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Aim To establish and validate a prognostic nomogram of cholangiocarcinoma (CCA) using independent clinicopathological and genetic mutation factors. Methods 213 patients with CCA (training cohort n = 151, validation cohort n = 62) diagnosed from 2012 to 2018 were included from multi-centers. Deep sequencing targeting 450 cancer genes was performed. Independent prognostic factors were selected by univariate and multivariate Cox analyses. The clinicopathological factors combined with (A)/without (B) the gene risk were used to establish nomograms for predicting overall survival (OS). The discriminative ability and calibration of the nomograms were assessed using C-index values, integrated discrimination improvement (IDI), decision curve analysis (DCA), and calibration plots. Results The clinical baseline information and gene mutations in the training and validation cohorts were similar. SMAD4, BRCA2, KRAS, NF1, and TERT were found to be related with CCA prognosis. Patients were divided into low-, median-, and high-risk groups according to the gene mutation, the OS of which was 42.7 ± 2.7 ms (95% CI 37.5–48.0), 27.5 ± 2.1 ms (95% CI 23.3–31.7), and 19.8 ± 4.0 ms (95% CI 11.8–27.8) (p p Conclusion Gene risk has the potential to guide treatment decision for patients at different risks. The nomogram combined with gene risk showed a better accuracy in predicting OS of CCA than not.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal tumor with a poor prognosis. Serum biomarker carbohydrate antigen 19-9 (CA19-9) was the only well-established biomarker for PDAC with inadequate efficacy. This present study aimed to determine the ability of PIVKA-II to discriminate PDAC from pancreatic benign lesions and predict vascular invasion preoperatively. Methods: Patients who underwent pancreatic surgery from 2017 to 2020 were enrolled. We examined the differential diagnostic ability of protein induced by vitamin K absence II (PIVKA-II), CA19-9, and their combination and 138 with PDAC evaluated the predictive value of PIVKA-II for vascular invasion in PDAC. Methods: A total of 138 patients with PDAC and 90 patients with pancreatic benign lesions who underwent pancreatic surgery from 2017 to 2020 were enrolled. The clinicopathological characteristics were recorded. Results: There was a significant difference in levels of serum PIVKA-II between PDAC patients and patients with pancreatic benign lesions (p < 0.001). When the cut-off value was set to 28.9 mAU/mL according to the ROCs, the AUC, sensitivity, and specificity of PIVKA-II were 0.787, 68.1%, and 83.3%, respectively. The combined PIVKA-II and carbohydrate antigen 19-9 (CA19-9) enhanced the diagnostic accuracy, and the AUC, sensitivity, and specificity were 0.945, 87.7%, and 94.4%, respectively. PIVKA-II > 36.4 mAU/mL were independent predictive factors of vascular invasion in PDAC (p < 0.001). Conclusion: PIVKA-II was a potential diagnostic biomarker to differentiate PDAC from pancreatic benign lesions. PIVKA-II was complementary to CA19-9, and the combination enhanced the differential diagnostic performance. PIVKA-II > 36.4 mAU/mL was an independent predictive factor of vascular invasion in PDAC.

