Search

An experimental and analytical investigation of ultrahigh-performance concrete (UHPC) plate-concrete-filled steel tubular (CFST) laced composite columns are presented in this study. A total of 11 stub specimens under axial compression are conducted to quantify the column failure mechanism. Experimental results indicate that the compressive behavior in the UHPC plate dominated the failure mechanism of the UHPC composite columns, and the failure mode is dependent on the peak strain of the UHPC plate and CFST limb. The two main parameters in the tests are the thickness of the steel tube (t) and UHPC plates (tp), which significantly enhance the bearing capacity of UHPC composite columns. Herein, the finite element standard model is established to investigate the influence of various parameters on the compressive behavior of UHPC composite columns. The diameter of the steel tube D is the most sensitive parameter affecting the structural compressive performance, while the ratio of steel reinforcing bars has an ignorable influence on the compressive strength. Based on the ultimate limit states and parametric analysis, a unified formula for predicting the strength of UHPC composite columns is proposed, which is generally in good agreement with the experimental results.

Abstract The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.

Objective: Pembrolizumab plus chemotherapy is recommended as the first-line treatment for advanced oesophageal cancer. The objective of this study is to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy as first-line therapy for advanced oesophageal cancer from the healthcare system perspective in China.Methods: Based on the KEYNOTE-590 trial, a Markov model was constructed to estimate the cost and effectiveness of pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. Total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, probabilistic sensitivity analyses (PSA), and subgroup analyses were adapted to test the model robustness.Result: Compared with the placebo group, pembrolizumab group obtained an additional 1.05 QALY, but the cost was also increased by $121,478.76. The ICER was $115,391.84 per QALY gained, which was higher than the willingness-to-pay (WTP) of $31,304.31. The results of One-way sensitivity analyses showed that the ICER was sensitive to the hazard ratio of PFS and per cycle cost of pembrolizumab. At a WTP threshold of $31,304.31, the probability of pembrolizumab plus chemotherapy being cost-effective was 0%.Conclusion: From the perspective of China healthcare system, pembrolizumab plus chemotherapy as first-line treatment is not cost-effective for patients with advanced oesophageal cancer compared with placebo plus chemotherapy.

Objective: The objective of this study is to systematically review the economic evaluations of dapagliflozin in the treatment of patients with heart failure (HF) and describe their general and methodological features.Methods: This systematic review followed the PRISMA guidelines. MEDLINE/PubMed, Website Of Science, Embase, The Cochrane Library, ScienceDirect, CNKI, and Wanfang databases were searched to collect relevant studies, and the retrieval time ended on 31 October 2021. Articles on the economic evaluation of dapagliflozin in the treatment of heart failure were included. Secondary studies, incomplete economic indicators, and non-English-language and non-Chinese-language studies were excluded. Standard drug treatment was selected as the comparison. Basic characteristics, methods, and main results were extracted and analyzed systematically.Result: A total of eight studies were identified, and the overall quality was accepted, which were performed in nine developed countries (Austria, United States, Korea, Japan, Singapore, Spanish, Germany, and United Kingdom) and three developing countries (the Philippines, Thailand, and China). With the exception of the Philippines, the remaining countries considered that dapagliflozin was cost effective. In the analyses of all included studies, the incremental cost-effectiveness ratios were most sensitive to the cost of dapagliflozin, cardiovascular mortality, the duration of dapagliflozin effectiveness, and the probability of HF hospitalization.Conclusion: Dapagliflozin in the treatment of patients with heart failure with reduced ejection fraction was considered cost effective. Further studies are needed to evaluate the comprehensive value of dapagliflozin on HF.

Objective: To investigate whether LY01008, a locally developed bevacizumab biosimilar agent, is appropriate for widespread use among Chinese advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC) patients, our current study was designed to evaluate the cost-effectiveness of first-line LY01008 combined with platinum-doublet chemotherapy versus chemotherapy alone from the perspective of the Chinese healthcare system.Material and Methods: This economic evaluation designed a Markov model to compare the healthcare cost and quality-adjusted life-year (QALY) of first-line LY01008 combined with chemotherapy versus first-line chemotherapy. Transition probabilities, including disease progression, survival, and adverse event (AE)-related discontinuation of first-line treatment, were estimated using data from the clinical trials. Costs and health utilities were derived from local databases, hospitals, and published literature. Our base case analysis and scenario analysis focused on the cost-effectiveness of chemotherapy combined with a clinical trial dosage (15 mg/kg every 3-week cycle) and a real-world dosage (7.5 mg/kg every 3-week cycle) of LY01008, respectively.Results: In the base case analysis, first-line LY01008 combined with chemotherapy was associated with an increase of 0.48 QALYs in effectiveness and an increase of CNY 189,988 (US$ 26,240) in healthcare costs compared with first-line chemotherapy, resulting an incremental cost-effectiveness ratio (ICER) of CNY 375,425 (US$ 54,430)/QALY. In the scenario analysis, first-line LY01008 combined with chemotherapy was associated with a mean healthcare cost of CNY 265,060 (US$ 38,429), resulting an ICER of CNY 221,579 (US$ 32,125/QALY) between first-line LY01008 combined with chemotherapy versus first-line chemotherapy. The parameters that determine the cost of LY01008 have the greatest impact on the cost-effectiveness results.Conclusion: From the perspective of the Chinese healthcare system, first-line LY01008 at a real-world dosage combined with chemotherapy is likely to represent a cost-effective strategy compared with first-line chemotherapy alone for Chinese advanced or recurrent nonsquamous NSCLC patients.

ABSTRACT p53, as an important tumor suppressor protein, has recently been implicated in host antiviral defense. The present study found that the expression of mandarin fish (Siniperca chuatsi) p53 (Sc-p53) was negatively associated with infectious spleen and kidney necrosis virus (ISKNV) and Siniperca chuatsi rhabdovirus (SCRV) proliferation as well as the expression of glutaminase 1 (GLS1) and glutaminolysis pathway-related enzymes glutamate dehydrogenase (GDH) and isocitrate dehydrogenase 2 (IDH2). This indicated that Sc-p53 inhibited the replication and proliferation of ISKNV and SCRV by negatively regulating the glutaminolysis pathway. Moreover, it was confirmed that miR145-5p could inhibit c-Myc expression by targeting the 3′ untranslated region (UTR). Sc-p53 could bind to the miR145-5p promoter region to promote its expression and to further inhibit the expression of c-Myc. The expression of c-Myc was proved to be positively correlated with the expression of GLS1 as well. All these suggested a negative relationship between the Sc-p53/miR145-5p/c-Myc pathway and GLS1 expression and glutaminolysis. However, it was found that after ISKNV and SCRV infection, the expressions of Sc-p53, miR145-5p, c-Myc, and GLS1 were all significantly upregulated, which did not match the pattern in normal cells. Based on the results, it was suggested that ISKNV and SCRV infection altered the Sc-p53/miR145-5p/c-Myc pathway. All of above results will provide potential targets for the development of new therapeutic strategies against ISKNV and SCRV. IMPORTANCE Infectious spleen and kidney necrosis virus (ISKNV) and Siniperca chuatsi rhabdovirus (SCRV) as major causative agents have caused a serious threat to the mandarin fish farming industry (J.-J. Tao, J.-F. Gui, and Q.-Y. Zhang, Aquaculture 262:1–9, 2007, https://doi.org/10.1016/j.aquaculture.2006.09.030). Viruses have evolved the strategy to shape host-cell metabolism for their replication (S. K. Thaker, J. Ch’ng, and H. R. Christofk, BMC Biol 17:59, 2019, https://doi.org/10.1186/s12915-019-0678-9). Our previous studies showed that ISKNV replication induced glutamine metabolism reprogramming and that glutaminolysis was required for efficient replication of ISKNV and SCRV. In the present study, the mechanistic link between the p53/miR145-5p/c-Myc pathway and glutaminolysis in the Chinese perch brain (CPB) cells was provided, which will provide novel insights into ISKNV and SCRV pathogenesis and antiviral treatment strategies.

