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Background. Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function and high short-term mortality. Clusterin, with biological functions similar to small heat shock proteins, can protect cells from apoptosis induced by various stressors. The aim of this study was to detect the level of serum clusterin in hepatitis B virus- (HBV-) related ACLF and to assess the predictive value of clusterin for the short-term prognosis of HBV-ACLF. Methods. We detected serum clusterin by ELISA in 108 HBV-ACLF patients, 63 HBV-non-ACLF patients, and 44 normal controls. Results. Serum clusterin was markedly lower in HBV-ACLF patients (median, 51.09 μg/mL) than in HBV-non-ACLF patients (median, 188.56 μg/mL) and normal controls (median, 213.45 μg/mL; allP<0.05). Nonsurviving HBV-ACLF patients who died within 90 days had much lower clusterin levels than did surviving patients, especially those who died within 28 days (nonsurvival group vs. survival group:39.82±19.34vs.72.26±43.52,P<0.001; survivaltime≤28vs. survivaltime>28: median 28.39 vs. 43.22,P=0.013). The results showed that for identifying HBV-ACLF, the sensitivity of clusterin (93.7%) was similar to the sensitivities of the international normalized ratio (INR; 94.4%) and total bilirubin (TBIL; 94.8%), but its specificity (90.7%) was higher than that of prothrombin activity (PTA; 65.8%) and TBIL (69.8%) and was similar to INR (88.9%). As the concentration of clusterin increased, the mortality of HBV-ACLF patients decreased significantly from 59.3% to 7.0%. Clusterin had better ability for predicting the prognosis of HBV-ACLF patients than did the model for end-stage liver disease (MELD) score and the chronic liver failure consortium (CLIF-C) ACLF score (MELD vs. clusterin:P=0.012; CLIF-C ACLF vs. clusterin:P=0.031). Conclusion. Serum clusterin is a potential biomarker for HBV-ACLF which can be used to assess clinical severity and the short-term prognosis of patients with this disease and may help clinicians identify HBV-ACLF with greater specificity and improved prognostic accuracy than existing prognostic markers.

Background. To compare the efficacies of transcatheter arterial chemoembolization (TACE) with radiofrequency ablation (RFA) (TACE + RFA) and TACE alone in patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI). Methods. In total, 664 patients having HCC with MVI were included. Of these patients, 141 were treated with TACE + RFA, 254 with TACE alone, and 269 with supportive therapy (control group). The overall survival (OS) was compared among these groups. Propensity score matching (PSM) was performed for balancing the characteristics of the three groups. Results. After one-to-one PSM, the 12-month OS rates were higher in the TACE and TACE + RFA groups than in the control group (p=0.0009 and p=0.0017, respectively). Furthermore, higher 12-month OS rates were observed in the TACE + RFA group than in the TACE group (p=0.0192). The 12-month OS rates of patients were remarkably higher in α-fetoprotein (AFP) p=0.0122, p=0.0090, p=0112, and p=0.0071, respectively). Conclusions. TACE + RFA provides a superior survival outcome than TACE alone in HCC patients, especially in AFP

Long non-coding RNAs (lncRNAs) have been identified as critical players in tumorigenesis. Previous studies revealed that lncRNA SBF2-AS1 was involved in tumor progression. However, the role and underlying mechanism of SBF2-AS1 in cervical cancer (CC) remain unknown. In the present study, our data showed that SBF2-AS1 expression was significantly increased in CC. High SBF2-AS1 expression was associated with advanced FIGO stage and lymph node metastasis of CC patients. Function assays showed that SBF2-AS1 inhibition significantly reduced CC cells proliferation both in vitro and in vivo. Mechanistically, we showed that SBF2-AS1 upregulation restrained the activity of miR-361-5p and led to overexpression of FOXM1 in CC cells. Furthermore, we found that miR-361-5p inhibitors could rescue the effects of SBF2-AS1 inhibition on CC cells proliferation. Taken together, we demonstrated that the SBF2-AS1/miR-361-5p/FOXM1 axis might play an important role in CC progression. SBF2-AS1 might serve as a potential therapeutic target for CC treatment.