Xiaoyu Wang,1 Guangbing Li,1,2 Changfa Guo,3 Jiayao Zhang,1 Junjie Kong,1,2 Jingyi He,1,2 Feiyu Li,1 Yong Liu,1 Yang Yang,1 Ziwen Lu,1 Jun Liu1,2 1Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, Cheeloo College of Medicine, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Jun LiuDepartment of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of ChinaEmail dr_liujun1967@126.comBackground: The AMP-activated protein kinase alpha (AMPKα) pathway has widely been considered a key factor in energy metabolism. Ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl] acetate (TMPA) is a novel AMPK agonist, which influences the stability of Nuclear Receptor Subfamily 4, Group A, Member 1 (Nur77)-serine-threonine kinase 11 (LKB1) in the nucleus. A recent study has determined that TMPA can ameliorate the reduction of insulin resistance in type II db/db mice. However, the role of TMPA in hepatocyte lipid metabolism has not been elucidated.Objective: To investigate whether TMPA could ameliorate liver lipid accumulation under the stimulation of free fatty acids (FFAs) in vitro.Methods: We evaluated differences of Nur77 and AMPK pathway in mice fed a high-fat diet and those fed a normal diet. In vitro, TMPA was added to HepG2 cells and primary hepatocytes before FFAs stimulation. Oil red O staining, Nile red staining were used to evaluate lipid deposition. Western blot and immunofluorescence were used to quantify related proteins.Results: Nur77, AMPKα, LKB1, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), acetyl-CoA carboxylase phosphorylation (p-ACC), and carnitine palmitoyltransferase 1 (CPT1A) showed significant differences in vivo. Under the intervention of TMPA, HepG2 cells and primary hepatocytes showed considerable amelioration of lipid deposition and improved the expression of phosphorylated (p)-AMPKα (p-AMPKα), p-LKB1, p-ACC, and CPT1A. Furthermore, Western blotting and immunofluorescence studies indicated that LKB1 dramatically increased expression in the cytoplasm but decreased in the nucleus. Further, AMPKα phosphorylation (p-AMPKα) also showed a higher expression in cytoplasm instead of the nucleus.Conclusion: TMPA ameliorated lipid accumulation by influencing the stability of Nur77-LKB1 in vitro.Keywords: ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl] acetate, Nur77, AMPK pathway, HepG2 cells, primary hepatocytes

Purpose. This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). Methods. HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan–Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. Results. COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio OR = 1.616 , >20 vs. ≤20, p < 0.05 ), stage ( OR = 1.744 , III vs. I, p < 0.05 ), and grade ( OR = 1.746 , G4+G3 vs. G2+G1, p < 0.05 ). Kaplan–Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression ( p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio HR = 1.068 , p < 0.0001 ) and multivariate Cox ( HR = 2.011 , p < 0.05 ) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. Conclusion. COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.

Background Histological grade (HG) is an important prognostic factor for hepatocellular carcinoma. With the development of precision medicine, diagnosis with a sequencing technology has become increasingly accepted. It is vital to discuss their similarities and differences to bridge or improve the traditional HG diagnosis with the novel sequencing technique. Methods A total of 658 tumor samples were collected from 602 Chinese hepatocellular carcinoma patients and sequenced for a panel of pan-cancer genes. Nucleotide usage bias, genomic variation-related scores, driver genes, and biological processes were compared among different HGs. These results were further verified using a cohort dataset from the Western population. Results Genomic variation subtypes, such as C>G substitution, maximum somatic allele frequency (MSAF), and TP53, and biological processes including “angiogenesis” and “regulation of homotypic cell-cell adhesion” were found to be significantly associated with HG in both Chinese and Western populations. Conclusions The association identified between genomic variation and HG could aid our understanding of HG as an important clinical measure, and potentially be used to predict HG for hepatocellular carcinoma.

