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Background: This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is limited. Our aim is to investigate incidence, mortality, prescription patterns and provide a comprehensive overview of healthcare utilization trends for asthma from 2009 to 2018. Methods: We included patients diagnosed with asthma between 2009 and 2018. We excluded patients with missing demographic data. Our analysis covered comorbidities, including diabetes mellitus, hypertension, allergic rhinitis, eczema, atopic dermatitis, coronary artery disease, congestive heart failure, chronic kidney disease, chronic hepatitis, stroke, and cancer. Investigated medications comprised oral and intravenous steroids, short-acting beta-agonists, inhaled corticosteroids (ICS), combinations of ICS and long-acting beta-agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists montelukast. We also assessed the number of outpatient visits, emergency visits, and hospitalizations per year, as well as the average length of hospitalization and average medical costs. Results: The study included a final count of 88,244 subjects from 1,998,311 randomly selected samples between 2000 and 2019. Over the past decade, there was a gradual decline in newly diagnosed asthma patients per year, from 10,140 to 6,487. The mean age annually increased from 47.59 in 2009 to 53.41 in 2018. Over 55% of the patients were female. Eczema was diagnosed in over 55% of the patients. Around 90% of the patients used oral steroids, with a peak of 97.29% in 2018, while the usage of ICS varied between 86.20% and 91.75%. Intravenous steroids use rose from 40.94% in 2009 to 54.14% in 2018. The average annual hospital stay ranged from 9 to 12 days, with a maximum of 12.26 days in 2013. Lastly, the average medical expenses per year ranged from New Taiwan dollars 5558 to 7921. Conclusions: In summary, both asthma incidence and all-cause mortality rates decreased in Taiwan from 2009 to 2018. Further analysis of medical expenses in patients with asthma who required multiple hospitalizations annually revealed an increase in outpatient and emergency visits and hospitalizations, along with longer hospital stays and higher medical costs.

IMPORTANCE: Transarterial chemoembolization (TACE) is commonly used to treat patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) and positive microvascular invasion (MVI); however, TACE alone has demonstrated unsatisfactory survival benefits. A previous retrospective study suggested that TACE plus sorafenib (SOR-TACE) may be a better therapeutic option compared with TACE alone. OBJECTIVE: To investigate the clinical outcomes of SOR-TACE vs TACE alone for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI. DESIGN, SETTING, AND PARTICIPANTS: In this phase 3, open-label, multicenter randomized clinical trial, patients with recurrent intermediate-stage HCC and positive MVI were randomly assigned in a 1:1 ratio via a computerized minimization technique to either SOR-TACE treatment or TACE alone. This trial was conducted at 5 hospitals in China, and enrolled patients from October 2019 to December 2021, with a follow-up period of 24 months. Data were analyzed from June 2023 to September 2023. INTERVENTIONS: Randomization to on-demand TACE (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter: 150-350 μm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 μm or 300-500 μm]) (TACE group) or sorafenib, 400 mg, twice daily plus on-demand TACE (SOR-TACE group) (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter, 150-350 μm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 μm or 300-500 μm]). MAIN OUTCOMES AND MEASURES: The primary end point was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment. RESULTS: A total of 162 patients (median [range] age, 55 [28-75] years; 151 males [93.2%]), were randomly assigned to be treated with either SOR-TACE (n = 81) or TACE alone (n = 81). The median overall survival was significantly longer in the SOR-TACE group than in the TACE group (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001). SOR-TACE also prolonged progression-free survival (16.2 months vs 11.8 months; HR, 0.54; P < .001), and improved the objective response rate when compared with TACE alone based on the modified Response Evaluation Criteria in Solid Tumors criteria (80.2% vs 58.0%; P = .002). Any grade adverse events were more common in the SOR-TACE group, but all adverse events responded well to treatment. No unexpected adverse events or treatment-related deaths occurred in this study. CONCLUSIONS AND RELEVANCE: The results of this randomized clinical trial demonstrated that SOR-TACE achieved better clinical outcomes than TACE alone. These findings suggest that combined treatment should be used for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04103398

IMPORTANCE: Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence. OBJECTIVE: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus. DESIGN, SETTING, AND PARTICIPANTS: This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included. INTERVENTIONS: Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib. MAIN OUTCOMES AND MEASURES: The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment. RESULTS: Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group. CONCLUSION AND RELEVANCE: In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04143191

Byline: Yingtian. Wei, Yueyong. Xiao, Zhongmin. Wang, Xiaokun. Hu, Guang. Chen, Xiaoyi. Ding, Yong. Fan, Yue. Han, Kaiwen. Huang, Xuequan. Huang, Ming. Kuang, Xu. Lang, Hailiang. Li, Chengli. Li, Jiakai. [...]