ABSTRACT Largemouth bass (Micropterus salmoides) is an important and fast-growing aquaculture species in China. In 2017, an epidemic associated with severe mortality occurred in fingerlings of largemouth bass in Guangdong, China. The causative pathogen was identified and named as largemouth bass Birnavirus (LBBV) by virome analysis, viral isolation, electron microscopy, genome sequencing, Western blot, indirect immunofluorescence, experimental challenge, and so on. Virome sequencing results showed that the relative abundance reads related to the family Birnaviridae were the highest, occupied ∼25% of the total viral reads. Electron microscopy revealed large numbers of nonenveloped virus particles in the spleen of diseased fish with a diameter of about 53 nm. LBBV was isolated and propagated in Chinese perch brain cells and induced a typical cytopathic effect. LBBV was stable to chloroform, heat, and 5-bromo-2′-deoxyuridine, but sensitive to acid (pH 3.0). The complete genome of LBBV was comprised of segment A with a size 3525 bp and segment B with a size 2737 bp. Phylogenetic analysis basing on RdRp and VP2 protein sequences revealed that LBBV were clustered into one clade with Lates calcarifer Birnavirus (LCBV), sharing 98.7% or 91.9% sequence identity with LCBV, respectively, but only sharing 59.7% and 52.7% sequence identity with Blosnavirus, suggesting that LBBV and LCBV probably belonged to a new genus. Challenge experiments results indicated that clinical disease symptoms similar to those observed naturally were replicated and the cumulative mortality reached 100% at 3 dpi by i.p. injection. The investigation of prevalence of LBBV infection showed that 41.5% (17/41) sample pools collected from diseased ponds was positive during 2017-2020, indicating that an emerging outbreak of this disease may be spreading within the largemouth bass in China. Above results confirmed that LBBV is a novel Birnavirus associated with massive mortality for fingerlings of largemouth bass. This provides a basis for prevention and control of this emerging viral disease. IMPORTANCE Pathogen isolation and identification are vital for emerging infectious outbreaks. Here we report the isolation, determination and characterization of a novel largemouth bass Birnavirus (LBBV) associated with massive mortality in largemouth bass. And genome of LBBV is determined and analyzed. Based on phylogenetic and alignment analysis of genome, we suggest LBBV belongs to a new genus (designated as Perbirnavirus genus) in Birnaviridae family. Our findings will provide a basis for the further study on prevention and control of this emerging viral disease.

Abstract The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins. Prefoldin plays a crucial role in the pathogenesis of common neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease). The important role of prefoldin in emerging fields (such as nanoparticles, biomaterials) and tumors has attracted widespread attention. Also, each of the prefoldin subunits has different and independent functions from the prefoldin complex. It has abnormal expression in different tumors and plays an important role in tumorigenesis and development, especially c-Myc binding protein MM-1. MM-1 can inhibit the activity of c-Myc through various mechanisms to regulate tumor growth. Therefore, an in-depth analysis of the complex functions of prefoldin and their subunits is helpful to understand the mechanisms of protein misfolding and the pathogenesis of diseases caused by misfolded aggregation.

Objective: The ORIENT-32 clinical trial revealed that sintilimab plus bevacizumab biosimilar significantly improved the median progression-free survival and median overall survival (OS) compared with sorafenib. This analysis evaluated the cost-effectiveness of sintilimab plus bevacizumab biosimilar as a first-line treatment for unresectable hepatocellular carcinoma from the Chinese perspective of healthcare system.Materials and methods: A Markov model with three mutual health states was constructed to evaluate the economic outcome of sintilimab plus bevacizumab biosimilar. The model cycle was 21 days, and the simulation time horizon was a lifetime. The output parameters of the model were the total cost, life-year (LY), quality-adjusted LY (QALY), and incremental cost-effectiveness ratio (ICER). Sensitivity analyses were conducted to assess the robustness of the results.Results: The base-case results found that sintilimab plus bevacizumab biosimilar provided an improvement of 1.27 QALYs and 1.84 LYs compared with sorafenib, and the ICER was $23,352/QALY. The hazard ratio for OS had the greatest influence on the ICER. The probability of sintilimab plus bevacizumab biosimilar was 85% at willingness-to-pay thresholds of $30,552/QALY.Conclusion: The findings of this analysis suggested that sintilimab plus bevacizumab biosimilar was a cost-effective first-line therapy for patients with unresectable hepatocellular carcinoma.

ABSTRACT Under oxidative stress, viruses prefer glycolysis as an ATP source, and glutamine is required as an anaplerotic substrate to replenish the TCA cycle. Infectious spleen and kidney necrosis virus (ISKNV) induces reductive glutamine metabolism in the host cells. Here we report that ISKNV infection the increased NAD+/NADH ratio and the gene expression of glutaminase 1 (GLS1), glutamate dehydrogenase (GDH), and isocitrate dehydrogenase (IDH2) resulted in the phosphorylation and activation of mammalian target of rapamycin (mTOR) in CPB cells. Inhibition of mTOR signaling attenuates ISKNV-induced the upregulation of GLS1, GDH, and IDH2 genes expression, and exhibits significant antiviral activity. Moreover, the expression of silent information regulation 2 homolog 3 (SIRT3) in mRNA level is increased to enhance the reductive glutamine metabolism in ISKNV-infected cells. And those were verified by the expression levels of metabolic genes and the activities of metabolic enzymes in SIRT3-overexpressed or SIRT3-knocked down cells. Remarkably, activation of mTOR signaling upregulates the expression of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, leading to increased expression of SIRT3 and metabolic genes. These results indicate that mTOR signaling manipulates reductive glutamine metabolism in ISKNV-infected cells through PGC-1α-dependent regulation of SIRT3. Our findings reveal new insights on ISKNV–host interactions and will contribute new cellular targets to antiviral therapy. IMPORTANCE Infectious spleen and kidney necrosis virus (ISKNV) is the causative agent of farmed fish disease that has caused huge economic losses in fresh and marine fish aquaculture. The redox state of cells is shaped by virus into a favorable microenvironment for virus replication and proliferation. Our previous study demonstrated that ISKNV replication induced glutamine metabolism reprogramming, and it is necessary for the ISKNV multiplication. In this study, the mechanistic link between the mTOR/PGC-1α/SIRT3 pathway and reductive glutamine metabolism in the ISKNV-infected cells was provided, which will contribute new insights into the pathogenesis of ISKNV and antiviral treatment strategies.

Objective To compare the cost-effectiveness of the combination of pembrolizumab and chemotherapy (Pembro+Chemo) versus pembrolizumab monotherapy (Pembro) as the first-line treatment for metastatic non-squamous and squamous non-small-cell lung cancer (NSCLC) with PD-L1expression ≥50%, respectively, from a US health care perspective.Material and Methods A comprehensive Makrov model were designed to compare the health costs and outcomes associated with first-line Pembro+Chemo and first-line Pembro over a 20-years time horizon. Health states consisted of three main states: progression-free survival (PFS), progressive disease (PD) and death, among which the PFS health state was divided into two substates: PFS while receiving first-line therapy and PFS with discontinued first-line therapy. Two scenario analyses were performed to explore satisfactory long-term survival modeling.Results In base case analysis, for non-squamous NSCLC patients, Pembro+Chemo was associated with a significantly longer life expectancy [3.24 vs 2.16 quality-adjusted life-years (QALYs)] and a substantially greater healthcare cost ($341,237 vs $159,055) compared with Pembro, resulting in an ICER of $169,335/QALY; for squamous NSCLC patients, Pembro+Chemo was associated with a slightly extended life expectancy of 0.22 QALYs and a marginal incremental cost of $3,449 compared with Pembro, resulting in an ICER of $15,613/QALY. Our results were particularly sensitive to parameters that determine QALYs. The first scenario analysis yielded lower ICERs than our base case results. The second scenario analysis founded Pembro+Chemo was dominated by Pembro.Conclusion For metastatic non-squamous NSCLC patients with PD-L1 expression ≥50%, first-line Pembro+Chemo was not cost-effective when compared with first-line Pembro. In contrast, for the squamous NSCLC patient population, our results supported the first-line Pembro+Chemo as a cost-effective treatment. Although there are multiple approaches that are used for extrapolating long-term survival, the optimal method has yet to be determined.

