Modulate synthesis of CeMn solid solution using various alcohols for toluene catalytic oxidation: synergistic effect of Ce-Mn and reaction mechanism.

A redox co-precipitation method was employed to synthesize CeMn homogeneous solid solutions, utilizing various alcohols as activating agents. Ethanol effectively orchestrated the precipitation of CeO2 and MnOx, promoting their co-growth. As a result, the CeMn-EA achieved 90 % toluene conversion at 218 â„ƒ (T90 =218 â„ƒ) with a weight hourly space velocity (WHSV) of 48000 ml/(g·h). It also demonstrated high adaptability to increased WHSV, suggesting its potential for industrial-scale applications. The uniform dispersion of Ce and Mn accelerated the coupling between Ce3+/Ce4+ and Mn4+/Mn3+, engineering numerous oxygen vacancies, which enhanced the activation of gas-phase oxygen and the mobility of lattice oxygen. In situ DRIFTS confirmed that toluene oxidation accommodated both Langmuir-Hinshelwood (L-H) and Mars-van Krevelen (MvK) mechanisms, with benzoate identified as a pivotal intermediate. Enhanced oxygen mobility facilitated the cleavage of the benzene ring, which was the rate-determining step. Additionally, the introduction of H2O significantly enhanced the dissociation and adsorption of toluene and facilitated the activation of gas-phase oxygen. At higher temperatures, H2O could further activate lattice oxygen engaging in toluene oxidation. ENVIRONMENTAL IMPLICATION: Volatile organic compounds (VOCs) have emerged as major air pollutants due to the changes in air pollution patterns. They can act as precursors to near-surface ozone and haze. Toluene, a typical VOC, is primarily released from anthropogenic sources and poses significant risks to human health and the environment. Ce-based catalysts have been demonstrated efficiency in toluene oxidation due to their excellent oxygen storage and release properties. This study synthesized CeMn homogeneous solid solutions utilizing various alcohols as activating agents, which possessed abundant oxygen vacancies and optimum oxygen activation capacity to oxidize toluene in time.

PIK3IP1: structure, aberration, function, and regulation in diseases.

Phosphoinositide 3-kinase (PI3K) pathway, controlling diverse functions in cells, is one of the most frequently dysregulated pathways in cancer. Several negative regulators have been reported to intricately constrain the overactivation of PI3K pathway. Phosphatidylinoinosidine-3-kinase interacting protein 1 (PIK3IP1), as a unique transmembrane protein, is a newly discovered negative regulator of PI3K pathway. PIK3IP1 negatively regulates PI3K activity by directly binding to the p110 catalytic subunit of PI3K. It has been reported that PIK3IP1 is frequently low expressed in tumors and autoimmune diseases. In tumor cells and impaired cardiomyocyte, PIK3IP1 inhibits cell proliferation and survival. Consistently, the expression of PIK3IP1 is related with the condition of cancer. In addition, PIK3IP1 inhibits the inflammatory response and immune function via maintaining the quiescent state of immune cells. Thus, low expression of PIK3IP1 represents the severe condition of autoimmune diseases. PIK3IP1 is regulated by transcription factors, epigenetic factors or micro-RNAs to facilitate its normal function in different cellular contexts. This review integrates the total findings on PIK3IP1 in different disease, and summaries the structure, biological functions and regulatory mechanisms of PIK3IP1.

Ce-based three-dimensional mesoporous microspheres with Mn homogeneous incorporation for toluene oxidation.

