Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy.
In this ...open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti-programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%.
In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6
6.3 months; hazard ratio HR, 0.70 95% CI, 0.57 to 0.85; one-sided
= .0001), and in patients with TAP ≥ 10% (median, 10.3 months
6.8 months; HR, 0.54 95% CI, 0.36 to 0.79; one-sided
= .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3%
9.8%) and a more durable antitumor response (median, 7.1 months
4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8%
55.8%) with tislelizumab versus chemotherapy.
Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.
Xin-Ji-Er-Kang (XJEK) is traditional Chinese formula presented excellent protective effects on several heart diseases, but the potential components and targets are still unclear. The aim of this ...study is to elucidate the effective components of XJEK and reveal its potential mechanism of cardioprotective effect in myocardial ischemia-reperfusion (MIR) injury.
Firstly, the key compounds in XJEK, plasma and heart tissue were analyzed by high resolution mass spectrometry. Bioinformatics studies were also involved to disclose the potential targets and the binding sites for the key compounds. Secondly, to study the protective effect of XJEK on MIR injury and related mechanism, mice subjected to MIR surgery and gavage administered with XJEK for 6 weeks. Cardiac function parameters and apoptosis level of cardiac tissue were assessed. The potential mechanism was further verified by knock down of target protein in vitro.
Pharmacokinetics studies showed that Sophora flavescens alkaloids, primarily composed with matrine, are the key component of XJEK. And, through bioinformatic analysis, we speculated JAK2 could be the potential target for XJEK, and could form stable hydrogen bonds with matrine. Administration of XJEK and matrine significantly improved heart function and reduced apoptosis of cardiomyocytes by increasing the phosphorylation of JAK2 and STAT3. The anti-apoptosis effect of XJEK and matrine was also observed on AC16 cells, and could be reversed by co-treatment with JAK2 inhibitor AG490 or knock-down of JAK2.
XJEK exerts cardioprotective effect on MIR injury, which may be associated with the activation of JAK2/STAT3 signaling pathway.
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•Matrine is the dominant component of Xin-Ji-Er-Kang.•JAK2 is the target for matrine on treating myocardial infarction-reperfusion.•Xin-Ji-Er-Kang activated the JAK-STAT signaling pathway.•STAT3 was activated and prevented cardiomyocyte apoptosis.
With the increase of the number of electric vehicles (EVs), it is of vital importance to develop the efficient and effective charging scheduling schemes for all the EVs. In this article, we aim to ...maximize the social welfare of all the EVs, charging stations (CSs) and power plant (PP), by taking into account the changing demand of each EV, the changing price, the capacity and the congestion balance between different CSs. To this end, two efficient scheduling algorithms, i.e., Centralized Charging Strategy (CCS) and Distributed Charging Strategy (DCS) are proposed. CCS has a slightly better performance than the DCS, as it takes all the information and make the decision in the central control unit. On the other hand, DCS dose not require the private information from EVs and can make decentralized decision. Extensive simulation are conducted to verify the effectiveness of the proposed algorithms, in terms of the performance, congestion balance, and computing complexity.
Small nucleolar RNA （snoRNA） dysfunctions have been associated with cancer development. SNORD126 is an orphan C/D box snoRNA that is encoded within introns 5-6 of its host gene, cyclin Bl-interacting ...protein 1 （CCNBIIP1）. The cancer-associated molecular mechanisms triggered by SNORD126 are not fully understood. Here, we demonstrate that SNORD126 is highly expressed in hepatoceUular carcinoma （HCC） and colorectal cancer （CRC） patient samples. SNORD126 increased Huh-7 and SW480 cell growth and tumorigenicity in nude mice. Knockdown of SNORD126 inhibited HepG2 and LS174T cell growth. We veri- fied that SNORD126 was not processed into small RNAs with miRNA activity. Moreover, SNORD126 did not show a significant expression correlation with CCNBIlP1 in HCC samples or regulate CCNBIlP1 expression. Our gene expression profile analysis indicated that SNORD126-upregulated genes frequently mapped to the PI3K-AKT pathway. SNORD126 overexpression increased the levels of phosphorylated AKT, GSK-3p, and p7056K and elevated fibroblast growth factor receptor 2 （FGFR2） expression. siRNA-mediated knockdown or AZD4547-mediated inactivation of FGFR2 in SNORD126-overexpressing Huh-7 cells inhibited AKT phosphorylation and suppressed cell growth. These findings indicate an oncogenic role for SNORD126 in cancer and suggest its potential as a therapeutic target.