ObjectiveOur previous economic assessment found that nivolumab was not cost-effective for Chinese patients with advanced non-small cell lung cancer (NSCLC) and without EGFR mutations or ALK translocations, when compared with the standard second-line drug docetaxel. However, a greater survival benefit with nivolumab was observed for patients with 1% or greater tumor programmed death ligand 1 (PD-L1) expression. In view of this, we designed the present analysis to explore whether it is cost-effective to use the PD-L1 test to guide second-line nivolumab treatment in China.Material and MethodsA Markov model was established to project the lifetime costs and quality-adjusted life-years (QALYs) of three second-line treatment strategies: nivolumab and docetaxel (strategies without a PD-L1 test) and PD-L1 test-based strategy. Deterministic and probabilistic sensitivity analyses were performed to examine the robustness of our results. Additional price reduction and willingness-to-pay (WTP) threshold scenario analyses were performed to explore the impact of economic and health policies with Chinese characteristics on our results.ResultsThe PD-L1 test-based strategy costs approximately CNY 194,607 (USD 28,210) or more and yielded an additional 0.27 QALYs compared to the docetaxel strategy without a PD-L1 test, equating an incremental cost-effectiveness ratio (ICER) of CNY 731,089 (USD 105,978)/QALY. Deterministic sensitivity analyses showed that the price of nivolumab was the strongest source of variation in the ICERs. Probability sensitivity analysis showed that the probability for the PD-L1 test-based strategy being cost-effective increases with the increase of WTP thresholds.ConclusionFrom the perspective of the Chinese healthcare system, using a PD-L1 test to guide second-line nivolumab treatment was not cost-effective. The National Healthcare Security Administration negotiation on the price reduction of nivolumab was found to be the most effective action to improve its cost-effectiveness in China.

Objective: Three immune checkpoint inhibitors (ICIs), pembrolizumab, atezolizumab and cemiplimab, have been successively approved as first-line treatments for advanced non-small-cell lung cancer (NSCLC) patients with programmed cell death ligand 1(PD-L1) expression of at least 50%. This study was designed to compare the cost-effectiveness of these three novel therapies in this patient population.Material and Methods: Using Markov model and network meta-analysis, we conducted separate cost-effectiveness analyses for cemiplimab, pembrolizumab and atezolizumab among advanced NSCLC patients with PD-L1 of at least 50% from the United States health care sector perspective. Health states included progression-free survival, progressive disease, end-stage disease, and death. Clinical efficacy and safety data were derived from phase III clinical trials and health state utilities and costs data were collected from published resources. Two scenario analyses were conducted to assess the impact of varying subsequent anticancer therapies on the cost-effectiveness of these 3 ICIs and cost-effectiveness of pembrolizumab combined with chemotherapy versus these 3 first-line ICI monotherapies.Results: In base case analysis, cemiplimab compared with pembrolizumab was associated with a gain of 0.44 quality-adjusted life-years (QALYs) and an increased cost of $23,084, resulting in an incremental cost-effectiveness ratio (ICER) of $52,998/QALY; cemiplimab compared with atezolizumab was associated with a gain of 0.13 QALYs and a decreased cost of $104,642, resulting in its dominance of atezolizumab. The first scenario analysis yielded similar results as our base case analysis. The second scenario analysis founded the ICERs for pembrolizumab plus chemotherapy were $393,359/QALY, $190,994/QALY and $33,230/QALY, respectively, compared with cemiplimab, pembrolizumab and atezolizumab.Conclusion: For advanced NSCLC patients with PD-L1 of at least 50%, cemiplimab was a cost-effective option compared with pembrolizumab and a dominant alternative against atezolizumab. Our scenario analysis results supported the cemiplimab plus chemotherapy as a second-line therapy and suggested an extended QALY but overwhelming cost linking to pembrolizumab plus chemotherapy.

A case of Rickettsia sibirica subspecies sibirica BJ-90 infection in China was identified by metagenomic analysis of an eschar biopsy specimen and confirmed by nested PCR. Seroprevalence of spotted fever group Rickettsia was ≈17.4% among the local population. This report highlights the threat of rickettsioses to public health in the Qinghai–Tibet Plateau.

ObjectiveThe use of ipilimumab plus anti-PD-1 has recently been shown to significantly improve the survival of patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy. The study assessed the cost-effectiveness of ipilimumab plus anti-PD-1 therapy in this population from the US payer perspective.Materials and MethodsA Markov model was created based on a retrospective analysis of patients with metastatic melanoma who were resistant to anti-PD-(L)1. Cost information was obtained from the Centers for Medicare and Medicaid Services and literature-based costs. The utility value was derived from the published literature. The results of the model was the total cost, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was addressed through sensitivity analysis. In addition, we also conducted subgroup analysis.ResultsIpilimumab plus anti-PD-1 provided an improvement of 1.39 QALYs and 2.48 LYs, at a ICER of $73,163 per QALY. The HR of OS was the variable that had the greatest impact on ICER. Compared to ipilimumab, the probability of ipilimumab plus anti-PD-1 being cost-effective was 94% at the WTP of $150,000/QALY. The results of the subgroup analysis showed that the ICER in the majority of the subgroups was less than $150,000/QALY.ConclusionsIpilimumab plus anti-PD-1 was likely to be cost-effective compared to ipilimumab for patients with metastatic melanoma who are resistant to anti-PD-(L)1 at a WTP threshold of 150,000/QALY.

Cerebral small vessel disease (cSVD)—a common cause of stroke and vascular dementia—is a group of clinical syndromes that affects the brain's small vessels, including arterioles, capillaries, and venules. Its pathogenesis is not fully understood, and effective treatments are limited. Increasing evidence indicates that an elevated total serum homocysteine level is directly and indirectly associated with cSVD, and endothelial dysfunction plays an active role in this association. Hyperhomocysteinemia affects endothelial function through oxidative stress, inflammatory pathways, and epigenetic alterations at an early stage, even before the onset of small vessel injuries and the disease. Therefore, hyperhomocysteinemia is potentially an important therapeutic target for cSVD. However, decreasing the homocysteine level is not sufficiently effective, possibly due to delayed treatment, which underlying reason remains unclear. In this review, we examined endothelial dysfunction to understand the close relationship between hyperhomocysteinemia and cSVD and identify the optimal timing for the therapy.

Shale oil and gas have become important areas of petroleum exploration and development. Successful shale oil and gas exploration depends on the accurate evaluation of sweet spots, which are the commercial targets. This paper proposes a comprehensive new method for sweet spot evaluation based on average estimated ultimate recovery in barrels of oil equivalent (EUR_BOE) in conjunction with key geological factors, engineering and technical conditions, and economic and technical indicators. Research results from 72 systematically cored wells, 991 sets of core analyses, and production data from 1317 horizontal wells in the lower Eagle Ford Shale (EFS) of the U.S. Gulf Basin show that marine shale oil and gas sweet spots depend primarily on four key factors: oil and gas resources, oil and gas storage capacity, fluidity, and fracability. These conclusions are based on quantitative evaluation models relating to EUR_BOE and key geological parameters. Model outcomes are controlled by inputs for total organic carbon (TOC), vitrinite reflectance (%Ro), original formation and hydrostatic pressure difference (ΔPf–h) or formation pressure gradient (Pindex), effective shale thickness (Heshale), clay volume content (Vclay), fracture porosity (Φf)and other geological parameters pertaining to EUR_BOE. Shale oil and gas sweet spots in non-fractured zones must satisfy certain conditions including TOC ≥2.3 wt%, Ro ≥ 0.9%, Heshale ≥ 15 m, Vclay ≤ 25 vol%, and ΔPf–h between ∼3 and 35 MPa or Pindex between ∼1.15 and 1.85 MPa/100 m. Defining shale oil and gas sweet spots in fractured zones is more complex, because developing fractures and the application of advanced engineering technology will increase EUR_BOE; sweet spots are impacted by sealing conditions, fracture and fault development, and technical engineering conditions. The proposed method for evaluating shale oil and gas sweet spots is validated through the determination of sweet spots in the lower EFS, and provides a basis for the evaluation of shale oil and gas sweet spots in similar marine deposits.

