Search

This paper proposes a new variant of particle swarm optimization (PSO), namely, multiple learning PSO with space transformation perturbation (MLPSO-STP), to improve the performance of PSO. The proposed MLPSO-STP uses a novel learning strategy and STP. The novel learning strategy allows each particle to learn from the average information on the personal historical best position ( pbest ) of all particles and from the information on multiple best positions that are randomly chosen from the top 100 p % of pbest . This learning strategy enables the preservation of swarm diversity to prevent premature convergence. Meanwhile, STP increases the chance to find optimal solutions. The performance of MLPSO-STP is comprehensively evaluated in 21 unimodal and multimodal benchmark functions with or without rotation. Compared with eight popular PSO variants and seven state-of-the-art metaheuristic search algorithms, MLPSO-STP performs more competitively on the majority of the benchmark functions. Finally, MLPSO-STP shows satisfactory performance in optimizing the operating conditions of an ethylene cracking furnace to improve the yields of ethylene and propylene. [ABSTRACT FROM AUTHOR]

HY0721 is a novel inhibitor of sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. The study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. The administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. This study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. ChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Objective: Erenumab is the first-in-class, selective, and competitive human monoclonal antibody antagonist of the calcitonin gene-related peptide (CGRP) receptor that has been shown to be effective and well-tolerated in the preventive therapy of episodic and chronic migraine. The pharmacokinetics of erenumab may be affected by differences in race and ethnicity, which can lead to suboptimal outcomes. The present study was conducted to assess the single-dose pharmacokinetics and safety of erenumab in healthy Chinese subjects. Methods: This was an open-label, randomized, parallel group, non-confirmatory, single-dose study in healthy Chinese subjects. A total of 24 healthy Chinese subjects of both sexes aged between 14 and 45 years were administered a single subcutaneous injection of erenumab 70 mg or 140 mg. The serum concentration of erenumab was quantified using a validated enzyme-linked immunosorbent assay method and pharmacokinetic parameters were determined using non-compartmental models. Safety was also assessed. Results: A total of 55 subjects were screened for eligibility and 25 subjects were randomized to receive study treatments (12 subjects to the 70-mg erenumab group and 13 subjects to the 140-mg erenumab group). Erenumab was absorbed slowly with maximum serum concentration (Cmax) occurring 3–11 days after administration. The mean Cmax and area under the serum concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase (AUC0-∞) were 9.20 µg/mL and 296 day·µg/mL for the 70 mg dose group, and 15.6 µg/mL and 569 day·µg/mL for the 140 mg dose group, respectively. Serum concentrations of erenumab exhibited low to high variability, with variable coefficients ranging from 17.1 to 72.2% for the 70-mg dose and 32.5 to 88.5% for the 140-mg dose. All adverse events were mild or moderate in intensity, and all resolved without intervention. Conclusions: Erenumab was safe and well tolerated after a single subcutaneous injection in healthy Chinese subjects. The systemic exposure in Chinese subjects in terms of AUC0-∞ was 70% higher than that in White subjects as previously reported. Chinese Clinical Trial Registry no.: ChiCTR2000032435. [ABSTRACT FROM AUTHOR]

• There are dense adsorption layers of cation near the GO surface. • The imidazole rings and alkyl side chains mostly paralleled to GO surface. • The confined IL/GO system is more favorable for capturing gases than bulk IL. • The larger layer spacing reduces dissolution selectivity and enhances diffusion selectivity. • [Bmim][TF 2 N]/GO membrane presents high dissolution and diffusion selectivity for CO 2 /CH 4. Ionic liquids (ILs)/graphene oxide (GO) membranes have been regarded as a prospective alternative in CO 2 separation. However, the correlation between the microstructure of ILs/GO and CO 2 separation performance is unclear. In this work, the dynamic properties and interactions for CO 2 /CH 4 in 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF 6 ]), 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF 4 ]) and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Bmim][TF 2 N]) confined between two GO sheets with different layer spacings were studied using molecular dynamics simulation. The number density and angular orientation of cations suggest that there is a dense cation adsorption layer near GO with the imidazole rings and alkyl side chains mostly paralleled to GO surface. The strong interaction of GO-cations weakens the interaction of cations-anions, facilitating the adsorption of CO 2. The overlapping distribution regions of the number density of CO 2 /CH 4 with the cations and anions reveal that CO 2 /CH 4 mainly distribute around the ILs area of the ILs/GO membrane, which improves the gas selectivity. The RDFs results of CO 2 /CH 4 -ILs indicate that the confined ILs/GO system is more favorable for capturing gases than bulk ILs. The stronger interaction of CO 2 -anions/cations and the faster diffusion of CO 2 than CH 4 reflect the high solubility selectivity and diffusion selectivity for CO 2 /CH 4 in ILs/GO membrane. In addition, it was found that decreasing the layer spacing would increase the solubility selectivity, but could decrease the diffusion selectivity. However, solubility selectivity plays a dominant role, thus 2 nm is the optimal layer spacing. Furthermore, the low viscosity ILs were found to be beneficial to improve the diffusion selectivity. Finally, [Bmim][TF 2 N]/GO membrane is predicted to possess superior CO 2 /CH 4 separation performance than [Bmim][PF 6 ]/GO and [Bmim][BF 4 ]/GO membranes. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Pharmacokinetics and Safety of Erenumab after a Single Subcutaneous Injection Dose in Healthy Chinese Subjects." The correction addresses mistakes in the original article, specifically regarding the comparison of systemic exposure in Chinese and White subjects. The corrected details clarify that the comparison was based on a study of limited sample size and should not be generalized to the broader population. Other factors such as safety, efficacy, and variability of exposure should also be considered for ethnic comparison. The correction also acknowledges the contribution of the China NIBR team to the study. [Extracted from the article]