ObjectiveWhether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC.DesignMetabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77Sand AKT1C224Sknock-in cells, Zdhhc17and Zdhhc24knockout mice and Akt1C224Sknock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies.ResultsBy screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis.ConclusionsOur findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m6A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (log rank test, p < 0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m6A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitroand in vivo. The oncogenic function of METTL5 is corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m6A modification that hampers ribosome synthesis and inhibits translation of G-quadruplex-containing mRNAs that are enriched in the transforming growth factor (TGF)-β pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA m6A modification in ICC and unravels the mechanism of rRNA m6A modification-mediated oncogenic mRNA translation control.

Byline: Rui. Cui, Jie. Yu, Ming. Kuang, Feng. Duan, Ping. Liang We aim to evaluate the efficacy and safety of microwave ablation (MWA) versus other treatment modalities for hepatocellular carcinoma [...]

Radiofrequency heat ablation is an ideal radical treatment for hepatocellular carcinoma (HCC). However, insufficient radiofrequency ablation (IRFA) could lead to high recurrence of HCC. N7-methylguanosine (m7G) on tRNAs, an evolutionally conservative modification in mammals and yeast, modulates heat stress responses and tumor progression, while its function in HCC recurrence after IRFA remains unknown. Here, we found that IRFA significantly upregulates the level of m7G tRNA modification and its methyltransferase complex components METTL1/WDR4 in multiple systems including HCC patient-derived xenograft (PDX) mouse, patients’ HCC tissues, sublethal-heat-treated models of HCC cell lines, and organoids. Functionally, gain-/loss-of-function assays showed that METTL1-mediated m7G tRNA modification promotes HCC metastasis under sublethal heat exposure both in vitroand in vivo. Mechanistically, we found that METTL1 and m7G tRNA modification enhance the translation of SLUG/SNAIL in a codon frequency-dependent manner under sublethal heat stress. Overexpression of SLUG/SNAIL rescued the malignant potency of METTL1 knockdown HCC cells after sublethal heat exposure. Our study uncovers the key functions of m7G tRNA modification in heat stress responses and HCC recurrence after IRFA, providing molecular basis for targeting METTL1-m7G-SLUG/SNAIL axis to prevent HCC metastasis after radiofrequency heat ablation treatment.

Background:Primary liver cancer, of which around 75–85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary:Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages:The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the “Health China 2030 Blueprint.”

Fireflies produce light through luciferase-catalyzed reactions involving luciferin, oxygen, and adenosine triphosphate, distinct from other luminescent organisms. This unique feature has revolutionized molecular biology and physiology, serving as a valuable tool for cellular research. Luciferase-based bioluminescent imaging enabled the creation of transgenic animals, such as Firefly Rats. Firefly Rats, created in 2006, ubiquitously express luciferase and have become a critical asset in scientific investigations. These rats have significantly contributed to transplantation and tissue engineering studies. Their low immunogenicity reduces graft rejection risk, making them ideal for long-term tracking of organ/tissue/cellular engraftments. Importantly, in the islet transplantation setting, the ubiquitous luciferase expression in these rats does not alter islet morphology or function, ensuring accurate assessments of engrafted islets. Firefly Rats have illuminated the path of transplantation research worldwide for over a decade and continue accelerating scientific advancements in many fields.

Pancreatic islet transplantation is one of the clinical options for certain types of diabetes. However, difficulty in maintaining islets prior to transplantation limits the clinical expansion of islet transplantations. Our study introduces a dynamic culture platform developed specifically for primary human islets by mimicking the physiological microenvironment, including tissue fluidics and extracellular matrix support. We engineered the dynamic culture system by incorporating our distinctive microwell-patterned porous collagen scaffolds for loading isolated human islets, enabling vertical medium flow through the scaffolds. The dynamic culture system featured four 12 mm diameter islet culture chambers, each capable of accommodating 500 islet equivalents (IEQ) per chamber. This configuration calculates > five-fold higher seeding density than the conventional islet culture in flasks prior to the clinical transplantations (442 vs 86 IEQ/cm2). We tested our culture platform with three separate batches of human islets isolated from deceased donors for an extended period of 2 weeks, exceeding the limits of conventional culture methods for preserving islet quality. Static cultures served as controls. The computational simulation revealed that the dynamic culture reduced the islet volume exposed to the lethal hypoxia (< 10 mmHg) to ~1/3 of the static culture. Dynamic culture ameliorated the morphological islet degradation in long-term culture and maintained islet viability, with reduced expressions of hypoxia markers. Furthermore, dynamic culture maintained the islet metabolism and insulin-secreting function over static culture in a long-term culture. Collectively, the physiological microenvironment-mimetic culture platform supported the viability and quality of isolated human islets at high-seeding density. Such a platform has a high potential for broad applications in cell therapies and tissue engineering, including extended islet culture prior to clinical islet transplantations and extended culture of stem cell-derived islets for maturation.

ObjectiveIntrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy.DesignTumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo.ResultsPolymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N7-methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8in human and Cxcl5in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models.ConclusionsOur data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies.

ObjectiveRevealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.DesignWe performed 5’and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts.ResultsAnalyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells’ cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novorecurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients.ConclusionTrue and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jcrimjus.2009.07.006 Byline: Shih-Ya Kuo (a), Steven J. Cuvelier (b), Kuang-Ming Chang (c) Abstract: Routine activities and lifestyle-exposure theories were shaped and substantially tested in Western societies; this study extended their application to a non-Western context in Taiwan. Using the most recent but underutilized 2005 Taiwan Areas Criminal Victimization Survey, responses from a random sample of 18,046 participants were analyzed for robbery, assault, and personal larceny victimization. The findings showed that the risk factors associated with criminal victimization in Taiwan resembled those in Western nations, but anomalies also appeared. Females faced a higher risk of being robbed than males; married and affluent persons were more likely to be victims of personal larceny than not married or less affluent persons; and those who stayed home at night were more likely to be assaulted than those who went out at night. The discussion of these findings suggest that explaining victimization patterns involve more than victims' attributes or lifestyles; the social and cultural context should be considered as well. Author Affiliation: (a) Department of Criminal Justice, West Virginia State University, Institute, WV 25112, United States (b) College of Criminal Justice, Sam Houston State University, Huntsville, TX 77341, United States (c) Department of Police Administration, Central Police University, Taoyuan, Taiwan

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.im.2008.12.004 Byline: I-Chiu Chang (a), Hsin-Ginn Hwang (a)(d), Ming-Chien Hung (b), Kuang-Ming Kuo (a), David C. Yen (c) Keywords: Electronic Data Interchange; Electronic healthcare; Electronic health record; Electronic Medical Record; Social Exchange Theory; Transaction Cost Theory Abstract: Adopting Electronic Medical Record (EMR) exchange may save patients' lives and also improve their health. Most Electronic Data Interchange studies have considered commercial enterprises and necessary funding to support business activities, EMR exchange focuses on saving patients' lives. Our study combined transaction cost and sociological perspectives to identify factors that affect a hospitals' willingness to implement EMR exchange. A survey was conducted with regional hospitals and medical centers in Taiwan to justify the validity of a resulting model. Our findings indicated that the model was valuable and determined which factors influenced the decision to implement EMR exchange at these hospitals (perceived benefits, uncertainty, influence, and reciprocal investments). Based on these findings, healthcare policy makers can promote EMR exchange and hospitals can identify desirable partners that will form a strategic alliance to meet the dynamic challenges in the healthcare industry. Author Affiliation: (a) Department of Information Management, National Chung Cheng University, 168 University Rd., Min-Hsiung, Chia-Yi, Taiwan, ROC (b) Department of Electronic Commerce, WuFeng Institute of Technology, No. 117, Sec. 2, Jianguo Rd., Min-Hsiung, Chia-Yi, Taiwan, ROC (c) Department of Decision Sciences and Management Information Systems, Miami University, Oxford, OH 45056, United States (d) Chi-Mei Medical Center, 901 Chung-Hwa Rd., Yong-Kang City, Tainan, Taiwan, ROC Article History: Received 26 December 2006; Revised 11 November 2008; Accepted 24 December 2008

In the literature, a min–max programming model with addition-min-product fuzzy relational inequalities constraints has been proposed to explore network congestion and data transmission problems in a BitTorrent-like peer-to-peer file-sharing system. In this paper, we slightly extend its objective function and provide a new method for finding an optimal solution. We show that solving our generalized min–max optimization problem can be reduced into a single-variable optimization problem. A polynomial-time interactive approach is then to obtain its optimal value. When a linear function is in the place of its objective subject to the same addition-min-product constraints, the optimization problem can be solved by a linear programming approach. Numerical examples are given to illustrate the procedures.

To evaluate the postsurgical prognostic implication of contrast‐enhanced ultrasound (CEUS) for combined hepatocellular‐cholangiocarcinoma (CHC). To build a CEUS‐based early recurrence prediction classifier for CHC, in comparison with tumor–node–metastasis (TNM) staging. The CEUS features and clinicopathological findings of each case were analyzed, and the Liver Imaging Reporting and Data System categories were assigned. The recurrence‐free survival associated factors were evaluated by Cox proportional hazard model. Incorporating the independent factors, nomograms were built to estimate the possibilities of 3‐month, 6‐month, and 1‐year recurrence and whose prognostic value was determined by time‐dependent receiver operating characteristics, calibration curves, and hazard layering efficiency validation, comparing with TNM staging system. In the multivariable analysis, the levels of carbohydrate antigen 19‐9, prothrombin time and total bilirubin, and tumor shape, the Liver Imaging Reporting and Data System category were independent factors for recurrence‐free survival. The LR‐M category showed longer recurrence‐free survival than did the LR‐4/5 category. The 3‐month, 6‐month, and 1‐year area under the curves of the CEUS‐clinical nomogram, clinical nomogram, and TNM staging system were 0.518, 0.552, and 0.843 versus 0.354, 0.240, and 0.624 (P= .048, .049, and .471) vs. 0.562, 0.545, and 0.843 (P= .630, .564, and .007), respectively. The calibration curves of the CEUS‐clinical model at different prediction time pionts were all close to the ideal line. The CEUS‐clinical model effectively stratified patients into groups of high and low risk of recurrence in both training and validation set, while the TNM staging system only works on the training set. Our CEUS‐clinical nomogram is a reliable early recurrence prediction tool for hepatocellular‐cholangiocarcinoma and helps postoperative risk stratification.

