HDAC6-G3BP2 promotes lysosomal-TSC2 and suppresses mTORC1 under ETV4 targeting-induced low-lactate stress in non-small cell lung cancer.

TSC-mTORC1 inhibition-mediated translational reprogramming is a major adaptation mechanism upon many stresses, such as low-oxygen, -ATP, and -amino acids. But how cancer cells hijack the adaptive pathway to survive under low-lactate stress when targeting glycolysis-related signaling remains uncertain. ETV4 is an oncogenic transcription factor frequently dysregulated in human cancer. We previously found that ETV4 is associated with tumor progression and poor prognosis in non-small cell lung cancer (NSCLC). In this study, we report that ETV4 controls HK1 expression and glycolysis-lactate production to activate mTORC1 by relieving TSC2 repression of Rheb in NSCLC cells. Targeting ETV4-induced low-lactate stress is an important input for TSC2 to inhibit mTORC1 and global protein synthesis, while the core stress granule components G3BP2 and HDAC6 are selectively translated. Mechanistically, G3BP2 recruits lysosomal-TSC2 to suppress mTORC1. HDAC6 deacetylates TSC2 to sustain protein stability and associates with G3BP2 to facilitate more recruiting of TSC2 to inactivate mTORC1. In addition, the microtubule retrograde transport activity of HDAC6 drives the aggregate-like perinuclear-mTOR distribution paralleled by lower mTORC1 activity under stress. Thus, HDAC6-G3BP2 is the key complex that promotes lysosomal-TSC2 and suppresses mTORC1 when targeting ETV4, which might represent a critical adaptive mechanism for cell survival under low-lactate challenges.

Point and interval prediction of crude oil futures prices based on chaos theory and multiobjective slime mold algorithm.

Crude oil is the most important energy source in the world, and fluctuations in oil prices can significantly influence investors, companies, and governments. However, crude oil prices have numerous characteristics, including randomness, sudden structural changes, intrinsic nonlinearity, volatility, and chaotic nature. This makes the accurate forecasting of crude oil prices a difficult and challenging task. In this paper, a hybrid prediction model for crude oil futures prices is proposed, the accuracy and robustness of which are demonstrated via controlled experiments and sensitivity analysis. This study uses a new data denoising method for data processing to improve the accuracy and stability of the predictions of crude oil prices. Furthermore, the chaotic time-series prediction method, shallow neural networks, linear model prediction methods, and deep learning methods are adopted as submodels. The results of interval forecasts with narrow widths and high prediction accuracies are derived by introducing a confidence interval adjustment coefficient. The results of the simulation experiments indicate that the proposed hybrid prediction model exhibits higher accuracy and efficiency, as well as better robustness of the forecasting than the control models. In summary, the proposed forecasting framework can derive accurate point and interval forecasts and provide a valuable reference for the price forecasting of crude oil futures.

Trend analysis and obstacle factor of inter provincial water resources carrying capacity in China: from the perspective of decoupling pressure and support capacity.

The high distribution of water resources among provinces in China considerably impacts the development of society and economy in each region. Thus, it is of great practical significance to examine the water resources carrying capacity (WRCC) of each Chinese province. This paper constructs a comprehensive evaluation index system for the WRCC from two aspects: pressure and support. First, it analyzes dynamic changes in the WRCC of 31 Chinese provinces in China by using the decoupling model (DM). Second, it analyzes the key factors that hinder the improvement of WRCC by using the obstacle degree model (ODM). The study found that there are significant inter-provincial differences in China's WRCC. Provinces with greater natural water resources have a higher WRCC. Under the condition of similar natural water resources, WRCC in economically developed provinces is higher. From 2008 to 2015, China's overall WRCC has been increasing. Moreover, three-fifth of China's provinces can be classified as Upward-type (Upward I, Upward II, and Upward III) provinces and their WRCC is in a good state by considering the decoupling type and trend of WRCC in two periods together. The main obstacle factors hindering the improvement of the WRCC are total water resources ([Formula: see text]), water supply per capita ([Formula: see text]), total water supply ([Formula: see text]), forest cover rate ([Formula: see text]), soil erosion control area ([Formula: see text]), water consumption saving ([Formula: see text]), and water usage penetration rate ([Formula: see text]). This study can provide a scientific basis for understanding change trend of WRCC in Chinese provinces and improve their WRCC.

