinking. Relevant policies and measures are thus needed to urge heavy drinking patients to quit excessive drinking