Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver ...transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data.
Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.
Extracellular vesicles (EVs) are heterogeneous nanoparticles actively released by cells that comprise highly conserved and efficient systems of intercellular communication. In recent years, numerous ...studies have proven that EVs play an important role in the field of bone tissue engineering (BTE) due to several advantages, such as good biosafety, stability and efficient delivery. However, the application of EVs therapies in bone regeneration has not been widely used. One of the major challenges for the application of EVs is the lack of sufficient scaffolds to load and control the release of EVs. Thus, in this review, we describe the most advanced current strategies for delivering EVs with various biomaterials for the use in bone regeneration, the role of EVs in bone regeneration, the distribution of EVs mediated by biomaterials and common methods of promoting EVs delivery efficacy with a focus on biomaterial properties.
The incidence rate of human hepatocellular carcinoma (HCC) is approximately three times higher in males than in females. A better understanding of the mechanisms underlying HCC development in males ...could lead to more effective therapies for HCC. Our previous study found that FBXW10 played a critical role in promoting HCC development in male mice and patients, but the mechanism remains unknown. Here, we found that FBXW10 promoted K63-linked ANXA2 polyubiquitination and activation in HCC tissues from males, and this process was required for S6K1-mediated phosphorylation. Activated ANXA2 further translocated from the cytoplasm to the cell membrane to bind KRAS and then activated the MEK/ERK pathway, leading to HCC proliferation and lung metastasis. Interfering with ANXA2 significantly blocked FBXW10-driven HCC growth and lung metastasis in vitro and in vivo. Notably, membrane ANXA2 was upregulated and positively correlated with FBXW10 expression in male HCC patients. These findings offer new insights into the regulation and function of FBXW10 signaling in HCC tumorigenesis and metastasis and suggest that the FBXW10-S6K1-ANXA2-KRAS-ERK axis may serve as a potential biomarker and therapeutic target in male HCC patients with high FBXW10 expression.
•FBXW10 promotes ANXA2 polyubiquitination, activation, and membrane localization in male HCC tumors.•FBXW10-mediated ANXA2 ubiquitination depends on phosphorylation at S12/26 by S6K1.•Ubiquitinated ANXA2 interacts with KRAS and activates MEK/ERK signaling.•Targeting or interfering of ANXA2-KRAS-ERK axis blocks oncogenic functions of FBXW10.•A positive correlation between FBXW10 and membrane ANXA2 in male HCC patients.
Autism spectrum disorder (ASD) is a neurodevelopmental disease with a strong heritability, but recent evidence suggests that epigenetic dysregulation may also contribute to the pathogenesis of ASD. ...Especially, increased methylation at the MECP2 promoter and decreased MECP2 expression were observed in the brains of ASD patients. However, the causative relationship of MECP2 promoter methylation and ASD has not been established. In this study, we achieved locus-specific methylation at the transcription start site (TSS) of Mecp2 in Neuro-2a cells and in mice, using nuclease-deactivated Cas9 (dCas9) fused with DNA methyltransferase catalytic domains, together with five locus-targeting sgRNAs. This locus-specific epigenetic modification led to a reduced Mecp2 expression and a series of behavioral alterations in mice, including reduced social interaction, increased grooming, enhanced anxiety/depression, and poor performance in memory tasks. We further found that specifically increasing the Mecp2 promoter methylation in the hippocampus was sufficient to induce most of the behavioral changes. Our finding therefore demonstrated for the first time the casual relationship between locus-specific DNA methylation and diseases symptoms in vivo, warranting potential therapeutic application of epigenetic editing.
Abstract
Aiming at the streak defects on the surface of high-quality automobile steel SP121 after stamping, the surface profile of the streak defects was analyzed by a confocal laser scanning ...microscope (CLSM). The micro-morphology and element content of the streak defects area were analyzed by scanning electron microscope (SEM) and energy dispersive spectrometer (EDS). The results show that compared with the normal area of the strip steel surface, the surface roughness features of the streak defects area of SP121 after stamping are not apparent. There are many linear defects and dot defects perpendicular to the streak defects. The energy spectrum detection shows no element abnormality in the streak defects area. The surface streak defects of SP121 after stamping are caused by the poor contact between the strip steel and the stamping die, which leads to the poor fluidity of the materials during stamping, and finally, the streak defects are formed.
•A set of laboratory grouting devices was developed to grout the precracked rock specimen.•The strength of grouted rock is observed to be determined by the interface between rock and cement.•A ...numerical simulation method of grouting was developed based on the Fish language of PFC2D.
Grouting is a common reinforcement method that is widely used in various geotechnical engineering applications. Studying the mechanical properties of grouted rock masses under different stress conditions is of great significance to geotechnical engineering, so a set of laboratory grouting devices was developed for this study. The mechanical properties of compressively precracked sandstone before and after grouting were studied by triaxial compression tests with different confining pressures, and the crack and cementation morphologies of precracked specimens were revealed by X-ray CT (Computed Tomography) scanning. According to the findings of the study, grouting significantly improves the integrity and mechanical properties of cracked specimens. The grouted specimens exhibit higher strengths and Mohr–Coulomb parameters (c and φ), and these increments vary with confining pressures. The strength of grouted specimens depends mainly on the micromechanical properties of the contact surface between sandstone and cement grout. Affected by the mechanical properties of cement grout, the elastic modulus of the grouted specimens is lower than that of uncracked sandstone, and the deformation of the grouted specimen also exhibits an obvious ideal plasticity state under triaxial stress conditions. Thus, the grouted sandstone does not break suddenly. In addition, a numerical method of grouting was also developed in the PFC2D program to investigate the micro mechanisms of fracturing and grouting sandstone. The numerical simulations represent the strength and progressive failure process of both intact and grouted specimens very well and reveal the micromechanical behaviors of the grouted rock mass.