Covalent organic framework (COF) membranes show great potential for gas separation, but their large pore size make it hard to effectively separate gases with similar kinetic diameters. A promising strategy is to cover the surface of COF membranes with an ultrathin film of ionic liquids (ILs) to improve the selectivity of gas permeation. Here, we investigated the CO 2 /CH 4 separation performance of composite membranes composed of COF (CTF-1) and 20 kinds of ILs, respectively, using molecular simulations. The [C 4 mim][PF 6 ]/COF membrane is found to exhibit the best separation performance, with CO 2 permeability up to 7.93 × 104 GPU and CO 2 /CH 4 selectivity of 12.33 when the IL thickness is 8 Å. By studying the microstructure of the composite membrane, it was found that there is a relatively dispersed distribution of cations and anions on the COF surface, which is beneficial to the diffusion of gas molecules. The gas permeation process results reveal that CO 2 rapidly achieves equilibrium in both the adsorption and dissolution layers simultaneously, thereby enhancing the permeation rate of gas molecules. The analysis of interaction energy and PMF indicates that the improved selectivity is due to the stronger interaction between IL and CO 2 than that for CH 4. [Display omitted] • 20 types of ultrathin IL-covered COF membranes for separating CO 2 /CH 4 were proposed. • [C 4 mim][PF 6 ]/COF membrane exhibits the highest separation performance. • The dispersed and uniform ionic distribution on the COF surface permits rapid gas diffusion. • The stronger IL-CO 2 interaction compared to CH 4 enhances selectivity. [ABSTRACT FROM AUTHOR]

We report the design and simple fabrication process of a perfect absorber based on carbon nanotube films, which enable omnidirectional high absorption efficiency over the wavelength range from 250 nm to 20 μm with polarization independence. The absorber is fabricated using layers of super-aligned carbon nanotube (SACNT) films assembled in a unique manner, which could be easily prepared on stretchable or rigid substrates or suspended. The promising absorption characteristics of the SACNT films were attributed to not only the intrinsic optical properties of the carbon nanomaterials but also the unique surface nanostructures that efficiently trapped light. Moreover, the absorber and its fabrication method exhibit excellent compatibility with various composed materials and treatment processes. Through combination with ultraviolet-curable resist, a robust, ultrathin, and ultralight absorber with good mechanical properties was fabricated on stretchable substrates. The developed fabrication method opens a new path to realize high absorption performance using carbon nanomaterials and the obtained absorber has broad prospects in aerospace and military applications. Image 1 [ABSTRACT FROM AUTHOR]

Intravenous ibuprofen, a nonsteroidal anti-inflammatory drug, is widely used as an antipyretic and analgesic in adults and children. This study was designed to evaluate ethnic differences by comparing the pharmacokinetics of intravenous ibuprofen in Caucasian and Chinese populations using physiologically based pharmacokinetics (PBPK) modeling and simulation. A PBPK model for intravenous ibuprofen was developed in adults and children utilizing the Simcyp Simulator. The model was tested and verified against published literature and unpublished data obtained from the Caucasian adult population, Caucasian pediatric population and Chinese adult population. The developed PBPK model could adequately pilot the pharmacokinetics of intravenous ibuprofen, and the major observed values were within the 90% prediction interval in both adults and children. Both folding errors of the maximum peak concentration (C max) and area under the concentration–time curve (AUC) were 1.5-fold less in the Caucasian and Chinese populations. In addition, no significant differences in weight-normalized C max and AUC were observed between the Caucasian and Chinese adult populations. Moreover, there were no obvious pharmacokinetic differences between the Caucasian and Chinese pediatric populations with intravenous infusion (10 minutes) of 10 mg/kg by age group. This study indicates that the pharmacokinetic profile and the parameters of intravenous ibuprofen are analogous in Caucasian and Chinese populations, either adults or children. In addition, this study provides effective evidence that the dosing scheme of intravenous ibuprofen in Chinese children can remain the same as the regimen that the original company (Caldolor®) provided. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • The monolayer nanoporous graphene oxide supported ionic liquid membrane was proposed. • The NPGO-[EMIM][TF 2 N] membrane has a CO 2 permeance of ∼104 GPU and no CH 4 passed with 11 Å thickness. • The cations are suspended above the pore center to dynamically modulate the pore size. • The enhanced selectivity is attributed to the synergistic effect of cations and anions. Nanoporous graphene oxide (NPGO) with a single atomic layer thickness and good mechanical strength has been regarded as a promising candidate in gas separation. However, it is challenging to precisely control the pore size to match the target gas. In this work, the pore size was modulated by supporting ionic liquid (IL) on the monolayer NPGO membrane (NPGO-SILM). The separation performance and mechanism for CO 2 /CH 4 in NPGO-[EMIM][BF 4 ], NPGO-[EMIM][PF 6 ] and NPGO-[EMIM][TF 2 N] were investigated by molecular dynamics simulation. It was found that the pore size of NPGO greatly affects the permeability and selectivity, and 5.6 Å is the most suitable pore size. After coating IL on NPGO, the CO 2 /CH 4 selectivity is obviously enhanced. With the IL thickness increasing from 5 to 11 Å, the CO 2 permeance decreased from ∼105 to ∼104 GPU, while the selectivity increased, and almost no CH 4 passed through the membrane with 11 Å thickness. Among the studied three types of ILs, the NPGO-[EMIM][TF 2 N] membrane shows the best CO 2 /CH 4 separation performance due to the strongest adsorption capacity between [TF 2 N] anion and CO 2. The interaction energy, PMF and probability distribution results suggest that the improved selectivity is attributed to the synergistic effect of cations and anions. The anions are responsible for the adsorption of large amounts of CO 2. At the same time, the cations are mainly distributed around the center of the NPGO pore because of the strong interaction between cation and NPGO, which would be favorable for dynamically adjusting pore size to allow the passage of CO 2 and prevent CH 4 from passing through the membrane. [ABSTRACT FROM AUTHOR]

