Trace Selenium Doping for Improving the Reaction Kinetics of ZnS Cathode for Aqueous Zn-S Batteries.

Aqueous Zinc-sulfur (Zn-S) batteries are promising for the field of energy storage due to their low cost, high theoretical capacity, and safety. However, the large volume expansion and the inherently poor conductivity of sulfur would result in electrode cracking and sluggish reaction kinetics, limiting the practical application of Zn-S batteries. Herein, commercial zinc sulfide (ZnS) is employed instead of S as cathode and proposed a doping modification strategy to solve the above problems. The designed ZnS0.93Se0.07 cathode shows good cycle stability and much-improved reaction kinetics, which is due to the smaller bandgap of ZnS0.93Se0.07 (1.40 eV) compared to ZnS (1.86 eV). As a result, the obtained ZnS0.93Se0.07 cathode exhibits a high specific capacity of 552 mAh g-1 (1672.6 mAh g-1 based on S) at 0.1 A g-1 and 330 mAh g-1 (1000 mAh g-1 based on S) at 2 A g-1. Moreover, the ZnS0.93Se0.07 cathode can provide a high areal capacity of 3.8 mAh cm-2 at a high mass loading of 10 mg cm-2 and limited electrolyte (4 µL mg-1). This work provides a simple and effective cathode modification strategy, which is conducive to promoting the practical application of Zn-S batteries.

Phase Engineering of Nonstoichiometric Cu2-xSe as Anode for Aqueous Zn-Ion Batteries.

Aqueous zinc-ion batteries (AZIBs) are receiving widespread attention due to their abundant resources, low material cost, and high safety. However, the susceptibility of Zn metal anodes to corrosion and hydrogen evolution limits their further practical applications. Replacing Zn metal with intercalation-type anode material and constructing rocking-chair-type batteries could be an effective way to significantly prolong the cycle life of AZIBs. Herein, we present copper selenide with different crystal phase structures through a facile redox reaction as an anode for AZIBs. By comparing and analyzing different copper selenide phases, it is found that the cubic Cu2-xSe shows superior structural stability and highly reversible Zn2+ storage. Theoretical calculation results further demonstrate that the cubic Cu2-xSe possesses an increased electrical conductivity, higher Zn2+ adsorption energy, and reduced diffusion barrier, thereby promoting the storage reversibility and (de)intercalation kinetics of the Zn2+ ion. Thus, the Cu2-xSe anode delivers a long-term service life of over 15 000 cycles and impressive cumulative capacity. Furthermore, the full-cells assembled with the MnO2/CNT cathode operate stably for over 1500 cycles at 6 mA cm-2 at a negative/positive (N/P) capacity ratio of ∼1.53. This work provides a more ideal Zn-metal-free anode, which helps to push the practical applications of AZIBs.

Arsenic Accumulation and Physiological Response of Three Leafy Vegetable Varieties to As Stress.

Arsenic (As) in leafy vegetables may harm humans. Herein, we assessed As accumulation in leafy vegetables and the associated physiological resistance mechanisms using soil pot and hydroponic experiments. Garland chrysanthemum (Chrysanthemum coronarium L.), spinach (Spinacia oleracea L.), and lettuce (Lactuca sativa L.) were tested, and the soil As safety threshold values of the tested leafy vegetables were 91.7, 76.2, and 80.7 mg kg−1, respectively, i.e., higher than the soil environmental quality standard of China. According to growth indicators and oxidative stress markers (malondialdehyde, the ratio of reduced glutathione to oxidized glutathione, and soluble protein), the order of As tolerance was: GC > SP > LE. The high tolerance of GC was due to the low transport factor of As from the roots to the shoots; the high activity of superoxide dismutase, glutathione peroxidase, and catalase; and the high content of phytochelatin in the roots. Results of this work shed light on the use of As-contaminated soils and plant tolerance of As stress.

An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity.

