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Tumor immunotherapy as a promising method for tumor treatment received tremendous attention. However, the problem of low clinical response rate still needs to be solved, especially in the poorly immunogenic tumors. The enhancement of tumor antigens presentation can effectively activate dendritic cells (DCs) and improve the tumor immunotherapy. In this work, TAK-243 as an inhibitor of the ubiquitin activating enzyme (UAE), was fabricated into cationic lipid-assisted nanoparticle (CLANTAK-243). The obtained CLANTAK-243 could act as an effective tumor immunotherapy enhancer to promote the maturation of DCs as well as antigen presentation, which obviously stimulated the T cells activation and proliferation. Such CLANTAK-243 injected intravenously could well trigger immune response to tumor cells in vivo. Importantly, mice treated with CLANTAK-243 could obtain a long immune memory effect to protect themselves from re-challenged tumor cells. Therefore, this work presented an effective immunotherapy strategy for poorly immunogenic tumor.

The role of tumor-infiltrating lymphocytes (TILs) in the growth and progression of hepatocellular carcinoma (HCC) has attracted widespread attention.To evaluate the feasibility of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for massive HCC by exploring the role of TIL in the tumor microenvironment.Fifteen massive HCC patients who underwent ALPPS treatment and 46 who underwent hemi-hepatectomy were selected for this study. Propensity score matching was utilized to match patients in ALPPS and hemi-hepatectomy groups (1:1). Quantitative analysis of TILs in tumor and adjacent tissues between the two groups was performed by immunofluorescence staining and further analyses with oncological characteristics. In the meantime, trends of TILs in peripheral blood were compared between the two groups during the perioperative period.Continuous measurement of tumor volume and necrosis volume showed that the proportion of tumor necrosis volume on the seventh day after stage-I ALPPS was significantly higher than the pre-operative value (TIL infiltration level maintained a dynamic balance during the preoperative period of ALPPS. Compared with right hemi-hepatectomy, the ALPPS procedure does not cause severe immunosuppression with the decrease in TIL infiltration and pathological changes in immune components of peripheral blood. Our results suggested that ALPPS is safe and feasible for treating massive HCC from the perspective of immunology. In addition, high CD8

Metastasis is the main cause of poor postoperative survival of hepatocellular carcinoma (HCC) patients. Cytoskeleton rearrangement is a key event in cancer metastasis. However, the significance of microtubule (MT), one of the core components of cytoskeleton, in this process is only beginning to be revealed. Here, we find that the MT dynamics regulator end-binding protein 2 (EB2) is highly expressed in HCC and predicts poor prognosis of HCC patients. Functional studies show that EB2 overexpression promotes HCC proliferation, invasion and metastasis in vitro and in vivo, while EB2 knockdown has opposite results. Mechanistically, EB2 mediates MTs destabilization, increases Src (Src proto-oncogene non-receptor tyrosine kinase) activity, and thus facilitates extracellular signal-regulated kinase (ERK) signaling activation, which could in turn promote EB2 expression in HCC, eventually resulting in enhanced HCC proliferation, invasion and metastasis. Furthermore, U0126, a specific ERK inhibitor, could effectively inhibit EB2-mediated HCC proliferation and metastasis in vitro and in vivo. In conclusion, EB2 coordinates MT cytoskeleton and intracellular signal transduction, forming an EB2–MT–ERK positive feedback loop, to facilitate HCC proliferation, invasion and metastasis. EB2 could serve as a promising prognostic biomarker and potential therapeutic target for HCC; HCC patients with high EB2 expression may benefit from treatment with ERK inhibitors.

Selenocysteine (Sec), which is a biological selenol incorporated into selenoproteins specifically, plays vital roles in physiological processes and cancer treatment. However, there are limited fluorescent probes for selective detection of Sec and in only one case is a near-infrared (IR) fluorescent probe applied in biological imaging of Sec in living animals. In this work, we have synthesized a new fluorophore, boron-dibenzopyrromethene (B-Bodipy), with an absorption maximum at 650–660 nm, and constructed two deep red fluorescent probes, Sel-p1 and Sel-p2, which are two ethers composed of a 2,4-dinitrobenzenoxy and B-Bodipy moiety. Experiments in solution show that the two probes can react effectively with selenols to release the fluorophore via aromatic nucleophilic substitution (SNAr), with a low limit of detection (16 nM and 9 nM), high selectivity and excellent photostability. The potential application for the detection of Sec in cells has been demonstrated by cell imaging experiments of Sel-p2, including detection of exogenous Sec and selenite-induced Sec in living cells. Furthermore, Sel-p2 as a red fluorescent probe can achieve the detection of Sec in animals by mice imaging experiments.

