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Wei Xu,1,* Bolun Li,1,* Zhanwei Yang,1,* Jingdong Li,2,* Fei Liu,1 Yu Liu3 1Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, The First Hospital Affiliated with Hunan Normal University, Changsha, People’s Republic of China; 2Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China; 3Department of Pathology, Hunan Provincial People’s Hospital, The First Hospital Affiliated with Hunan Normal University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Xu, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, The First Hospital Affiliated with Hunan Normal University, Changsha, People’s Republic of China, Tel +8613873159491, Fax +8673182278012, Email xuwei0209@163.com Jingdong Li, Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China, Tel +8615881750153, Fax +868172222856, Email lijingdongnc@163.comBackground: Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy closely related to background chronic liver disease. This study aimed to explore predictive factors associated with background liver fibrosis burden in patients with HCC and sought to construct a practical predictive model for clinical use.Methods: This large two-center retrospective cohort study evaluated data from Chinese medical centers. Uni- and multivariate ordinal logistic regression analyses were performed to identify variables associated with liver fibrosis stages. Predictive models based on variables identified by multivariate analysis were established in the Derivation Cohort and subjected to internal and external validation. Model performance was evaluated for discriminative and calibration abilities.Results: Multivariate ordinal logistic regression analysis identified liver fibrosis severity score (LFSS), portal hypertension (PH) severity, plateletcrit (PCT) and model for end-stage liver disease-sodium (MELD-Na) as independent predictors of liver fibrosis stage in HCC patients. Nomograms that integrated these factors disclosed that the area under receiver operating characteristic curves (AUROCs) to predict S1 in the Derivation and External Validation cohorts were 0.850 and 0.919, respectively. Internal validation disclosed C-indexes of 0.823 and 0.833 in the Derivation and External Validation cohorts, respectively, indicating that the nomogram had good and excellent performance for distinguishing between S1 and non-S1 patients. Nomogram performance in the Derivation and External Validation cohorts, respectively, was fair and good to predict stage S2 (AUROCs 0.726, 0.806; C-indexes 0.713, 0.791); poor for S3 (AUROCs 0.648, 0.698; C-indexes 0.616, 0.666); good for S4 (AUROCs 0.812, 0.824; C-indexes 0.804, 0.792); and good for S3+S4 (AUROCs 0.806, 0.840; C-indexes 0.795, 0.811).Conclusion: We propose new predictive models for the staging of background liver fibrosis in patients with HCC that can be implemented into clinical practice as important complements to hepatic imaging to inform HCC management strategy.Keywords: hepatocellular carcinoma, liver fibrosis, portal hypertension, MELD-Na, plateletcrit

Pickering stabilizers with additional antioxidant, photostabilizing, and metal-chelating properties are suitable for structuring multifunctional Pickering emulsion systems. Tannic acid (TA) is a potential material which when adsorbed onto the interface may impart antioxidant, UV-light-shielding, and chelating properties to Pickering stabilizers. Herein, we report a type of TA polyelectrolyte nanoparticles (NPs) fabricated following a complexation between TA and aminated sugar beet pectin (SBP-NH