The ethylene cracking furnace system is crucial for an olefin plant. Multiple cracking furnaces are used to convert various hydrocarbon feedstocks to smaller hydrocarbon molecules, and the operational conditions of these furnaces significantly influence product yields and fuel consumption. This paper develops a multiobjective operational model for an industrial cracking furnace system that describes the operation of each furnace based on current feedstock allocations, and uses this model to optimize two important and conflicting objectives: maximization of key products yield, and minimization of the fuel consumed per unit ethylene. The model incorporates constraints related to material balance and the outlet temperature of transfer line exchanger. The self-adaptive multiobjective teaching-learning-based optimization algorithm is improved and used to solve the designed multiobjective optimization problem, obtaining a Pareto front with a diverse range of solutions. A real industrial case is investigated to illustrate the performance of the proposed model: the set of solutions returned offers a diverse range of options for possible implementation, including several solutions with both significant improvement in product yields and lower fuel consumption, compared with typical operational conditions. [ABSTRACT FROM AUTHOR]

• Unidirectional inversion of ibuprofen enantiomers in Chinese neonates is unclear. • High-throughput UHPLC-MS/MS method to determine ibuprofen enantiomers. • Unexpected pharmacokinetics profile of rac -ibuprofen in Chinese preterm neonates with PDA. Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) – tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 μm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d 3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 μg/mL to 50.00 μg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA. [ABSTRACT FROM AUTHOR]

Parameters identification of photovoltaic (PV) model based on measured current-voltage characteristic curves plays an important role in the simulation and evaluation of PV systems. To accurately and reliably identify the PV model parameters, a self-adaptive teaching-learning-based optimization (SATLBO) is proposed in this paper. In SATLBO, the learners can self-adaptively select different learning phases based on their knowledge level. The better learners are more likely to choose the learner phase for improving the population diversity, while the worse learners tend to choose the teacher phase to enhance the convergence rate. Thus, learners at different levels focus on different searching abilities to efficiently enhance the performance of algorithm. In addition, to improve the searching ability of different learning phases, an elite learning strategy and a diversity learning method are introduced into the teacher phase and learner phase, respectively. The performance of SATLBO is firstly evaluated on 34 benchmark functions, and experimental results show that SATLBO achieves the first in ranking on the overall performance among nine algorithms. Then, SATLBO is employed to identify parameters of different PV models, i.e., single diode, double diode, and PV module. Experimental results indicate that SATLBO exhibits high accuracy and reliability compared with other parameter extraction methods. [ABSTRACT FROM AUTHOR]

The ethylene cracking furnace system is central to an olefin plant. Multiple cracking furnaces are employed for processing different hydrocarbon feeds to produce various smaller hydrocarbon molecules, such as ethylene, propylene, and butadiene. We develop a new cyclic scheduling model for a cracking furnace system, with consideration of different feeds, multiple cracking furnaces, differing product prices, decoking costs, and other more practical constraints. To obtain an efficient scheduling strategy and the optimal operational conditions for the best economic performance of the cracking furnace system, a diversity learning teaching-learning-based optimization (DLTLBO) algorithm is used to simultaneously determine the optimal assignment of multiple feeds to different furnaces, the batch processing time and sequence, and the optimal operational conditions for each batch. The performance of the proposed scheduling model and the DLTLBO algorithm is illustrated through a case study from a real-world ethylene plant: experiments show that the new algorithm out-performs both previous studies of this set-up, and the basic TLBO algorithm. [ABSTRACT FROM AUTHOR]

• The ultrathin-IL-covered MXene membrane was proposed. • The [BMIM][TF 2 N]/MXene membrane has a CO 2 permeance of up to 104 GPU, and no N 2 passed. • The permselectivity of the composite membrane is dominated by the diffusion selectivity. • The excellent CO 2 /N 2 separation performance is ascribed to the synergistic effect of IL on the surface of MXene and anions in the nanoslit. MXene-based membranes exhibit great potential in the gas separation but still suffer from the poor selectivity for gases with similar dynamic diameters, such as CO 2 and N 2. Here, we propose a prototype of composite membrane in atomistic scale theoretically, which is constructed by covering MXene with an ultrathin layer of ionic liquid (IL) and potentially has very good performance on the separation of CO 2 /N 2 mixtures. A series of molecular dynamics simulations were carried out to investigate the influences of the MXene-slit width and the IL-film thickness on CO 2 /N 2 separation performance. The gas separation performance is significantly enhanced after covering the IL film, and the IL-film thickness acts as a major factor to determine the performance. With the amounts of the IL increased from one to two layers, the CO 2 permeance decreases from 2.3 × 104 to 2.6 × 103 GPU, while the N 2 permeance declines more sharply, resulting in an increased selectivity. Compared to the IL-film thickness, the MXene-slit width has less influence on the gas permeance. However, the CO 2 /N 2 selectivity decreases as the slit width enlarges. Finally, we concluded that the composite membrane composed of the MXene with 8 Å slit and 40 pairs of IL (about one and a half layers) exhibits the best CO 2 /N 2 separation performance, with the CO 2 permeance up to 104 GPU, and no N 2 passing through the membrane during the simulations. Furthermore, the interaction of gas-membrane and the penetration process of gas were also investigated. The excellent CO 2 /N 2 separation performance is ascribed to the synergistic effect of IL on the surface of the MXene and anions in the slit. [ABSTRACT FROM AUTHOR]