Background The current definitions and etiologies of acute-on-chronic liver failure (ACLF) are clearly very different between East and West. Aims This study aimed to develop an effective prognostic nomogram for acute-on-chronic hepatitis B liver failure (ACHBLF) as defined by the Asia Pacific Association for the Study of the Liver (APASL). Methods The nomogram was based on a retrospective study of 573 patients with ACHBLF, defined according to the APASL, at the Beijing Ditan Hospital. The results were validated using a bootstrapped approach to correct for bias in two external cohorts, including an APASL ACHBLF cohort (10 hospitals, N = 329) and an EASL-CLIF ACHBLF cohort (Renji Hospital, N = 300). Results Multivariate analysis of the derivation cohort for survival analysis helped identify the independent factors as age, total bilirubin, albumin, international normalized ratio, and hepatic encephalopathy, which were included in the nomogram. The predictive value of nomogram was the strongest compared with CLIF-C ACLF, MELD and MELD-Na and similar to COSSH-ACLF in both the derivation and prospective validation cohorts with APASL ACHBLF, but the CLIF-C ACLF was better in the EASL-CLIF ACHBLF cohort. Conclusions The proposed nomogram could accurately estimate individualized risk for the short-term mortality of patients with ACHBLF as defined by APASL.

IntroductionOvarian cancer (OC) is the malignant tumor with the highest mortality among gynecological cancers. Chemotherapy resistance is a major obstacle to OC therapy. Circular RNAs (circRNAs) play crucial roles in cancer development and chemoresistance. However, the role and potential mechanism of has-circ-001567 (circ-VPS13C) in chemoresistance of OC remain unknown.Material and methodsThe levels of circ-VPS13C, miR-106b-5p and 14-3-3 zeta (YWHAZ) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell Counting Kit-8 (CCK-8) assay was used to assess cell viability and calculate the half inhibition concentration (IC50) of cisplatin (DDP). The levels of autophagy-related markers were measured by western blot assay. Cell apoptosis and migration were evaluated by flow cytometry and transwell assay, respectively. The binding relationship between miR-106b-5p and circ-VPS13C or YWHAZ was confirmed by dual-luciferase reporter assay. Xenograft assay was performed to explore the role of circ-VPS13C in vivo.ResultsCirc-VPS13C and YWHAZ were up-regulated, while miR-106b-5p was down-regulated in DDP-resistant OC tissues and cells. Knockdown of circ-VPS13C enhanced DDP sensitivity by repressing autophagy in DDP-resistant cells. Circ-VPS13C increased DDP resistance via sponging miR-106b-5p. Moreover, miR-106b-5p directly targeted YWHAZ. Up-regulation of YWHAZ alleviated the decrease in DDP resistance caused by circ-VPS13C depletion. In addition, circ-VPS13C silencing decreased DDP resistance in vivo.ConclusionsCirc-VPS13C knockdown enhanced DDP sensitivity of OC through modulation of autophagy via the miR-106b-5p/YWHAZ axis, providing a new biomarker for improving the efficacy of OC chemotherapy.

Gardeniae Fructus (Zhizi in Chinese, ZZ in brief), a commonly used herbal medicine, has aroused wide concern for hepatotoxicity, but the mechanism remains to be investigated. This study was aimed at investigating the mechanism of ZZ-induced liver injury in vivo and in vitro based on metabolomics and evaluating the hepatotoxicity prediction ability of the in vitro model. SD rats were administered with extracted ZZ and HepG2 cells were treated with genipin, the major hepatotoxic metabolite of ZZ. Liver, plasma, intracellular and extracellular samples were obtained for metabolomics analysis. As a result, ZZ caused plasma biochemical and liver histopathological alterations in rats, and induced purine and amino acid metabolism disorder in the liver and pyrimidine, primary bile acids, amino acid metabolism and pantothenate and CoA biosynthesis disorder in the plasma. Pyrimidine, purine, amino acid metabolism and pantothenate and CoA biosynthesis were also found to be disturbed in the genipin-treated HepG2 cells, which exhibited similarity with the result in vivo. This study comprehensively illustrates the underlying mechanism involved in ZZ-related hepatotoxicity from the aspect of metabolome, and provides evidence that identifying hepatotoxicity can be achieved in cells, representing a non-animal alternative for systemic toxicology.