Engineering nanoparticles of reasonable surface poly(ethylene glycol) (PEG) length is important for designing efficient drug delivery systems. Eliminating the disturbance by other nanoproperties, such as size, PEG density, etc., is crucial for systemically investigating the impact of surface PEG length on the biological behavior of nanoparticles. In the present study, nanoparticles with different surface PEG length but similar other nanoproperties were prepared by using poly(ethylene glycol)-block-poly(e-caprolactone) (PEG-b -PCL) copolymers of different molecular weights and incorporating different contents of PCL 3500 homopolymer . The molecular weight of PEG block in PEG-PCL was between 3400 and 8000 Da, the sizes of nanoparticles were around 100 nm, the terminal PEG density was controlled at 0.4 PEG/nm 2 (or the frontal PEG density was controlled at 0.16 PEG/nm2 ). Using these nanoproperties well-designed nanoparticles, we demonstrated PEG length-dependent changes in the biological behaviors of nanoparticles and exhibited nonmonotonic improvements as the PEG molecular weight increased from 3400 to 8000 Da. Moreover, under the experimental conditions, we found nanoparticles with a surface PEG length of 13.8 nm (MW = 5000 Da) significantly decreased the absorption with serum protein and interaction with macrophages, which led to prolonged blood circulation time , enhanced tumor accumulation and improved antitumor efficacy. The present study will help to establish a relatively precise relationship between surface PEG length and the in vivo behavior of nanoparticles.

Hierarchical targeting strategy can combat the sequential drug delivery barriers by changing their properties with response to tumor stimuli. Among these strategies, much less attention has been paid to address the issues of rapid tumor clearance and insufficient cellular translocation. In this work, we demonstrate that a transactivator of transcription (TAT)-presenting nanomedicine (DATAT-NP/Pt), apart from improving tumor accumulation and cellular uptake, can simultaneously enhance tumor retention and promote nuclear translocation of encapsulated platinum prodrugs, and thus improve therapeutic efficacy. Specifically, a protecting 2,3-dimethylmaleic anhydride (DA) corona on the nanomedicine prevented the TAT peptide from serum. DATAT-NP/Pt efficiently accumulated at the tumor site through the enhanced permeability and retention (EPR) effect, followed by acid-triggered TAT presenting within the tumor acidic microenvironment (pH ~ 6.8). The exposed TAT peptide augmented tumor retention and nuclear translocation of DATAT-NP/Pt. We used a tumor-on-a-chip microfluidic system to real-time mimic and analyze tumor accumulation and retention at physiological flow conditions and revealed that surface absorption of nanomedicines on tumors was critical in determining their tumor retention and clearance. Furthermore, the TAT peptide rapidly translocated the DATAT-NP/Pt into the perinuclear region, allowing for higher nuclear platinum concentrations and increased Pt-DNA adduct formation in nuclei, which consequently reversed cisplatin resistance. Our work presents a new strategy to overcome pathophysiological barriers of tumor clearance and insufficient cellular translocation and provides new insights for the design of cancer nanomedicines.

Nanoparticle (NP) drug delivery systems have been successfully designed and implemented to orally deliver siRNAs for inflammatory disorders. However, the influence of surface charge on orally administered siRNA nanocarriers has not been investigated. In this study, we prepared structurally related poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (PEG5K-b-PLGA10K) NPs with the assistance of a synthesized lipid featuring surface amine groups for subsequent charge tuning. NPs were prepared by a double emulsion method, and their surface charge could be tuned and controlled by a succinylation reaction to yield NPs with different surface charges, while maintaining their size and composition. The prepared NPs were termed as aminated NPs (ANPs), plain NPs (PNPs), or carboxylated NPs (CNPs) based on their surface charge. All NPs exhibited the desired structural stability and siRNA integrity after enzymatic degradation. In vivo studies showed that ANPs significantly accumulated in inflamed colons, and they were successful in decreasing TNF-α secretion and mRNA expression levels while maintaining colonic histology in a murine model of acute ulcerative colitis (UC). This study described a methodology to modify the surface charge of siRNA-encapsulating polymeric NPs and highlighted the influence of surface charge on oral delivery of siRNA for localized inflammatory disorders.

The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo. More importantly, after further encoding a guide RNA targeting Ntn1 (sgNtn1) into the plasmid, the resultant CLANpM330/sgNtn1 successfully disrupted the Ntn1 gene in macrophages and their precursor monocytes in vivo, which reduced expression of netrin-1 (encoded by Ntn1) and subsequently improved type 2 diabetes (T2D) symptoms. Meanwhile, the Ntn1 gene was ...