Background: Bromodomain-containing protein 4 (BRD4) has been widely studied as an attractive therapeutic target of prostate cancer (PCa). Currently, a number of BRD4 inhibitors or degraders have been discovered. However, recent studies revealed that SPOP mutant of prostate cancer patients leads to BRD4 stabilization and resulted in JQ1-resistant. Therefore, to reveal the mechanism underlying BRD4 stability may improve the clinical response rate and efficacy of BRD4-targeted therapy in PCa patients. Methods: To evaluate the level of BRD4 during the mitosis phase, we applied a Confocal microscope and WB. In vitro kinase assay and Mass spectrometry were applied to test the phosphorylation of BRD4 by PLK1. A homemade phosphorylation-specific antibody was used to verify p-BRD4 in PCa cells and a tissue micro-array. A PDX-tumor model was used to evaluate the combination efficacy of Taxol to overcome JQ1-resistant. Result: We found that the level of BRD4 obviously decreased during the mitosis phase of PCa cells. Upon releasing from M-phase arrest, BRD4 level increased along with PLK1 decreasing in PCa cell lines, suggesting PLK1 might be involved in the degradation of BRD4 in the M-phase. We found that PBD domain of PLK1 was responsible for interacting with CTD of BRD4. Enforced overexpression of PLK1 promoted BRD4 dramatically reduced. Reversely, tet-induced depletion or inhibition of PLK1 led to BRD4 stabilization. Furthermore, applying gain or loss of function assay, we found that PLK1 directly phosphorylated BRD4 and triggered its phosphorylation-dependent degradation in M-phase, which was confirmed in clinical samples that high level of PLK1 was negatively correlated with BRD4. Accordingly, we found that overexpression of PLK1 lowered the stabilized BRD4 caused by SPOP mutant in PCa cells and consequently made cells sensitive to JQ1. Intriguingly, upon treated with Taxol, a commonly used medicine for PCa patients, PLK1 level was dramatically elevated as well as p-BRD4 status but total BRD4 downregulated in PCa cells. Moreover, sequential treatment of Taxol and JQ1 resulted in significant inhibition of proliferation, colony formation, and PDX tumor carrying SPOP mutant, indicating application of Taxol overcame JQ-1 resistant. Conclusion: Collectively, our results suggested that PLK1 phosphorylates BRD4 and consequently triggers its phosphorylation-dependent degradation in PCa cells. Sequential treatment of Taxol and JQ1 overcomes SPOP mutant-related BETi-resistant in prostate cancer. Citation Format: Yanquan Zhang, Ka Will Fong, Fengyi Mao, Ruixin Wang, Yifan Kong, Chaohao Li, Jinghui Liu, Zhiguo Li, Derek B. Allison, Dana Napier, Daheng Li, Jinpeng Liu, Chi Wang, Yeqing Zhang, Guangbing Li, Xiaoqi Liu. Taxol-elevated PLK1 overcomes BETi-resistant in prostate cancer via triggering phosphorylation-dependent degradation of BRD4. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4992.

In this paper, we study a consumption, investment and life insurance strategy model in which agent has time-inconsistent preferences. We numerically find that time-inconsistent preferences lead age...

Aging is an inevitable natural process, leading to faded performances of soil amendments. Understanding long-term aging features is crucial for the risk management of contaminated soil. In this study, a novel quantitative aging method, namely, the "soil coin" method, was developed, which can simulate the effects of natural aging on metal(loid) immobilization performances. To better depict the aging features, two models on the basis of conditional probability-induced failure were developed. To effectively immobilize soil arsenic (As) and antimony (Sb), magnesium (Mg) and iron (Fe) oxides were simultaneously introduced to either fresh or pre-oxidized biochar via a facile method. Although post-application aging is harmful, pre-aging (i.e., pre-oxidation using H2O2) in turn served as an effective means to introduce more metal oxides, thereby rendering better short-term and long-term effectiveness for metalloid immobilization. Experimental and modeling approaches suggested that precipitation accounted for long-term immobilization, while a constant aging rate is the key feature for a promising soil amendment. It is suggested that to further calibrate this method and better understand the immobilization performances in the long run, more evidence from the field is needed.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Apatinib is a small molecule TKI inhibitor. Its efficacy and safety for unresectable HCC patients have been demonstrated in randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. We are aiming to evaluate the efficacy and safety of apatinib in real world.MethodsPatients of older than 18 years with unresectable HCC confirmed by IHC (Immunohistochemistry) or CT and MR Imaging were enrolled in the study. All patients received apatinib monotherapy or combined with other treatments including TACE and chemotherapy. The enrolled patients were treated until disease progression, death, or severe intolerable toxicity, etc. The primary endpoint was overall response rate (ORR), and secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were also recorded.ResultsFrom February, 2019 to May, 2020, a total of 233 patients were enrolled. Among them, 66 (28.33%) patients received apatinib monotherapy and 167 (71.67%) patients received combination therapy. Patients with a history of hepatitis accounted for 70%. 8 patients achieved complete response (CR), 64 patients achieved partial response (PR), 120 patients achieved stable disease (SD), and 41 patients had progressive disease (PD), illustrating an ORR of 30.90% and a DCR of 82.40%. Median PFS and OS were 6.93 months (95% CI, 6.19-7.68 months) and 11.36 months (95% CI, 9.96-12.77 months), respectively. The safety profile indicated that the most common drug-related adverse events were hypertension (37.90%), hand-foot-skin reaction (27.39%), fatigue (19.11%), thrombocytopenia (16.02%). Grade 3/4 treatment related AEs included thrombocytopenia (4.30%), hypertension (3.82%), neutropenia (2.73%). After symptomatic treatment, all the adverse events were treated properly, and no unexpected adverse events were observed. Conclusions In current study, apatininb showed good tolerance with acceptable toxicity and high tumor response rate that translated into promising PFS and OS in unresectable HCC patients. ChiCTR1900021822 Citation Format: Jun Liu, Guangbing Li, Qiang He, Shijun Sun, Chuanlin Zhao, Chuandong Sun, Bo Zhang, Yi Cui, Yongqiang Ye, Xuting Zhi, Shiping Li, Shiping Li, Guozheng Pan, Changlin Ma, Jinhua Hu, Jun Li, Suling Wang, Yuangang Qiao, Wanhua Ren, Qi Meng. Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5249.