Diabetic coronary heart disease (DM-CHD) poses a major threat to the world. The newly described T cell subset-Th9 cells and related cytokine interleukin (IL)-9 play important roles in the pathogenesis of diabetes and atherosclerosis. B lymphocyte-induced maturation protein 1 (Blimp-1) has been indicated to negatively regulate Th9 development in allergic asthma, but its role in DM-CHD remains unclear. Hence, this study was designed to investigate the role of Blimp-1 in DM-CHD and to elucidate whether the mechanism was associated with regulation of Th9 cell differentiation. Our results showed that serum Blimp-1 mRNA level was decreased whereas proportion of Th9 cells (IL-9+ CD4+ T cells) and serum level of Th9-related IL-9 were increased in DM-CHD patients. Furthermore, serum Blimp-1 mRNA level was negatively correlated with IL-9 level in DM-CHD patients. Importantly, administration of lentiviruses expressing Blimp-1 (LV-Blimp-1) significantly inhibited Th9 cell differentiation and alleviated the severity of atherosclerotic lesions in the aorta and coronary artery, dyslipidemia, inflammation, vascular endothelial dysfunction, and oxidative stress in DM-CHD model rats. Collectively, Blimp-1 exerts a protective effect in DM-CHD rats and the mechanism might involve inhibition of Th9 cell differentiation.

Mounting evidence indicates that long non-coding RNAs influence the progression of cervical cancer, but the precise function of LINC01503 in the pathogenesis of the disease remains unknown. Here, we found higher levels of LINC01503 in cervical cancer tissues. High LINC01503 expression was associated with enhanced progression of cervical cancer as indicated by advanced FIGO stage, increased metastasis of tumor cells to lymph nodes, and invasion into deeper cervical tissues. LINC01503 inhibition markedly suppressed the invasion and proliferative ability of tumor cells. Mechanistically, LINC01503 was demonstrated to negatively modulate the expression of miR-615-3p in cervical cancer. CCND1 was found to be a target of miR-615-3p. Rescue experiments indicated that LINC01503 inhibition suppressed the invasion and proliferative ability of the tumor cells, a phenomenon that was reversed following miR-615-3p inhibition or CCND1 overexpression. Collectively, these data indicate that LINC01503 enhances the progression of cervical cancer cells via interaction with miR-615-3p/CCND1 axis.

Background Probiotic therapy has been shown to be beneficial against some liver diseases. However, there is still uncertainty regarding the clinical efficacy of probiotics for the treatment of variceal rebleeding. This research explored the efficacy of probiotics in variceal rebleeding. Material/Methods This was a retrospective study of 704 consecutive patients with liver cirrhosis who recovered from esophagogastric variceal bleeding after endoscopic treatment. Patients were subdivided into a probiotics cohort (n=214) and a non-probiotics cohort (n=490) based on the cumulative defined daily dose (cDDD) of probiotics received during follow-up. Propensity score matching was utilized to obtain a relatively balanced cohort of 200 patients per group for the analysis. Patients were monitored for rebleeding during the one-year follow-up. Results Multivariate Cox regression analysis revealed that probiotic therapy (≥28cDDD) was an independent protector against rebleeding (AHR=0.623; 95% CI=0.488–0.795; P90 cDDD groups, respectively; P=0.011). The median rebleeding interval in the probiotics cohort (n=95) was significantly longer than that in the non-probiotics cohort (n=261) (147.0 vs. 91.0 days; P

Exosomes are cell-derived, phospholipid bilayer-enclosed vesicles that play important roles in intercellular interactions and regulate many biological processes. Accumulating evidence suggests that serum exosomes are potential biomarkers for the early diagnosis of cancer. To aid the downstream molecular analyses of tumour-secreted exosomes, purified exosomes are highly desirable. However, current techniques for exosome isolation are time-consuming and highly instrument-dependent, with limited specificity and recovery. Thus, rapid and efficient methods are strongly needed for both basic research and clinical applications. Here, we present a novel strategy for facile exosome isolation from human serum by taking advantage of the specific interaction of TiO2 with the phosphate groups on the lipid bilayer of exosomes. Due to their simplicity and highly affinitive binding, model exosomes can be reversibly isolated with a high recovery (93.4%). Downstream characterization and proteome profiling reveal that high-quality exosomes can be obtained from human serum by this TiO2-based isolation method in 5 min, which is a fraction of the time required for the commonly used ultracentrifugation method. We identified 59 significantly up-regulated proteins by comparing the serum exosomes of pancreatic cancer patients and healthy donors. In addition to the 30 proteins that were reported to be closely related to pancreatic cancer, we found an additional 29 proteins that had not previously been shown to be related to pancreatic cancer, indicating the potential of this novel method as a powerful tool for exosome isolation for health monitoring and disease diagnosis.