Surface charge plays an important role in determining the interactions of nanoparticles with biological components. Substantial studies have demonstrated that surface charge affects the fate of nanoparticles after intravenous administration; however, few studies have investigated the effect of surface charge on the bioavailability and absorption of nanoparticles after oral administration. In this study, polymeric nanoparticles with a similar particle size and surface polyethylene glycol (PEG) density, but with varying surface charges (positive, negative and neutral), were developed to study the effect of surface charge on the oral absorption of polymeric nanoparticles. The nanoparticles were constructed from polyethylene glycol-block-polylactic acid (PEG-PLA) with the incorporation of lipid components with different charges. Our results suggested that the positive surface charge facilitated the cellular uptake and transport of nanoparticles through both Caco-2 cells in vitro and small intestinal epithelial cells in vivo. The positively charged nanoparticles showed a favorable distribution in the small intestine, and significantly improved the oral bioavailability. This study presents valuable information towards the design of nanoparticles for improved oral drug delivery.

Nitric oxide (NO) is an important signaling molecule involved in many physiological and pathological processes. To understand these NO-mediated processes, it is a key to develop rapid and specific detection methods for NO. In the past 2 decades, numerous excellent fluorescent probes for NO have been designed; however, it still remains limitations such as slow response, low selectivity, and short excitation wavelength (600 nm). In this Article, a two-photon fluorescent probe, NO-QA5, has been developed with 3-dimethylaminophenyl linking at the 6-position of 5-aminoquinoline as both the active site and prefluorophore for detection of NO. The nonfluorescent NO-QA5 can fast react with NO via a diazonium intermediate to generate two azoic regioisomers, one of which exhibits intramolecular charge transfer (ICT) emission, and two-photon absorption behavior (δΦ = 57 GM), giving a turn-on fluorescence rapid response. The sensing reaction is pH-insensitive in the range of 6-11 and highly selective and well sensitive (LOD = 15 nM), possible undergoing the same intermediate diazonium with the reaction under diazotization condition (NaNO

Polymeric nanoparticles (NPs) are an important category of drug delivery systems, and their in vivo fate is closely associated with delivery efficacy. Analysis of the protein corona on the surface ...

The NE-trending Longmen Shan (LMS) thrust belt, located between the Songpan-Garze terrane and the Yangtze craton, is one of the steepest topographic margins around the Tibetan Plateau. However, the exhumation history and the fault activity of the southern segment of the LMS have remained poorly constrained, particularly in the range front, where little thermochronology ages have been reported. Herein, we report 17 apatites (U-Th)/He (AHe) ages from the southern LMS along the Qingyi River across the Dachuan–Shuangshi Fault (DSF), the Yanjing–Wulong Fault (YWF), and the Gengda–Longdong Fault (GLF). The AHe ages in the hanging-wall of the DSF are ca. 6–11 Ma, which increase to ca.19–23 Ma in the footwall of the DSF. New AHe ages reveal that exhumation rates across the DSF increased significantly from 0.05 to 0.1 km/Myr in the footwall to 0.2–0.4 km/Myr in the hanging-wall since the Late Miocene. The width of the high exhumation rate (0.4–0.6 km/Myr) belt concentrated between the DSF and the GLF, and towards DSF eastward and GLF westward, the exhumation rates decrease rapidly. The results show that continuous crustal shortening along the DSF. Our results support the upper crustal thrusting model that emphasizes crustal shortening deformation along the eastern Tibetan Plateau margin.

To evaluate the effects of enhancement release of Chum salmon (Oncorhynchus keta) in Suifen River, the homing Chum salmon was monitored in Dongning section of Suifen River from 2012 to 2017. A total of 462 samples were collected, 41 samples out of which were tagged indivi-duals which were cut off adipose fin before they were released. The recapture rate and the effects of Chum salmon enhancement release were analyzed and evaluated based on the releasing information. The results showed that the entire recapture rate of Chum salmon from 2010 to 2012 was 0.295%, and the input-output ratio of enhancement release was 1:2.87. Both the tagged and non-tagged groups were composed of 1为评估绥芬河大麻哈鱼增殖放流效果,本研究于2012—2017年在绥芬河东宁段对大麻哈鱼溯河洄游群体进行跟踪监测.共采集样本462尾,其中,标记个体(剪脂鳍)41尾.根据调查数据,计算了大麻哈鱼增殖放流回捕率,评估了增殖放流效果.结果表明: 2010—2012年的大麻哈鱼增殖放流回捕率为0.295%,大麻哈鱼增殖放流数量效益为1∶2.87.标记组和非标记组群体年龄组均为1