Hepatocellular carcinoma (HCC) is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy. A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs (ceRNAs) bind to the same microRNAs. However, the contribution of such mechanisms in HCC has not been well studied. Herein, potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages, identifying the mTORC2 component RICTOR as a potential HMGB1 ceRNA in HBV+ early stage HCC. Indeed, elevated HMGB1 mRNA was found to promote the expression of RICTOR mRNA through competitively binding with the miR-200 family, especially miR-429. Functional assays employing overexpression or interference strategies demonstrated that the HMGB1 and RICTOR 3'untranslated regions (UTR) epigenetically promoted the malignant proliferation, self-renewal, and tumorigenesis in HCC cells. Intriguingly, interference against HMGB1 and RICTOR in HCC cells promoted a stronger anti-PD-L1 immunotherapy response, which appeared to associate with the production of PD-L1+ exosomes. Mechanistically, the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms, activating a positive feedback loop involving mTORC2-AKT-C-MYC to upregulate glutamine synthetase (GS) expression, and inducing mTORC1 signaling to derepress SIRT4 on glutamate dehydrogenase (GDH). Meanwhile, this crosstalk network could impede the efficacy of immunotherapy through mTORC1-P70S6K dependent PD-L1 production and PD-L1+ exosomes activity. In conclusion, our study highlights the non-coding regulatory role of HMGB1 with implications for RNA-based therapeutic targeting together with a prediction of anti-PD-L1 immunotherapy in HCC.

Corrosion behavior of high nitrogen nickel-free austenitic stainless steel in the presence of artificial saliva and Streptococcus mutans.

High nitrogen nickel-free austenitic stainless steels (HNSs) have great potentials to be used in dentistry owing to its exceptional mechanical properties, high corrosion resistance, and biocompatibility. In this study, HNSs with nitrogen of 0.88 wt% and 1.08 wt% displayed much lower maximum pit depths than 316L stainless steel (SS) after 21 d of immersion in abiotic artificial saliva (2.2 µm and 1.7 µm vs. 4.5 µm). Microbiologically influenced corrosion (MIC) evaluations revealed that Streptococcus mutans biofilms led to much severer corrosion of 316L SS than HNSs. Corrosion current densities of HNSs were two orders of magnitude lower than that of 316L SS after incubation of 7 d (37.5 nA/cm2 and 29.9 nA/cm2 vs. 5.63 µA/cm2). The pitting potentials of HNSs were at least 550 mV higher than that of 316L SS in the presence of S. mutans, confirming the better MIC resistance of HNSs. Cytotoxicity assay confirmed that HNSs were not toxic to MC3T3-E1 cells and allowed better sessile cell growth on them than on 316L SS. It can be concluded that HNSs are more suitable dental materials than the conventional 316L SS.

Concentrations of polycyclic aromatic hydrocarbons in street dust from bus stops in Qingyang city: Estimates of lifetime cancer risk and sources of exposure for daily commuters in Northwest China.

Lifetime cancer risk and exposure of daily commuters to polycyclic aromatic hydrocarbons (PAHs) in cities of Northwest China were determined from a study of street dust samples obtained from bus stops in Qingyang city. The sum of 16 priority PAHs (Σ16 PAHs) concentrations in the dust samples ranged from 0.8 to 18.3 mg kg-1 (mean 3.0 mg kg-1) and the distribution of individual, carcinogenic, combustion specific, low (2-3 rings) and high molecular weight (4-6 rings) PAHs was determined. The benzo[a]pyrene toxic equivalents of Σ16 PAHs ranged from 0.01 to 12.2 mg kg-1 (mean 0.8 mg kg-1). Incremental lifetime cancer risk from exposure to PAHs in dust at bus stops in Qingyang city was estimated at 1.9 × 10-6 for adults and 3.5 × 10-6 for children (confidence limit ≥ 95%). Emission source analysis of PAHs in bus stop dust showed that they were mainly derived from residential coal, oil and biomass combustion, e.g. from boilers, traffic vehicles, and Kang heaters. Higher concentrations of PAHs were obtained at bus stops near transport hubs, commercial districts, and administrative institutions.

Transarterial chemoembolization versus percutaneous microwave coagulation therapy for recurrent unresectable intrahepatic cholangiocarcinoma: Development of a prognostic nomogram.

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) are commonly used to treat intrahepatic recurrent liver cancers. However, there is no information regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma (ICC) after resection. METHODS: A total of 275 patients with localized recurrent ICC who received either TACE (n = 183) or PMCT (n = 92) were studied. A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT. Prognostic factors for TACE and PMCT were identified respectively. Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values. RESULTS: Both TACE and PMCT provided curativeness in partial patients (5-year overall survival: 21.4% and 6.1%, respectively), but TACE provided better survival benefit in both overall patients (hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.50-0.97; P = 0.034) and propensity score matching analysis (HR = 0.69; 95% CI: 0.47-0.98; P = 0.041). Independent prognostic factors for TACE were tumor size >5 cm, poor differentiation, and major resection, whereas poor differentiation, hepatitis B virus infection, cholelithiasis, and lymph node metastasis were identified for PMCT. Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70, respectively. CONCLUSIONS: TACE provided better survival benefits compared to PMCT. However, there was a disparity in prognostic factors, suggesting evaluation of the two nomograms may be supportive in modality selection. Further prospective validation studies are required for the results to be applied in clinical medicine.

Deep-learning-based information mining from ocean remote-sensing imagery.

With the continuous development of space and sensor technologies during the last 40 years, ocean remote sensing has entered into the big-data era with typical five-V (volume, variety, value, velocity and veracity) characteristics. Ocean remote-sensing data archives reach several tens of petabytes and massive satellite data are acquired worldwide daily. To precisely, efficiently and intelligently mine the useful information submerged in such ocean remote-sensing data sets is a big challenge. Deep learning-a powerful technology recently emerging in the machine-learning field-has demonstrated its more significant superiority over traditional physical- or statistical-based algorithms for image-information extraction in many industrial-field applications and starts to draw interest in ocean remote-sensing applications. In this review paper, we first systematically reviewed two deep-learning frameworks that carry out ocean remote-sensing-image classifications and then presented eight typical applications in ocean internal-wave/eddy/oil-spill/coastal-inundation/sea-ice/green-algae/ship/coral-reef mapping from different types of ocean remote-sensing imagery to show how effective these deep-learning frameworks are. Researchers can also readily modify these existing frameworks for information mining of other kinds of remote-sensing imagery.

Biomechanical compatibility of high strength nickel free stainless steel bone plate under lightweight design.

High nitrogen nickel-free stainless steel (HNNFSS) has excellent mechanical properties, corrosion resistance and biocompatibility, but its strength advantage is not fully used even though with one time higher than that of the conventional 316 L stainless steel. In this work, the lightweight design of HNNFSS bone plate was studied using finite element analysis, and the effect of lightweight plate fixation on histological and biomechanical behavior of healing bone were also researched on fractured rabbit femur. The finite element analysis results showed that the lightweight plate within 18.2% thickness reduction had higher bending strength and more homogeneous stress distribution compared with 316 L stainless steel plate. There was no obvious difference in radiography, histology analysis of callus and expression pattern of insulin like growth factor-1(IGF-1) of callus between the lightweight HNNFSS plate group and 316 L stainless steel plate group in animal test, and the IGF-1 concentrations of callus and the biomechanical bending test results also showed no statistical significance (p > 0.05), even though the data of the lightweight HNNFSS plate group were relatively better than that of 316 L stainless steel plate group. Therefore, the high nitrogen nickel-free stainless steel has the lightweight potential to keep good fixing function and improve bone healing compared with 316 L stainless steel plate.

Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3.

BACKGROUND AND PURPOSE: Necroptosis is a form of programmed, caspase-independent, cell death, mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan-Raf inhibitor TAK-632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK-632 by targeting RIPK1 and RIPK3. EXPERIMENTAL APPROACH: Cell viability was measured by MTT, propidium staining, or CellTiter-Glo luminescent assays. Effects of TAK-632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK-632 were identified by a drug affinity responsive target stability assay and a pull-down assay with biotinylated TAK-632. A mouse model of TNF-α-induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK-632 in protecting against necroptosis-associated inflammation in vivo. KEY RESULTS: TAK-632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK-632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK-632 alleviated TNF-induced SIRS. Furthermore, we performed a structure-activity relationship analysis of TAK-632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3. CONCLUSIONS AND IMPLICATIONS: TAK-632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3.