To construct a preoperative model for survival prediction in intrahepatic cholangiocarcinoma (ICC) patients using ultrasound (US) based radiographic‐radiomics signatures. Between April 2010 and September 2015, 170 patients with ICC who underwent curative resection were retrospectively recruited. Overall survival (OS)‐related radiographic signatures and radiomics signatures based on preoperative US were built and assessed through a time‐dependent receiver operating characteristic curve analysis. A nomogram was developed based on the selected predictors from the radiographic‐radiomics signatures and clinical and laboratory results of the training cohort (n = 127), validated in an independent testing cohort (n = 43) by the concordance index (C‐index), and compared with the Tumor Node Metastasis (TNM) cancer staging system as well as the radiographic and radiomics nomograms. The median areas under the curve of the radiomics signature and radiographic signature were higher than that of the TNM staging system in the testing cohort, although the values were not significantly different (0.76–0.82 versus 0.62, P= .485 and .264). The preoperative nomogram with CA 19‐9, sex, ascites, radiomics signature, and radiographic signature had C‐indexes of 0.72 and 0.75 in the training and testing cohorts, respectively, and it had significantly higher predictive performance than the 8th TNM staging system in the testing cohort (C‐index: 0.75 versus 0.67, P= .004) and a higher C‐index than the radiomics nomograms (0.75 versus 0.68, P= .044). The preoperative nomogram integrated with the radiographic‐radiomics signature demonstrated good predictive performance for OS in ICC and was superior to the 8th TNM staging system.

To evaluate the diagnostic performance of LR‐5 for diagnosing poorly differentiated hepatocellular carcinoma (p‐HCC). To build a contrast‐enhanced ultrasound (CEUS) signature for improving the differential diagnostic performance between p‐HCC and intrahepatic cholangiocarcinoma (ICC). The B‐mode ultrasound (BUS) and CEUS features of 60 p‐HCCs and 56 ICCs were retrospectively analyzed. The CEUS LI‐RADS category was assigned according to CEUS LI‐RADS v2017. A diagnostic CEUS signature was built based on the independent significant features. An ultrasound (US) signature combining both BUS and CEUS features was also built. The diagnostic performances of the CEUS signature, US signature, and LR‐5 were evaluated by receiver operating characteristic (ROC) analysis. One (1.7%) p‐HCC and 26 (46.4%) ICC patients presented cholangiectasis or cholangiolithiasis (P< .001). Fifty‐four (90.0%) p‐HCCs and 8 (14.3%) ICCs showed clear boundaries in the artery phase (P< .001). The washout times of p‐HCCs and ICCs were 81.0 ± 42.5 s and 34.7 ± 8.6 s, respectively (P< .001). The AUC, sensitivity, and specificity of the CEUS signature, US signature, and LR‐5 were 0.955, 91.67%, and 90.57% versus 0.976, 96.67%, and 92.45% versus 0.758, 51.67%, and 100%, respectively. The AUC and sensitivity of CEUS LI‐RADS were much lower than those of the CEUS and US signatures (P< .001). LR‐5 had high specificity but low sensitivity in diagnosing p‐HCC. When the washout time and tumor boundary were included in the CEUS signature, the sensitivity and AUC were remarkably increased in the differentiation between p‐HCC and ICC.

Results indicate that high-intensity aerobic exercise affects the mitochondrial energy status and the vitality of peripheral blood leukocytes. Data point out that leucocyte mitochondrial transmembrane potential is a marker for inner distress caused by overtraining.

ObjectiveAltered metabolites are important for the tumourigenicity of hepatocellular carcinoma (HCC). We performed integrative metabolomics analysis of the metabolites changes in portal venous blood and in comparison with the metabolites changes in liver tissues and stool samples of HCC patients and healthy liver donors.DesignSerum (portal and central vein), liver tissue (HCC tumour and adjacent non-tumour, normal liver) and stool samples were collected from 102 subjects (52 HCC patients and 50 healthy controls) in the discovery cohort; and 100 subjects (50 HCC patients and 50 healthy controls) in an independent validation cohort. Untargeted metabolomic profiling was performed using high-performance liquid chromatography-mass spectrometry. The function of candidate metabolites was validated in hepatocyte cell lines.ResultsDetailed metabolomic evaluation showed distinct clusters of metabolites in serum, liver tissue and stool samples from patients with HCC and control individuals (p<0.001). HCC patients had significantly higher levels of portal vein serum and HCC tissue metabolites of DL-3-phenyllactic acid, L-tryptophan, glycocholic acid and 1-methylnicotinamide than healthy controls, which were associated with impaired liver function and poor survival. On the other hand, HCC patients had lower levels of linoleic acid and phenol in portal vein and stool samples than healthy controls. Linoleic acid and phenol significantly inhibited HCC proliferation, inferring their anti-HCC function as protective metabolites.ConclusionsThe integrative metabolome analysis of serum, tissue and stool metabolites revealed unreported metabolic alterations in HCC patients. In portal vein, we identified elevated and depleted metabolites signifying that they might play a role in HCC development.