Electrochemically functional porous membranes of low cost are appealing in various electrochemical devices used in modern environmental and energy technologies. Herein we describe a scalable strategy ...to construct electrochemically active, hierarchically porous carbon membranes containing atomically dispersed semi‐metallic Se, denoted SeNCM. The isolated Se atoms were stabilized by carbon atoms in the form of a hexatomic ring structure, in which the Se atoms were located at the edges of graphitic domains in SeNCM. This configuration is different from that of previously reported transition/noble metal single atom catalysts. The positively charged Se, enlarged graphitic layers, robust electrochemical nature of SeNCM endow them with excellent catalytic activity that is superior to state‐of‐the‐art commercial Pt/C catalyst. It also has long‐term operational stability for hydrazine oxidation reaction in practical hydrazine fuel cell.
Se cells: A scalable strategy to give a hierarchically structured porous carbon membrane containing atomically dispersed semimetallic selenium atoms has been developed. The membrane functions as a binder‐free, high performance anode for hydrazine oxidation reaction in a practical hydrazine fuel cell.
Catharanthus roseus (L.) G. Don consists of a range of dimeric indole alkaloids with significant antitumor activities. These alkaloids have been found to possess apoptosis-inducing activity against ...tumor cells in vitro and in vivo mediated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, in which DNA damage and mitochondrial dysfunction play important roles. In this study, a unique bisindole alkaloid named cathachunine, along with five known dimeric indole alkaloids, was obtained from C. roseus and investigated in vitro.
The aim of this study was to investigate the antitumor activity of isolated alkaloids and the mechanism through which cathachunine exerts its antitumor effect.
Cell growth inhibition was assessed by WST-1 and lactate dehydrogenase (LDH) assays in HL60, K562 leukemia cells and EA.hy926 umbilical vein cells. Induction of apoptosis in HL60 cells was confirmed by observation of nuclear morphology, a caspase-3 activity assay and annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) double staining. The intrinsic apoptotic pathway induced by cathachunine was evidenced by B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) dysregulation, loss of mitochondrial membrane potential, translocation of cytochrome c, and cleavage of caspase-3 and poly-ADP ribose polymerase (PARP). Reactive oxygen species (ROS) production after cathachunine treatment was determined by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Cell cycle arrest of the S phase was also observed in HL60 cells after cathachunine treatment.
The WST-1 and LDH assays showed that Catharanthus alkaloids were cytotoxic toward human leukemia cells to a greater extent than toward normal human endothelial cells, and the anti-proliferation and pro-apoptosis abilities of cathachunine were much more potent than other previously reported alkaloids. The induction of apoptosis by cathachunine occurred through an ROS-dependent mitochondria-mediated intrinsic pathway rather than an extrinsic pathway, and was regulated by the Bcl-2 protein family.
An unprecedented bisindole alkaloid cathachunine which lost C-18′ and C-19′ was isolated from C. roseus. It exerted a potent antitumor effect toward human leukemia cells through the induction of apoptosis via an intrinsic pathway. Thus, this study provides evidence for a new lead compound from a natural source for anti-cancer investigations.
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The one-dimensional organic–inorganic hybrid compound bis(cyclohexylammonium) tetrachlorocadmate(II) (1), in which the adjacent infinite CdCl4 n – chains are connected to each other though Cd···Cl ...weak interactions to form perovskite-type layers of corner-sharing CdCl6 octahedra separated by cyclohexylammonium cation bilayers, was synthesized. It undergoes two successive structural phase transitions, at 215 and 367 K, which were confirmed by systematic characterizations including differential scanning calorimetry (DSC) measurements, variable-temperature structural analyses, and dielectric and second harmonic generation (SHG) measurements. A precise structural analysis discloses that the phase transition at 215 K is induced by the disorder–order transition of cyclohexylammonium cations, while the phase transition at 367 K derives from changes in the relative location of Cd atoms. Emphatically, both the dielectric constant and SHG intensity of 1 show a striking change between low and high states at around 367 K, which reveals that 1 might be considered as a potential dielectric and nonlinear optical (NLO) switch with high-temperature response characterization, excellent reversibility, and obvious change of states.
This study investigated a compact, uniplanar wideband, differential-fed transparent filtenna. The filtenna incorporated one circular radiator with a ring-slot, two shorting stubs, a defected ground ...structure, and two coplanar waveguide differential feedlines. These elements were printed on the same side of a section of transparent glass clad with 2 μm thick copper mesh, which had a sheet resistance of 0.15 Ω/square and an optical transparency of around 80%. Due to the generation of three radiation nulls, the filtenna exhibits F L = 1.02 and F U = 0.79 for selectivity and more than 9.5 dB for stopband suppression. The study also fabricated, assembled, and tested a transparent prototype. The measured results agreed with the corresponding simulated values and revealed the antenna to have a −10 dB impedance fractional bandwidth of 20.34% despite its compact size of 0.35 × 0.46 × 0.005 λ L 3 . The corresponding measured peak realized gain and overall efficiency values were 1.88 dBi and 58%, respectively.
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