• A UPLC–MS/MS method for quantitative analysis of valsartan, sacubitril and its major metabolite in human plasma, urine and peritoneal dialysis fluid were developed and validated. • This is the first report on a UPLC–MS/MS method for the simultaneous determination of valsartan, sacubitril and LBQ657 concentration in peritoneal dialysis fluid. • This method allowed to better characterize the pharmacokinetic of sacubitril/ valsartan in peritoneal dialysis patients with end-stage renal disease and provided evidence that peritoneal dialysis had an effect on the clearance of sacubitril/valsartan. Sacubitril/valsartan was indicated for the treatment of heart failure and hypertension in patients with end-stage renal disease on peritoneal dialysis therapy. Herein, a rapid, sensitive and robust method based on ultra-liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) was developed and validated for the determination of the concentrations of valsartan, sacubitril and its major metabolite LBQ657 in plasma, urine and peritoneal dialysis fluid. Samples were extracted from various biological fluids using protein precipitation. Extracts were subjected to UPLC–MS/MS with electrospray ionization in positive-ion mode. The developed method was fully validated over a concentration range of 8.00–8000 ng/mL for valsartan, 2.00–2000 ng/mL for sacubitril and 30.0–30,000 ng/mL for LBQ657 in plasma, 2.00–1000 ng/mL for valsartan, 1.00–500 ng/mL for sacubitril and 20.0–10000 ng/mL for LBQ657 in urine, and 0.200–100 ng/mL for valsartan, 0.0400–20.0 ng/mL for sacubitril and 2.00–1000 ng/mL for LBQ657 in peritoneal dialysis fluid. The intra- and inter-day precisions for all analytes in various matrices were less than 12.3%, and the intra- and inter-day accuracies results were all between 88.0% and 109.2%. All analytes were stable for at least 8 h at room temperature (25°C), five freeze–thaw cycles, and 37 days at −40°C and −80°C in plasma, urine and peritoneal dialysis fluid. In conclusion, this developed method is reliable, sensitive and specific for determining the concentrations of valsartan, sacubitril and LBQ657 in plasma, urine and peritoneal dialysis fluid. The assay was available to pilot the pharmacokinetics study of sacubitril/valsartan in patients with end-stage renal disease on peritoneal dialysis, and it could provide evidence that peritoneal dialysis had an effect on the clearance of sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

• A sensitive and robust UPLC–MS/MS method for simultaneous quantification of lidocaine, monoethylglycinexylidide (MEGX) and glycinexylidideme (GX) in human plasma was developed and fully validated. • A simple one-step protein precipitation method was used for the pretreatment of plasma sample. • The fully validated UPLC–MS/MS method was successfully applied to the clinical pharmacokinetics study of lidocaine in liver cancer patients undergoing laparoscopic hepatectomy. • Our results demonstrated that the reasons why the metabolism of lidocaine and MEGX were slightly prolonged might be related to the duration of hepatic blood flow occlusion. Lidocaine, widely used as a local anesthetic, has anti-inflammatory and inhibitory effects on tumor recurrence and metastasis. To investigate the pharmacokinetics of lidocaine in liver cancer patients undergoing laparoscopic hepatectomy, a fast and sensitive analytical technique was developed. The method was adequately validated with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) to simultaneously determine the concentration of lidocaine and its metabolites in plasma. The chromatographic separation was achieved on an Acquity UPLC BEH C 18 column (2.1 × 50 mm, 1.7 µm) by gradient elution with a mobile phase of A (formic acid–water (1:1000, v/v)) and B (formic acid-acetonitrile (1:1000, v/v)). The accuracy and precision were verified within the concentration ranges of 10–5000 ng/mL for lidocaine, 2–1000 ng/mL for monoethylglycinexylidide (MEGX) and 2–500 ng/mL for glycinexylidide (GX). The selectivity, carry-over effect, interference between the analytes and internal standard (IS), precision and accuracy, matrix effect extraction recovery, dilution integrity and stability were satisfactory for the relevant guideline standards. The method was successfully applied to the pharmacokinetic study of lidocaine in liver cancer patients undergoing laparoscopic hepatectomy. After receiving a bolus and continuous infusion, the mean peak concentration of lidocaine was 2097 ng/mL for lidocaine, 336.6 ng/mL for MEGX and 72.66 ng/mL for GX, respectively. The mean peak time was 2.89 h for lidocaine, 5.14 h for MEGX and 9.88 h for GX, respectively. In addition, the mean half-life was 4.19 h for lidocaine and 6.92 h for MEGX. In this study, we found that the metabolism of lidocaine and MEGX might be affected by the hepatic blood flow occlusion or liver injury. [ABSTRACT FROM AUTHOR]

The ionic liquids (ILs) have been widely used in many areas. However, because of its hydrophilicity, it is very difficult to be purified and recycled, which is one of the great puzzles to the scientific community. In order to study water absorption and desorption of ILs, the free energy of a water molecule crossing IL plate was calculated in this work. As the vapor-liquid interface is necessary for the hydrophilicity of ILs, the vapor-liquid interface for 1-butyl-3-methylimidazolium tetrafluoroborates([Bmim][BF 4 ])-water system was also studied by molecular dynamics simulations. It is very interesting to find that there is a good linear relationship between surface tension and water content in the interface layer, although it was reported that there is a nonlinear relationship between the surface tension and the water content of ILs aqueous solution. Our calculation is based on the composition at the interface, while the latter is based on the total water content. It was worth mentioning that water tended to be distributed in the inner layer of the interface, while IL was distributed in the outer layer of the interface, and the alkyl chain pointed to the vapor phase. The above findings could explain the nonlinear change of surface tension with total water content in the literature. The change rule of interface structure with water content was investigated by means of number density distribution and angle distribution. Besides, the excess chemical potential of the vapor-liquid phase was calculated, and the free energy of one water molecule crossing the IL slab has also been calculated. • The water absorption and desorption process in 4 kinds of imidazole ILs were analyzed through potential of mean force (PMF). • A good linear relationship between surface tension and water content in the interface layer was found. • The nonlinear change of surface tension with total water content was explained at molecular level. • Number density distribution and angle distribution were investigated to depict the interface structure. [ABSTRACT FROM AUTHOR]

In the field of solar photovoltaic (PV) systems, the accurate and reliable extraction of parameters from PV models is crucial for effective simulation, evaluation, and control. Although various optimization algorithms have been widely used for parameter extraction in solar PV systems, the accuracy and reliability of the parameters extracted by these methods usually fall short of the expected standards. To address these shortcomings, a novel hybrid algorithm that combines the improved marine predators algorithm (MPA) with the equilibrium optimizer (EO), named IMPAEO, is proposed. In the IMPAEO, an elite opposition-based learning strategy is introduced to expand the exploration range of the algorithm to enhance population diversity; an adaptive weight coefficient is employed to improve the updating rule of the MPA, facilitating a balance between global exploration and local exploitation; the EO operator is integrated to enhance the performance of the MPA in the local exploitation phase to improve the solution quality and convergence speed; and the linear population size reduction (LPSR) technique is introduced to dynamically reduce the population size and improve the search performance. The effectiveness of the proposed IMPAEO is validated using the CEC2017 benchmark test suite, which is also applied to extract parameters of the single diode model, the double diode model, and three different PV modules. Comparative analysis with other algorithms demonstrates that the IMPAEO exhibits significant advantages in terms of solution quality, convergence speed, and algorithm stability. Consequently, the proposed IMPAEO not only proves to be efficient and reliable in parameter extraction for solar PV models but also offers a promising alternative in this field., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