For nonresponding intermediate stage hepatocellular carcinoma, three sessions of transarterial chemoembolization are recommended before abandonment.

Background: Various training models have been developed for laparoscopic training. Inanimate models including cadavers, ex-vivo simulator, and virtual reality (VR), are less realistic and often fail to display specific events such as bleeding, bile leakage, etc. Animal models provide more realistic experience, but constraints like cost involved, anesthetic requirement, and ethical approval have limited its application. We have designed a new training ex-vivo simulator—Smagister to address these issues. Methods: The Smagister consists of a normothermic machine perfusion platform, multivisceral organ of porcine abdominal cavity (liver, gallbladder, pancreas, stomach, intestine, kidney, uterus, bladders, etc.), high-definition display, and software system. Blood gas analysis and number of peristalsis per hour were recorded. A questionnaire was used to subjectively assess vitality of the organ cluster every hour. Three laparoscopic procedures including cholecystectomy (LC), enterotomy closure (LEC) and hepatectomy (LLR) were performed on Smagister, with demonstration of specific events for each procedure. Six experts compared the procedures with actual surgery in terms of feasibility to complete procedures and demonstration of complications. Results: The fluctuation of perfusate glucose (6.1–8.2 mmol/L) and lactate (5.82–6.55 mmol/L) suggested metabolic function of the multivisceral organs. The mean number of peristalsis was 2.2/min. The simulated surgical view and anatomic structures closely resembled actual surgery during continuous perfusion (3.5?±?1.0, 3.8?±?0.8, respectively). The evaluation scores of haptic feedbacks were 3.8?±?0.8, resembling live tissue handling. LC, LEC, and LLR were performed well on the Smagister, with clear display of the specific events. All six experts considered Smagister as a suitable training modality for both basic and advanced laparoscopic surgery. Conclusion: The amalgamation of live animal model and ex-vivo simulation in Smagister centralizes the virtue of both modalities, expands the training field, and provides high-fidelity laparoscopic training for both novice and senior surgeons.

Three novel dimeric bithiophenes, echinbithiophenedimers A–C (1–3), along with two known thiophenes, 4and 5, were obtained from Echinops latifolius, and their structures were identified through extensive spectroscopic analysis and electronic circular dichroism calculations. Compounds 1–3possessed new carbon skeletons; they are dimeric bithiophenes with 1and 2featuring an unprecedented 1,3-dioxolane ring system and 3featuring an unusual 1,4-dioxane ring. These compounds are the first examples of bithiophene dimers furnished by different cyclic diethers. Dimeric bithiophenes 1–3had good antifungal activities against five phytopathogenic fungi, and compound 3showed excellent activity against Alternaria alternateand Pyricularia oryzae, with a minimal inhibitory concentration value of 8 μg/mL, which was close to or higher than that of carbendazim. Moreover, its effect on the mycelial morphology was observed by scanning electron microscopy. Compounds 1–3, which were demonstrated to be nonphototoxic thiophenes, exhibited better nematicidal activity than the commercial nematicide ethoprophos against Meloidogyne incognita. This study revealed that dimeric bithiophenes containing 1,3-dioxolane or 1,4-dioxane rings could be used as novel antifungal and nematicidal agents for controlling plant fungal and nematode pathogens.

Germinating seeds can release diverse phytochemicals that repel, inhibit, or kill pathogens such as root-knot nematodes and seed-borne fungi. However, little is known about the composition of these phytochemicals and their effects on pathogens. In this study, we demonstrated that tomato seed exudates can attract the nematode Meloidogyne incognitausing a dual-choice assay. Eighteen compounds were then isolated and identified from the exudates. Of these, esters (1–3), fatty acids (4–6), and phenolic acids (10–12) were proven to be the signaling molecules that facilitated the host-seeking process of second-stage juveniles (J2s) of nematodes, while alkaloids (17and 18) disrupted J2s in locating their host. Furthermore, some phenolic acids and alkaloids showed antifungal effects against seed-borne fungi. In particular, ferulic acid (12) showed obvious activity against Aspergillus flavus(minimum inhibitory concentration (MIC), 32 μg/mL), while dihydrocapsaicin (17) showed noticeable activity against Fusarium oxysporum(MIC, 16 μg/mL). Overall, this study presents the first evidence that M. incognitacan be attracted to or deterred by various compounds in seed exudates through identification of the structures of the compounds in the exudates and analysis of their effects on nematodes. Furthermore, some antifungal compounds were also found. The findings of this work suggest that seed exudates are new source for finding insights into the development of plant protective substances with nematocidal and antifungal effects.