Tight gas reservoir is easily damaged by liquid phase because of the small pores and throats in the formation. Hydraulic fracturing is usually used in this kind of reservoir to improve well productivity; however, sometimes the productivity declines instead of increasing after treatments because of the damage of the water-based stimulation fluids. This paper introduces a production decline case in the HTHP tight gas reservoir in Tarim Basin, Western China, and provides a new solution. Dixi gas reservoir belongs to the formation of Jurassic Ahe Group, with burial depth of about 5000m. The formation porosity is between 3.0-7.0%, and the permeability is less than 0.1mD. The average DST production rates of three wells in this area were more than 30×104 m3/d. However, the production declined by 40% after completion. Acidizing and proppant fracturing were both conducted to regain their productivities; however, the production rates were reduced even further after the treatments. One of these wells’ daily production rate declined by 78% compared to DST production after use of acid fracturing and hydraulic fracturing. A series of core flow tests were carried out to find out the causes and solutions. The results showed that the retention of fracturing fluid in the formation caused "water blocking damage", which leaded to a significant increase of water saturation and rapid decline of gas phase permeability. This is considered the main cause of well productivity decline. Therefore, minimizing the capillary force in the formation is considered the main approach to remove the damage. Three series of alternative fracturing fluids were developed and evaluated. The first one is fracturing fluid with methanol. 5%-20% methanol was added to the fracturing fluid to relieve water blocking damage. The results showed that most of the wells fractured by methanol fracturing fluid gained good post-fracturing productivity. Fluorocarbon surfactant fracturing fluid was also developed, in which the concentration of guar gum was reduced to 0.35% to decrease the residual damage. Experimental tests showed that its surface tension was reduced to 0.85mN/m, and the contact angle was increased to 65.47°. Besides, a new nano-scale additive was developed, which can reduce the surface tension of the fracturing fluid from 72.7mN/m to 30.0 mN/m, and increase the contact angle from 38.5° to 126.0°. Thus the capillary force was reduced from 91.78 kPa to -28.44 kPa. Core flow tests under reservoir conditions also showed that the flowback rate of the fracturing fluid with this nano-scale additive was increased by 15% and its displacement pressure was reduced by more than 50% compared with the fracturing fluid without this additive. Besides, the gas-phase permeability of core after treatment with this fracturing fluid was 30% higher than that of normal fracturing fluid. In this paper, the causes of water blocking damage in an HTHP tight gas reservoir during well stimulation were analyzed. Three sets of alternative fracturing fluids were introduced and their laboratory test results were illustrated. The field application of methanol fracturing fluid was also introduced, which showed a good function of water blocking removal effectiveness. The other two fluids are also expected to obtain effective results in the field.

Well K1002 is the first highly deviated ultra-deep well in Tarim Oilfield of China, with the reservoir depth 7060m and the well deviation of 60° ∼ 77.6° in the fractured interval. Because of large deviation angle, high breakdown pressure and in-situ stress, poor effectiveness of natural fractures, large reservoir thickness, it is difficult and risky to implement hydraulic fracturing. In this paper, the fractured well was taken for a case study to illustrate the holistic optimization to guarantee the treatment success, a world-wide difficulty with high engineering risk. For figuring out a reasonable treatment design, comprehensive lab experiments and numerical simulation were conducted to analyze and benchmark the reservoir characteristics, rock mechanics and geological model. Systematic study on reducing breakdown pressure, development of natural fractures evaluation, multi-size combination of diverting agent, separated layer stimulation and fracture parameters optimization, treatment fluid formulation, proppant screening and operation program were carried out. Considering the wellbore trajectory and rock mechanics characteristics of well K1002, a breakdown pressure prediction model was established to optimize the perforation orientation. The best perforation orientation was 28° and 208°, the worst perforation orientation was 148° and 328°, and the breakdown pressure range was 168-175MPa with 60° phase angle. Combination with "imaging logging (0-3m) + far detection acoustic logging (0-30m) + geomechanics (0-300m)", the comprehensive evaluation and prediction of natural fractures in near wellbore area and far wellbore area were realized. Based on this, the stimulation technology of "mechanical layering + diverting agent" was optimized to connect the fracture development zone in near wellbore and far wellbore area. According to the Tight Packing Theory, the idea of "multi-size particles combination of diverting agent" was put forward. Through the experiment study, the combination of 1-5mm and 5-10mm particles was optimized, and the optimal chart of diverting agent size combination was made under different reservoir temperatures. For the fracturing job, totally 2562m3 KCL weighted fracturing fluid and 159.2m3 ceramic proppant of 40-70 mesh were pumped. The operation parameters were in reasonable agreement with the design. The initial test production was 10 times higher than before. The experience gained in this case study has some guiding significance for improving the success rate of hydraulic fracturing treatments in the highly deviated ultra-deep well and for effectively developing such fractured tight sandstone reservoirs, both theoretically and practically.