Summary Physiochemical properties of nanomedicines determine their in vivo fate and ultimate therapeutic efficacy. Establishing correlations between nanoparticle properties and their physiological response is vitally important for nanomedicine design and optimization. To date, the correlation between surface charge, a fundamental property of a nanomedicine, and its therapeutic efficacy remains poorly understood. Here, we systematically investigated the influence of surface charge on the pharmacokinetics, tumor accumulation, penetration, and antitumor efficacy of nanoparticles constructed from PEG- b -PLA, loaded with docetaxel, and tuned by various lipids to yield three groups of ∼100 nm nanoparticles with positive, neutral or negative charge. Our results indicate that cationic PEGylated nanoparticles, although slightly inferior in blood circulation time and tumor accumulation, outperform their anionic or neutral counterparts in inhibiting tumor growth in five different tumor models. Docetaxel-loaded cationic nanoparticles significantly suppressed tumor growth with an inhibition ratio of ∼90%, compared with the ∼60% achieved by their anionic or neutral counterparts. Further studies reveal that better tumor penetration and 2.5-fold higher cellular uptake of cationic PEGylated nanoparticles is responsible for their superior treatment efficacy. This fundamental study provides a foundation for engineering the next generation of nano-delivery systems for in vivo applications.

Poly(ethylene glycol) (PEG) is usually used to protect nanoparticles from rapid clearance in blood. The effects are highly dependent on the surface PEG density of nanoparticles. However, there lacks a detailed and informative study in PEG density and in vivo drug delivery due to the critical techniques to precisely control the surface PEG density when maintaining other nano-properties. Here, we regulated the polymeric nanoparticles' size and surface PEG density by incorporating poly(ε-caprolactone) (PCL) homopolymer into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) and adjusting the mass ratio of PCL to PEG-PCL during the nanoparticles preparation. We further developed a library of polymeric nanoparticles with different but controllable sizes and surface PEG densities by changing the molecular weight of the PCL block in PEG-PCL and tuning the molar ratio of repeating units of PCL (CL) to that of PEG (EG). We thus obtained a group of nanoparticles with variable surface PEG densities but with other nano-properties identical, and investigated the effects of surface PEG densities on the biological behaviors of nanoparticles in mice. We found that, high surface PEG density made the nanoparticles resistant to absorption of serum protein and uptake by macrophages, leading to a greater accumulation of nanoparticles in tumor tissue, which recuperated the defects of decreased internalization by tumor cells, resulting in superior antitumor efficacy when carrying docetaxel.

Aberrant expression of Abelson interactor 1 (ABI1) has been reported in multiple cancers. However, its clinical significance and potential biological roles in hepatocellular carcinoma (HCC) have not been fully elucidated. In this study, we found that ABI1 was obviously upregulated in HCC tissues compared with non-tumor tissues. Moreover, high ABI1 expression was significantly correlated with tumor size (P=0.041), tumor number (P

To explore the exogenous Sr2+ sedimentation on otolith of chum salmon embryos, chum salmon embryos were exposed to culture water contained Sr2+ at Sr2+ concentration of 50, 100, 200 or 400 mg . L-1 for 48 h to imitate Sr2+ sedimentation. After a culturing period of 12 d and 100 d, the otoliths of the chum salmon were taken to detect exogenous Sr2+ sedimentation with electro-probe microanalyzer (EPMA). The results showed that obvious deep red strontium signatures were produced in the otolith of chum salmon at different concentrations of Sr2+. The mean and extreme values of peak strontium area were not stable for the same Sr2+ dose, but the lowest of all the peak values was 35.1 times as much as that of control. Overall, the strontium value increased with the increase of Sr2+concentration. The strontium peak had no signs of abating after a culture period of 100 d. The results also showed that strontium was gradually deposited in the otolith, and had obvious hysteresis to immersion. Strontium sedimentation could also return to a normal level after the peak. These characteristics accorded exactly with the requirement of discharge tag technology, which indicated that exogenous Sr2+ was suitable in the marking of salmon otolith.