Nowadays, major methods of in vitro hepatotoxicity research are still based on traditional static two- or three-dimensional cell culture, although these means could investigate some toxic chemicals ...induced hepatotoxicity, but most of these toxicities failed to reappear in human, at least not in similar or calculable dose level. These failures may cause by the monoculture of only hepatocytes, ignored the signal communication to other non-parenchymal cells in liver tissue, also other complex microenvironment such as endothelial barrier, shear stress and other factors which were really existed in vivo but absent here, final leading to a low reliability of experimental results. In this study, a three-dimensional dynamic multi-cellular liver-on-a-chip device (3D-DMLoC) was developed to reproduce the microenvironment of in vivo liver tissue, including the simulation of hepatic sinusoid, perisinusoidal space and continuous liquid perfusion, hepatocytes could gather to some 3D cell spheroids in this chip. The perfusion could bring a real-time exchange of chemicals, nutrients, metabolites, supply suitable oxygen and a weak shear stress. The pressure and oxygen distribution inner the chip were simulated and evaluated by COMSOL Multiphysics software. HepaRG were co-cultured with HUVEC for 7 days in this chip, expression of hepatic polarization protein ZO-1 and MRP2, liver function factors ALB, UREA and CYP450s were almost all higher than in traditional static culture. Several drugs and heavy metal ions induced hepatotoxicity were then investigated, LDH released from hepatocyte spheroids in mostly 3D-DMLoC groups were higher than same-dosed 2D group, indicated the spheroids were more sensibility to the toxins. The hepatoxicity might be induced by acute hepatocytes injury according to the ratios of secreted AST/ALT contents. In conclusion, a liver-on-a-chip device was successfully developed and verified for better reproducing the in vivo physiological microenvironment of liver. It could be applied for easily, efficiently, and accurately screening the potential hepatotoxic chemicals in future.
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•A 3D liver-on-a-chip with endothelial and hepatic cells co-culture was developed for in vitro hepatotoxicity screening.•Liver functions of hepatocytes could be improved by co-cultured endotheliocytes.•Excellent sealing performance for real-time fluid perfusion.•A unique positive mold was developed for easily producing microwell array.•Less medium consumption with more hepatocyte spheroid supply was achieved compared to traditional culture manners.
Introduction
Sleep apnea/hypopnea syndrome (SAHS) can change brain structure and function. These alterations are related to respiratory event-induced abnormal sleep, however, how brain activity ...changes during these events is less well understood.
Methods
To study information content and interaction among various cortical regions, we analyzed the variations of permutation entropy (PeEn) and symbolic transfer entropy (STE) of electroencephalography (EEG) activity during respiratory events. In this study, 57 patients with moderate SAHS were enrolled, including 2804 respiratory events. The events terminated with cortical arousal were independently researched.
Results
PeEn and STE were lower during apnea/hypopnea, and most of the brain interaction was higher after apnea/hypopnea termination than that before apnea in N2 stage. As indicated by STE, the respiratory events also affected the stability of information transmission mode. In N1, N2, and rapid eye movement (REM) stages, the information flow direction was posterior-to-anterior, but the anterior-to-posterior increased relatively during apnea/hypopnea. The above EEG activity trends maintained in events with cortical arousal.
Conclusions
These results may be related to the intermittent hypoxia during apnea and the cortical response. Furthermore, increased frontal information outflow, which was related to the compensatory activation of frontal neurons, may associate with cognitive function.