Controversy exists over the relationship between postoperative complications (POCs) and long-term survival for hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to evaluate the impact of POCs on overall survival (OS) and disease-free survival (DFS) for HCC after liver resection. The PubMed, EMBASE, and Cochrane Library databases were used to search for eligible studies published through 18 April 2020, and studies comparing the long-term outcomes between HCC patients with and without POCs after hepatectomy were included. A random-effects model was used to calculate the pooled hazard ratio (HR) with a 95% confidence interval (CI). Subgroup analysis and meta-regression were performed to assess the potential influence of study-, patient-, and tumor-related factors on the relationship between POCs and oncologic outcomes and to adjust their effect. This study was registered at the International Prospective Register of Systematic Reviews (CRD42019136109). Thirty-seven studies, including 14,096 patients, were deemed eligible and included in this study. Compared with those without POCs, patients who developed POCs had a significant reduction in OS (HR 1.39, 95% CI 1.28–1.50, P < 0.001; prediction interval 1.04–1.85) and tended to have worse DFS (HR 1.25, 95% CI 1.16–1.35, P < 0.001; prediction interval 0.98–1.60). Contour-enhanced funnel plots suggested a risk of publication bias. Subgroup analysis and meta-regression showed that POCs remained a threat to OS and DFS regardless of the influence of clinicopathological factors. This study demonstrated that POCs had an adverse impact on OS and DFS in HCC patients after liver resection.

In this article, from the perspective of rice processing loss, this paper proposes a method to evaluate the processing loss of rice produced by enterprises using data analysis. The specific content of this method is to build a fitting simulation model of unit power consumption and rice production rate based on production data of various types of enterprises across the country at different scales, equipment, and technological processes, thereby establishing a rice processing loss evaluation system; Based on the production data of the enterprise to be evaluated, an enterprise data fitting optimization model of unit power consumption and rice production rate was constructed; and the results of evaluation and diagnosis were combined with processing losses of rice processing enterprises. The application process of this evaluation method found the change law of unit power consumption and rice production rate in different dimensions, and gave evaluation conclusions and optimization plans for the evaluation of the production status of the enterprise. The application of this evaluation method to the grain industry can be a rice processing enterprise. Provide practical guidance on energy saving and consumption reduction during processing.