[Effects of copper content on the antibacterial performance and corrosion resistance of CoCrMoCu alloy].

OBJECTIVE: This study aimed to determine the effects of copper content on the corrosion resistance of CoCrMoCu alloy and its in vitro antibacterial performance. METHODS: CoCrMoCu specimens with different Cu contents (2%, 3%, 5%, and 7%) were prepared by vacuum melting method. CoCrMo without Cu served as control. The corrosion resistance of the specimens was measured by electrochemistry. The antibacterial effects of the specimens on Staphylococcus aureus and Escherichia coli were analyzed by coating-film method. RESULTS: Compared with CoCrMo without Cu, the addition of 2%-5% Cu to CoCrMo improved the pitting and uniform corrosion of CoCrMo alloy and decreased the corrosion current density. The antibacterial performance of CoCrMoCu alloy increased with increased Cu content. The antibacterial rate of alloy was 99% when Cu content exceeded 5%. CONCLUSIONS: Cu addition had a statistically significant influence on the corrosion resistance and antibacterial performance of CoCrMoCu. CoCrMoCu has better corrosion resistance and antibacterial performance when Cu content is 5%.

Design and characterization of a novel nickel-free cobalt-base alloy for intravascular stents.

Co-Cr-W-Ni alloy (L605) with high tensile strength is used in coronary stents. The thickness of individual strut of the stent is reduced which can decrease the stent restenosis rate. However, about 10% Ni element content in L605 is found to cause allergic reactions and pulmonary embolism, similar to the traditional 316L stainless steel. In this study, a novel nickel-free cobalt-base alloy Co-20Cr-12Fe-18Mn-2Mo-4W-N (wt%) was designed and fabricated in order to efficiently avoid the potential hazards of Ni element. Fe and Mn, essential elements of human body, were added in the alloy to substitute part of Co element. In comparison to L605 alloy, the tensile strength of the new alloy was higher than 1000MPa while elongation was above 55%. The pitting potential of the new alloy was measured close to 1000mV, also higher than that of L605 alloy. CCK-8 test indicated that the cytotoxicity of the new alloy is grade 1, reflecting that Co-20Cr-12Fe-18Mn-2Mo-4W-N alloy has no cytotoxic effects. There was no significant difference in the apoptosis rates between Co-20Cr-12Fe-18Mn-2Mo-4W-N and L605 alloy. The newly developed cobalt-base alloy showed excellent mechanical, corrosion resistance and biological properties, which could make it a desirable material for future clinical investigations.

Biological behaviour of human umbilical artery smooth muscle cell grown on nickel-free and nickel-containing stainless steel for stent implantation.

To evaluate the clinical potential of high nitrogen nickel-free austenitic stainless steel (HNNF SS), we have compared the cellular and molecular responses of human umbilical artery smooth muscle cells (HUASMCs) to HNNF SS and 316L SS (nickel-containing austenitic 316L stainless steel). CCK-8 analysis and flow cytometric analysis were used to assess the cellular responses (proliferation, apoptosis, and cell cycle), and quantitative real-time PCR (qRT-PCR) was used to analyze the gene expression profiles of HUASMCs exposed to HNNF SS and 316L SS, respectively. CCK-8 analysis demonstrated that HUASMCs cultured on HNNF SS proliferated more slowly than those on 316L SS. Flow cytometric analysis revealed that HNNF SS could activate more cellular apoptosis. The qRT-PCR results showed that the genes regulating cell apoptosis and autophagy were up-regulated on HNNF SS. Thus, HNNF SS could reduce the HUASMC proliferation in comparison to 316L SS. The findings furnish valuable information for developing new biomedical materials for stent implantation.

Effect of cold deformation on pitting corrosion of 00Cr18Mn15Mo2N0.86 stainless steel for coronary stent application.

The high nitrogen nickel-free stainless steel has offered an alternative to further improve the performance of the coronary stents, and simultaneously avoids the potential harms of nickel element. Both cold deformation and pitting corrosion are very important for coronary stents made of stainless steel. In this work, the effect of cold deformation on the pitting corrosion resistance of a high nitrogen nickel-free stainless steel (00Cr18Mn15Mo2N0.86) in 0.9% saline solution was investigated. The results showed that the pitting corrosion of the steel was nearly unchanged with increases of the cold deformation up to 50%, indicating that the higher nitrogen content can reduce the negative effect of cold deformation on the pitting corrosion resistance, which is beneficial for the long term service of coronary stents in blood vessel.