Background Acute decompensation (AD) has been shown to be associated with a high mortality rate for cirrhosis patients. This study aimed to develop a prognostic nomogram to evaluating the individual prognosis for AD of cirrhosis in chronic hepatitis B (CHB). Methods The nomogram was developed using data from a retrospective study on 509 patients hospitalized for AD of CHB cirrhosis from October 2008 to February 2014 at the Beijing Ditan Hospital, Capital Medical University. The predictive accuracy, discriminative ability, and clinical net benefit were evaluated by concordance index (C-index), calibration curves, and decision curve analysis (DCA). The results were validated on 620 patients consecutively enrolled from January 2005 to December 2010 at the Renji Hospital, Shanghai Jiao Tong University,. Results On multivariate analysis of the derivation cohort, independent factors included in the nomogram were age, previous decompensation, bacterial infection, hepatic encephalopathy, and total bilirubin. The calibration curve for the probability of survival showed good agreement between the nomogram and actual observation. The nomogram had a C-index of 0.897, which was statistically higher than the C-index values of CTP (0.793), MELD (0.821), SOFA (0.868), or the Chronic Liver Failure Consortium AD (CLIF-C AD) (0.716) scores (p

Background. Portal vein tumor thrombosis (PVTT) is one of the major predictive factors for patients with hepatocellular carcinoma (HCC). The objective of this study was to establish a prognostic nomogram for identifying individual survival outcomes in patients with HCC and PVTT on conservative treatment based on specific factors. Methods. Two hundred and ten patients with HCC and PVTT on conservative treatment in Beijing Ditan Hospital between June 2008 and May 2017 were studied retrospectively as a derivation cohort. We built a nomogram based on independent risk factors for survival prediction. The concordance index (c-index) and a calibration curve were used to evaluate the predictive accuracy. During the study, 102 patients were included at the Putuo Hospital and Third People’s Hospital of Changzhou as a validation cohort. Results. In the derivation cohort, the independent factors for overall survival were identified by multivariate analysis, namely, aspartate aminotransferase ≥119 IU/L, gamma-glutamyl transferase ≥115 IU/L, Child–Pugh class C liver function, creatinine ≥91 μmoI/L, α-fetoprotein ≥400 ng/ml, and largest tumor diameter ≥5 cm. The nomogram had a c-index of 0.737 (95% confidence interval, 0.692–0.782) and the calibration curves fitted well. The median survival time was 4.2 months in the derivation cohort, with an MST of 5 months for BCLC C stage and 1.8 months for BCLC D stage patients. Kaplan–Meier analysis showed significant statistical differences in the 6-month overall survival rates of the primary and validation cohorts after the total scores were divided into three quartiles (low risk: 0–85; intermediate risk: 86–210; high risk: ≥211; p<0.0001 in both cohorts). Conclusions. The nomogram can be a more accurate and individualized prediction for 6-month overall survival of patients with HCC and PVTT on conservative treatment, and it is possible to consider further active interventions for patients in the low-risk group (0–85 scores) to achieve the aim of prolonging survival.

Background Hepatocellular carcinoma (HCC) is a common malignant tumor with limited treatment options. Conventional antitumor therapy combined with traditional Chinese medicine (TCM) to limit tumor progression has gradually become the focus of complementary and alternative therapies for HCC treatment. The Fuzheng Jiedu Xiaoji formulation (FZJDXJ) alleviates the clinical symptoms of patients and inhibits tumor progression, but its curative effect still requires extensive clinical research and mechanistic analysis. Purpose To explore the effectiveness of FZJDXJ in HCC patients and investigate its biological function and mechanism underlying anticancer therapy. Methods This randomized controlled clinical trial enrolled 291 HCC patients receiving transcatheter arterial chemoembolization (TACE) therapy; patients received either FZJDXJ combined with standard treatment, or standard treatment alone, for 48 weeks. Statistical analyses were performed according to survival time at the end of the trial. The main constituents of the FZJDXJ extracts were identified and evaluated using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and molecular docking. The antitumor effects of FZJDXJ and its specific biological mechanism of action were studied. Results After 48 weeks of treatment, one-year overall survival (OS) and progression-free survival (PFS) were significantly different between the two groups. Co-administration of FZJDXJ and TACE prolonged the OS of HCC patients, especially in BCLC A or B stage. FZJDXJ and TACE treatment effectively extended the PFS of patients, especially in the BCLC B stage. HPLC-MS/MS identified 1619 active constituents of FZJDXJ, including formononetin, chlorogenic acid (CGA), caffeic acid, luteolin, gallic acid, diosgenin, ergosterol endoperoxide, and lupeol, which may function through the AKT/CyclinD1/p21/p27 pathways. Through molecular docking, CGA and gallic acid could effectively combine with Thr308, an important phosphorylation site of AKT1. FZJDXJ inhibited tumor growth in nude mice. In vitro, FZJDXJ-mediated serum inhibited the proliferation, migration, and invasion of liver cancer cells, and promoted cell apoptosis. Conclusion Clinically, FZJDXJ combined with TACE therapy significantly prolonged OS and PFS and reduced the mortality rate of HCC patients. Mechanistically, FZJDXJ effectively inhibited the proliferation and migration of liver cancer cells through the modulation of the AKT/CyclinD1/p21/p27 pathways, and may be a promising TCM drug for anti-HCC therapy.