Jingyi He,1,2 Guangbing Li,1,2 Xihan Liu,3 Liye Ma,1,2 Jiayao Zhang,1,2 Shunzhen Zheng,1,2 Jianping Wang,1,2 Jun Liu1,2 1Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; 2Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; 3Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, ChinaCorrespondence: Jun LiuDepartment of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 324, Jing 5 Road, Jinan 250021, Shandong, ChinaTel +86 531 87925615Email dr_liujun1967@126.comPurpose: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant tumor characterized by high malignancy and poor prognosis. Although the efficacy of sorafenib against cholangiocarcinoma cell lines has been demonstrated in vivo and in vitro, limited clinical data are available on the efficacy of sorafenib in patients with cholangiocarcinoma. Sorafenib can enhance endoplasmic reticulum (ER) stress-mediated apoptosis, and ER stress and unfolded protein response are also the mechanisms by which cancer cells resist drug therapy. Mesencephalic astrocyte-derived neurotrophic factor (MANF), initially identified as a neurotrophic factor, can be regulated by ER stress activation. There are no available studies on the diagnostic value and therapeutic significance of MANF in ICC. Hence, the purpose of this study was to evaluate the role of MANF in cholangiocarcinoma, investigating the possibility of whether sorafenib could become a reliable strategy for cholangiocarcinoma therapy.Methods: In this study, the expression level of MANF in ICC patients was investigated by bioinformatic analysis and the results were verified by tissue microarray assay. Cholangiocarcinoma cell lines were also used to determine how MANF regulates the therapeutic effect of sorafenib and to identify the underlying mechanisms.Results: The results showed that MANF was correlated with poor prognosis and MANF knockdown could facilitate sorafenib-mediated apoptosis and increase the sensitivity of sorafenib treatment by activating excessive ER stress.Conclusion: MANF is a prognostic marker of cholangiocarcinoma. MANF knockdown increases sorafenib-mediated ER stress and apoptosis in the cholangiocarcinoma cell lines. This mechanism may lead to a new therapeutic strategy in cholangiocarcinoma.Keywords: intrahepatic cholangiocarcinoma, MANF, sorafenib, prognosis

We study consumption behavior, retirement decisions, and endogenous growth within a dynamic equilibrium when individuals have present-biased preferences. Compared to individual with exponential preferences, individual with hyperbolic preferences will choose to retire early for present-biased preferences but to delay retirement for the initial time preference rate. We extend the benchmark equilibrium model to age-dependent survival law and solve numerically the equilibrium effects. It shows that, at the same age, the consumption-capital ratio may have slightly positive effect on increasing life expectancy before retirement but has a significantly positive effect on it after retirement.

BACKGROUND Hepaticojejunostomy is a common biliary reconstruction procedure in hepatobiliary surgery. The suture technique plays a key role in the procedure. The conventional suture technique is complex and time-consuming. To facilitate the procedure, we performed it with a modified suture technique. In the present study, we evaluated the efficacy and safety of the technique in hepaticojejunostomy. MATERIAL AND METHODS We enrolled 120 adult patients who underwent hepaticojejunostomy. The patients were divided into a conventional group and a modified suture group according to the suture technique used. Clinical data were collected for analysis. RESULTS No significant differences were found between the 2 groups in terms of demographic data. No significant differences were found between the 2 groups in terms of serum bilirubin, albumin, AST, ALT, or hemoglobin (p>0.05). There were no significant differences between the 2 groups in terms of bile hemorrhage, fever, or cholangitis (p>0.05). The incidences of stenosis and cholelithiasis were similar in the 2 groups (p>0.05). The incidence of bile leakage was lower in the modified suture group than in the conventional group (p=0.04). The average bile duct diameter was 25±6 mm in the modified continuous suture group and 29±7mm in the conventional group, but the difference was not statistically significant (p=0.5). The duration of the anastomosis procedure was 15.4±4.4 min in the modified continuous suture group, which was shorter than in the conventional group (p