A fast-linear mixed model for genome-wide haplotype association analysis: application to agronomic traits in maize.

BACKGROUND: Haplotypes combine the effects of several single nucleotide polymorphisms (SNPs) with high linkage disequilibrium, which benefit the genome-wide association analysis (GWAS). In the haplotype association analysis, both haplotype alleles and blocks are tested. Haplotype alleles can be inferred with the same statistics as SNPs in the linear mixed model, while blocks require the formulation of unified statistics to fit different genetic units, such as SNPs, haplotypes, and copy number variations. RESULTS: Based on the FaST-LMM, the fastLmPure function in the R/RcppArmadillo package has been introduced to speed up genome-wide regression scans by a re-weighted least square estimation. When large or highly significant blocks are tested based on EMMAX, the genome-wide haplotype association analysis takes only one to two rounds of genome-wide regression scans. With a genomic dataset of 541,595 SNPs from 513 maize inbred lines, 90,770 haplotype blocks were constructed across the whole genome, and three types of markers (SNPs, haplotype alleles, and haplotype blocks) were genome-widely associated with 17 agronomic traits in maize using the software developed here. CONCLUSIONS: Two SNPs were identified for LNAE, four haplotype alleles for TMAL, LNAE, CD, and DTH, and only three blocks reached the significant level for TMAL, CD, and KNPR. Compared to the R/lm function, the computational time was reduced by ~ 10-15 times.

Therapeutic drug monitoring and safety of voriconazole in elderly patients.

BACKGROUND: Data on therapeutic drug monitoring of voriconazole in elderly patients are limited. Impaired liver function and an inflammatory state in elderly individuals are hypothesized to impact the voriconazole serum level. METHODS: A total of 166 adult patients (317 trough concentrations) who underwent voriconazole therapeutic drug monitoring were enrolled. The voriconazole trough concentration, its associated covariates, and its correlation with adverse effects in 73 elderly (≥60 years) patients (116 trough concentrations) were analyzed and compared to those in 93 adult (<60 years) patients. RESULTS: The voriconazole trough concentration was 4.31 ± 3.03 µg/mL (range, 0.4-15.5 µg/mL) in the elderly patients, which was significantly higher than the 3.11 ± 2.13 µg/mL (range, 0.4-14.3 µg/mL) in the adult patients (P = 0.001). The proportion of voriconazole trough concentrations higher than 5 µg/mL was 35.3% in the elderly patients, which was also significantly higher than the 15.4% in the adult patients (P < 0.001). A stepwise multivariable linear regression model showed that procalcitonin and gamma-glutamyl transpeptidase were independently associated factors in the elderly patients (OR = 2.590, 95% confidence interval [CI] = 1.506-3.673, P = 0.001; OR = -0.016, 95% CI = -0.027 to -0.006, P = 0.005). Receiver operating characteristic (ROC) curve analysis indicated that procalcitonin concentrations of ≥1.31 ng/mL increased the incidence of a voriconazole trough concentration higher than 5 µg/mL (95% CI = 0.53-0.87 µg/mL) (P = 0.03). The incidence of decreased albumin concentrations was higher in the elderly cohort than that in the adult cohort independent of the voriconazole trough concentration (P < 0.05). CONCLUSIONS: The voriconazole trough concentrations in the elderly patients were significantly higher than those in the adult patients who received voriconazole therapy and were significantly affected by severe inflammation as evaluated by the procalcitonin concentration. Frequent monitoring of the voriconazole serum concentration and procalcitonin concentration during and after severe inflammation is critical to maintain the voriconazole serum concentration within the therapeutic range.

Short-term differences in drug prices after implementation of the national essential medicines system: A case study in rural Jiangxi Province, China.