[Characteristics and Formation Mechanism of a Multi-Day Haze in the Winter of Shijiazhuang Using a Single Particle Aerosol Mass Spectrometer (SPAMS)].

A multi-day haze episode occurred in Shijiazhuang during November 18-26, 2014. The characteristics were studied based on the data collected by the single particle aerosol mass spectrometer (SPAMS) located in the automatic monitoring station (20 meters) of Shijiazhuang. In accordance with the source spectral library of atmospheric pollutant emissions in Shijiazhuang, the main sources were distinguished and analyzed. The mass concentration of particulate matters and meteorological conditions being taken in account, the causes of haze in winter were also studied. It turned out that fine particulate matters in the Shijiazhuang air were mainly from 7 different sources: the tracer ion of coal source was Al; the tracer ions of industry sources were OC, Fe, and Pb; the tracer ion of motor vehicle tail gas source was EC; the tracer ions of dust source were Al, Ca and Si; the tracer ions of biomass burning source were K and levoglucosan; the tracer ions of pure secondary inorganic source were SO4-, NO2-, and NO3-, and the tracer ion of dining source was HOC. Of the above mentioned, OC, HOC, EC, HEC, ECOC, rich potassium particles minerals and heavy metals were 8 dominant polluting groups in hazy days. OC and ECOC particles were the majority, which accounted for more than 50% and 20% of the overall measured particles. OC particles were mainly discharged from coal combustion and industrial processes, and ECOC particles were mainly from coal combustion and vehicle exhaust emissions. When haze occurred in Shijiazhuang the proportion of pollutant particles of NH4+, SO4- , NO2- and NO3- increased, of which NH4+ was the most sharply increased. The mixed degree between EC, OC and NH4+, So4-, NO3- in the haze was higher than usual, of which NH4+ was the most sharply increased. In the static and stable weather gaseous (SO2, NO(x), NH3, VOCs) pollutants and particles were difficult to spread and accumulated rapidly, which were discharged from coal combustion, the process of the medical industry and the automobile exhaust. The gaseous pollutants tended to react for the second time and formed the ammonium nitrate and ammonium sulfate particles. Secondary particles were formed by collision and mixed with each other adequately or mildly, which caused the reduction of atmospheric visibility. This was the main cause for the haze during the winter in Shijiazhuang.

Interleukin-1ß/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis.

UNLABELLED: Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up-regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)-1ß was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL-1ß/interleukin-1 receptor-associated kinase 1 (IRAK-1) signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK-1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time polymerase chain reaction, or immunoblotting further confirmed the up-regulation of Gankyrin by IL-1ß/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein p300 (p300) or CREB-binding protein (CBP) to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1ß stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK), and p300 and enhances recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1ß/IRAK-1 signaling-mediated up-regulation of Gankyrin. CONCLUSION: The finding of IL-1ß/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis.

Reduction of in-stent restenosis risk on nickel-free stainless steel by regulating cell apoptosis and cell cycle.

High nitrogen nickel-free austenitic stainless steel (HNNF SS) is one of the biomaterials developed recently for circumventing the in-stent restenosis (ISR) in coronary stent applications. To understand the ISR-resistance mechanism, we have conducted a comparative study of cellular and molecular responses of human umbilical vein endothelial cells (HUVECs) to HNNF SS and 316L SS (nickel-containing austenitic 316L stainless steel) which is the stent material used currently. CCK-8 analysis and flow cytometric analysis were used to assess the cellular responses (proliferation, apoptosis, and cell cycle), and quantitative real-time PCR (qRT-PCR) was used to analyze the gene expression profile of HUVECs exposed to HNNF SS and 316L SS, respectively. Flow cytometry analysis revealed that 316L SS could activate the cellular apoptosis more efficiently and initiate an earlier entry into the S-phase of cell cycle than HNNF SS. At the molecular level, qRT-PCR results showed that the genes regulating cell apoptosis and autophagy were overexpressed on 316L SS. Further examination indicated that nickel released from 316L SS triggered the cell apoptosis via Fas-Caspase8-Caspase3 exogenous pathway. These molecular mechanisms of HUVECs present a good model for elucidating the observed cellular responses. The findings in this study furnish valuable information for understanding the mechanism of ISR-resistance on the cellular and molecular basis as well as for developing new biomedical materials for stent applications.