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and its prognosis is still poor. Mesencephalic astrocyte-derived neurotrophic factor (MANF) plays a key role in endoplasmic reticulum stress. ER stress plays a key role in HCC carcinogenesis. To confirm the clinical and prognostic value of MANF in HCC, we investigated the expression level of MANF in HCC as recorded in databases, and the results were verified by experiment. Survival analysis was probed by the Kaplan–Meier method. Cox regression models were used to ascertain the prognostic value of MANF in HCC tissue microarray. The diagnostic value of MANF in HCC was evaluated by receiver operating characteristic curve analysis. Potential correlation between MANF and selected genes was also analyzed. Results showed that MANF was overexpressed in HCC. Patients with high MANF expression levels had a worse prognosis and higher risk of tumor recurrence. Furthermore, the expression level of MANF had good diagnostic power. Correlation analysis revealed potential regulatory networks of MANF in HCC, laying a foundation for further study of the role of MANF in tumorigenesis. In conclusion, MANF was overexpressed in HCC and related to the occurrence and development of HCC. It is a potential diagnostic and prognostic indicator of HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer related death worldwide. However, the mechanisms underlying HCC progression and metastasis are still in obscure. Here, we used bioinformatic analysis to identify miRNAs that regulate GP73, a specific marker for HCC diagnosis and prognosis. The correlations between miR-141-3p and clinic-pathological factors were analyzed in HCC patient samples; proliferation, migration, invasion, and colony formation were studied using established HCC cell lines. Expression levels of target genes (miR-141-3p, GP73, E-cadherin, N-cadherin, occludin, vimentin, and cytokeratin 18) were detected by either Western blot or qRT-PCR analysis. Xenograft models were established to evaluate tumor growth and metastasis. MiR-141-3p was significantly reduced in HCC tumors and cell lines, highly correlated with tumor progression. In contrast, GP73 was negatively correlated with miR-141-3p in HCC tumors. MiR-141-3p overexpression significantly decreased HCC cell proliferation, migration, and invasion by inhibiting epithelial-mesenchymal transition (EMT). GP73 overexpression partially restored the inhibitory effects of miR-141-3p, while miR-141-3p overexpression markedly inhibited tumor growth and pulmonary metastasis, which were partially reversed by GP73 overexpression. Our findings suggest that miR-141-3p targets GP73 to reverse EMT, subsequently inhibiting HCC progression and metastasis. Thus, overexpression of miR-141-3p could serve as a therapeutic strategy to arrest HCC.

Background: Leucine zipper protein (LUZP) plays key roles in development. Overexpression of LUZP was documented in several types of solid tumors. In this study, expression of LUZP messenger RNA (LUZP mRNA) in human hepatocellular carcinoma (HCC) was examined, and the correlations of LUZP mRNA level with patients’ characteristics and prognosis were also investigated. Methods: Total RNA was extracted from HCC and paired noncancerous liver tissues of 77 patients. Expression of LUZP mRNA in the tissues was determined by real-time quantitative reverse transcriptase polymerase chain reaction. Using average LUZP mRNA level in noncancerous liver tissues as the cutoff, patients with HCC were categorized into high-expression group and low-expression group. Correlations of LUZP mRNA with clinical parameters were analyzed. Overall survival of the patients in the 2 groups was analyzed by Kaplan-Meier method. Results: The LUZP mRNA level was significantly higher in HCC samples than in the noncancerous liver tissues (1.87 ± 0.11 vs 0.58 ± 0.05, P < .01). Significant differences were found between the 2 groups in terms of portal vein invasion, Tumor Lymph Node Metastasis (TNM) stage, and recurrence of HCC. The current study failed to find significant differences between the 2 groups in clinical characteristics such as age, gender, lymph node metastasis, hepatitis B virus infection, family HCC history, and alcohol intake. Overall survival in high-expression group was 12 months while that in the low-expression group was 34 months ( P = .03). Conclusion: The LUZP mRNA is a prognostic indicator in HCC, and overexpression is associated with poor prognosis in patients with HCC.

The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration (LR) is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation, mainly by deactivating antioncogenes. However, in this work, we identified an unexpected role of Wip1 in LR. In contrast to its known role in promoting cell proliferation in extrahepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PHx). Deletion of Wip1 increased the rate of LR after PHx. Enhanced LR in Wip1-deficient mice was a result of the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mTOR. Interestingly, inhibition of Wip1 also activated the p53 pathway during LR. Disruption of the p53 pathway further enhanced LR in Wip1-deficient mice. Therefore, inhibition of Wip1 has a dual role in LR, i.e., promoting hepatocyte proliferation through activation of the mTORC1 pathway, meanwhile suppressing LR through activation of the p53 pathway. However, the proregenerative role of mTORC1 overwhelms the antiproliferative role of p53. Furthermore, CCT007093, a Wip1 inhibitor, enhanced LR and increased the survival rate of mice after major hepatectomy. Conclusion: mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. These findings have clinical applications in cases where LR is critical, including acute liver failure, cirrhosis, or small-for-size liver transplantations. (Hepatology 2015;61:2030-2041)