It remains unclear whether dosage adjustment of intravenous lidocaine is necessary during general anesthesia for elderly patients over 75 years old. This study aimed to investigate the effects of age on the pharmacokinetics (PK) and safety of intravenous lidocaine in patients undergoing general anesthesia. A total of 599 plasma samples were collected from 76 general anesthesia patients across three age groups: 18-64, 65-74, and ≥ 75 years. Lidocaine was administered intravenously at a dose of 1.5 mg/kg for the 18-64 and 65-74 years groups, while the dose was adjusted to 1.0 mg/kg for the ≥ 75 years group. The plasma concentrations of lidocaine and its active metabolites were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were analyzed using a noncompartmental analysis. The results revealed no significant age-related differences in the PK of lidocaine and its metabolites. Among the three age groups, over 90 % of patient achieved a lidocaine concentration within a safe and effective range when the dosage was normalized to 1.5 mg/kg. In conclusion, age-based dosage adjustment was unnecessary for intravenous lidocaine in patients below 86 years undergoing general anesthesia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

With the knowledge of female reproductive tract microbiota gradually increasing, the connection between vaginal microbiota (VMB) and its related diseases is increasingly highlighted. Manifestation of VMB keeps changing with various dominated bacteria, which can affect the immune response of mucosal barrier and the entrance of pathogens. Human papillomavirus (HPV), as an oncogenic virus, is closely related to viral-associated cancer, such as cervical cancer. According to HPV infection status, VMB can transform into different types, and result in accelerating or restraining the progression of diseases, which have exposed the inner link between VMB and HPV. Therefore, probiotics therapy promises to be a new complementary therapy to rebuild a healthy VMB for patients, but there's still a long way to go before its ready for the clinic. This review focuses on composition, immune response, and application of VMB in HPV and its associated diseases and aims to provide the new ideas and directions for the research on VMB., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy., Methods: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy., Results: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 μg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 μg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007., Conclusion: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Flexible robots (FRs) are generally designed to be lightweight to achieve rapid motion. However, accompanying vibrations and modeling errors influence tracking control, especially in situations involving reference signal loss. This article develops a two-time scale primal-dual inverse reinforcement learning (PD-IRL) framework for FRs to perform tracking tasks with incomplete reference signals. First, consider the admissible policy as a nonconvex input constraint to guarantee the stable operation of the equipment. Then, FRs imitate the demonstration behaviors of an expert, including both rigid and flexible motions, to achieve a balance in tracking speed and vibration suppression. During the imitation process, nonconvex optimization problems of FRs are transformed into corresponding dual problems to obtain the global optimal policy. Moreover, employing multiple linearly independent paths to explore the state space simultaneously can improve convergence speed. Convergence and stability are studied rigorously. Finally, simulations and comparisons show the effectiveness and superiority of the proposed method.

There is presently no efficient dose individualization strategy for the use of antiseizure medications in epileptic pregnant patients. This study aimed to develop a population pharmacokinetics model for levetiracetam and propose a tailored adaptive individualized dosage strategy for epileptic pregnant patients. A total of 322 levetiracetam plasma concentrations from 238 patients with epilepsy were included, including 216 women with epilepsy (20.83% of whom were pregnant). The levetiracetam plasma concentration was measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were modeled using a nonlinear mixed-effects model. The resultant model served as the basis for simulating the dosage adjustment strategy. A one-compartment model with first-order elimination best described the pharmacokinetic data of levetiracetam. The apparent clearance (CL/F) was 3.43 L/h (95% CI 3.30-3.56) and the apparent volume of distribution was 43.7 L (95% CI 40.4-47.0) for a typical individual of 57.2 kg. Pregnancy and body weight were found to be significant covariates of CL/F of levetiracetam. The recommended regimen of levetiracetam could be predicted by the population pharmacokinetic model based on body weight, gestational age, and the daily dose of levetiracetam taken before pregnancy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Meropenem is an ultrabroad-spectrum antimicrobial agent that is often recommended for the treatment of bacterial meningitis (BM) in children. However, a subtherapeutic phenomenon occurred in BM children complicated with augmented renal clearance (ARC) at the recommended dose of meropenem. To support its pharmacokinetics, a sensitive, fast and robust ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to measure meropenem concentrations in serum and cerebrospinal fluid (CSF). The method involved protein precipitation, and samples were diluted with a large proportion of water to eliminate solvent effects. The separation of samples was performed on a Waters Acquity™ BEH C 18 column (2.1 × 50 mm i.d., 1.7 μm) with a gradient profile. The mobile phases were formic acid-water (1:1000, v/v) and acetonitrile. The linear range was good, with a concentration range of 0.100-100 μg/mL for serum and 0.0400-20.0 μg/mL for CSF. The intra-day and inter-day precisions were less than 8.0%, and the intra-day and inter-day accuracies varied -6.6% from 6.5% for the both serum and CSF. The selectivity, carry-over, dilution integrity, matrix effect, recovery and stability were validated according to international guidelines. The developed UPLC-MS/MS method successfully determined the meropenem concentrations in the serum and CSF of children with BM complicated with ARC. The results indicated that under the recommended dosing regimen (40 mg/kg every 8 h), the time to reach the effective treatment target of 50%T > MIC was only approximately 3 h and lower CSF concentrations of meropenem were observed in children with BM with ARC., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zhenlei Wang reports financial support was provided by National Natural Science Foundation of China. Zhenlei Wang reports financial support was provided by Sichuan Science and Technology Program. Cuiyao He reports financial support was provided by Chongqing Science and Health Joint Medical Scientific Research Project. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Although levetiracetam (LEV) has favorable linear pharmacokinetic properties, therapeutic drug monitoring (TDM) is necessary for pregnant women with epilepsy. This study aims to build a simple, reliable, and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining LEV concentrations in plasma and saliva samples, to support the routine TDM of LEV in Chinese pregnant women with epilepsy. The stable isotope-labeled LEV-d 6 was used as the internal standard. The extracted samples were analyzed using a UPLC-MS/MS system with positive electrospray ionization. Mobile phase A was water containing 5 mM ammonium acetate and 0.1% formic acid, and phase B was 1:1 methanol-acetonitrile with 0.1% formic acid. The method was validated and utilized to determine LEV concentrations in non-pregnant and pregnant patients with epilepsy. The developed method was validated in both plasma and saliva samples over a concentration range of 0.1-50 μg/mL. The intra- and inter-batch accuracy for LEV ranged from -7.0% to 2.9%, with precisions between 2.7% and 9.3%. In pregnant patients, the mean dose-standardized LEV trough plasma concentrations were significantly lower than those in non-pregnant patients (4.73 ± 2.99 vs. 7.74 ± 3.59 ng/mL per mg/day; P < 0.0001). It is recommended that the TDM of LEV should be routinely performed during the different stages of pregnancy., (© 2023 John Wiley & Sons, Ltd.)