Ce-based three-dimensional (3D) mesoporous microspheres with Mn homogeneous incorporation were synthesized. The CeMn-0.4, characterized by a Ce/Mn molar ratio of 6:4, demonstrated exceptional catalytic activity and stability. The formation of CeMn solid solution strengthened the Ce-Mn interaction, yielding higher concentrations of Ce3+ and Mn4+. Mn4+ initiated toluene preliminary activation owing to its robust oxidative properties, while Ce3+ contributed to oxygen vacancy generation, enhancing the activation of gaseous oxygen and lattice oxygen mobility. Integrating experiments and Density Functional Theory (DFT) calculations elucidated the oxygen reaction mechanisms. A portion of oxygen was converted into surface reactive oxygen species (Oads) that directly oxidized toluene. Additionally, the presence of oxygen vacancies promoted the participation of oxygen in toluene oxidation by converting it into lattice oxygen, which was crucial for the deep oxidation of toluene. Diffuse Reflectance Fourier Transform Infrared Spectroscopy (DRIFTS) indicated the accumulation of benzene-ring intermediates on the catalyst surface hindered continuous toluene oxidation. Thus, the abundant oxygen vacancies in CeMn-0.4 played a pivotal role in sustaining the oxidation process by bolstering the activation of gaseous oxygen and the mobility of lattice oxygen.

The regulation mechanism of transition metal doping on Hg0 adsorption and oxidation on Ce/TiO2(001) surface: A DFT study.

The mercury oxidation performance of Ce/TiO2 catalyst can be further enhanced by transition metal modifications. This study employed density functional theory (DFT) calculations to investigate the adsorption and oxidation mechanisms of Hg0 on Ce/TiO2(001) and its transition metal modified surfaces. According to the calculation results, Ru-, Mo-, Nb-, and Mn-doping increased the affinity of the Ce/TiO2(001) surface towards Hg0 and HCl, thereby facilitating the efficient capture and oxidation of Hg0. The increased adsorption energy (Eads) of the intermediate HgCl on the modified surfaces could promote its conversion to the final product HgCl2. The modification of transition metals impeded the desorption of the final products HgCl2 and HgO, but it did not serve as the rate-determining step. The oxidation of Hg0 by lattice oxygen and HCl followed the Mars-Maessen and Langmuir-Hinshelwood mechanisms, respectively. HCl exhibited higher mercury oxidation ability than lattice oxygen. The reactivity of lattice oxygen could be further improved by doping transition metals, their promotion order was Ru > Nb > Mo > Mn. In a HCl atmosphere, Mn modification could significantly reduce the energy barrier for HCl activation and HgCl2 formation, providing the optimal enhancement for the mercury oxidation ability of Ce/TiO2 catalyst. The screening method of transition metal modified components based on surface adsorption reaction and oxidation energy barrier was proposed in this study, which provided theoretical guidance for the development of CeTi based catalysts with high mercury oxidation activity.

Lightweight, Flexible, and Thermal Insulating Carbon/SiO2 @CNTs Composite Aerogel for High-Efficiency Microwave Absorption.

A complex electromagnetic environment is a formidable challenge in national defense areas. Microwave-absorbing materials are considered as a strategy to tackle this challenge. In this work, lightweight, flexible, and thermal insulating Carbon/SiO2 @CNTs (CSC) aerogel is successfully prepared coupled with outstanding microwave absorbing performance, through freeze-drying and high-temperature annealing techniques. The CSC aerogel shows a strong reflection loss (-55.16 dB) as well as wide effective absorbing bandwidth (8.5 GHz) in 2-18 GHz. It also retains good microwave absorption properties under tension and compression. Radar cross-sectional (RCS) simulation result demonstrates the CSC processing a strong reduction ability of RCS compared with a metal plate. Further exploration shows amazing flexibility and good thermal insulation properties of CSC. The successful preparation of this composite aerogel provides a broad prospect for the design of microwave-absorbing materials.

Application of Northern Goshawk Back-Propagation Artificial Neural Network in the Prediction of Monohydroxycarbazepine Concentration in Patients with Epilepsy.