In this paper, we study the following quasilinear Schrodinger equations of the form \begin{eqnarray} -\Delta u+V(x)u-[\Delta(1+u^2)^{\alpha/2}]\frac{\alpha u}{2(1+u^2)^{(2-\alpha)/2}}=\mathrm{g}(x,u)， \end{eqnarray} where $1 \le \alpha \le 2$, $N \ge 3$, $V\in C(R^N, R)$ and $\mathrm{g}\in C(R^N\times R, R)$. By using a change of variables, we get new equations, whose respective associated functionals are well defined in $H^1(R^N)$ and satisfy the geometric hypotheses of the mountain pass theorem. Using the special techniques, the existence of positive solutions is studied.

Background & aims The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy. Methods A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174). Results The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort. Conclusions Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.

Hepatocellular carcinoma (HCC) is a primary cancer of the liver. Target therapy may improve prognosis of HCC. In the present study, we evaluated the inhibition of the Wnt/β-catenin pathway as a potential therapeutic approach. HepG2 cells were treated with the β-catenin inhibitor FH535. β-catenin protein expression was semi-quantitatively assessed using western blot analysis. Cell proliferation was examined with a 3‑(4,5-dimethyl-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay. The mRNA expression of nitric oxide synthase (iNOS) was detected by reverse transcription polymerase chain reaction. The Griess assay was used to determine nitric oxide (NO) concentration. FH535 inhibited the proliferation of HepG2 cells and decreased β-catenin protein expression. mRNA expression of iNOS, a target gene of the Wnt/β-catenin pathway, was decreased in FH535‑treated HepG2 cells compared to the control group. NO production was also reduced by FH535. In conclusion, the β-catenin inhibitor FH535 may inhibit HCC cell proliferation via downregulation of the Wnt/β-catenin pathway. Thus, targeting this pathway may be useful in HCC therapy.

Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Department of Liver Transplantation and Hepatobilliary Surgery, Provincial Hospital Affilliated to Shandong University, Jinan 250021, China; Bioinformatics Research Group, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China

Background and Objectives: Primary liver cancer (PLC) presenting as pyogenic liver abscess (PLA) is potentially life-threatening, but has been occasionally reported, especially for cholangiocarcinoma. Methods: Medical records of nine patients who presented as PLA, but were eventually confirmed as hepatocellular carcinoma (HCC; n ¼ 5) or intrahepatic cholangiocarcinoma (IHCC; n ¼ 4), from September 1997 through April 2011, were retrospectively reviewed. Results: Presenting symptoms included fever, chills, right-upper-quadrant abdominal pain, nausea, vomiting, weight loss, and diarrhea. Physical signs included tenderness in the right-upper-quadrant abdomen, jaundice, and ascites. With the exception of elevated alpha-fetoprotein (AFP) in HCC patients and elevated carbohydrate antigen 19-9 (CA19-9) in IHCC patients, lab results were not significantly different between these nine patients and PLA patients. All the nine patients underwent invasive treatment in addition to antibiotics. Conclusions: Elevated AFP and CA19-9 could suggest HCC and IHCC in patients with symptoms/signs typical of PLA. Contrast-enhanced computed tomography could be helpful in patients with normal AFP and CA19-9. Making an accurate and early diagnosis and seizing the opportunity of surgery are essential to improve the management strategies of patients with PLC mimicking PLA. J. Surg. Oncol. 2011 Wiley Periodicals, Inc.

Background and Aim: Serum Golgi protein 73 (sGP73) is a novel and promising biomarker for hepatocellular carcinoma (HCC). However, there are few reports on the pattern of GP73 expression in HCC and the relationship of this expression to clinicopathologic features of patients. This study aimed to investigate the expression of GP73 and it correlation with clinical parameters. Methods: We examined GP73 expression in HCC and adjacent paracarcinomatous liver (PCL) tissue in 36 HCC patients, and took 14 normal liver (NL) samples from hepatic hemangioma patients. Western blot analysis and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) were used for analyses. Results: GP73 expression in HCC was significantly higher than in the corresponding PCL and NL samples at both protein and mRNA levels (P