Macroscopic vascular invasion cannot be properly predicted in advance in hepatocellular carcinoma patients based on clinical characteristics and imaging features. To develop a predictive scoring model of macroscopic vascular invasion in hepatocellular carcinoma patients after transcatheter arterial chemoembolization combined with radiofrequency ablation based on specific laboratory and tumor indicators. A predictive scoring model, which estimates the incidence of macroscopic vascular invasion at 1-year follow-up, was constructed based on a derivation cohort of 324 patients with hepatocellular carcinoma; a validation cohort of 120 patients was prospectively included. The prognostic value of the scoring model was determined by concordance index, time-dependent receiver operating characteristics, and calibration curves. Cox multivariate analysis of the derivation cohort identified prothrombin time, aspartate aminotransferase, and Barcelona clinic liver cancer (BCLC) staging as independent predictive factors of macroscopic vascular invasion. The areas under the receiver operating characteristic curves of the predictive scoring model were 0.832 and 0.785 in the derivation and validation cohorts, respectively, and the calibration curves fitted well. Kaplan–Meier analysis showed that the incidence of macroscopic vascular invasion was significantly higher in the high-risk group (score 0–2) than in the low-risk group (score 3–4) in both the derivation and validation cohorts (P

Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3'-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity.

Aim The CANONIC study proposed the Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C ACLF) prognostic model at the European Association for the Study of the Liver-CLIF diagnosis. This study aimed to develop and validate a prognostic model for predicting the short-term mortality of hepatitis B virus (HBV) ACLF as defined by the Asia-Pacific Association for the Study of the Liver. Patients and methods A retrospective cohort of 381 HBV ACLF patients and a prospective cohort of 192 patients were included in this study. Independent predictors of disease progression were determined using univariate and multivariate Cox proportional hazard regression analysis, and a regression model for predicting prognosis was established. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank tests. The area under the receiver operating characteristic curve was used to compare the performance of various current prognostic models. Results Our model was constructed with five independent risk factors: hepatic encephalopathy, international normalized ratio, neutrophil-lymphocyte ratio, age, and total bilirubin, termed as the HINAT ACLF model, which showed the strongest predictive values compared with CLIF-C ACLF, CLIF-C Organ Failure, Sequential Organ Failure Assessment, CLIF-Sequential Organ Failure Assessment, Model for End-stage Liver Disease, Model for End-stage Liver Disease-sodium, and Child-Turcotte-Pugh scores; this model reduced the corresponding prediction error rates at 28 and 90 days by 16.4-54.5% after ACLF diagnosis in both the derivation cohort and the validation cohorts. Conclusion The HINAT ACLF model can accurately predict the short-term mortality of patients with HBV ACLF as defined by Asia-Pacific Association for the Study of the Liver.