The multifracture competitive growth from a horizontal well is an essential issue in multi-cluster fracturing design. In recent years, extremely limited entry (ELE) fracturing has been implemented to promote uniform multifracture growth. However, the mechanism of multifracture growth and ELE design remain unclear. Based on the planar three-dimensional multifracture propagation model, a multi-cluster horizontal well fracturing model that considers ELE design has been developed. The model considers flow in the wellbore and fluid filtration loss in the fracture. The simulator enables the simulation and analysis of non-uniform in situ stress, filtration loss, and fracture properties. Using this program, we simulated the propagation process of multiple clusters of fractures in ELE fracturing of horizontal wells. The results show the following: The perforation friction in the ELE fracturing can counteract the difference in fluid allocation caused by stress interference, allowing all clusters of perforations to have even fluid allocation but to differ significantly in fracture geometry. The in situ stress profile and 3D fracture stress interference determine the fracture geometry, and the fracture of the middle cluster could cross through the layer with relatively higher in situ stress, resulting in a decrease in effective fracture area in the pay zone. Furthermore, an increase in perforation diameter causes the flow-limiting effect of the perforations to decrease. The fluid volumes entering different clusters of perforations become less uniform. The difference in fracture toughness within a perforated stage has a minor influence on the fluid allocation between different clusters, while the in situ stress distribution within a perforated stage has a significant impact on the fluid allocation between different perforation clusters in the stage. Fractures preferentially propagate at the perforation points with lower in situ stress and stress interference. This study can be helpful to understand multifracture competitive growth and the optimization of ELE fracturing design.

This study aimed to describe Enzymolysis-ultrasonic assisted extraction of flavanoid from Cyclocarya paliurus (Batal) Iljinskaja: HPLC profile, antimicrobial and antioxidant activity. An enzymolysis-ultrasonic assisted extraction (EUAE) method was developed and optimized for the extraction of Cyclocarya paliurus flavonoids in liquid form (CPF). The key factor influencing the extraction yield of Cyclocarya paliurus flavonoids was identified by two-level Plackett-Burman Design (PBD) with eight factors. Plackett-Burman Design determined the following four key factors as significant for the extraction yield of Cyclocarya paliurus flavonoids viz. Enzymatic temperature, enzymatic pH, complex enzyme concentration and ultrasonic power. The Box-Behnken Design (BBD) was subsequently applied to optimize the four key factors identified from Box-Behnken Design. Chemical composition of Cyclocarya paliurus flavonoids was investigated by high performance liquid chromatography (HPLC). Antimicrobial activity was carried out with the disc diffusion method. Antioxidant activities were investigated by DPPH assays, O2·− assays, ABTS+ assays and the reducing power. The optimal extraction conditions were as follow: enzymatic temperature of 50.71 °C, enzymatic pH of 5.08, complex enzyme concentration of 3.23% and ultrasonic power of 108.03 W. Under the optimal extraction conditions, the extraction yield of Cyclocarya paliurus flavonoids was 34.24 ± 0.32 mg/g, which was well-matched with the predicted value (34.47 mg/g). Isoquercetin, quercetin-3-O-α- l -rhamnoside, kaempferol-3-O-α- l -rhamnoside, quercetin and kaempferol were identified from Cyclocarya paliurus flavonoids with the content of 2.37%, 1.94%, 15.77%, 4.86% and 2.64%, respectively. The inhibition zones diameters of Cyclocarya paliurus flavonoids at the concentration of 80 μg/mL against Staphylococcus aureus, Salmonella and Escherichia coli were 21.5 ± 0.45, 17.5 ± 0.35 and 13.5 ± 0.25 mm, respectively. Results also showed a dose dependent scavenging activity as evidenced by IC50 values for superoxide (0.152 mg/mL) and ABTS+ (0.185 mg/mL) radicals. These results indicated that Cyclocarya paliurus flavonoids could be used as antimicrobial and antioxidant agents applying in pharmaceutical, functional foods and natural cosmetics.