Studies have shown silver nanoparticles (AgNPs) exposure can result in a series of toxic effects in fish gills. However, it is still unclear how AgNPs affect metabolite expression and their related molecular metabolic pathways in fish gills. In this study, we employed untargeted metabolomics to study the effects of AgNPs and silver supernatant ions on fish gill metabolites. The results showed that AgNPs can induce significant changes in 96 differentially expressed metabolites, which mainly affect amino acid metabolism and energy metabolism in fish gills. Among these metabolites, AgNPs specifically induce significant changes in 72 differentially expressed metabolites, including L-histidine, L-isoleucine, L-phenylalanine, and citric acid. These metabolites were significantly enriched in the pathways of aminoacyl-tRNA biosynthesis, ABC transporters, and the citrate cycle. In contrast, Ag+ supernatant exposure can specifically induce significant changes in 14 differentially expressed metabolites that mainly interfere with sphingolipid metabolism in fish gills. These specifically regulated fish gill metabolites include sphinganine, sphingosine, and phytosphingosine, which were significantly enriched in the sphingolipid metabolism pathway. Our results clearly reveal the effects and potential toxicity mechanisms of AgNPs on fish gill metabolites. Furthermore, our study further determined the unique functions of released silver ions in AgNPs toxicity in fish gills.

Objective: This study evaluated the cost-effectiveness of nivolumab plus ipilimumab vs. chemotherapy in the first-line setting for patients with advanced non-small-cell lung cancer (NSCLC) from the US payer perspective.Materials and methods: A Markov model wasdeveloped to evaluate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy in the first-line treatment of advanced NSCLC. The survival benefits of nivolumab plus ipilimumab were based on the results of the CheckMate 227 trial. The main endpoints of the model were cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). Univariable and probabilistic sensitivity analyses were conducted to assess model uncertainty. Additonal subgroup analyses were also performed.Results: nivolumab plus ipilimumab produced a gain of 0.62 QALYs, at a cost of $104238 per QALY. The variables that had the greatest influence on the ICER were body weight and overall survival (OS) hazard ratio (HR). The probability of nivolumab plus ipilimumab being cost-effectiveness compared to chemotherapy is 50.7 and 66.2% when the willingness-to-pay (WTP) value is $ 100,000 and $ 150,000 per QALY. The results of subgroup analyses showed the ICER remained below $150,000/QALY regardless of the PD-L1 expression level.Conclusions: nivolumab plus ipilimumab was estimated to be cost-effective compared with chemotherapy for patients with advanced NSCLC at a WTP threshold from 100,000/QALY to 150,000/QALY.

Soil fungal communities, which drive many ecosystem processes, vary across soil horizons. However, how fungal communities are influenced by soil horizon layers remains largely unstudied. In this study, soil samples were collected from the organic horizon (O horizon) and mineral matter horizon (M horizon) in two sites of Dabie Mountain, China, and the effects of the two horizons on the soil fungal community composition were assessed based on Illumina MiSeq sequencing. Our results showed that soil fungal community composition varied with soil horizons, and soil fungal species richness and diversity in the O horizon were significantly higher than that in the M horizon. Total organic carbon (TOC), total organic nitrogen (TON), alkali-hydrolyzable nitrogen (AHN), available potassium (AK), and available phosphorus (AP) significantly influenced fungal community composition, abundance, and diversity across the two horizons (P < 0.05). Furthermore, precipitation was found to have a significant effect on fungal community composition. Our results demonstrate changes in fungal communities across soil horizons and highlight the importance of soil organic matter on fungal communities and diversity.

Campus loans have become a part of the lives of Chinese college students. While such loans are convenient for students, they can also create considerable difficulties. In the context of unbalanced economic development between Western and Eastern China, this study aimed to understand the factors affecting the campus loan behaviors of college students in Western China. A sample of 568 undergraduate and graduate students from four universities in Western China was taken as the research object. Binary logistic regression and orderly logistic regression were used to study campus loan consumption factors. Students without state-subsidized loans were found to have stronger campus loan consumption intention and higher loan amounts, and recreational consumption was the main loan purpose. The factors affecting campus loan consumption included students’ family structure, parents’ education level, peer students’ consumption status, grade level, relationship status, and ability to assess loan risk. Based on the findings, suggestions are made for managing campus loan behavior from the perspectives of the individual, family, school, and government. This study can provide guidance for standardizing campus loans and adjusting college students’ consumption attitudes and behaviors.

ObjectiveThis study aimed to assess the cost-effectiveness of two recently approved first-line chemo-immunotherapies [atezolizumab combined with etoposide and platinum (AEP) and durvalumab combined with etoposide and platinum (DEP)] for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the United States.Material and MethodsA Markov model was built to compare the cost and effectiveness of AEP, DEP, and etoposide plus platinum (EP) over a 10-year time horizon. Clinical efficacy and safety data were extracted from the IMpower 133 and CASPIAN trials. Health state utilities were obtained from published literature. Costs were collected from an US payer perspective. Deterministic and probabilistic sensitivity analyses were used to explore the uncertainty bound to model parameters.ResultsFor the model cohort of adult patients with treatment-naive ES-SCLC, AEP was associated with marginal improved quality adjusted life years (QALYs) by 0.016 and reduced costs by $5,737 compared with DEP. When comparing the two chemo-immunotherapies with EP chemotherapy, AEP and DEP increased the QALYs by 0.162 QALYs and 0.146, respectively. However, both chemo-immunotherapies were associated with substantially health costs than EP, resulting in ICERs of $382,469 per QALY and $464,593 per QALY, respectively.ConclusionIn this cost-effectiveness study, first-line AEP represented a dominant treatment strategy compared with DEP. Despite neither first-line AEP nor first-line DEP was cost-effective compared with EP chemotherapy, AEP was able to provide a more efficient balance between incremental cost and QALY than DEP. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of these drugs may be essential to achieving cost-effectiveness.

Abstract Reprogramming of cancer metabolism is a newly recognized hallmark of malignancy. The aberrant glucose metabolism is associated with dramatically increased bioenergetics, biosynthetic, and redox demands, which is vital to maintain rapid cell proliferation, tumor progression, and resistance to chemotherapy and radiation. When the glucose metabolism of cancer is rewiring, the characters of cancer will also occur corresponding changes to regulate the chemo- and radio-resistance of cancer. The procedure is involved in the alteration of many activities, such as the aberrant DNA repairing, enhanced autophagy, oxygen-deficient environment, and increasing exosomes secretions, etc. Targeting altered metabolic pathways related with the glucose metabolism has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of glucose metabolism in chemo- and radio-resistance malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

RAS-related C3 botulinum toxin substrate 1 (Rac.1) is one of the important members of Rho GTPases. It is well known that Rac1 is a cytoskeleton regulation protein that regulates cell adhesion, morphology, and movement. Rac1 is highly expressed in different types of tumors, which is related to poor prognosis. Studies have shown that Rac1 not only participates in the tumor cell cycle, apoptosis, proliferation, invasion, migration and angiogenesis, but also participates in the regulation of tumor stem cell, thus promoting the occurrence of tumors. Rac1 also plays a key role in anti-tumor therapy and participates in immune escape mediated by the tumor microenvironment. In addition, the good prospects of Rac1 inhibitors in cancer prevention and treatment are exciting. Therefore, Rac1 is considered as a potential target for the prevention and treatment of cancer. The necessity and importance of Rac1 are obvious, but it still needs further study.