Purpose: The search for effective and low-risk treatment methods for colorectal cancer (CRC) is a pressing concern, given the inherent risks and adverse reactions associated with traditional therapies. Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment, offering advantages such as non-radiation, non-invasiveness, and targeted treatment. Consequently, the development of nanoparticles with high stability, biocompatibility, and photothermal effects has become a significant research focus within the field of PTT., Methods: In this study, TiO 2 -Ti 3 C 2 nanocomposites were synthesized and characterized, and their photothermal conversion efficiency in the near-infrared region II (NIR-II) was determined. Then studied the in vivo and in vitro photothermal activity and anti-tumor effect of TiO 2 -Ti 3 C 2 in human colorectal cancer cell lines and nude mice subcutaneous tumor model., Results: The results showed that TiO 2 -Ti 3 C 2 nanocomposites have strong absorption ability in the NIR-II, and have high photothermal conversion efficiency under 1064 nm (0.5 W/cm 2 , 6 min) laser stimulation. In addition, in vitro experiments showed that TiO 2 -Ti 3 C 2 nanocomposites significantly inhibited the invasion, migration, and proliferation of colorectal cancer cells, and induced cell apoptosis; in vivo, experiments showed that TiO 2 -Ti 3 C 2 nanocomposites-mediated PTT had good biocompatibility and efficient targeted inhibition of tumor growth., Conclusion: In conclusion, TiO 2 -Ti 3 C 2 nanocomposites can be used as NIR-II absorption materials in PTT to suppress the invasion, migration, and proliferation of colorectal cancer cells, induce colorectal cancer cell apoptosis, and thus inhibit the development of CRC. Therefore, TiO 2 -Ti 3 C 2 nanocomposites can be used as potential anti-tumor drugs for photothermal ablation of colorectal cancer cells., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Wang et al.)

This study aims to optimize the processing of Myristica fragrans Houtt. by talcum powder simmering using single-factor and orthogonal experimental methods, and the overall desirability values of dehydrodiisoeugenol and essential oils content were selected as indicators of the process. The new process reduced the total content of the three toxic components, namely myristicin, safrole and elemicin, from 1.91% to 1.16% before and after processing, indicating that the toxic components were reduced by 39%. The IC 50 of the essential oils before and after processing were 1.002 ± 0.05 and 0.233 ± 0.05 mg/mL for DPPH scavenging activity and 0.132 ± 0.04 and 0.057 ± 0.05 mg/mL for ABTS scavenging activity, respectively. And the absorbance of the antioxidant activity against Ferric reducing power ranged from 0.213 to 0.709 and from 0.225 to 0.755, respectively. The minimum inhibitory concentration for Staphylococcus aureus , Bacillus pumilus and Escherichia coli were all lower after processing than before. The antioxidant activity and antibacterial activity of the essential oils after processing were better than before. The results of the survival of zebrafish embryos at different concentrations of essential oils at 0-168 h post fertilisation were higher after processing than before. These findings suggest that processing plays the role of reducing toxicity and increasing beneficial effects. They provide a scientific basis not only for the processing of M. fragrans , but also for the processing of other foods.

Background: By observing the changes of lung imaging airway structure in patients with advanced lung squamous cell carcinoma（ALUSC）, the relationship between the different types of COPD pulmonary structural remodeling and the prognosis of patients with ALUSC was analyzed., Methods: We reviewed the medical records of 278 patients with ALUSC. The degree of emphysema and the percentage of bronchial wall thickness（WT%） on chest HRCT were calculated by Synapse3D software, Lung structural remodeling can be divided into there types: airway remodeling dominated, emphysema dominated, and mixed types., Results: Compared with the diagnosis, the Goddard score increased, the proportion of airway remodeling dominated type decreased and the proportion of mixed type increased during the progression of ALUSC. In Kaplan-Meier analysis, whether with or without COPD, the mPFS and mOS of patients with mixed type were the shortest, and the difference was statistically significant. Univariate and multivariate Cox proportional hazard regression analysis showed that mixed type was an independent risk factor for poor PFS and OS in patients with ALUSC., Conclusion: Patients with ALUSC all have varying degrees of lung structural remodeling, and patients with mixed lung structural remodeling have the worst prognosis. In addition, the aggravation of emphysema during tumor progression is more pronounced than the thickening of the airway wall, and the changes of emphysema was more powerful in predicting the progression of ALUSC.Clinicians must pay more attention to the changes of COPD (especially emphysema) in the process of diagnosis and treatment of ALUSC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: Kukoamine B (KB) is a novel sepsis therapeutic drug targeting lipopolysaccharide and CpG DNA. This study aims to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple doses of KB in healthy volunteers., Methods: Healthy volunteers were randomized at a 1:1:1:1 ratio to receive multiple intravenous infusion doses of KB 0.06 mg/kg, 0.12 mg/kg, 0.24 mg/kg or placebo (administered every 8 h per day) for 7 days and subsequently followed up for another 7 days at Peking Union Medical College Hospital. Primary endpoints were adverse events (AEs), and the secondary endpoints were PK parameters of the first administration and the last administration., Results: Data of the 18 health volunteers in KB groups and 6 in the placebo group were pooled and analyzed. AEs occurred in 12 (66.67%) volunteers in the KB groups and 4 (66.67%) volunteers in the placebo group. Treatment-related adverse events (TRAEs) occurred in 8 (44.44%) volunteers in the KB groups and 2 (33.33%) volunteers in the placebo group. Hypertriglyceridemia (4 [22.22%] vs. 2 [33.33%]) and sinus bradycardia (3 [16.67%] vs. 0) were the most common AEs. The mean elimination half-life, clearance, and distribution volume of KB were 3.40-4.88 h, 9.35-13.49 L/h, and 45.74-101.90 L, respectively. The average accumulation ratios of area under the plasma concentration-time curve and maximum plasma concentration were 1.06 and 1.02, respectively., Conclusion: Single and multiple intravenous infusions of KB at a dose range of 0.06-0.24 mg/kg are safe and tolerable in healthy volunteers., Trial Registration: ClinicalTrials.gov identifier, NCT02690961., (© 2023. The Author(s).)