INTRODUCTION: A northern goshawk back-propagation artificial neural network (NGO-BPANN) model was established to predict monohydroxycarbazepine (MHD) concentration in patients with epilepsy. METHODS: The data were collected from 108 Han Chinese patients with epilepsy on oxcarbazepine monotherapy. The results of 14 genotype variates were selected as the input layer in the first BPANN model, and the variables that had a more significant impact on the plasma concentration of MHD were retained. With demographic characteristics and clinical laboratory test results, the genotypes of SCN1A rs2298771 and SCN2A rs17183814 were used to construct the BPANN model. The BPANN model was comprehensively validated and used to predict the MHD plasma concentration of five patients with epilepsy in our hospital. RESULTS: The model demonstrated favorable fitness metrics, including a mean squared error of 0.00662, a gradient magnitude of 0.00753, an absence of validation tests amounting to zero, and a correlation coefficient of 0.980. Sex, BMI, and the genotype SCN1A rs2298771 were ranked highest by the absolute mean impact value (MIV), which is primarily associated with the concentration of MHD. The test group exhibited a range of - 20.84% to 31.03% bias between the predicted and measured values, with a correlation coefficient of 0.941 between the two. With BPANN, the MHD nadir concentration could be predicted precisely. CONCLUSION: The NGO-BPANN model exhibits exceptional predictive capability and can be a practical instrument for forecasting MHD concentration in patients with epilepsy. CLINICAL TRIAL REGISTRATION: www.chiCTR-OOC-17012141 .

Physiologically Based Pharmacokinetic Modeling of Lacosamide in Patients With Hepatic and Renal Impairment and Pediatric Populations to Support Pediatric Dosing Optimization.

PURPOSE: Lacosamide (LCM) is a new-generation anti-seizure medication that is efficacious in patients with focal seizures with or without secondary generalization. Until now, the efficacy, safety, and tolerability of LCM are still lacking in Chinese epilepsy patients, particularly for pediatric populations and patients with renal or hepatic impairment. METHODS: This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model to characterize the pharmacokinetics of LCM in Chinese populations and predict the pharmacokinetics of LCM in Chinese pediatric populations and patients with renal or hepatic impairment. Using data from clinical investigations, the developed PBPK model was validated by comparing predicted and observed blood concentration data. FINDINGS: Doses should be reduced to approximately 82%, 75%, 63%, and 76% of the Chinese healthy adult dose in patients with mild, moderate, and severe renal impairment and end-stage renal disease; and approximately 89%, 72%, and 36% of the Chinese healthy adult dose in patients with Child Pugh-A, B, and C hepatic impairment. For pediatric populations, intravenous doses should be adjusted to 1.75 mg/kg for newborns, 2.5 mg/kg for toddlers, 2.2 mg/kg mg for preschool and school age, and 2 mg/kg mg for adolescents to achieve an equivalent plasma exposure of 2 mg/kg LCM in adults. The oral doses should be adjusted to 20 mg for toddlers, 32 mg for preschool, 45 mg for school age, and 95 mg for adolescents to achieve an approximately equivalent plasma exposure of 100 mg LCM in adults. IMPLICATIONS: The PBPK model of LCM can be utilized to optimize dosage regimens for special populations.

Direct Observation of the Mutual Coupling Effect in the Protein-Water-Glycerol Mixture by Combining Neutron Scattering and Selective Deuteration.

Numerous studies have discussed the impact of cosolvents on the structure, dynamics, and stability of proteins in aqueous solutions. However, the dynamics of cosolvents in the protein-water-cosolvent ternary system is largely unexplored in experiments due to technical difficulty. Consequently, a comprehensive understanding of the interplay among proteins, water, and cosolvents is still lacking. Here, we employed selective deuteration and neutron scattering techniques to characterize the individual motions of each component in the protein/water/glycerol (GLY) mixture across various temperatures. The consistent dynamic onset temperatures and the correlation between the MSD of the protein and the viscosity of solvents revealed the mutual coupling effects among the three components. Furthermore, our experimental and simulation results showed that the hydrogen bond relaxation energy barrier in the ternary system is ∼43 kJ/mol, whereas in the protein-water binary system it is merely ∼35 kJ/mol. Therefore, we suggest that GLY can enhance hydrogen bond interactions in the ternary system through the mutual coupling effect, thereby serving as one of the protective mechanisms of protein preservation by GLY.

Physiologically based pharmacokinetic modeling of apixaban to predict exposure in populations with hepatic and renal impairment and elderly populations.