Background:We aimed to evaluate the performance of a deep learning (DL)-based Radiomics strategy designed for analyzing contrast-enhanced ultrasound (CEUS) to not only predict the progression-free survival (PFS) of radiofrequency ablation (RFA) and surgical resection (SR) but also optimize the treatment selection between them for patients with very-early or early-stage hepatocellular carcinoma (HCC). Methods:We retrospectively enrolled 419 patients examined by CEUS within 1 week before receiving RFA or SR (RFA: 214, SR: 205) from January 2008 to 2016. Two Radiomics signatures were constructed by the Radiomics model R-RFA and R-SR to stratify PFS of different treatment groups. Then, RFA and SR nomograms were built by incorporating Radiomics signatures and significant clinical variables to achieve individualized 2-year PFS prediction. Finally, we applied both Radiomics models and both nomograms to each enrolled patient to investigate whether there were space for treatment optimization and how much prognostic improvement could be expected. Results:R-RFA and R-SR showed remarkable discrimination (C-index: 0.726 for RFA, 0.741 for SR). RFA and SR nomograms provided good 2-year PFS prediction accuracy and good calibrations. We identified 17.3% RFA patients and 27.3% SR patients should swap their treatment, so their average probability of 2-year PFS would increase 12 and 15%, respectively. Conclusions:The proposed Radiomics models and nomograms achieved accurate preoperative prediction of PFS for RFA and SR, and they could facilitate the optimized treatment selection between them for patients with very-early or early-stage HCC.

To explore the value of ultrasomics in temporal monitoring of tumor changes in response to gene therapy in hepatocellular carcinoma compared with methods according to the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). Hepatocellular carcinoma–bearing mice were injected intratumorally with microRNA‐122 (miR‐122) mimics and an miR‐122 negative control in the treatment and control groups, respectively. The injections were performed every 3 days for 5 times (on days 0, 3, 6, 9, and 12). Before each injection and at the experiment ending, 2‐dimensional ultrasound imaging was performed for tumor size measurement with RECIST and computing a quantitative imaging analysis with ultrasomics. To analyze the tumor perfusion by mRECIST, perfusion parameters were analyzed offline based on dynamic contrast‐enhanced ultrasound image videos using SonoLiver software (TomTec, Unterschleissheim, Germany) on day 13. Tumor miR‐122 expression was then analyzed by real‐time reverse transcription–polymerase chain reaction experiments. Tumors in mice treated with miR‐122 mimics demonstrated a mean ± SD 763‐ ± 60‐fold increase in miR‐122 levels compared with tumors in the control group. With RECIST, a significant therapeutic response evaluated by tumor size changes was detected after day 9 (days 9, 12, and 13; P< .001). With mRECIST, no parameters showed significant differences (P> .05). Significant different features of the 2‐dimensional ultrasound images between the groups were detected by the ultrasomics analysis, and the model could be successfully built. The ultrasomics score values between the groups were statistically significant after day 6 (days 6, 9, 12, and 13; P< .05). Ultrasomics revealed significant changes after the second injection of miR‐122, showing the potential as an important imaging biomarker for gene therapy.

To construct a prediction model based on peritumoral radiomics signatures from CT images and investigate its efficiency in predicting early recurrence (ER) of hepatocellular carcinoma (HCC) after curative treatment. In total, 156 patients with primary HCC were randomly divided into the training cohort (109 patients) and the validation cohort (47 patients). From the pretreatment CT images, we extracted 3-phase two-dimensional images from the largest cross-sectional area of the tumor. A region of interest (ROI) was manually delineated around the lesion for tumoral radiomics (T-RO) feature extraction, and another ROI was outlined with an additional 2 cm peritumoral area for peritumoral radiomics (PT-RO) feature extraction. The least absolute shrinkage and selection operator (LASSO) logistic regression model was applied for feature selection and model construction. The T-RO and PT-RO models were constructed. In the validation cohort, the prediction efficiencies of the two models and peritumoral enhancement (PT-E) were evaluated qualitatively by receiver operating characteristic (ROC) curves, calibration curves and decision curves and quantitatively by area under the curve (AUC), the category-free net reclassification index (cfNRI) and integrated discrimination improvement values (IDI). By comparing AUC values, the prediction accuracy in the validation cohort was good for the PT-RO model (0.80 vs. 0.79, P= 0.47) but poor for the T-RO model (0.82 vs. 0.62, P< 0.01), which was significantly overfitted. In the validation cohort, the ROC curves, calibration curves and decision curves indicated that the PT-RO model had better calibration efficiency and provided greater clinical benefits. CfNRI indicated that the PT-RO model correctly reclassified 47% of ER patients and 32% of non-ER patients compared to the T-RO model (P < 0.01); additionally, the PT-RO model correctly reclassified 24% of ER patients and 41% of non-ER patients compared to PT-E (P= 0.02). IDI indicated that the PT-RO model could improve prediction accuracy by 0.22 (P < 0.01) compared to the T-RO model and by 0.20 (P= 0.01) compared to PT-E. The CT-based PT-RO model can effectively predict the ER of HCC and is more efficient than the T-RO model and the conventional imaging feature PT-E.