Due to the mismatch between the quarter-wave plate and the wavelength of the light source, the circularly polarized field photoelastic stress analysis method has an impact on the measurement of the phase delay and the stress direction angle. In particular, the measurement of the phase delay is inaccurate for weakly stressed samples with phase delays less than a quarter-wavelength. In this paper, we first give a method for calculating the mismatch value δ , which requires only one air calibration without prior calibration of the parameters of the quarter-wave plate with other equipment. We then introduce δ into the correction process for the phase delay, derive the correction equation, and give a theoretical comparison of the relative error curves. The results show that the correction method can theoretically limit the maximum amount of error. Finally, we have verified the accuracy of the method by measurements of the internal lens stress before and after the correction and by stitching measurements on SiC wafers.

Coagulation with aluminum salts is an important method for fluoride removal from groundwater. However, the hydration of aluminum salts generating a large number of H + usually leads to limited defluorination performance due to the optimum pH of active aluminum phase for fluoride removal around 5.5-6.5. In this work, enhanced fluoride removal from groundwater through precise regulation of active aluminum phase by CaCO 3 was investigated. Precipitation products were characterized by XPS, FTIR, XRD, and SEM, respectively, and the mechanism of the high fluoride removal efficiency was discussed and compared with the traditional coagulation of Al 2 (SO 4 ) 3 . In the Al 2 (SO 4 ) 3  + CaCO 3 (ASCC) system, CaCO 3 can stably regulate the pH at the optimum range for active aluminum phase existence and has the best fluoride removal effect. CaCO 3 accurately regulated the activity of the aluminum phase by slowly releasing OH - and fine tuning pH, thereby achieving effective fluoride removal. Undissolved CaCO 3 particles exist as the carrier of defluorination flocs to accelerate precipitation and improve stability. The work here provides a new method for fluoride removal and may shed light on the application of CaCO 3 coagulants for other pollutants., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

LncRNAs and metabolism represents two factors involved in cancer initiation and progression. However, the interaction between lncRNAs and metabolism remains to be fully explored. In this study, lncRNA FEZF1-AS1 (FEZF1-AS1) was found upregulated in colon cancer after screening all the lncRNAs of colon cancer tissues deposited in TCGA, the result of which was further confirmed by RNAscope staining on a colon tissue chip. The results obtained using FEZF1-AS1 knockout colon cancer cells (SW480 KO and HCT-116 KO) constructed using CRISPR/Cas9 system confirmed the proliferation, invasion, and migration-promoting function of FEZF1-AS1 in vitro . Mechanistically, FEZF1-AS1 associated with the mitochondrial protein phosphoenolpyruvate carboxykinase (PCK2), which plays an essential role in regulating energy metabolism in the mitochondria. Knockdown of FEZF1-AS1 greatly decreased PCK2 protein levels, broke the homeostasis of energy metabolism in the mitochondria, and inhibited proliferation, invasion, and migration of SW480 and HCT-116 cells. PCK2 overexpression in FEZF1-AS1 knockout cells partially rescued the tumor inhibitory effect on colon cancer cells both in vitro and in vivo . Moreover, PCK2 overexpression specifically rescued the abnormal accumulation of Flavin mononucleotide (FMN) and succinate, both of which play an important role in oxidative phosphorylation (OXPHOS). Overall, these results indicate that FEZF1-AS1 is an oncogene through regulating energy metabolism of the cell. This research reveals a new mechanism for lncRNAs to regulate colon cancer and provides a potential target for colon cancer diagnosis and treatment., Competing Interests: The authors declare no conflict of interest., (© 2021 Wang et al.)