// Xue Yang 1 , Xieqiong Ye 1 , Le Sun 2 , Fangyuan Gao 1 , Yuxin Li 1 , Xiaomin Ji 1 , Xuejiang Wang 3, 4 , Ying Feng 1 and Xianbo Wang 1 1 Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China 2 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China 3 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China 4 Beijing Key Laboratory for Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, China Correspondence to: Xianbo Wang, email: wangxb@ccmu.edu.cn Ying Feng, email: ann_fengying@sina.com Keywords: RAB27B, PI3K/AKT, p21, cell proliferation, hepatocellular carcinoma Received: November 09, 2016 Accepted: April 25, 2017 Published: May 19, 2017 ABSTRACT Previous study revealed that elevated expression of RAB27B in tissues is correlated with hepatocellular carcinoma (HCC) progression; however, the mechanisms involved in promoting HCC development are still unclear. Moreover, HCC tissues are not readily obtained during routine diagnosis. Therefore, to further explore its potential value in early diagnosis, we examined RAB27B expression in patient sera. First, the correlation between serum RAB27B expression and survival, as well as TNM and Barcelona Clinic Liver Cancer stages, were evaluated in patients with HCC. Second, lentiviral vector plasmids carrying interference sequences and plasmids harboring the complete open reading frame of RAB27B were designed to knockdown or overexpress RAB27B in BEL7402 or HuH-7 cells to determine its biological function. Compared with healthy controls and patients with chronic hepatitis B infection, serum RAB27B was significantly increased in patients with HCC. After down-regulating expression of RAB27B, the proliferation of BEL7402 cells was remarkably inhibited both in vitro and in vivo . Additionally, activation of the PI3K/AKT pathway was significantly diminished. Moreover, cell cycle progression of the knockdown cells was notably arrested in the G1/S phase, and upregulation of p21 contributed to this effect. Restoration experiments to recover RAB27B expression revealed opposing results. These findings indicated RAB27B might regulate cell cycle through the PI3K/AKT/p21 pathway by releasing cytokines via exocytosis, thereby modulating the proliferation of HCC cells. RAB27B could potentially be a valuable serum biomarker for the early diagnosis of, and a therapeutic target in, HCC.

Aim Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) has significant morbidity and mortality. There is no standard approach for the management of HBV-related ACLF with nucleos(t)ide analogs. Our objective was to compare the short-term mortality between entecavir (ETV) and lamivudine (LAM) in patients with HBV-related ACLF. Methods We recruited 311 inpatients with HBV-related ACLF from December 2002 to January 2015. The patients were treated with ETV (n=143) or LAM (n=168). The primary endpoint was mortality rate at week 8. Virological and biochemical responses were also studied. Results By week 8, 53 (37.06%) patients in the ETV group and 57 (33.93%) patients in the LAM group died, and the two groups had similar mortality (P=0.414). Multivariate analysis showed that age, total bilirubin, international normalized ratio, and model for end-stage liver disease (MELD) score were independent factors for mortality at week 8. The best cut-off value of the MELD score was 24.5 for 8-week mortality. Twenty-nine of the 170 (17.06%) patients with MELD score less than 24.5 died at week 8, and the ETV and LAM groups had similar mortality (P=0.743). Eighty-one of the 141 (57.45%) patients with MELD score of at least 24.5 died at week 8 and the LAM group had lower mortality than the ETV group (P=0.018 at week 4; P=0.039 at week 8). Both groups showed similar virological and biochemical responses at 4 weeks. Conclusion LAM reduces the 8-week mortality rate significantly in patients with HBV-related ACLF who had MELD score of at least 24.5.

Epigenetic modulation is an important mechanism of miRNA dysregulation in cervical cancer. In this study, we firstly studied how this mechanism contributes to miR-375 downregulation in cervical cancer cells. Then, we further studied the association between miR-375 and MALAT1 (metastasis associated lung adenocarcinoma transcript 1) in epithelial mesenchymal transition (EMT) of the cancer cells. HPV-16 positive SiHa and CaSki cells were used as in vitro model. Our data showed that HPV-16 E6 positively modulated DNMT1 expression in both SiHa and CaSki cells. Knockdown of DNMT1 partly restored miR-375 levels in the cells. The following methylation-specific PCR (MSP) assay and qRT-PCR analysis showed that methylation was common in the promoter region of miR-375 in both SiHa and CaSki cells and demethylation partly restored miR-375 levels in the cells. Therefore, we infer that miR-375 is downregulated partly due to promoter hypermethylation mediated by DNMT1 in HPV-16 positive cervical cancer cells. Our bioinformatics analysis showed that MALAT1 has three putative binding sites with miR-375 and the following dual luciferase assay confirmed two of them. QRT-PCR analysis showed that miR-375 overexpression significantly reduced MALAT1 expression, while MALAT1 overexpression reversely suppressed miR-375 levels. Therefore, we infer that there is a reciprocal regulation between miR-375 and MALAT1 in the cells. In SiHa cells, miR-375 overexpression or MALAT1 siRNA partly restored E-cadherin expression, significantly reduced N-cadherin and also reduced invasion capacity of SiHa cells. Therefore, these results suggest that miR-375 and MALAT1 form a functional axis modulating EMT in cervical cancer.