High expression of proline-rich tyrosine kinase 2 is associated with poor survival of hepatocellular carcinoma via regulating phosphatidylinositol 3-kinase/AKT pathway.

BACKGROUND: The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism. METHODS: Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. RESULTS: Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P < 0.001). However, only higher peritumoral Pyk2 density was related to lower disease-free survival (P = 0.014) and vascular invasion (P = 0.035). A significant correlation between Pyk2 and VEGF density in tumor or peritumoral liver tissue was observed (r = 0. 3133, P = 0.0002; r = 0.5176, P < 0.0001, respectively). Immunoblotting showed that Pyk2 activated PI3K-AKT pathway to upregulate VEGF expression in HL-7702, SMMC-7721 and HepG2 cells. CONCLUSIONS: High Pyk2, especially peritumoral Pyk2 was associated with poor survival, disease recurrence, and metastasis in HCC. PI3K-AKT pathway was involved in Pyk2-mediated VEGF expression during HCC progression and invasion.

The tyrosine kinase c-Met contributes to the pro-tumorigenic function of the p38 kinase in human bile duct cholangiocarcinoma cells.

Pro-tumorigenic function of the p38 kinase plays a critical role in human cholangiocarcinogenesis. However, the underlying mechanism remains incompletely understood. Here, we report that c-Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), contributes to the pro-tumorigenic ability of p38 in human cholangiocarcinoma cells. Both p38 and c-Met promote the proliferation and invasion of human cholangiocarcinoma cells. Importantly, inhibition or knockdown of p38 decreased the basal activation of c-Met. Tyrosine phosphatase inhibitor studies revealed that p38 promotes the activity of c-Met, at least in part, by inhibiting dephosphorylation of the receptor. Moreover, density enhanced phosphatase-1 (DEP-1) is involved in p38-mediated inhibiting dephosphorylation of c-Met. Furthermore, p38 inhibits the degradation of c-Met. Taken together, these data provide a potential mechanism to explain how p38 promotes human cholangiocarcinoma cell proliferation and invasion. We propose that the link between p38 and c-Met is implicated in the progression of human cholangiocarcinoma.

Disturbance of Ca2+ homeostasis converts pro-Met into non-canonical tyrosine kinase p190MetNC in response to endoplasmic reticulum stress in MHCC97 cells.

c-Met, the tyrosine-kinase receptor for hepatocyte growth factor, plays a critical role in the tumorigenesis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains incompletely understood. The mature c-Met protein p190Met(αß) (consists of a α subunit and a ß subunit) is processed from pro-Met. Here we show that pro-Met is processed into p190Met(NC) by sarco/endoplasmic reticulum calcium-ATPase (SERCA) inhibitor thapsigargin. p190Met(NC) compensates for the degradation of p190Met(αß) and protects human HCC cells from apoptosis mediated by endoplasmic reticulum (ER) stress. In comparison with p190Met(αß), p190Met(NC) is not cleaved and is expressed as a single-chain polypeptide. Thapsigargin-initiated p190Met(NC) expression depends on the disturbance of ER calcium homeostasis. Once induced, p190Met(NC) is activated independent of hepatocyte growth factor engagement. p190Met(NC) contributes to sustained high basal activation of c-Met downstream pathways during ER calcium disturbance-mediated ER stress. Both p38 MAPK-promoted glucose-regulated protein 78 (GRP78) expression and sustained high basal activation of PI3K/Akt and MEK/ERK are involved in the cytoprotective function of p190Met(NC). Importantly, the expression of p190Met(NC) is detected in some HCC cases. Taken together, these data provide a potential mechanism to explain how c-Met promotes HCC cells survival in response to ER stress. We propose that context-specific processing of c-Met protein is implicated in HCC progression in stressful microenvironments.