A breakthrough in shale gas exploration was made in the lacustrine shale of Qianfoya Formation located in the Sichuan Basin; a gas analysis has shown that the reservoir therein is a condensate gas reservoir. To enhance the production of shale gas in the Sichuan Basin, reduce the exploration risk, and facilitate development, the marine dry gas shale of the Longmaxi Formation was selected as a comparison to analyze the pore structure characteristics of condensate and dry gas reservoirs. The results showed that the dry gas shale reservoir is mainly developed as organic matter (OM) pores, followed by clay mineral (CM) pores. In condensate gas shale reservoirs, the OM pores, CM pores, intragranular dissolution (ID) pores, and microfractures are common. In the dry gas shale reservoir, the surface porosities of the organic matter, clay minerals, brittle minerals, and microfractures were 10%–65%, 0%–23%, 0%–22%, and 0%–13%, respectively. Micropores were mainly provided by OM pores; mesopores were mainly provided by OM and CM pores; macropores were mainly provided by OM, CM, and ID pores. In the condensate gas shale reservoir, the surface porosities of the organic matter, clay minerals, brittle minerals, and microfractures were 0%–52%, 6%–34%, 0%–18%, and 0%–21%, respectively. Micro-mesopores were mainly provided by OM and CM pores, while macropores were mainly provided by CM pores and microfractures. Because of the influences of material composition, diagenetic evolution, and hydrocarbon generation at the burial depth, there were significant differences in the surface porosities of the matrix components and the distribution and proportions of the different pores between the dry and condensate gas shale reservoirs. This essentially led to a difference in the reservoir space.

A number of wells in the Sichuan Basin of China have tested industrial gas flow pressure arising from the shale of the Da’anzhai section of the Ziliujing Formation, revealing good exploration potential. Microfractures in shales affect the enrichment and preservation of shale gas and are important storage spaces and seepage channels for gas. In order to increase productivity and to reduce the risks associated with shale gas exploration, the types, connectivity, and proportion of microfractures in the Da’anzhai Member have been studied in this work by core and thin section observations, micro-CT, scanning electron microscopy, nitrogen adsorption, and high-pressure mercury intrusion. The results show that four types of fractures have developed in the shale of the Da’anzhai section: microfractures caused by tectonic stress, diagenetic shrinkage fractures of clay minerals, marginal shrinkage fractures of organic matter, and microfractures inside mineral particles. Among these, structural fractures and organic matter contraction fractures are the main types and are significant for shale reservoirs and seepage. The structural microfractures are mainly opened and are well-developed in the shale, with a straight shape, mainly between bedding, with the fracture surface being curved, fully opened, and mainly tensile. Organic matter fractures often develop on the edge of the contact between organic matter and minerals, presenting a slit-like appearance. The fractures related to bedding in the shale are particularly developed, with larger openings, wider extensions, intersecting and expanding, and forming a three-dimensional interconnected pore-fracture system. Based on image recognition, generally speaking, microfractures account for about 20% of the total pore volume. However, the degree of the microfractures’ development varies greatly, depending upon the structural environment, with the proportion of microfractures in fault-wrinkle belts and high-steep zones reaching 40% to 90% of the total pore space. On the other hand, micro-fractures in areas with underdeveloped structures account for about 10% of the total pore space.

Genome-wide DNA methylation was used to study the lipid-lowering effect of Cyclocarya paliurus (Batal) Iljinskaja polysaccharide (CPP). The objective of this study was to investigate the hypolipidemic effects and the potential underlying mechanisms of action of CPP-2 in high-fat emulsion (HFE)-induced mice. The results showed that CPP-2 reduced the level of genome-wide DNA methylation in the liver of HFE-induced mice, which had a lipid-lowering effect by regulating the AMP-activated protein kinase (AMPK) signaling-, fatty acid metabolism-, fatty acid biosynthesis- and adipocytokine signaling pathways. A series of lipid metabolism genes were screened out by conjoint analysis of the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Hereafter, fatty acid synthase (FAS) and peroxisome proliferators-activated receptor α (PPARα) as target genes were selected to validate the accuracy of the results. The findings demonstrated that CPP-2 might be effective in lowering the lipid content, thereby protecting against HFE-induced hyperlipidemia.