BACKGROUND: Apixaban is a factor Xa inhibitor with a limited therapeutic index that belongs to the family of oral direct anticoagulants. The pharmacokinetic (PK) behavior of apixaban may be altered in elderly populations and populations with renal or hepatic impairment, necessitating dosage adjustments. METHODS: This study was conducted to examine how the physiologically based pharmacokinetic (PBPK) model describes the PKs of apixaban in adult and elderly populations and to determine the PKs of apixaban in elderly populations with renal and hepatic impairment. After PBPK models were constructed using the reported physicochemical properties of apixaban and clinical data, they were validated using data from clinical studies involving various dose ranges. Comparing predicted and observed blood concentration data and PK parameters was utilized to evaluate the model's fit performance. RESULTS: Doses should be reduced to approximately 70% of the healthy adult population for the healthy elderly population to achieve the same PK exposure; approximately 88%, 71%, and 89% of that for the elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 96%, 81%, and 58% of that for the Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment elderly populations, respectively to achieve the same PK exposure. CONCLUSION: The findings indicate that the renal and hepatic function might be considered for apixaban therapy in Chinese elderly patients and the PBPK model can be used to optimize dosage regimens for specific populations.

Physiologically based pharmacokinetic modeling of candesartan to predict the exposure in hepatic and renal impairment and elderly populations.

Background: Candesartan cilexetil is a widely used angiotensin II receptor blocker with minimal adverse effects and high tolerability for the treatment of hypertension. Candesartan is administered orally as the prodrug candesartan cilexetil, which is wholly and swiftly converted to the active metabolite candesartan by carboxylesterase during absorption in the intestinal tract. In populations with renal or hepatic impairment, candesartan's pharmacokinetic (PK) behavior may be altered, necessitating dosage adjustments. Objectives: This study was conducted to examine how the physiologically based PK (PBPK) model characterizes the PKs of candesartan in adult and geriatric populations and to predict the PKs of candesartan in elderly populations with renal and hepatic impairment. Design: After developing PBPK models using the reported physicochemical properties of candesartan and clinical data, these models were validated using data from clinical investigations involving various dose ranges. Methods: Comparing predicted and observed blood concentration data and PK parameters was used to assess the fit performance of the models. Results: Doses should be reduced to approximately 94% of Chinese healthy adults for the Chinese healthy elderly population; approximately 92%, 68%, and 64% of that of the Chinese healthy adult dose in elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 72%, 71%, and 52% of that of the Chinese healthy adult dose in elderly populations with Child-Pugh-A, Child-Pugh-B, and Child-Pugh-C hepatic impairment, respectively. Conclusion: The results suggest that the PBPK model of candesartan can be utilized to optimize dosage regimens for special populations.

Background: Candesartan cilexetil is a widely used angiotensin II receptor blocker with minimal adverse effects and high tolerability for the treatment of hypertension. Candesartan cilexetil is wholly and swiftly converted to the active metabolite candesartan by carboxylesterase during absorption in the intestinal tract. Candesartan's pharmacokinetic behavior may be altered in patients with renal or hepatic impairment. Methods: We developed PBPK models using the reported physicochemical properties of candesartan and clinical data. We validated the PBPK models. Results: We found that the elderly population needs dosage adjustments.1. Doses should be reduced to approximately 94% of Chinese healthy adults for the Chinese healthy elderly population2. Doses should be reduced to approximately 92%, 68%, and 64% of that of the Chinese healthy adult dose in elderly populations with mild, moderate, and severe renal impairment3. Doses should be reduced to approximately 72%, 71%, and 52% of that of the Chinese healthy adult dose in elderly populations with Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment. Conclusion: The PBPK model of candesartan can be utilized to optimize dosage regimens for special populations.

Develop a physiologically based pharmacokinetic model of candesartan to predict the exposure in Chinese elderly populations.

Bioequivalence Study of Epalrestat for Healthy Chinese Subjects.

