Effects of Lactobacillus paracasei N1115 on gut microbial imbalance and liver function in patients with hepatitis B-related cirrhosis.

BACKGROUND: Hepatitis B cirrhosis (HBC) is a chronic disease characterized by irreversible diffuse liver damage and aggravated by intestinal microbial imbalance and metabolic dysfunction. Although the relationship between certain single probiotics and HBC has been explored, the impact of the complex ready-to-eat Lactobacillus paracasei N1115 (LP N1115) supplement on patients with HBC has not been determined. AIM: To compare the changes in the microbiota, inflammatory factor levels, and liver function before and after probiotic treatment in HBC patients. METHODS: This study included 160 HBC patients diagnosed at the General Hospital of Ningxia Medical University between October 2018 and December 2020. Patients were randomly divided into an intervention group that received LP N1115 supplementation and routine treatment and a control group that received routine treatment only. Fecal samples were collected at the onset and conclusion of the 12-wk intervention period. The structure of the intestinal microbiota and the levels of serological indicators, such as liver function and inflammatory factors, were assessed. RESULTS: Following LP N1115 intervention, the intestinal microbial diversity significantly increased in the intervention group (P < 0.05), and the structure of the intestinal microbiota was characterized by an increase in the proportions of probiotic microbes and a reduction in harmful bacteria. Additionally, the intervention group demonstrated notable improvements in liver function indices and significantly lower levels of inflammatory factors (P < 0.05). CONCLUSION: LP N1115 is a promising treatment for ameliorating intestinal microbial imbalance in HBC patients by modulating the structure of the intestinal microbiota, improving liver function, and reducing inflammatory factor levels.

miR-199a/b-3p inhibits HCC cell proliferation and invasion through a novel compensatory signaling pathway DJ-1\Ras\PI3K/AKT.

Several studies have reported the effects of DJ-1 gene and miR-199a/b-3p on HCC development. However, whether miR-199a/b-3p regulates HCC progression through a novel compensatory signaling pathway involving DJ-1, Ras, and PI3K/AKT remains unknown. We used (TCGA, HPA, miRWalk and Target scan) databases, cancer and para-tissue HCC patients, dual-luciferase reporter gene analysis, proteomic imprinting, qPCR, cell proliferation, scratch, transport, and flow cytometry to detect the molecular mechanism of DJ-1 and miR-199a/b-3p co-expression in HCC cell lines. Bioinformatics analysis showed that DJ-1 was highly expressed in HCC ((P < 0.001) were closely associated with tumor stage (T), portal vein vascular invasion, OS, DSS, and PFI (P < 0.05); miR-199a/b-3p was lowly expressed in HCC (P < 0.001), which was the upstream regulator of DJ-1. Spearman coefficient r = -0.113, P = 0.031; Dual luciferase gene report verified the negative targeting relationship between them P< 0.001; Western blotting demonstrated that miR-199a/b-3p could inhibit the protein expression of DJ-1, Ras and AKT(P < 0.05); The results of CCK8, cell scratch, Transwell migration and flow cytometry showed that OE + DJ-1 increased the proliferation, migration and invasion ability of HepG2 cells, and decreased the apoptosis process, and the differences were statistically significant (P < 0.05), while miR-199a/b-3p had the opposite effect (P < 0.05).

Prognostic value of systemic immune-inflammation index/ albumin for transcatheter arterial chemoembolization treatment.

Background and objective: In the process of tumor occurrence, evolution and development, immune, inflammation and nutrition are principal elements. The purpose of this study was to assess the prognostic value of systemic immune-inflammation index/albumin (SII/ALB) for patients with HBV-related hepatocellular carcinoma (HCC) who underwent transcatheter arterial chemoembolization (TACE). Methods: A total of 125 HBV-related HCC patients met inclusion criteria and were all enrolled in this research. The survminer R package. was used to calculate the best SII/ALB cutoff values. Chi-square test was used to analyze the relationship between SII/ALB and clinicopathological parameters. Kaplan-Meier curves and Cox proportional hazards models were used to investigate the effect of SII/ALB on overall survival (OS). Results: The cutoff value of SII/ALB was 2.992. In the derivation cohort, the patients were divided into SII/ALB-low (SII/ALB≤2.992) and SII/ALB-high (SII/ALB >2.992) groups. SII/ALB-high was found in patients with tumor size ≥3 (cm), white blood cell ≥3.5 (109/L), platelet ≥100 (109/L), neutrophils ≥1.8 (109/L), PT ≥ 14(s), SII ≥100, NLR ≥1.50 and PLR ≥60, (P < 0.05). The Kaplan-Meier curves showed that elevated SII/ALB were associated with decreased OS. OS rate of SII/ALB-low and SII/ALB-high groups at 1 and 2 years were 96.6% vs. 70.3% and 87.8% vs. 48.5%, respectively (C2 = 9.804, P = 0.002). The BCLC stage, tumor number, tumor size, vascular invasion, AST, SII/ALB, SII, NLR and PNI were all significant prognostic indicators of OS. The SII/ALB (HR: 17.98; 95%CI: 1.82-177.32) and tumor size (HR: 3.26; 95%CI: 1.27-8.35) were all independent prognostic factors for OS, (p < 0.05).Conclusion: we found that SII/ALB could be an important prognostic parameter for HBV-related HCC patients after TACE treatment.