The ethanol extracts of Chimonanthus nitens Oliv. leaves were prepared sequentially by ethanol gradient elution and tested for their α-glucosidase inhibitory. The fraction of 50% ethanol eluate (EE) exhibited the notable inhibition with IC50 of 0.376mg/mL. Also, 50% EE was chemically characterized by liquid chromatography-mass spectrometry (LC-MS) analysis. Eight compounds including rutin (1), hyperin (2), isoquercitrin (3), luteoloside (4), astragalin (6), quercetin (13), naringenin (14), kaempferol (15) were identified by compared with standard substances as well as proper luteolin-5-O-glucoside (5), kaempferol-7-O-rhamnoside (9), 5,7,8-trihydroxy-2-methoxyl-flavone-7-O-glucoside (10), kaempferol-7-O-acetyl-galactoside (11). The experiments of ultra-filtration combined with liquid chromatography-mass spectrometry (UF-LC-MS) guided quercetin and kaempferol as the key factors for 50% EE showing highly inhibitory activity on α-glucosidase. Quercetin and kaempferol inhibited yeast α-glucosidase in a mixed-type manner with IC50 of 66.8 and 109μg/mL, respectively. These results would provide theoretical underpinning for the C. nitens Oliv. leaves ethanol extracts used as nutraceutical health supplement in the management of type 2 diabetes.

Summary This paper details the study of a new fracturing fluid that is based on a supramolecular complex between associative polymer and viscoelastic surfactant (VES). The crosslinked complex gel was based on weak physical attractive forces, such as van der Waals, hydrogen bonding, and electrostatic interaction between associative polymer and wormlike micelles of VES. The concentration of surfactant in the new fluid is 10 times less than that of VES fracturing fluid. The combination of VES and associative polymer synergistically enhances the viscosity to several times more than that of the individual components alone. The fluid system was optimized by experimental design. The microstructure of wormlike micelles and complex formation was verified by electron microscopy. The fluid is shear stable at high temperature for 1 hour. The dynamic rheological properties of the supramoleulcar fluid show high viscoelasticity, in which the elastic moduli are higher than the loss moduli below an angular frequency of 0.1 rad/s. The proppant-transport test in a large-scale fracture simulator showed good proppant-suspension ability. The fluid has 50% lower formation damage than conventional guar. The fluid was prepared with fewer additives, formed gel instantly, and can be mixed on the fly in the field. The gel can be completely broken with almost no residue. Field application of the new fracturing fluid in a gas well showed the enhancement of gas production by more than 100%. The fluid has 20% lower friction pressure than guar fluid. Hence, the new supramolecular fluid is an effective fracturing fluid.

This study was designed to study the chemical composition of Cyclocarya paliurus polysaccharide and inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage. A new elution (0.3% NaCl aqueous solution) of Cyclocarya paliurus polysaccharide (CPP-3) was characterized by different methods such as fourier transform infrared spectra (FT-IR), UV-vis, gas chromatography-mass spectrometry (GC-MS), high performance gel chromatography (HPGLC) and scanning electron microscopy (SEM). Cell viability was measured by MTT test, phagocytosis assay was measured by Neutral red uptake assay, nitrite was measured by Griess assay, TNF-α and IL-1β analysis were measured by ELISA, PGE2 was measured by enzyme immunoassay system. The results showed that CPP-3 was comprised of two polysaccharides with average molecular weight (Mw) of 5.69×104Da and 4.94×103Da. CPP-3 contains six monosaccharides, of which are rhamnose (Rha), arabinose (Ara), xylose (Xyl), mannose (Man), glucose (Glu), galactose (Gal), the molar ratio of six monosaccharides is 0.060:0.109:0.053:0.128:0.293:0.357. CPP-3 increased the amount of NO released from mouse macrophage RAW264.7 and significantly increased the levels of TNF-α, IL-1β and PGE2 (P

The objective of this study was to analyse the structure of CPP-2, and to observe the pharmacological effects of CPP-2 on lipid metabolism and oxidative stress. CPP-2, eluted as two main fractions comprised of two polysaccharides with Mw of 307 and 3.7kDa, was mainly consisted of rhamnose, mannose, glucose and galactose in a molar ratio of 1.00:0.78:3.22:0.45. The results showed that treatment with CPP-2 could improve blood lipid levels (TC, TG, HDL-C and LDL-C), liver lipid levels (TC and TG) and antioxidant status (SOD, T-AOC, GSH-PX, MDA and LPO). In addition, the histopathological observations of mice livers and the GPT activities indicated that CPP-2 could attenuate liver cell injury. The present findings demonstrated that CPP-2 might be effective in lowering lipid and protecting against HFE-induced hyperlipidemia and non-alcoholic fatty liver.