Deep insights into the movability of the retained shale oil are of great significance to shale oil. Rock and crude oil samples were collected from well J174 in the Jimsar Sag, Junggar Basin. Rock samples were subjected to different extraction followed by analysis of the component in the extracts, and measurement of porosity in conjunction with nuclear magnetic resonance and high-pressure mercury injection analysis. The results of these analyses were used to establish an experimental method for quantitative assessment of movable shale oil. The extract content of the component varied among different extraction and between mud shale and non-mud shale samples. The saturated hydrocarbon in the extracts of the mud shale was similar to those of the non-mud shale after extraction with CHCl3 alone or after sequential extraction with nC6 + CHCl3. The aromatic hydrocarbon in the extract were significantly lower for the mud shale than for the non-mud shale after extraction with nC6, but the opposite was observed after sequential extraction with nC6 + CHCl3. The contents of the non-hydrocarbon in the extract were significantly lower for the mud shale than for the non-mud shale after extraction with nC6, but the opposite was observed after extraction with CHCl3 or nC6 + CHCl3. The contents of the asphaltene in the extract were not significantly different for the mud shale and non-mud shale after extraction with nC6, but the contents were higher for the mud shale than for the non-mud shale after extraction with nC6 + CHCl3 or CHCl3. The viscosity of the crude oil was negatively correlated with the saturated hydrocarbon, was positively correlated with the aromatic hydrocarbon and non-hydrocarbon, and was not correlated with the asphaltene. For the mud shale and non-mud shale, their porosity after extraction with nC6 or CHCl3 was higher than their original porosity. Moreover, their porosity after extraction with CHCl3 was higher than after extraction with nC6. The movable oil was significantly correlated with the lithology, with sandstone allowing for a higher fluid movability than mud shale and dolomite allowing for a higher fluid movability than siliceous rocks.

This study proposes a method to calculate the retained oil content (WO) in cores collected by a sealed tool from organic-rich shale with thermal maturity around%Ro = 0.8 in the Ordos Basin, China. Approaches such as soaking cores at low temperature, multiple extractions, multiple pyrolysis, and multiple chromatographic analyses were conducted and then the relationships between total retained oil content and mineral compositions were analyzed. The total retained oil content measured by the method proposed in this paper is 60–260% higher than that measured by a conventional pyrolysis method and 34–69% higher than the sum (WO) of two extractions with dichloromethane (WO3) and chloroform (WO4). After extractions with dichloromethane and chloroform (WO5), the oil retained in the organic-rich shale was 4.7–11.6%, which has not been extracted. Positive correlations exist between WO (i.e., WO3 + WO4) and total organic carbon (TOC) and S1 (absorbed hydrocarbon by rock pyrolysis), and WO has the highest correlation coefficient with the former. The method can provide important guidance for the objective analysis of retained oil in organic-rich shale, and it is reliable for the evaluation of shale oil reserves.

The Lucaogou Formation in the Jimsar Sag is a typical lacustrine shale oil development area where the first large-scale shale oil field in China was discovered, and a large number of studies have been conducted on the genesis and distribution of the shale oil in this formation. However, few detailed studies have been conducted on the comparison between the characteristics of the hydrocarbons in the shale and the adjacent tight reservoirs in the same shale sequence package. In this study, the total scanning fluorescence (TSF) quantitative fluorescence technique, which has been rarely applied to and studied in the Lucaogou Formation in the Jimsar Sag, was used to conduct systematic quantitative fluorescence analysis of the shale, tight reservoirs, and crude oils in the Lucaogou Formation. The geochemical analysis was also carried out for all samples. The results revealed that the shale, tight reservoirs, and oils have similar single-peak TSF spectrograms, and different values of the TSF parameters in the Lucaogou Formation. The TSF parameters R1 and R2 values of the blocky shale, fractured shale, tight reservoirs, and produced oils are decreased successively. The TSF parameters can be used as indicators of hydrocarbon composition, physical properties, thermal maturity, migration, and oil-producing layers. The values of TSF parameters R1 and R2 are generally smaller in the upper section of the Lucaogou Formation (P2l2) than in the lower section (P2l1), indicating that the hydrocarbons in the upper section have better physical properties and higher thermal maturity. The distribution of TSF parameters R1 and R2 in the upper section of the Lucaogou Formation is relatively scattered, indicating that the hydrocarbons have undergone obvious lateral migration. Based on the TSF parameter comparison of core and oil samples, it was preliminarily determined that the shale oil in the upper and lower sections of the Lucaogou Formation was mainly produced from the tight reservoirs in the shale sequence. The results of this study provide new data and ideas for fine studies of the shale oil in the Lucaogou Formation in the Jimsar Sag.

Background The phase III KEYNOTE-604 study confirmed the benefit of pembrolizumab combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC). Taken into account the clinical benefits of pembrolizumab and its high cost, this study aimed to assess the cost-effectiveness of adding pembrolizumab to standard first-line etoposide-platinum (EP) for patients with ES-SCLC from the US payer perspective. Methods A Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of pembrolizumab plus EP and placebo plus EP over a 10-year time horizon. Clinical efficacy and safety data were pooled from the KEYNOTE-604 trial. Utilities were obtained from published resources. Costs were mainly collected from Medicare in 2020. Sensitivity analyses were performed to examine the robustness of our model. Results Adding pembrolizumab to standard first-line EP resulted in the better effectiveness than EP chemotherapy alone for ES-SCLC by 0.22 QALYs. Pembrolizumab plus EP was dominated economically by placebo plus EP, leading to an incremental cost-effectiveness ratio (ICER) of $334,373/ QALY. Deterministic sensitivity analyses indicated that the uncertainty in model parameters exerted no substantial effect on our results. Probability sensitivity analysis indicated that probabilities for pembrolizumab plus EP being cost-effective within a wide range of willingness to pay were modest. Conclusion From the US payer perspective, the first-line treatment for ES-SCLC with pembrolizumab plus EP was not cost-effective compared with placebo plus EP. Although pembrolizumab combination chemotherapy was beneficial to the survival of ES-SCLC, price reduction may be the necessary to improve its cost-effectiveness.

Shale is of strong heterogeneity. The mineral composition has a significant influence on the diagenetic evolution, pore network formation, hydrocarbon content, oil mobility, and reservoir stimulation of shale. Accurate mineral analysis of shale is an essential precondition for scientific research and industrial production. In this study, we present a new quantitative method for shale mineral analysis based on high-resolution images, using a combination of QEMSCAN and MAPS technology. We overcome the problem of errors between the morphology and content of certain minerals identified by QEMSCAN technology and the actual results and take full advantage of high-resolution large-scale backscatter scanning electron microscopy (MAPS technology) to process clay-grade mineral image data with complex contact relationships. Specifically, we realize the correction of QEMSCAN mineral quantitative analysis results through image smoothing, image alignment, image segmentation, morphological analysis, and other image processing technologies. The method enables the precise and fast measurement of mineral types, contents, and two-dimensional (2D) distributions. It provides a more credible result consistent with geological reality than QEMSCAN. A straightforward application of the new method is refined mineralogical analysis, including the characterization of pores, fractures, organic matter, and/or mineral grains in geological materials.

A π-conjugated thiophene-containing oligomer with a D-A-D-A-D (D: donor, A: acceptor) architecture, namely, 2,6-bis{[4-(7-n-hexylthiophen-2-yl)thiophen-2-yl]-(dibenzothiophene-5,5-dioxide-3,3΄-diyl)}-bis((2-ethyl-hexyl)oxy)benzo[1,2-b:4,5-b’]dithiophen (BDT(DBTOTTH)2), was synthesized by Stille coupling reactions. There are obvious shifts in the Ultraviolet-visible (UV-vis) and photoluminescence (PL) spectra of the thin film relative to its solution, indicating the existence of the π-π stacking in the solid state of the oligomer BDT(DBTOTTH)2. The optical band gap of the oligomer determined from its absorption onset in UV-Vis spectra is 2.25 eV. It agrees with the value of 2.29 eV determined from the cyclic voltammetry (CV) measurement. Its highest occupied and lowest unoccupied molecular orbital (HOMO/LUMO) energy levels, which were calculated from its onset of oxidation and reduction waves in CV curve, are −5.51 and −3.22 eV, respectively. The oligomer is a P-type semiconductor material with a good thermal stability and solubility, which can be used to fabricate organic field effect transistors (OFETs) by the spin coating technique. The OFET with n-octadecanylltrichlorosilane (OTS)-modified SiO2 dielectric layer exhibited a mobility of 1.6 × 10−3 cm2/Vs.