MiR-21 is an important microRNA (miRNA) modulating radiosensitivity of cervical cancer cells. However, the underlying mechanism of miR-21 upregulation in radioresistant cervical cancer has not been fully understood. In addition, autophagy may either promote or alleviate radioresistance, depending on the types of cancer and tumor microenvironment. How autophagy affects radiosensitivity in cervical cancer and how miR-21 is involved in this process has not been reported. This study showed that miR-21 upregulation in radioresistant cervical cancer is related to HIF-1α overexpression. MiR-21 overexpression decreases PTEN, increases p-Akt, and subsequently increases HIF-1α expression, while miR-21 inhibition results in increased PTEN, decreased p-Akt, and then decreased HIF-1α. Therefore, we inferred that there is a HIF-1α-miR-21 positive feedback loop through the PTEN/Akt/HIF-1α pathway in cervical cancer cells. In addition, we also demonstrated that miR-21 confers decreased autophagy in cervical cancer cells after IR via the Akt-mTOR signaling pathway. Decreased autophagy is one of the potential mechanisms of increased radioresistance in cervical cancer cells. These findings expand our understanding of radioresistance development in cervical cancer.

The neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with prognosis in various types of cancer. We evaluated pretreatment NLR as a predictor of poor prognosis in patients with hepatocellular carcinoma (HCC), and we compared the prognostic value of NLR with other prognostic scores.We retrospectively analyzed 825 patients diagnosed with HCC between October 2008 and May 2012. Baseline data, including the NLR and the Child-Pugh class or Model for End-Stage Liver Disease (MELD) score, were recorded before treatment. The relationships between overall survival (OS) and the study variables were assessed using univariate and multivariate analyses and receiver operating characteristic (ROC) curves. The prognostic value of NLR was assessed using a Kaplan-Meier survival analysis and compared with that of the Barcelona-Clinic Liver Cancer (BCLC) and Tumor, Node, Metastasis (TNM) staging.The NLR, γ-glutamyltranspeptidase, α-fetoprotein ≥ 400 ng/mL, tumor number ≥ 3, tumor size ≥ 5 cm, lymph node metastasis, portal vein involvement, and Child-Pugh class were significantly associated with OS. The NLR demonstrated the strongest prognostic value (area under ROC curve = 0.811). An NLR ≥ 2.7 was a significant predictor of poor OS (P < 0.0001), and the survival period of patients with an NLR ≥ 2.7 decreased with more advanced BCLC and TNM stage.Pretreatment NLR is a useful prognostic biomarker in HCC patients. The prognostic value of NLR ≥ 2.7 is superior to that of MELD stage or Child-Pugh class, and correlates with that of BCLC and TNM staging scores.

Background The purpose of this study was to develop an effective nomogram capable of estimating the individual survival outcomes of patients with hepatocellular carcinoma (HCC), and compare the predictive accuracy and discriminative ability with other staging systems. Methods The nomogram was established based on a retrospective study of 661 patients newly diagnosed with HCC at the Beijing Ditan Hospital (Beijing, China), Capital Medical University, between October 2008 and July 2012. The predictive accuracy and discriminative ability of the previously developed nomogram were assessed by C-index and calibration curves, and were compared to seven current commonly used staging systems. The results were validated, using a bootstrap approach to correct for bias, in a prospective study of 220 patients consecutively enrolled between August 2012 and March 2013. Results Multivariate analysis of the primary cohort for survival analysis identified the independent factors to be aspartate aminotransferase, ɣ-glutamyl transpeptidase, white blood cell count, neutrophil-to-lymphocyte ratio, prothrombin activity, α-fetoprotein, tumor number and size, lymph node metastasis, and portal vein involvement, which were all included to build the nomogram. The calibration curve for predicting the probability of survival showed consistency between the nomogram and the actual observation. The C-index of the nomogram was 0.81 (95% confidence interval, 0.79–0.82), which was statistically better than that of the Tumor, Node, Metastasis staging (0.71), Barcelona Clinic Liver Cancer staging (0.77), Okuda (0.62), Japan Integrated Staging (0.73), Cancer of the Liver Italian Program score (0.76), Chinese University Prognostic Index (0.68), and the Groupe d’ Etude et de Traitement du Carcinome Hepatocellulaire Prognostic classification (0.65) (p