The paper investigated the antihyperglycemic and antihyperlipidemic efficacy and antioxidant capacity of Chimonanthus nitens Oliv. leaf extract (COE) in combination of high-glucose-fat diet-fed and streptozotocin-induced diabetic model mice. Various physiological indexes in diabetic model mice were well improved especially by oral administration of high dose of COE; the results were listed as follows. Fast blood glucose (FBG) level and serum triglyceride (TC), total cholesterol (TG), low-density lipoprotein cholesterol (LDLC), and malondialdehyde (MDA) as well as MDA in liver were significantly reduced; fasting serum insulin (FINS) and insulin sensitivity index (ISI) were both increased; high-density lipoprotein cholesterol (HDLC) in serum was significantly increased; total antioxidant capacity (T-AOC), activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in serum and liver were apparently enhanced; liver coefficient (LC), liver transaminase, and alkaline phosphatase (ALP) were decreased. Furthermore, pancreas islets and liver in diabetic model mice showed some extend of improvement in morphology and function after 4 weeks of COE treatment. In consequence, COE was advantageous to regulate glycolipid metabolism and elevate antioxidant capacity in diabetic model mice. Thus, the present study will provide a scientific evidence for the use of COE in the management of diabetes and its related complications.

Polysaccharide is one of the important active ingredients of Cyclocarya paliurus (Batal.) Iljinskaja leaves. The aims of this work were to analyze the structure of the polysaccharide of Cyclocarya paliurus (Batal.) Iljinskaja leaves (CPP), and to investigate the antihyperlipidemic effect of CPP on high-fat emulsion (HFE)-induced hyperlipidaemic rats. CPP, comprised of two polysaccharides with average molecular weight (Mw) of 1.35×10(5)Da and 9.34×10(3)Da, was consisted of rhamnose, arabinose, xylose, mannose, glucose and galactose in the molar ratio of 1.00:2.23:0.64:0.49:0.63:4.16. Oral administration of CPP could significantly decrease levels of serum total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), increase high density lipoprotein (HDL-C) in hyperlipidemic rats. CPP exerts therapeutic effects on hyperlipidaemic rats, by up-regulating expressions of adipose triglyceride lipase (ATGL) and peroxisome proliferator-activated receptor alpha (PPARα), via down-regulating fatty acid synthase (FAS) and hydroxy methylglutaryl coenzyme A reductase (HMG-CoA). This study demonstrates that CPP may be beneficial for the treatment of hyperlipidemia.

A new fracturing fluid based on supramolecular complex of associative polymer and wormlike micelle was developed and applied in a gas well in China. The crosslink complex gel was based on weak physical attractive force such as van der waals, hydrogen bonding and electrostatic interaction between associative polymer and wormlike micelle. The fluid contained much less surfactant than that of conventional viscoelastic surfactant. The associative polymer is used at less than 0.25% by weight. The gel is reversible, and has 50% lower formation damage than that of conventional guar. The mixture of the two fluids synergistically enhances the viscosity ten times more than individually combined. The viscosity of fluid can maintain at the test temperature and suspend proppant up under static condition. The dynamic proppant transport test in flow tube also showed good proppant suspension ability. The fluid was simple to prepare with less additives, and formed gel instantly upon mixing in the field. The gel can be completely broken with no residue by an internal breaker. Field application of the new fracturing fluid in a gas well of Sulige basin in China showed the enhancement of gas production over 100%. The fracture height is also well controlled. The fluid also has 20% lower friction pressure than that of guar fluid. Hence, the supramolecular complex gel provides a new fracturing fluid system with less formation damage for fracturing operation.