The electrochemical properties of sulfur cathodes based on commercially available sulfur powder (S) and water-soluble binder have been investigated. The mixture of styrene butadiene rubber (SBR) and ...sodium carboxyl methyl cellulose (CMC) is used as the binder. Compared with conventional poly(vinylidene fluoride) (PVDF) binder, the SBR–CMC binder significantly improves cycling performance of the sulfur cathode. A high specific capacity of 580 mA h g–1 after 60 cycles has been achieved. Studies on the electrode slurries show that the SBR–CMC mixture is not only a high adhesion agent but also a strong dispersion medium, which favors the uniform distribution between insulating sulfur and conductive carbon black (CB) and ensures a good electrical contact, leading to a high sulfur utilization. Furthermore, our experiments show that the improvement in cyclability is ascribed to structural stability of the sulfur cathode promoted by the SBR–CMC binder during charge/discharge cycles due to the combined effects of homogeneous distribution of the S and CB particles in the composite cathode, the low electrolyte uptake, and the suppressed agglomeration of Li2S.
An ultrasonic-assisted extraction (UAE) protocol using deep eutectic solvent (DES) was employed to extract phenolic compounds from foxtail millet bran (FMB). DES composed with betaine and glycerol in ...a 1:2 M ratio was selected basing on the total phenolic content (TPC) extraction yield, with the optimal extraction technology investigated using response surface methodology (RSM) with Box-Behnken design (BBD). The optimized process obtained was as follows: DESs with water content of 29 mL/100 mL, ultrasonic power at 247 W, extraction temperature of 61 °C, and extraction time of 31 min. The TPC of the extract was 7.80 ± 0.09 mg ferulic acid equivalent (FAE)/g under the optimum extraction conditions, with the result corresponding well with the model prediction. DES-based UAE produced higher total phenolics, total flavonoids, in vitro antioxidant activity and acetylcholinesterase inhibitory activity than the conventional solvent extraction. The phenolic extract from FMB with DES-based UAE was mainly composed of fifteen phenolic compounds, with p-coumaric acid, apigenin-C-dihexoside, and N′, N″-di-p-coumaroylspermidine being the predominant phenolic compounds. Additionally, 1-O-p-coumaroylglycerol was detected for the first time in FMB. The microstructure differences of the FMB samples following extraction were confirmed using scanning electron microscopy (SEM).
•Amounts of 1-O-p-coumaroylglycerol was detected for the first time in foxtail millet bran (FMB).•UAE-DES for extraction of phenolics from FMB were optimized by response surface methodology.•Fifteen phenolic constituents including three hydroxycinnamic acid amides were identified and quantified.•UAE-DES extracts show better antioxidant and acetylcholinesterase inhibitory activity.
Allergic rhinitis (AR) is a serious systemic allergic disease, which together with comorbid asthma causes major illness and disability worldwide. Recent epidemiological studies have revealed wide ...variations in the increasing prevalence of AR and allergies globally, including in China. Despite a markedly higher population than western countries, and a landmass close to Europe in area, little epidemiological data is available on AR in China. Thus, the present study reviewed the prevalence, comorbid allergic diseases, trends and pattern of sensitizing allergens in adults and children suffering from AR in China. Available data indicated that despite variations in the prevalence of AR in different regions of the country, the prevalence of AR has increased in both adults and children over the last 2 decades. Similarly, there has been an increase in a "western"-type lifestyle, industrialization and air pollution over this period, which may have contributed to the increased prevalence of AR observed in China.
LncRNA PVT1 was reported to be elevated in septic myocardial tissue. The underlying mechanism by which PVT1 aggravated sepsis induced myocardial injury needs further investigation.
Mice was subjected ...to LPS injection to mimic in vivo sepsis model. HE staining was applied to observe tissue injury. Cardiac function of mice was determined by echocardiography. Bone marrow derived macrophage (BMDM) was used to confirm the regulatory effect of PVT1 in macrophage polarization. Western blotting or qRT-PCR were performed to evaluate protein or mRNA levels, respectively. ELISA was conducted to determine cytokine levels. Interaction between PVT1 and miR-29a, miR-29a and HMGB1 were accessed by dual luciferase assay.
Expression of PVT1 was elevated in myocardial tissue and heart infiltrating macrophages of sepsis mice. PVT1 knockdown alleviated LPS induced myocardial injury and attenuated M1 macrophage polarization. The mechanic study suggested that PVT1 targeted miR-29a, thus elevated expression of HMGB1, which was repressed by miR-29a targeting. The effect of PVT1 on M1 macrophage polarization was dependent on targeting miR-29a.
PVT1 promoted M1 polarization and aggravated LPS induced myocardial injury via miR-29a/HMGB1 axis.
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