This study aimed to compare the efficacy of Sonazoid and SonoVue in subjects with focal liver lesions. The patients who had untreated focal solid liver lesions confirmed by B‐mode ultrasonography were eligible for the study. The target lesion and whole liver were scanned by gray scale ultrasonography; then, contrast‐enhanced ultrasonography was performed, and the results were evaluated blindly. The main end point was accuracy improvement with postcontrast versus precontrast ultrasound examination for diagnosis of the target lesion of interest as malignant or benign against the reference standard. There were 65 patients with 65 hepatic tumors enrolled in the study. The improvement of diagnostic accuracy was 0.30 in the Sonazoid group and 0.16 in the SonoVue group (95% confidence interval, –0.828–0.168; P= .24). Using 20% as the noninferiority margin, the upper limit of the 95% confidence interval (0.168) was less than 0.20. The number of lesions detected during the whole‐liver scanning in the Sonazoid group was significantly more than that detected in the SonoVue group (P= .024). The diagnosis value of Sonazoid is noninferior to SonoVue, and this new contrast agent can improves the whole‐liver image quality.

Patients with recurrent intermediate-stage hepatocellular carcinoma and microvascular invasion–positive status benefit from longer survival times by using a combined treatment of sorafenib with transarterial chemoembolization (TACE) compared with TACE alone.

A wide variety of transition metals, including copper and gold, have been successfully used as substrates for graphene growth. On the other hand, it has been challenging to grow graphene on silver, so realistic applications by combining graphene and silver for improved electrode stability and enhanced surface plasmon resonance in organic light-emitting diodes and biosensing have not been realized to date. Here, we demonstrate the surface passivation of silver through the single-step rapid growth of nanocrystalline multilayer graphene on silver via low-temperature plasma-enhanced chemical vapor deposition (PECVD). The effect of the growth time on the graphene quality and the underlying silver characteristics is investigated by Raman spectroscopy, X-ray diffraction, atomic force microscopy, X-ray photoelectron spectroscopy (XPS), and cross-sectional annular dark-field scanning transmission electron microscopy (ADF-STEM). These results reveal nanocrystalline graphene structures with turbostratic layer stacking. Based on the XPS and ADF-STEM results, a PECVD growth mechanism of graphene on silver is proposed. The multilayer graphene also provides excellent long-term protection of the underlying silver surface from oxidation after 5 months of air exposure. This development thus paves the way toward realizing technological applications based on graphene-protected silver surfaces and electrodes as well as hybrid graphene-silver plasmonics.

Background: The CRISPR-Cas13 system is an RNA-guided RNA-targeting system and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells. Results: Here, we find that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which may result from the collateral activity of RfxCas13d rather than the loss of target gene function or off-target effects. Mechanistically, we show that RfxCas13d exhibits collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAKα-JNK/p38-immediate early gene pathway. Conclusions: These findings provide new mechanistic insights into the collateral activity of RfxCas13d in mammalian cells and warn that the biosafety of the CRISPR-Cas13 system needs further evaluation before application to clinical treatments.

Patients with biliary tract cancer (BTC) show different responses to chemotherapy, and there is no effective way to predict chemotherapeutic response. We have generated 61 BTC patient-derived organoids (PDOs) from 82 tumors (74.4%) that show similar histological and genetic characteristics to the corresponding primary BTC tissues. BTC tumor tissues with enhanced stemness- and proliferation-related gene expression by RNA sequencing can more easily form organoids. As expected, BTC PDOs show different responses to the chemotherapies of gemcitabine, cisplatin, 5-fluoruracil, oxaliplatin, etc. The drug screening results in PDOs are further validated in PDO-based xenografts and confirmed in 92.3% (12/13) of BTC patients with actual clinical response. Moreover, we have identified gene expression signatures of BTC PDOs with different drug responses and established gene expression panels to predict chemotherapy response in BTC patients. In conclusion, BTC PDO is a promising precision medicine tool for anti-cancer therapy in BTC patients.