OBJECTIVES: China's 2009 national essential medicine system (NEMS) was designed to reduce prices through a zero-markup policy and a centralized bidding system. To analyze NEMS's short-term impact on drug prices, we estimated the retail and wholesale prices before and after the reform at health institutions in rural Jiangxi Province. MATERIALS AND METHODS: We undertook two cross-sectional surveys of prices of 39 medicines in November 2008 and May 2010, calculated inflation adjusted prices, and used the Wilcoxon signed-rank and rank-sum tests to examine price changes at different health institutions. RESULTS: Retail prices at pilot (P < 0.01) and nonpilot (P < 0.01) township health centers decreased significantly, whereas the declines at retail pharmacies (P = 0.57) and village clinics (P = 0.29) were insignificant. The decline at pilot township health centers was the largest, compared with other kinds of health institutions (P < 0.01). Retail prices of essential and non-essential medicines declined significantly at pilot facilities (P < 0.05); price drops for non-essential medicines occurred only at pilot facilities (P < 0.05). No significant decline of wholesale prices were found at pilot (P = 0.86) and nonpilot units (P = 0.18), retail pharmacies (P = 0.18), and village clinics (P = 0.20). The wholesale prices changes at pilot units before and after the reform were higher than at nonpilot public units (P < 0.05), retail pharmacies (P < 0.05), and village clinics (P < 0.05). CONCLUSION: While the NEMS zero-markup policy significantly reduced retail prices at pilot health institutions, the centralized bidding system was insufficient to lower wholesale prices. A drug price management system should be constructed to control medicine prices and a long-term price information system is needed to monitor price changes.

[Pharmacokinetics and tissue distribution of irinotecan hydrochloride nanoparticles].

To investigate the pharmacokinetics of irinotecan hydrochloride (CPT-11) in rats and the tissue distribution of CPT-11 in mice after injection of irinotecan hydrochloride nanoparticles (CPT-11 NPs) via tail veins, separately, a LC-MS/MS method was established to determine the concentration of CPT-11 in whole blood of rats and in different tissues of mice. The pharmacokinetics and tissue distribution of CPT-11 were compared after the intravenous injection of CPT-11 NPs and CPT-11 solution. Compared with CPT-11 solution, the elimination half-life of CPT-11 was prolonged from 2.28 h to 3.95 h after the intravenous injection of CPT-11 NPs, and its AUC was 1.47 times than that of CPT-11 solution. After the injection of CPT-11 NPs in mice, the concentrations of CPT-11 loaded in CPT-11 NPs were significantly higher in the whole blood, colon and lungs than those in CPT-11 solution, but lower in the spleen, liver, kidney and heart, but the least in brain. CPT-11 NPs could improve CPT-11 's AUC, and help CPT-11 to reach long circulation activity.

[Pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in Beagle dogs].

The object of this study is to investigate the pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in healthy adult Beagle dogs following single and multiple oral dose administration. A randomized, cross-over study was conducted with nine healthy adult Beagle dogs assigned to three groups. Each group was arranged to take atorvastatin calcium (A), pioglitazone hydrochloride (B), atorvastatin calcium and pioglitazone hydrochloride (C) orally in the first period, to take B, C, A in the second period, and to take C, A, B in the third period for 6 days respectively. The blood samples were collected at the first and the sixth day after the administration, plasma drug concentrations were determined by LC-MS/MS, a one-week wash-out period was needed between each period. The pharmacokinetic parameters of drug combination group and the drug alone group were calculated by statistical moment method, calculation of C(max) and AUC(0-t) was done by using 90% confidence interval method of the bioequivalence and bioavailability degree module DAS 3.2.1 software statistics. Compared with the separate administration, the main pharmacokinetic parameters (C(max) and AUC(0-t)) of joint use of pioglitazone hydrochloride and atorvastatin calcium within 90% confidence intervals for bioequivalence statistics were unqualified, the mean t(max) with standard deviation used paired Wilcoxon test resulted P > 0.05. There was no significant difference within t1/2, CL(int), MRT, V/F. Pioglitazone hydrochloride and atorvastatin calcium had pharmacokinetic interaction in healthy adult Beagle dogs.