Whether the Golgi protein 73 could be a diagnostic serological marker in hepatocellular carcinoma: a meta analysis.

BACKGROUND: The Value of Golgi protein 73 (GP73) in the diagnosis of Hepatocellular carcinoma (HCC) remains controversial, especially in its differentiation between HCC and cirrhosis. Besides, some papers showed that GP73 levels are correlated with liver fibrosis. This study conducts a meta-analysis to evaluate the value of GP73 in diagnosing HCC and differential diagnosing HCC from liver cirrhosis. METHODS: 36 studies with a sample size of 8314 cases concerning the accuracy of GP73 in the diagnosis of HCC were selected through a systematic review. Seven of these studies included a total of 438 HCC samples and 426 cirrhosis samples and calculated the sensitivity and specificity of GP73 for differential diagnosing HCC from cirrhosis. QUADAS (quality assessment of diagnostic accuracy studies) was used to evaluate the quality of literature. Statistical analyses were performed using StataSE16 software. RESULTS: The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and the area under the curve were 0.79(95%CI 0.74-0.83),0.85(95%CI 0.80-0.89),5.4(95%CI 3.8-7.5), 0.25(95%CI 0.20-0.31), 22(95%CI 13-35), and 0.88 for GP73 diagnosing HCC;0.74(95%CI 0.64-0.81),0.70(95%CI 0.49-0.85),2.40(95%CI 1.3-4.7),0.38(95%CI 0.23-0.61),6(95%CI 2-19), and 0.78 for GP73 differential diagnosing HCC from liver cirrhosis. CONCLUSION: The results suggest that GP73 has a high diagnostic value for HCC and a moderate value for differential diagnosis of HCC from liver cirrhosis.

The role of butyrylcholinesterase in the regulation of cognitive dysfunction in minimal hepatic encephalopathy: A potential blood marker of disease evolution.

Background and aims: Patients with cirrhosis commonly experience minimal hepatic encephalopathy (MHE), and alterations in neurotransmitters have been thought to be related to cognitive function. However, the relationship between alterations in peripheral and central butyrylcholinesterase (BuChE) with MHE disease progression remains unknown. As such, this study was designed to investigate potential changes in peripheral and central BuChE activity and their effects on cognitive function in the context of MHE. Materials and methods: We enrolled 43 patients with cirrhosis secondary to hepatitis B, 20 without MHE and 23 with MHE, and 25 with healthy controls (HC). All the selected subjects underwent resting-state functional MRI, and the original images were processed to obtain the regional homogeneity (ReHo) brain maps. Thereafter, the correlation of BuChE activity with ReHo, number connection test of type A (NCT-A), and digital symbol test (DST) scores with MHE patients were analyzed using Person correlation analysis. Meanwhile, we purchased 12 Sprague-Dawley (SD) rats and divided them into an experimental group (n = 6) and a control group (n = 6). The rats in the experimental group were intraperitoneally injected with thioacetamide (TAA) to prepare MHE model rats. After modeling, we used the Morris water maze (MWM) and elevated plus maze (EPM) to assess the cognition function and exploratory behavior of all rats. The activity of serum, hippocampus, and frontal lobe tissue BuChE was detected by ELISA. Results: BuChE activity gradually decreased among the HC, patients with cirrhosis, and MHE groups (all P < 0.01). We observed a linear correlation between serum BuChE and NCT-A and DST scores in MHE patients (all P < 0.01). We noted that BuChE activity can negatively correlate with ReHo values in the left middle temporal gyrus and left inferior temporal gyrus, and positively correlate with ReHo values in the right inferior frontal gyrus, and also found that the peripheral BuChE activity of MHE rats was significantly lower than their control counterparts, and the BuChE activity in frontal lobe extracts was significantly higher than the control rats (all P < 0.05). Conclusion: The altered activity of BuChE may contribute to cognitive impairment in MHE patients, which may be a potential biomarker of disease evolution in the context of MHE.