C-005 is a novel third-generation EGFR tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (NSCLC). To support its clinical trial, we developed a rapid and sensitive bioanalytical method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique for the quantification of C-005 and its major metabolite in NSCLC patients following international bioanalytical guidelines. After a simple and quick protein precipitation step, the supernatant was injected to a Waters Acquity BEH C 18 column (2.1 × 50 mm i.d., 1.7 mm), and the column was eluted with a gradient of buffer A (5 mM ammonium acetate and 0.1% formic acid in water) and buffer B (formic acid-acetonitrile (1:1000, v/v)). The eluates were subsequently detected by an AB QTRAP 5500 mass spectrometer with electrospray ionization using multiple-reaction monitoring mode. The method showed good linearity from 2.00 to 1000 ng/mL for C-005 and 1.00 to 500 ng/mL for M1. In conclusion, the validation results demonstrated the robustness of the method and its well-poised to support the first-in-patient study of C-005 in NSCLC patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Hetrombopag, a novel, oral small molecule thrombopoietin receptor agonist, exhibits an obvious thrombocytopoietic effect with good safety. Hetrombopag is currently under clinical development for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). The objectives of this study were to assess the effect of high-fat and high-calorie food on the pharmacokinetic and pharmacodynamic (PK/PD) profiles of hetrombopag in healthy volunteers., Methods: An independent, single-dose, open-label, randomized-sequence, crossover trial was conducted. Healthy volunteers received hetrombopag 7.5-mg tablets in the fasted state or with a high-fat, high-calorie breakfast. The effects of the high-fat and high-calorie food on the PK/PD profiles of hetrombopag were evaluated by using a noncompartmental analysis and a semi-physiological model., Findings: Twelve Chinese healthy volunteers were enrolled. Mean plasma AUC 0-t and C max decreased by 98.7% and 95.0%, respectively, when hetrombopag was administered with high-fat and high-calorie food. The semi-physiological PK/PD model analysis showed that the absorption rate constant at the first absorption site was almost halved at the fed condition. The change in platelet counts in the fed condition was not sufficiently as sensitive as that in the fasted condition., Implications: High-fat and high-calorie food were associated with significantly reduced systemic exposure and platelet count sensitivity. Thus, hetrombopag should be taken in a fasted state to avoid the impact of food on bioavailability and platelet counts. ClinicalTrials.gov identifier: NCT02409394., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Idiopathic thrombocytopenic purpura (ITP) especially refractory and (or) relapsed ITP, is a serious and global health burden and its clinical treatment is far from being satisfied. Hetrombopag is a novel, small-molecule thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura (CITP)., Objectives: This first-in-patient study aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose of hetrombopag in CITP patients., Methods: In this multicenter, first-in-patient study, CITP patients received hetrombopag in a dose escalation (2.5 mg/day, 5 mg/day, or 7.5 mg/day) cohort. All patients received hetrombopag in fasting condition once daily for 2 weeks., Results: Of 44 patients screened, 32 were enrolled and treated. Most adverse events were graded 1 to 2 (ie, mild to moderate), and the incidence and severity were similar for three study cohorts. The pharmacokinetics of hetrombopag were found to be nonlinear with greater than dose-proportional: 12.5% of patients (1/8) in the 2.5 mg/d cohort, 58.3% of patients (7/12) in the 5 mg/d cohort, 66.7% of patients (8/12) in the 7.5 mg/d cohort reached the primary study endpoint of a platelet count exceeding 50 × 10 9 /L on day 28., Conclusion: Hetrombopag was well tolerated and preliminarily efficacious. Efficacy, safety, and pharmacokinetic data suggest that 7.5 mg hetrombopag once daily was the anticipated therapeutic dose of hetrombopag in CITP patients and has been recommended for investigation in a later confirmatory clinical study of hetrombopag., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: T lymphocytes play an indispensably important role in clearing virus and tumor antigen. There is little knowledge about impacts of inhibitory molecules with cytokine on tumor-infiltrating CD4 + T-cells in the presence of gastric cancer (GC). This study investigated the distribution of tumor-infiltrating T-cells subset and the differentiation as well as inhibitory phenotype of T-cells from blood and tissues of GC patients., Materials and Methods: Patients with GC diagnosed on the basis of pre-operative staging and laparotomy findings were approached for enrollment between 2014 and 2015 at the Affiliated Cancer Hospital of Zhengzhou University, China. Phenotypic analysis based on isolation of tumor-infiltrating lymphocytes and intracellular IFN-γ staining assay is conducted. Statistical analysis is performed to show significance., Results: The results showed that the percentage of CD4 + T-cells among CD3 + cells in tumors was significantly higher than that in the matched paraneoplastic tissue. CD4 + CD25 high CD127 low regulatory T-cells (Tregs), PD-1 + , Tim-3 + , and PD-1 + Tim-3 + cells were up-regulated on tumor infiltrating T-cells from patients with GC compared to their expressions on corresponding peripheral blood and peritumoral T-cells. Blockades of PD-1 + and Tim-3 + were effective in restoring tumor infiltrating T-cells' production of interferon-gamma (IFN-γ). Combined PD-1 + and Tim-3 + inhibition had a synergistic effect on IFN-γ secretion by CD4 + T-cells., Conclusion: The results suggested that the composition, inhibitors, and location of the immune infiltrate should be considered when evaluating antitumor immunotherapy. A new insight into the mechanisms underlying T cell dysfunction is provided.

Cortactin (CTTN) is overexpressed in various tumors, including head and neck squamous cell carcinoma and colorectal cancer (CRC), and can serve as a biomarker of cancer metastasis. We observed that CTTN promotes cancer cell proliferation in vitro and increases CRC tumor xenograft growth in vivo. CTTN expression increases EGFR protein levels and enhances the activation of the MAPK signaling pathway. CTTN expression also inhibits the ubiquitin-mediated degradation of EGFR by suppressing the coupling of c-Cbl with EGFR. CoIP experiments indicate CTTN can interact with c-Cbl in CRC cells. These results demonstrate that CTTN promotes the proliferation of CRC cells and suppresses the degradation of EGFR.

Although miR-542-3p has been found to be aberrantly downregulated in variety of human tumors, little is known about its role in colorectal cancer (CRC). This study was designed to assess the prognostic value of miR-542-3p in CRC by examining the expression profile of miR-542-3p in patients with CRC and investigate the possible molecular mechanism underlying the function of miR-542-3p. Our results showed that low levels of miR-542-3p were significantly associated with advanced tumor stage and lymph node metastasis and miR-542-3p can serve as an independent prognostic marker for CRC. Furthermore, ectopic induced expression of miR-542-3p significantly suppressed cell proliferation, induced apoptosis, inhibited migration and invasion in vitro and in vivo. Mechanistically, we identified OTUB1 as a direct and functional target for miR-542-3p, at least partly responsible for the anti-tumor effect of miR-542-3p in CRC. Our study demonstrates the importance of miR-524-3p/OTUB1 signaling in CRC development and suggests that targeting this signaling may highlight a new therapeutic approach for treatment of CRC.