Objective To investigate the cost-effectiveness of ramucirumab plus erlotinib compared with placebo plus erlotinib in the first-line setting for patients with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) from the Chinese healthcare system perspective.Design A Markov model consisting of three health states using clinical survival data from the RELAY phase III randomised clinical trial, a lifetime horizon for costs and quality-adjusted life-years (QALYs) was constructed to analyse the cost-effectiveness of ramucirumab plus erlotinib. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model. Additional price reduction scenario analyses were performed.Setting The Chinese healthcare system perspective.Participants A hypothetical Chinese cohort of patients with confirmed previously documented ex19del or Leu858Arg mutation stage IV NSCLC, and without known epidermal growth factor receptor (EGFR) Thr790Met mutation and central nervous system metastases.Interventions Ramucirumab plus erlotinib versus placebo plus erlotinib.Primary outcome measure Costs, QALYs, incremental cost-effectiveness ratio (ICER).Results In base-case analysis, ramucirumab plus erlotinib yield an additional 4.21 QALYs at a cost of $540 590, resulting in an ICER of $128 302/QALY. In price reduction scenario analysis, the ICER ($65 227/QALY) was decreased significantly when the National Reimbursement Drug List (NRDL) negotiation was available for ramucirumab, and the ICER ($131 554/QALY) was increased slightly when the NRDL negotiation was unavailable for erlotinib. Sensitivity analyses demonstrated our results to be most sensitive to the unit cost of ramucirumab (10 mg/kg), and more than 52.1% reduction in the price of ramucirumab resulted in the ICER under the willingness-to-pay threshold set for affluent regions ($70 353/QALY).Conclusions Ramucirumab plus erlotinib is unlikely to be cost-effective for patients with untreated EGFR-mutated mNSCLC in China. Reducing the price of ramucirumab through the National Healthcare Security Administration negotiation was found to be the most realistic action to improve cost-effectiveness.

Background Women with congenital heart disease are considered at high risk for adverse events. Therefore, we aim to establish 2 prediction models for mothers and their offspring, which can predict the risk of adverse events occurred in pregnant women with congenital heart disease. Methods and Results A total of 318 pregnant women with congenital heart disease were included; 213 women were divided into the development cohort, and 105 women were divided into the validation cohort. Least absolute shrinkage and selection operator was used for predictor selection. After validation, multivariate logistic regression analysis was used to develop the model. Machine learning algorithms (support vector machine, random forest, AdaBoost, decision tree, k‐nearest neighbor, naïve Bayes, and multilayer perceptron) were used to further verify the predictive ability of the model. Forty‐one (12.9%) women experienced adverse maternal events, and 93 (29.2%) neonates experienced adverse neonatal events. Seven high‐risk factors were discovered in the maternal model, including New York Heart Association class, Eisenmenger syndrome, pulmonary hypertension, left ventricular ejection fraction, sinus tachycardia, arterial blood oxygen saturation, and pregnancy duration. The machine learning–based algorithms showed that the maternal model had an accuracy of 0.76 to 0.86 (area under the receiver operating characteristic curve=0.74–0.87) in the development cohort, and 0.72 to 0.86 (area under the receiver operating characteristic curve=0.68–0.80) in the validation cohort. Three high‐risk factors were discovered in the neonatal model, including Eisenmenger syndrome, preeclampsia, and arterial blood oxygen saturation. The machine learning–based algorithms showed that the neonatal model had an accuracy of 0.75 to 0.80 (area under the receiver operating characteristic curve=0.71–0.77) in the development cohort, and 0.72 to 0.79 (area under the receiver operating characteristic curve=0.69–0.76) in the validation cohort. Conclusions Two prenatal risk assessment models for both adverse maternal and neonatal events were established, which might assist clinicians in tailoring precise management and therapy in pregnant women with congenital heart disease.

SOX2OT is a long non-coding RNA that is highly expressed in embryonic stem cells. The SOX2OT gene is comprised of 10 exons and more than two transcription start sites. Dysregulation of SOX2OT is observed in various tumors, including lung cancer, gastric cancer, esophageal cancer, breast cancer, hepatocellular carcinoma, ovarian cancer, pancreatic ductal adenocarcinoma, laryngeal squamous cell carcinoma, cholangiocarcinoma, osteosarcoma, nasopharyngeal carcinoma, and glioblastoma, wherein it typically functions as an oncogene and possibly as a tumor suppressor gene. The mechanisms underlying the effects of SOX2OT are complex and involve multiple factors and signaling pathways. In this review, we describe the current evidence regarding the role and potential clinical utility of SOX2OT in human cancers.

As one of the ligands of aryl hydrocarbon receptor (AhR), baicalein, isolated from Scutellaria baicalensis Georgi, has been proved to exert potential therapeutic effects on ulcerative colitis (UC), but its therapeutic mechanism remains obscure. Authentically, ulcerative colitis can be alleviated by regulating the differentiation of naïve CD4+ T cells via AhR activation. So, our study planned to prove the hypothesis that baicalein protected mice against UC by regulating the balance of Th17/Treg cells via AhR activation. Immunofluorescence and western blot results showed that baicalein could promote AhR activation and induce it to transfer to the nucleus. We further determined the effect of baicalein on naïve CD4+ T cell differentiation in vitro by magnetic cell separation and drug intervention. The results showed that baicalein could promote Treg cell differentiation by activating AhR. In vivo study, UC mice were established by free drinking of dextran sulfate sodium (DSS) for 7 days and then were orally administrated by baicalein (10, 20, and 40 mg/kg), TCDD (AhR agonist), and CH223191 (antagonist). The results demonstrated that baicalein improved the symptoms of UC mice, regulated the balance of Th17/Treg cells, and restored the balance of proinflammatory cytokines such as IL-17, IL-6, and TNF-α; anti-inflammatory cytokines such as IL-10 and TGF-β; and epithelial protective cytokine IL-22 in UC mice, and these effects were related to AhR. Taken together, our research found that baicalein might be a potential drug for UC via regulating Treg cell differentiation and maintaining immune homeostasis and attempted to shed a light on the pivotal role of AhR in these effects.

AimThat clinical trial (RAINBOW) showed that a 7.4 months overall survival benefit with the combination therapy with ramucirumab (RAM) and paclitaxel (PAC) as second-line therapy for patients with recurrent or metastatic gastric or gastro-oesophageal junction adenocarcinoma, compared with placebo (PLA) plus paclitaxel. We performed an analysis to assess the cost-effectiveness of RAM from a Chinese perspective and recognized the range of drug costs.MethodsBy building a Markov model to estimate quality-adjusted life-years (QALYs), life-years (LYs) and lifetime costs. Transition probabilities, costs and utilities were estimated for the published literature, Chinese health care system and local price setting. We performed threshold analyses and probabilistic sensitivity analyses to evaluate the uncertainty of the model.ResultsCompared with PLA strategy, RAM strategy provided an incremental survival benefit of 1.22 LYs and 0.64 QALYs. The probabilistic sensitivity analysis showed that when RAM costs less than $151 or $753 per 4 weeks, the incremental cost-effectiveness ratio (ICER) approximated the willingness-to-pay threshold (WTP), suggesting that there was 50% likelihood that the ICER for RAM + PAC would be less than $44528.4 per QALY or $48121 per QALY, respectively.ConclusionsFor patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who fail first-line chemotherapy, our results are conducive to the multilateral drug price guidance negotiations of RAM in China.