Epalrestat is a reversible noncompetitive inhibitor of aldose reductase with selective inhibition of aldose reductase. It can inhibit the accumulation of sorbitol in red blood cells in patients with diabetic peripheral neuropathy and can improve patients' conscious symptoms and neurological dysfunction. This study was designed to evaluate the bioequivalence in healthy Chinese subjects of a new test formulation and reference formulation of oral epalrestat (50 mg) in the fasting state. The study was performed with 44 healthy Chinese subjects according to a randomized 2-way crossover design. The main pharmacokinetic parameters of test formulation and reference formulation as follows: 4793 and 4781 ng/mL for maximum plasma concentration, 8556 and 8431 ng h/mL for area under the plasma concentration-time curve extrapolated to infinity. The test formulation of epalrestat was bioequivalent to the reference formulation. The bioequivalence study of epalrestat in healthy Chinese subjects suggests that the test and reference formulations have similar pharmacokinetics and both formulations are well tolerated in the dose range studied in healthy Chinese subjects. All these findings provided valuable pharmacokinetic knowledge for further clinical development.

Inhibition of LSD1 induces ferroptosis through the ATF4-xCT pathway and shows enhanced anti-tumor effects with ferroptosis inducers in NSCLC.

Lysine-specific demethylase 1 (LSD1) has been identified as an important epigenetic target, and recent advances in lung cancer therapy have highlighted the importance of targeting ferroptosis. However, the precise mechanisms by which LSD1 regulates ferroptosis remain elusive. In this study, we report that the inhibition of LSD1 induces ferroptosis by enhancing lipid peroxidation and reactive oxygen species (ROS) accumulation. Mechanistically, LSD1 inhibition downregulates the expression of activating transcription factor 4 (ATF4) through epigenetic modification of histone H3 lysine 9 dimethyl (H3K9me2), which sequentially inhibits the expression of the cystine-glutamate antiporter (xCT) and decreases glutathione (GSH) production. Furthermore, LSD1 inhibition transcriptionally upregulates the expression of transferrin receptor (TFRC) and acyl-CoA synthetase long chain family member 4 (ACSL4) by enhancing the binding of histone H3 lysine 4 dimethyl (H3K4me2) to their promoter sequences. Importantly, the combination of an LSD1 inhibitor and a ferroptosis inducer demonstrates an enhanced anti-tumor effect in a xenograft model of non-small cell lung cancer (NSCLC), surpassing the efficacy of either agent alone. These findings reveal new insights into the mechanisms by which LSD1 inhibition induces ferroptosis, offering potential guidance for the development of new strategies in the treatment of NSCLC.

NRG1 promotes tumorigenesis and metastasis and afatinib treatment efficiency is enhanced by NRG1 inhibition in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC and its contribution to aggressiveness remain unknown. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC as well as the treatment strategy for ESCC with overexpression of NRG1. We firstly demonstrated the upregulation of NRG1 and a negative correlation trend between patients' overall survival (OS) and the expression level of NRG1 in esophageal cancer. And then we found NRG1 promoted cell proliferation, migration, inhibited apoptosis, and accelerated tumorigenesis and metastasis in ESCC using cell lines and xenograft models. Furthermore, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway, contributing to the metastatic phenotype in ESCC. Finally, we show that afatinib (FDA approved cancer growth blocker) could inhibit ESCC with overexpressed NRG1 and down-regulation of NRG1 along with afatinib treatment provides higher efficient strategy. This study uncovers the critical role and molecular mechanism of NRG1 in ESCC tumorigenesis and metastasis, suggesting its potential as a novel biomarker for ESCC treatment.

Pharmacokinetics, pharmacodynamics and safety of LPM3480392 in two phase I clinical trials in healthy Chinese male subjects.