The influence of microstructures with different heat treatments to stimulate the weld fusion zone and HAZ on corrosion properties of X80 pipeline steel was investigated in alkaline sand soil using electrochemical measurement and surface analysis(SEM, EDS and XRD). The results showed that the microstructure of X80 steel affected the properties of corrosion product layers. Generally, X80 steels with heat treatments had a higher corrosion rate than the as-received steel. The increase of pearlite content enhanced the corrosion of ferrite through a galvanic effect. The appearance of upper bainite and martenite increased further the activity of the steel. The corrosion product layer formed on as-received X80 steel was compact and complete, provided an effective protection to the underneath steel. However, the corrosion product layers on the heat-treated X80 steels were generally inhomogeneous, loose, porous and defective, and provided minor protectiveness. The cathodic/ anodic reactions of X80 steel are dominated by the oxygen reduction and formation of iron oxides that deposit on the steel surface which was through a physical block effect to afford the protection. We shall be able to publish your paper in electronic form on our web page http://www.scientific.net, if the paper format and the margins are correct. Your manuscript will be reduced by approximately 20% by the publisher. Please keep this in mind when designing your figures and tables etc.

Chemotherapy resistance has become a major challenge in the clinical treatment of lung cancer which is the leading cancer type for the estimated deaths. Recent studies have shown that nanoparticles as drug carriers can raise intracellular drug concentration by achieving effectively cellular uptake and rapid drug release, and therefore reverse the acquired chemoresistance of tumors. In this context, nanoparticles-based chemotherapy represents a promising strategy for treating malignancies with chemoresistance. In the present study, we developed cationic lipid assisted nanoparticles (CLAN) to deliver polylactide-cisplatin prodrugs to drug resistant lung cancer cells. The nanoparticles were formulated through self-assembly of a biodegradable poly(ethylene glycol)-block-poly(lactide) (PEG-PLA), a hydrophobic polylactide-cisplatin prodrug, and a cationic lipid. The cationic nanoparticles were proven to significantly improve cell uptake of cisplatin, leading to an increased DNA-Pt adduct and significantly promoted DNA damage in vitro. Moreover, our study reveals that cationic nanoparticles, although are slightly inferior in blood circulation and tumor accumulation, are more effective in blood vessel extravasation. The CLANs ultimately enhances the cellular drug availability and leads to the reversal of cisplatin resistance.

Diet compositions of alien clearhead icefish(Protosalanx hyalocranius)in Lake Xingkai were investigated monthly from June 2010 through January 2011. Protosalanx hyalocranius preyed mainly on cladoceran, copepoda, shrimp, and larvae or juvenile fish. In June, P. Hyalocranius were smaller than 60 mm standard length(SL), and their diets were composed of zooplankton only. In July, fish began to appear infrequently in the diet of P. Hyalocranius larger than 60 mm SL, and by August fish was occurring in the diets of P. hyalocranius larger than 80 mm, 100 mm in September, and 120 mm in October and thereafter, respectively. The increase in the minimum SL of P. hyalocranius preying on fish within a given season reflects changes in resource availability, largely attributed to the corresponding increase in prey fish size as seasons progress. Protosalanx hyalocranius and Hemiculter sp. were the dominant prey fish in the diets of P. hyalocranius.该文于2010年6月—2011年1月逐月分析中俄界湖兴凯湖外来种大银鱼食性,结果发现,大银鱼主要摄食枝角类、桡足类、虾类和鱼类。6月份大银鱼体长60 mm,以枝角类和桡足类为食,7月份体长60 mm群组、8月份体长80 mm群组、9月份体长100 mm群组与10月及之后体长120 mm群组等的食谱中均出现鱼类,且优势种类为大银鱼和?属鱼类。该摄食鱼类的大银鱼最小体长随季节而增加的现象,与饵料鱼类生长导致的食物资源可得性变动密切相关。

Distributed computing technique has increasingly been used in the network management. Furthermore, the agent technology has also been widely used in the performance and fault management of networks. This article put forward an INM (intelligent network management) architecture based on CORBA and intelligent agent technology in the domain of telecommunications network management, using intelligent agent distributed management and grouping managed objects to cache. An INM system has been designed and implemented, and it has provided intelligent network management policies, and thus enhanced the performance of network management with multiple object quick access.

With emerging problems of limited wireless spectrum resources and more and more wireless or mobile users in Internet, network congestion will be become an outstanding matter that needs be solved urgently in booming wireless mobile Internet. In order to meet the higher standard of wireless transmission in wireless mobile Internet via satellite for multimedia communication based on multi-information system with integrating speech, data, video and cartoon. A strategy for controlling congestion based on multi-information and fuzzy identification technologies is presented. The model of strategy for controlling congestion has a smart characteristic that used for analyzing and controlling congestion in wireless mobile Internet via satellite, moreover it possesses some basis functions for dynamically building wireless local area network oriented 3G and 4G and next generation Internet in the future communication networks and next generation network. Simulation shown: there are a certain self-adaptive control characters of congestion in the model of strategy for controlling congestion. However it is that maybe more developed to become an intelligence toolbox orient-large-scale network in building next generation Internet and next generation network.