Semi-solid powder forming (SPF) as a novel technology has been widely used to prepare composite materials. However, most of the present models used to simulate the complicated SPF process are based on the constitutive relationship of single dense or porous material, which cannot well satisfy the actual conditions. In this study, the process of semi-solid powder rolling was simulated by the combined constitutive formula of sintered and dense Al-Cu-Mg alloy materials obtained from semi-solid compression experiments. The results show that the semi-solid compression curves of dense and sintered materials are similar, and their peak stresses increase with the decreasing porosities. The grain or particle size of sintered materials after semi-solid compression becomes finer as powders crushed, but the grain size of dense materials becomes larger due to grain coarsening and deformation, which is the key advantage of SPF with fine microstructures. The combined constitutive model of semi-solid powder materials was established and verified, and then the numerical simulation of semi-solid powder rolling based on the model was proved that can well describe the rolling process, which provides a guidance for process optimization.

Background/Aims: Chronic inflammation plays an important role in the initiation and progression of gastric cancer (GC). However, the role and relationship of activated macrophages with gastric mucous epithelium cells in initiating and maintaining the inflammatory process during gastric carcinogenesis remains unclear. Methods: The tumour associated macrophages (TAMs) density of gastric cancer was characterized by immunohistochemistry, and the relationship between macrophages and gastric epithelium cells was analysed using an in vitro culture system that imitates the inflammatory microenvironment. The production of pro-inflammatory cytokines was detected by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR). MTT assays, Western blotting, qRT-PCR, and luciferase reporter assays were used to detect the effects of cell proliferation, as well as the NF-κB and STAT3 signalling pathways. Results: TAMs infiltrated with a high intensity in GC and were significantly correlated with histology grade (P = 0.012), metastasis (P = 0.001), TNM stage (P = 0.002), and poor prognosis in patients (PFS, P = 0.005; OS, P = 0.028). In addition, IL-6 and IL-8 were elevated in the serum of GC patients and significantly promoted the growth of GC. The exposure of BGC823 gastric cancer cells to a conditioned medium from LPS-treated D-THP-1 cells significantly induced the production of TNF-α, IL-6, IL-1β and IL-8 (P< 0.01). LPS and LPS-treated D-THP-1-conditioned media promoted gastric cancer cell proliferation and triggered the significant activation of NF-κB and STAT3 with a concomitant degradation of IκBα and an increase in JAK2 phosphorylation (P < 0.05). Moreover, gastric cancer cells markedly expressed cell membrane LPS receptors, such as TLR1, TLR4, TLR6, CD14 and MD2. Conclusions: TAMs are closely associated with the growth of GC and prognosis in GC patients. GC cells may directly sustain and amplify the local pro-inflammatory response upon encountering activated macrophages and LPS via NF-κB and STAT3 signalling pathways, thereby promoting tumour progression.

The present study was aimed at investigating the effects of four LBP fractions with different molecular weights (MWs), designated LBP2, LBP3, LBP4 and LBP5, on RAW264.7 macrophages function. Results showed that LBP fractions could significantly enhance the expression of CD86 and MHC-II molecules on RAW264.7 macrophages. LBP3, LBP4 and LBP5 could enhance the production of ROS, NO, TNF-α and IL-6, and the phagocytosis of RAW264.7 macrophages. LBP2 with an MW of larger than 350 kDa could only enhance the secretion of TNF-α. LBP3 enhanced the RAW264.7 macrophages function in a dose-dependent manner and also enhanced the iNOS mRNA expression in the cells. These results demonstrated that the immunomodulatory activity of LBP on RAW264.7 macrophages was closely related to its MW. It indicated that fractions with an MW smaller than 350 kDa were the main active fractions of LBP in enhancing macrophages function.

Volcanic hydrocarbon reservoirs are developed in the Mesozoic and Cenozoic strata in Bohai Bay Basin in China. There is more than one hundred million tons of proven oil reserves in the said reservoir. They performed different actors for oil and gas accumulation in the basin. Faults controlled the distribution and accumulation of oil and gas related to volcanic rocks in Bohai Bay Basin. Not to mention, the zone near the faults is favorable for the development of good reservoirs. Volcanic rocks and volcanism can serve several roles during the course of hydrocarbon generation and accumulation. Volcanism can promote hydrocarbon generation from source rocks. Simultaneously, volcanic activity can damage petroleum reservoirs. Volcanic rocks can be both the reservoirs and the cap-rocks or obscured layer in the basin. The occurrence of volcanic rocks in source rocks can form fractures more easily compared to that in sandstones. Finally, volcanic rocks also control the distribution of mantle-derived CO2 gas reservoirs in the basin.

Infectious spleen and kidney necrosis virus (ISKNV) resulted in severe systemic diseases with high morbidity and mortality in Siniperca chuatsi. Vaccination is the primary method for effective prevention and control of these diseases. The development of inactivated ISKNV vaccines made some progress, but the technique of quality evaluation is scarce. Herein, a measurement of the MCP (major capsid protein) antigen concentration for the inactivated ISKNV vaccine was developed by double-antibody sandwich ELISA. Firstly, mouse monoclonal antibodies against ISKNV particles and MCP were generated. Then, a double-antibody sandwich ELISA was developed using the monoclonal antibody 1C8 1B9 as the capture antibody and Biotin-3B12 6B3 as the detection antibody. A standard curve was generated using the MCP concentration versus OD value with the linear range of concentration of 4.69~300 ng/mL. The assay sensitivity was 0.9 ng/mL. The antigen content of three batches of inactivated ISKNV vaccines was quantitatively detected using the double-antibody sandwich ELISA. The results showed that MCP antigen contents of inactivated ISKNV vaccines were positively correlated with the viral titers. The newly established double-antibody sandwich ELISA provided a useful tool for the detection of antigen quality for ISKNV inactivated vaccines.

Mandarin fish (Siniperca chuatsi) is one of the important cultured fish species in China. Infectious spleen and kidney necrosis virus (ISKNV) and Siniperca Chuatsi rhabdovirus (SCRV) have hindered the development of mandarin fish farming industry. Vaccination is the most effective method for control of viral diseases, however viral vaccine production requires the large-scale culture of cells. Herein, a suspension culture system of Chinese perch brain cell (CPB) was developed on Cytodex 1 microcarrier in a stirred bioreactor. Firstly, CPB cells were cultured using Cytodex 1 microcarrier in 125 mL stirring flasks. With the optimum operational parameters, CPB cells grew well, distributed uniformly, and could fully cover the microcarriers. Then, CPB cells were digested with trypsin and expanded step-by-step with different expansion ratios from the 125 mL stirring bottle to a 500 mL stirring bottle, and finally to a 3-L bioreactor. Results showed that with an expansion ratio of 1:3, we achieved a high cell density level (2.25 × 106 cells/mL) with an efficient use of the microcarriers, which also confirmed the data obtained from the 125 mL stirring flask. Moreover, obvious cytopathic effects (CPE) were observed in the suspended CPB cells post-infection with ISKNV and SCRV. This study provided a large-scale culture system of CPB cells for virus vaccine production.