Drugs for acute postoperative pain and breakthrough cancer pain are still urgent in clinical. LPM3480392 is a G-protein-biased ligand at the µ-opioid receptor and showed potent analgesia in nonclinical studies. Two phase I studies of LPM3480392 were conducted in healthy Chinese male volunteers to explore its tolerability, pharmacokinetics and pharmacodynamics under single ascending doses (Study I 0.1-3.0 mg, 30 min) and different infusion times (Study II, 0.6-1.0 mg, 2-15 min). There was one serious adverse event (AE) observed in Study II, and the rest AEs were mild or moderate in severity and resolved by the end of the study. Plasma LPM3480392 maximum concentration (Cmax ) (under lower infusion rate) and area under the plasma concentration-time curve (AUCs) were generally increased with dose. Moreover, LPM3480392 at a dose of 0.6 mg under a 2 min infusion rate elicited effective analgesia as the peak effect within 10-30 min, which was measured by cold pain test and pupillometry. These findings suggest that LPM3480392 could be a potential treatment for acute pain management.

Drug-drug interaction of ciprofol injectable emulsion with mefenamic acid capsules in healthy subjects.

AIMS: To investigate the drug-drug interaction (DDI) of ciprofol injectable emulsion and mefenamic acid capsules in healthy subjects. METHODS: Twenty healthy subjects were enrolled in this single-centre, open-label, two-period DDI study. Ciprofol (0.4 mg kg-1 ) was administered as a single dose on days 1 and 5. A 500-mg oral loading dose of mefenamic acid was given on day 4 followed by a 250-mg maintenance dose every 6 h (a total of eight doses). Blood samples for pharmacokinetic analyses were collected. Depth of anaesthesia was monitored using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale and Bispectral Index scores (BISs). RESULTS: Compared with administration of ciprofol alone, administration with mefenamic acid showed no significant difference in exposure. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ), area under the plasma concentration-time curve calculated from 0 to the last measurement point (AUC0-last ) and AUC to infinity (AUC0-inf ) were 91.6% (86.5-96.9%), 103.3% (100.3-106.4%) and 107.0% (101.2-113.2%), respectively. The MOAA/S and BIS curves for the two treatment periods essentially coincided, indicating that the anaesthesia effect of ciprofol was not affected by mefenamic acid. Seven subjects (35%) reported eight adverse events (AEs) when ciprorol was administered alone and 12 subjects (60%) reported 18 AEs when ciprofol was administered in combination with mefenamic acid. All AEs were mild. CONCLUSIONS: Mefenamic acid, a UGT1A9 inhibitor, had no significant effect on the pharmacokinetics and pharmacodynamics of ciprofol in healthy subjects. Ciprofol was safe and well tolerated when administered with mefenamic acid.

MecDDI: Clarified Drug-Drug Interaction Mechanism Facilitating Rational Drug Use and Potential Drug-Drug Interaction Prediction.

Drug-drug interactions (DDIs) are a major concern in clinical practice and have been recognized as one of the key threats to public health. To address such a critical threat, many studies have been conducted to clarify the mechanism underlying each DDI, based on which alternative therapeutic strategies are successfully proposed. Moreover, artificial intelligence-based models for predicting DDIs, especially multilabel classification models, are highly dependent on a reliable DDI data set with clear mechanistic information. These successes highlight the imminent necessity to have a platform providing mechanistic clarifications for a large number of existing DDIs. However, no such platform is available yet. In this study, a platform entitled "MecDDI" was therefore introduced to systematically clarify the mechanisms underlying the existing DDIs. This platform is unique in (a) clarifying the mechanisms underlying over 1,78,000 DDIs by explicit descriptions and graphic illustrations and (b) providing a systematic classification for all collected DDIs based on the clarified mechanisms. Due to the long-lasting threats of DDIs to public health, MecDDI could offer medical scientists a clear clarification of DDI mechanisms, support healthcare professionals to identify alternative therapeutics, and prepare data for algorithm scientists to predict new DDIs. MecDDI is now expected as an indispensable complement to the available pharmaceutical platforms and is freely accessible at: https://idrblab.org/mecddi/.

Upregulation of PIK3IP1 monitors the anti-cancer activity of PI3Kα inhibitors in gastric cancer cells.