Recent studies indicated that insufficient radiofrequency ablation (RFA) could endow hepatocellular carcinoma (HCC) with higher aggressive potential. Stress-induced phosphoprotein 1 (STIP1), which was found highly expressed in HCC, is a chaperone molecule mediating cell homeostasis under thermal stress. We aimed to explore the role of STIP1 on the metastasis of residual HCC after RFA. Mice model with orthotopic HCC implants or caudal vein injection were employed to assess potential of lung metastasis and/or intrahepatic metastasis (IHM) of HCC cells. Cell culture model was used to determine cell invasion, mesenchymal marker genes expression, and underlying molecular mechanisms. Clinical specimens were collected to analyze the relationship between STIP1 and clinical outcome. We found that insufficient RFA elicited more IHM of HCCLM3 tumors, which could be reduced by silencing STIP1. Knockdown of STIP1 also significantly decreased lung metastatic potential of HCCLM3 cells. In vitro, HCCLM3 and HepG2 displayed a spindle-shaped morphology with upregulation of STIP1 and mesenchymal markers after sublethal heat exposure. Mechanistically, heat exposure induced the formation of STIP1-heat shock protein 90 (HSP90) complex, which could shuttle epithelial transcription repressor Snail1 into nucleus and regulate mesenchymal gene transcription. Blocking the HSP90–STIP1 complex reduced the invasive potential of HCC cells after heat exposure. Using clinical specimen, we found that STIP1 was expressed significantly higher in metastatic tumor tissues and in sera from metastatic HCC patients (p< 0.05). The high expression of STIP1 was significantly linked to shorter recurrence-free survival (p< 0.05). To sum up, our study found that STIP1 is positively associated with the sublethal heat-induced cancer cell metastasis through mediating the mesenchymal gene transcription. Blocking STIP1 activity may suppress HCC cell metastatic potential after RFA.

Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532-5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-κB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF-κB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-κB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-κB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment.

Sorafenib with combined transarterial chemoembolization and radiofrequency ablation yields better overall survival and time to progression and comparable safety when compared with sorafenib alone in patients with advanced recurrent hepatocellular carcinoma.

Mechanical stress can modulate the fate of cells in both physiological and extreme conditions. Recurrence of tumors after thermal ablation, a radical therapy for many cancers, indicates that some tumor cells can endure temperatures far beyond physiological ones. This unusual heat resistance with unknown mechanisms remains a key obstacle to fully realizing the clinical potential of thermal ablation. By developing a 3D bioprinting-based thermal ablation system, we demonstrate that hepatocellular carcinoma (HCC) cells in this 3D model exhibit enhanced heat resistance as compared with cells on plates. Mechanistically, the activation of transcription factor SP1 under mechanical confinement enhances the transcription of Interleukin-4-Induced-1, which catalyzes tryptophan metabolites to activate the aryl hydrocarbon receptor (AHR), leading to heat resistance. Encouragingly, the AHR inhibitor prevents HCC recurrence after thermal ablation. These findings reveal a previously unknown role of mechanical confinement in heat resistance and provide a rationale for AHR inhibitors as neoadjuvant therapy.

Purpose: The adoption of electronic medical records (EMR) is expected to better improve overall healthcare quality and to offset the financial pressure of excessive administrative burden. However, safeguarding EMR against potentially hostile security breaches from both inside and outside healthcare facilities has created increased patients’ privacy concerns from all sides. The aim of our study was to examine the influencing factors of privacy protection for EMR by healthcare professionals.Method: We used survey methodology to collect questionnaire responses from staff members in health information management departments among nine Taiwanese hospitals active in EMR utilisation. A total of 209 valid responses were collected in 2014. We used partial least squares for analysing the collected data.Results: Perceived benefits, perceived barriers, self-efficacy and cues to action were found to have a significant association with intention to protect EMR privacy, while perceived susceptibility and perceived severity were not.Conclusion: Based on the findings obtained, we suggest that hospitals should provide continuous ethics awareness training to relevant staff and design more effective strategies for improving the protection of EMR privacy in their charge. Further practical and research implications are also discussed.

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1+macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.

Seismic responses of the Zipingpu concrete face rockfill dam were analyzed using the finite element method. The dynamic behavior of rockfill materials was modeled with a viscoelastic model and an empirical permanent strain model. The relevant parameters were obtained either by back analysis using the field observations or by reference to parameters of similar rockfill materials. The acceleration responses of the dam, the distribution of earthquake-induced settlement, and the gap propagation under the concrete slabs caused by the settlement of the dam were analyzed and compared with site investigations or relevant studies. The mechanism of failure of horizontal construction joints was also analyzed based on numerical results and site observations. Numerical results show that the input accelerations were considerably amplified near the top of the dam, and the strong shaking resulted in considerable settlement of the rockfill materials, with a maximum value exceeding 90 cm at the crest. As a result of the settlement of rockfill materials, the third-stage concrete slabs were separated from the cushion layer. The rotation of the cantilever slabs about the contacting regions, under the combined action of gravity and seismic inertial forces, led to the failure of the construction joints and tensile cracks appeared above the construction joints. The effectiveness and limitations of the so-called equivalent linear method are also discussed.