Background: Sanwei Ganjiang Powder (SWGJ), derived from traditional Chinese medicine (TCM), has long demonstrated its effectiveness in long-term liver damage therapy. Recent studies indicated that it can also regulate the intestinal tract, although the underlying molecular mechanisms of this remain mysterious. The aim of the study is to investigate the mechanisms of SWGJ against dysbacteriosis and carbon tetrachloride (CCl4)-induced gut-liver axis damage underlying bile acid enterohepatic circulation. Methods: To observe the regulatory effects of SWGJ on Liver and Intestinal Damage, we explored two animal models. In model 1, sixty BALB/c mice were subjected to oral gavage with 12 g/kg of ceftriaxone sodium for 10d; during this time, SWGJ, bifendate and bifico were sequentially administered over 7d. In model 2, the model of chronic liver injury was induced by subcutaneous injection of 40% CCl4 oil solution twice per week for 8 weeks. From the 3rd week, SWGJ, bifendate and bifico were sequentially administered for 6 weeks. Intestinal flora (16S rDNA analysis), histology (H&E staining), tight connections (Immunohistochemistry, IHC), ultrastructure (Transmission electron microscopy, TEM), inflammatory cytokines and LPS (Enzyme-linked immunosorbent assay, ELISA) of the intestines were assessed, and liver function was also evaluated by methods including ALT, AST and H&E staining. The levels of protein associated with bile acid metabolism were assessed by western blot. Results: In model 1, SWGJ significantly decreased the activity of inflammatory cytokines and LPS compared with the ceftriaxone sodium group. In addition, SWGJ improved symptoms of intestinal flora imbalance; further, ZO-1 and occludin in the cytoplasm of intestinal villus epithelial cells was increased, and the histopathology of the ileum was improved. Notably, the expression of ALT and AST was significant increased, and disordered hepatic lobule structures were clearly observed in liver histopathology in model group; SWGJ can significantly improve these changes. Furthermore, the levels of proteins related to bile acid synthesis, such as CYP7A1, were significantly upregulated in the SWGJ group compared with the model, and proteins related to excretion and reabsorption, such as NTCP, Mrp2 and BESP, were also upregulated. Importantly, SWGJ increased the nuclear expression of nuclear factor-E2-related factor-2 (Nrf2). Similar results appeared in model 2. Conclusion: This study suggests that SWGJ may elicit significant effects on the treatment of gut-liver axis damage, potential mechanisms at least partially involve bile acid enterohepatic, and increasing of the nuclear Nrf2 levels.

Immunity due to immune balance contributes to disease prevention and treatment. Radix Codonopsis polysaccharide (RCP) is isolated from the root of the Chinese herb Codonopsis pilosula. Previous studies have indicated that RCP has immunomodulatory activities; however, the effects of RCP on immunity, especially immune balance, are still largely unknown. In the present study, we investigated the effects of RCP on T-cell balance in mice. The mice were pretreated intragastrically with or without RCP for 15 days and injected with hydrocortisone on days 10–15 to disturb the immune system. The spleen and thymus were weighed and used to calculate immune organ indexes. The percentages of CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, regulatory T cells (Tregs) and Th17 cells in peripheral blood were assayed by flow cytometry. Pro-inflammatory and anti-inflammatory cytokines, TNF-α, IL-1β and IL-10, in serum were determined by enzyme-linked immunosorbent assay (ELISA) kits. The results showed that RCP pretreatment could maintain the homeostasis of CD8+ T cells, Tregs, Th17 cells, TNF-α, IL-1β and IL-10 in hydrocortisone-treated mice. Furthermore, RCP pretreatment maintained the immune balance of CD4+/CD8+ T cells, Th1/Th2 cells, Tregs/Th17 cells, IL-10/TNF-α and IL-10/IL-1β. Taken together, RCP pretreatment had beneficial effects on the maintenance of T-cell balance against hydrocortisone disturbance in mice and potential to be developed into novel functional food.

In this study, a pot experiment was designed to elucidate the effect of varying dosages of silicon (Si) fertilizer application in Si-deficient and enriched paddy soils on rice phytolith and carbon (C) bio-sequestration within phytoliths (PhytOC). The maximum Si fertilizer dosage treatment (XG3) in the Si-deficit paddy soil resulted in an increase in the rice phytolith content by 100.77% in the stem, 29.46% in the sheath and 36.84% in the leaf compared to treatment without Si fertilizer treatment (CK). However, the maximum Si fertilizer dosage treatment (WG3) in the Si -enriched soil increased the rice phytolith content by only 32.83% in the stem, 27.01% in the sheath and 32.06% in the leaf. Overall, Si fertilizer application significantly (p < 0.05) increased the content of the rice phytoliths in the stem, leaf and sheath in both the Si-deficient and enriched paddy soils, and the statistical results showed a positive correlation between the amount of Si fertilizer applied and the rice phytolith content, with correlation coefficients of 0.998 (p < 0.01) in the Si-deficient soil and 0.952 (p < 0.05) in the Si-enriched soil. In addition, the existence of phytoliths in the stem, leaf, and sheath of rice and its content in the Si-enriched soil were markedly higher than that in the Si-deficient soil. Therefore, Si fertilizer application helped to improve the phytolith content of the rice plant.

Aims: We aimed to explore whether RELN contributes to the vulnerability and severity of clinical symptoms of schizophrenia (SZ) in a Chinese population.Methods: The following were conducted in an adult Han Chinese population from southern China: case–control association analyses of 30 representative single nucleotide polymorphisms (SNPs) that were screened according to specific programs based on bioinformatics tools and former research and quantitative trait locus analyses with SNPs and psychiatric symptoms evaluated with the positive and negative symptoms scale.Results: A 4-SNP haplotype consisting of rs362814, rs39339, rs540058, and rs661575 was found to be significantly associated with SZ even after Bonferroni correction (χ2 = 29.024, p = 6.42E-04, pBonf = 0.017), and the T-C-T-C haplotype was a protective factor for SZ (OR = 0.050, 95% CI = 0.004–0.705). Moreover, the 4-SNP haplotype showed a significant association with G16 (active social avoidance) after false discovery rate correction (χ2 = 28.620, p = 1.697E-04, pFDR = 0.025). In addition, P7 (hostility) was related to the haplotype comprising rs2229864, rs2535764, and rs262355 (χ2 = 31.424, p = 2.103E-05, padjustment = 0.019) in quantitative trait loci analyses.Conclusion: Overall, this study showed several positive associations between RELN and SZ, as well as psychiatric symptoms, which not only supports the proposition that RELN is a susceptibility gene for SZ but also provides information on a genotype-phenotype correlation for SZ in a Chinese population.

The semi-solid powder forming (SSPF) as a promising technology has a complicated process, but the formation mechanism of that remains unclear. The study of semi-solid compression of porous materials is an effective method to investigate the SSPF. Based on analyzing the influence of deformation strain, temperature, strain rate and initial relative density on microstructure evolution and relative density development of sintered porous 2024 aluminum alloy during semi-solid compression, the deformation mechanism and densification mechanism of semi-solid porous materials were proposed. The results show that main deformation mechanisms of porous materials during semi-solid compression are breakup of the solid skeleton or powders, and flowing of liquid with powders or fragments. Breakup mechanism is dominant at center area, whereas flowing mechanism dominates at the margin. With increasing strain and temperature and decreasing strain rate, breakup mechanism becomes primary. The densification mechanisms of porous materials during semi-solid compression are rearrangement of powders or fragments and filling of liquid, resulting from collapse of the solid skeleton or powders and flowing of liquid. The emergence of pores and densification occur simultaneously during semi-solid compression of porous materials.

The aim of the present study was to investigate whether fraction from Lycium barbarum polysaccharide (LBP) could reduce immunotoxicity and enhance antitumor activity of doxorubicin (Dox) in mice. A water-soluble LBP fraction, designated LBP3, was isolated from edible Chinese herbal Lycium barbarum and used in this study. To investigate the effect of LBP3 on Dox-induced immunotoxicity, tumor-free mice were used and treated with either normal saline, Dox, or Dox plus LBP3. To investigate the effect of LBP3 on antitumor activity of Dox, H22 tumor-bearing mice were used and treated with either normal saline, Dox, LBP3, or Dox plus LBP3. The results showed that LBP3 did not protect against the body weight loss caused by Dox, but it promoted the recovery of body weight starting at day 5 after Dox treatment in tumor-free mice. LBP3 also improved peripheral blood lymphocyte counts, promoted cell cycle recovery in bone marrow cells, and restored the cytotoxicity of natural killer cells. Furthermore, in H22 tumor-bearing mice, LBP3 enhanced antitumor activity of Dox and improved peripheral blood lymphocyte counts and the cytotoxicity of splenocytes. In brief, our results demonstrated that LBP3 could reduce the immunotoxicity and enhance antitumor activity of Dox.