Prediction of ROS1 and TRKA/B/C occupancy in plasma and cerebrospinal fluid for entrectinib alone and in DDIs using physiologically based pharmacokinetic (PBPK) modeling approach.

PURPOSE: Entrectinib (ENT) is a potent c-ros oncogene 1(ROS1) and neurotrophic tyrosine receptor kinase (NTRKA/B/C) inhibitor. To determine the optimum dosage of ENT using ROS1 and NTRKA/B/C occupancy in plasma and cerebrospinal fluid (CSF) in drug-drug interactions (DDIs), physiologically-based pharmacokinetic (PBPK) models for healthy subjects and cancer population were developed for ENT and M5 (active metabolite). METHODS: The PBPK models were built using the modeling parameters of ENT and M5 that were mainly derived from the published paper on the ENT PBPK model, and then validated by the observed pharmacokinetics (PK) in plasma and CSF from healthy subjects and patients. RESULTS: The PBPK model showed that AUC, Cmax, and Ctrough ratios between predictions and observations are within the range of 0.5-2.0, except that the M5 AUC ratio is slightly above 2.0 (2.34). Based on the efficacy (> 75% occupancy for ROS1 and NTRKA/B/C) and safety (AUC < 160 µM·h and Cmax < 8.9 µM), the appropriate dosing regimens were identified. The appropriate dosage is 600 mg once daily (OD) when administered alone, reduced to 200 mg and 400 mg OD with itraconazole and fluconazole, respectively. ENT is not recommended for co-administration with rifampicin or efavirenz, but is permitted with fluvoxamine or dexamethasone. CONCLUSION: The PBPK models can serve as a powerful approach to predict ENT concentration as well as ROS1 and NTRKA/B/C occupancy in plasma and CSF.

Carbon Reduction and Pollutant Abatement by a Bio-Ecological Combined Process for Rural Sewage.

In order to explore the treatment effect of a bio-ecological combined process on pollution reduction and carbon abatement of rural domestic wastewater under seasonal changes, the rural area of Lingui District, Guilin City, Guangxi Province, China was selected to construct a combined process of regulating a pond, biological filter, subsurface flow constructed wetland, and ecological purification pond. The influent water, effluent water, and the characteristics of pollutant treatment in each unit were investigated. The results showed that the average removal rates of COD, TN, and NH3-N in summer were 87.57, 72.18, and 80.98%, respectively, while they were 77.46, 57.52, and 64.48% in winter. There were significant seasonal differences in wastewater treatment results in Guilin. Meanwhile, in view of the low carbon:nitrogen ratio in the influent and the poor decontamination effect, the method of adding additional carbon sources such as sludge fermentation and rice straw is proposed to strengthen resource utilization and achieve carbon reduction and emission reduction. The treatment effect of ecological units, especially constructed wetland units, had a high contribution rate of TN treatment, but it was greatly impacted by seasons. The analysis of the relative abundance of the microbial community at the phylum level in constructed wetlands revealed that Proteobacteria, Acidobacteria, Chloroflexi, Firmicutes, Bacteroidetes, Planctomycetota, and Actinobacteria were the dominant phyla. The relative abundance of microbial communities of Proteobacteria, Chloroflexi, and Acidobacteria decreased to a large extent from summer to winter, while Firmicutes, Bacteroidetes, and Planctomycetota increased to varying degrees. These dominant bacteria played an important role in the degradation of pollutants such as COD, NH3-N, and TN in wetland systems.

Emission dynamics of greenhouse gases regulated by fluctuation of water level in river-connected wetland.