Many patients in China have portal hypertension secondary to liver cirrhosis. Splenectomy and devascularization have become an efficacious surgical procedure for portal hypertension, and has been recommended in China as the first choice for the treatment of portal hypertension for a long time. As a result of advances in laparoscopic equipment and techniques, splenectomy and esophagogastric devascularization have been carried out with laparoscope. From January 2012 to December 2017, 453 patients who were diagnosed with portal hypertension and serious gastroesophageal varices received surgical management in our institution. 250 patients chose laparoscopic splenectomy and esophagogastric devascularization and 203 underwent open splenectomy and esophagogastric devascularization. We retrospectively analyzed the perioperative data and follow-up data of these patients. The operation time of laparoscopic group was longer than open group (P ≤ .001). Intraoperative blood loss was less (P ≤ .001), the passing of flatus was earlier (P = .042), and postoperative hospital stay was shorter (P = .001) in the laparoscopic group. During postoperative follow-up of 4 to 75 months, the incidence of esophagogastric variceal rebleeding, encephalopathy, and secondary liver cancer showed no significant differences. Laparoscopic splenectomy and esophagogastric devascularization were safe and more effective than open surgery for portal hypertension and gastroesophageal varices.

Summary Hepatocellular carcinoma (HCC) is the second most common cause of cancer related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered a metabolic predisposition to liver cancer 1-5. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here, we show that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes leading to accelerated hepatocarcinogenesis. We also found that CD4+ T lymphocytes have greater mitochondrial mass than CD8+ T lymphocytes and generate higher levels of mitochondrially-derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4+ T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4+ T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumor surveillance.

Long noncoding RNAs (lncRNAs) have been attracting immense research interests. However, only a handful of lncRNAs had been thoroughly characterized. They were involved in fundamental cellular processes including regulation of gene expression at epigenetics as well as tumorogenesis. In this paper, we give a systematic and comprehensive review of existing literature about lncRNA involvement in hepatocellular carcinoma. This review exhibited that lncRNAs played important roles in tumorigenesis and subsequent prognosis and metastasis of hepatocellular carcinoma and elucidated the role of some specific lncRNAs such as MALAT1 and HOTAIR in the pathophysiology of hepatocellular carcinoma and their potential of being therapeutic targets.

Background Protein phosphatase magnesium-dependent 1δ (PPM1D) is an oncogene, overexpressed in many solid tumors, including ovarian cancer and breast cancer. The current study examined the expression and the prognostic value of PPM1D mRNA in human hepatocellular carcinoma (HCC). Methods Total RNA was extracted from 86 HCC and paired non-cancerous liver tissues. PPM1D mRNA expression was determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qPCR). Immunohistochemistry assay was used to verify the expression of ppm1d protein in the HCC and non-cancerous liver tissues. HCC patients were grouped according to PPM1D mRNA expression with the average PPM1D mRNA level in non-cancerous liver tissue samples as the cut-off. Correlations between clinicopathologic variables, overall survival and PPM1D mRNA expression were analyzed. Findings PPM1D mRNA was significantly higher in HCC than in the paired non-cancerous tissue (p

Serum Golgi protein 73 (sGP73) is a novel and promising biomarker for hepatocellular carcinoma (HCC). However, there are few reports on the pattern of GP73 expression in HCC and the relationship of this expression to clinicopathologic features of patients. This study aimed to investigate the expression of GP73 and it correlation with clinical parameters.We examined GP73 expression in HCC and adjacent paracarcinomatous liver (PCL) tissue in 36 HCC patients, and took 14 normal liver (NL) samples from hepatic hemangioma patients. Western blot analysis and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) were used for analyses.GP73 expression in HCC was significantly higher than in the corresponding PCL and NL samples at both protein and mRNA levels (P0.001). The elevated level of GP73 protein was strongly associated with tumor size, vein invasion, and tumor differentiation, suggesting augmented tumor invasion and metastasis. However, there was no association between GP73 expression and patient survival.Significant overexpression of GP73 at both protein and mRNA levels along with overexpression of GP73 protein is associated with aggressive behavior of HCC, but not overall patient survival. Further research is needed to determine the potential of GP73 as a therapeutic target.