Gastric cancer remains one of the most malignant cancers in the world. The target-based drugs approved by FDA for gastric cancer treatment include only three targets and benefit a small portion of gastric cancer patients. PIK3CA, a confirmed oncogene, mutates in 7-25% gastric cancer patients. PI3Kα inhibitor BYL719 has been approved for treating specific breast cancer. However, there is no comprehensive study about PI3Kα inhibitor in gastric cancer. In this study, we found pharmacological inhibition or knockdown of PI3Kα effectively inhibited the proliferation of partial gastric cancer cells. Then, we systematically explored the potential biomarkers for predicting or monitoring treatment response according to previous reports and found that basal expression of several receptor tyrosine kinases were related with the sensitivity of gastric cancer cells to BYL719. Next, RNA-seq technique was utilized and showed that BYL719 inhibited Myc targets V2 gene set in sensitive gastric cancer cells, and western blotting further verified that c-Myc was only inhibited in sensitive gastric cancer cells. More importantly, we firstly found BYL719 significantly elevated the expression of PIK3IP1 in sensitive gastric cancer cells, which was also observed in NCI-N87 cell derived xenograft mice models. Meanwhile, knockdown of PIK3IP1 partially rescued the cell growth inhibited by BYL719 in sensitive gastric cancer cells, suggesting the important role of PIK3IP1 in the antitumor activity of BYL719. In conclusion, our study provides biological evidence that PI3Kα is a promising target in specific gastric cancer and the elevation of PIK3IP1 could supply as a biomarker that monitoring treatment response.

A Novel Approach for Cable Tension Monitoring Based on Mode Shape Identification.

Estimation and monitoring of cable tension is of great significance in the structural assessment of cable-supported bridges. For short cables, the traditional cable tension identification method via frequency measurement has large errors due to the influence of complex boundaries, which affect the accuracy of estimation. A new cable tension estimation method based on mode shape identification with a multiple sensor arrangement on the cable can take the influence of boundary conditions into account and its accuracy has been verified. However, it requires more sensors compared to the traditional frequency-based method, which will significantly increase the cost of long-term monitoring in practice. Therefore, a novel approach for cable tension monitoring considering both cost and accuracy is further proposed in this study. The approach adopts multiple sensors to measure the influence of boundary conditions. Then, only a single sensor is required for long-term monitoring of the cable. In this paper, an analytical model of the cable is firstly established. The influence of boundary conditions is calculated, which ensures the accuracy of mode shape identification. Furthermore, a field experiment is carried out to verify the effectiveness of the new approach. The results have demonstrated the effectiveness and accurateness of the proposed method in long-term short cable tension monitoring.

First-in-human study to investigate the safety and pharmacokinetics of salvianolic acid A and pharmacokinetic simulation using a physiologically based pharmacokinetic model.

Salvianolic acid A (SAA) is a water-soluble phenolic acid component from Salvia miltiorrhiza Bunge currently under development for myocardial protection treatment for coronary heart disease (CHD). We investigated the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of SAA. Additionally, a physiologically based pharmacokinetic (PBPK) model was developed to simulate the pharmacokinetics of SAA. This was a first-in-human (FIH), randomized, double-blind, placebo-controlled, single, and multiple-dose study in 116 healthy Chinese subjects with the range of 10-300 mg and 60-200 mg SAA, respectively. SAA was well tolerated at all dose levels, following both single and multiple doses, with a low overall incidence of treatment-emergent adverse events (TEAEs) which appeared to be no dose-related. The main pharmacokinetic parameter of SAA, assessed by the power model, was the lack of proportionality with the dose range after single dosing. The 90% CIs of the slope ß of Cmax (1.214 [1.150-1.278]) and AUC0-t (1.222 [1.156-1.288]) were not within the predefined acceptance range, and the direction of the deviation was higher than expected. PBPK modeling suggested the transfer ability saturation of hepatic organic anion-transporting polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp) might result in a relatively low distribution rate at higher doses. Clinical plasma concentrations observed were in good agreement with PBPK prediction. SAA showed well-characterized pharmacokinetics and was generally well tolerated in the dose range investigated. The PBPK model provides valuable pharmacokinetic knowledge for further clinical development.