The application of reservoirs in the upper reaches of rivers will change the hydrological rhythm of river-connected wetlands in the lower reaches, causing changes in the distribution of wetland vegetation. The differences of carbon and nitrogen sequestration and emission potential in different vegetations may lead to the dynamics of greenhouse gas emissions from wetlands during hydrological periods. For a wetland connected to the Yangzi River, China, the dynamic changes of vegetation and water areas were identified by remote sensing, and the water level, the emission fluxes of greenhouse gases and the functional bacteria of carbon and nitrogen in soil were measured in-situ. Compared with drought period, the area of phragmites zone in flooding period increased by 28.2%, while the areas of carex and phalaris zones decreased by 42.9%. The carbon and nitrogen accumulation in the soil of phragmites zone is the highest, while the cumulative amount of phalaris is the lowest. The emission fluxes of CH4 and N2O in mud/water and various vegetations were positively correlated with water level and reached the maximum during flooding period. Although the global warming potential of mud/water was highest than that of vegetations, carex zone had the highest warming potential among vegetation zones. CH4 contributes 8-37 times as much as N2O to global warming potential in the wetland. The increase of flooding time promoted the emissions of CH4 and N2O in the wetland. The anaerobic condition caused by flooding stimulated the activities of denitrifying and methanogenic bacteria, thus increasing the emission of greenhouse gases. The sequestrations and emissions of carbon and nitrogen regulated by a reservoir in the upstream suggest that the operation of water conservancies should be considered to alleviate the greenhouse gas emission from river-connected wetland.

Tidal variation and litter decomposition co-affect carbon emissions in estuarine wetlands.

Estuarine wetlands play important roles in the regional and global carbon cycle as well as greenhouse gas emissions; however, the driving factors and potential carbon emissions mechanisms are unclear. Here, the carbon emission fluxes were investigated in situ from different vegetated areas in the Chongming wetlands. The results showed that the highest methane (CH4) and carbon dioxide (CO2) emissions of 178.1 and 21,482.5 mg∙m-2∙min-1 were in Scirpus mariqueter and Phragmites australis dominated areas, respectively. A series of microcosms was strategically designed to simulate the influence of tidal variation on carbon emissions and the litter decomposition on daily- and monthly-timescales in estuarine wetlands. All added litter promoted CH4 and CO2 emissions from the wetland soils. The CH4 and CO2 emission fluxes of the S. mariqueter treatment were higher (367.7 vs. 108.4; 1607.9 vs. 1324.3 mg∙m-2∙min-1) than those of the P. australis treatment without tidal variation on a monthly timescale, due to the higher total organic carbon (TOC) content of S. mariqueter. The decomposition of litter also released a large amount of nutrients, which enhanced the abundance of methane-producing archaea (MPA) and methane-oxidizing bacteria (MOB). However, the tidal water level was negatively correlated with CH4 and CO2 emission fluxes. The CH4 and CO2 emission fluxes in the S. mariqueter treatment at the lowest tide were 556.02 and 604.99 mg∙m-2∙min-1, respectively. However, the CH4 and CO2 emission fluxes did not change significantly on the daily timescale in the S. mariqueter treatment without tidal variations. Therefore, the prolonged timescales revealed increases in litter decomposition but a decrease in the contribution of tidal variations to carbon emissions in estuarine wetlands. These findings provide a theoretical basis for evaluating the carbon cycle in estuarine wetlands.

Migration of antibiotic ciprofloxacin during phytoremediation of contaminated water and identification of transformation products.

Phytoremediation is an effective and environmentally friendly approach to treat antibiotic contaminated water, however, the mechanisms of migration and transformation of antibiotics in plant tissues are still far from clear. In this study, the floating macrophyte Eichhornia crassipes was exposed to a series of antibiotic ciprofloxacin (CIP) concentrations. The results showed that the CIP was taken up and accumulated in the roots, which were the major accumulative tissue. CIP content increased with lipid content. During cultivation, the root bioconcentration factor (RCF) gradually increased. The average CIP content detected in aerial parts was 12.80 µg g-1, an order of magnitude lower than in the roots. At low CIP concentrations, the highest leaf bioconcentration factor (LCF) and transfer factor (TF) indicated highly efficient translocation from roots to aerial parts. The soluble protein growth rate of leaves, which is associated with metabolic activity, increased following CIP exposure. Overall, eight major transformation products in E. crassipes tissues were identified, and three possible transformation pathways were proposed involving the processes of desethylation, dehydroxylation, oxidation, hydroxylation and cleavage of the piperazine and quinoline rings. These findings could prove beneficial for improving the management or amelioration methods used for treating water contaminated with antibiotics.