Decreased brain noradrenaline in minimal hepatic encephalopathy is associated with cognitive impairment in rats.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a common neuropsychiatric complication in patients with cirrhosis. Alterations in monoamine neurotransmitters have been associated with the pathogenesis of MHE. We investigated the levels of hippocampal noradrenergic neurotransmitter in a rat model of thioacetamide-induced chronic liver failure-related MHE, and their role in cognitive impairment. MATERIALS: 18 male Sprague-Dawley (SD) rats were equally divided in MHE and control groups. A rat model of MHE was established by intraperitoneal injection of thioacetamide (TAA) for 12 weeks. Cognitive function was assessed using the Morris water maze (MWM) test and locomotor activity and exploratory behavior assessed with open field test. The concentration of hippocampal noradrenaline (NE) was detected by ELISA, and the magnetic susceptibility value in the hippocampus was detected by quantitative susceptibility mapping. Hippocampal iron content was quantified by Prussian blue staining. RESULTS: MHE rats performed significantly poorer than their control counterparts in the MWM test, as seen by decreased number of platform crossings and time in the target quadrant, and increased path length to reach the target zone (P < 0.05 for all parameters). In the open field test, the MHE group exhibited lower locomotor activity and exploratory behavior than the control group (P < 0.05 for all parameters). We detected pronounced iron staining in the hippocampus of MHE rats, whereas no iron-stained particles were found in control rats. We observed an imbalance of inflammatory (increased pro- and decreased anti-) cytokines in the hippocampus of MHE rats. Further analysis of the data showed that the level of hippocampal noradrenaline in MHE rats was significantly lower than that of control rats (P < 0.05). We observed a correlation between the level of inflammatory cytokine and noradrenaline land susceptibility value in the rat hippocampus of the MHE group. CONCLUSION: Our results suggest that MHE associated with TAA-induced chronic liver failure is associated with alterations in noradrenergic neurotransmission. We propose that iron imbalance in the brain might lead to reduction in the levels of noradrenaline, and cognitive impairment.

LncRNA FLJ33360 accelerates the metastasis in hepatocellular carcinoma by targeting miRNA-140/MMP9 axis.

This study aims to detect expression level of long non-coding RNA (lncRNA) FLJ33360 in hepatocellular carcinoma (HCC) and its regulatory effects on accelerating malignant progression of HCC. Expression levels of FLJ33360 in 29 matched HCC tissues and paracancerous tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection of sh-FLJ33360#1 in Bel-7402 and HepG2 cells, changes in migratory and invasive capacities were evaluated by Transwell and wound healing assay. Potential miRNAs targeting FLJ33360 were verified. The correlation between expression levels of FLJ33360 and miRNA-140 in HCC tissues was determined. At last, potential influences of FLJ33360/miRNA-140 regulatory loop on HCC phenotypes were determined by rescue experiments. FLJ33360 was upregulated in HCC tissues relative to paracancerous ones. After knockdown of FLJ33360, migratory and invasive capacities in Bel-7402 and HepG2 cells were attenuated. There were five miRNA candidates predicted to bind FLJ33360, and miRNA-140 was the most differentially expressed by FLJ33360 regulation. Dual-luciferase reporter gene assay confirmed the binding between FLJ33360 and miRNA-140. Besides, their expression levels were negatively correlated in HCC tissues. Moreover, knockdown of miRNA-140 could stimulate metastatic ability in HCC. At last, rescue experiments verified the involvement of miRNA-140 in FLJ33360-regulated HCC progression. LncRNA FLJ33360 is upregulated in HCC. It accelerates the metastasis of HCC through targeting miRNA-140/MMP9 axis.

A Meta-analysis of the Value of vWF in the Diagnosis of Liver Cirrhosis with Portal Hypertension.

Background and Aims: Studies have indicated that serum von Willebrand factor (vWF) has a positive correlation with hepatic venous pressure gradient. However, information on the value of vWF in the diagnosis of liver cirrhosis with portal hypertension has been lacking. The purpose of this meta-analysis was to assess the value of vWF in the diagnosis of liver cirrhosis with portal hypertension. Methods: Studies that analyzed the sensitivity, specificity, diagnostic odds ratio combined with likelihood ratios and test for heterogeneity of vWF in the diagnosis of liver cirrhosis with portal hypertension were found in the Cochrane Library, Ovid, VOS-SCI, CNKI, PubMed, Medline, EMBASE, CMB and Wanfang databases. In the end, the data was used to draw the summary receiver operating characteristic curve and to calculate the area under the curve. Results: Four studies involving 662 patients were analyzed. The results showed that serum vWF in liver cirrhosis with portal hypertension were significantly higher than in those without portal hypertension. Sensitivity combined was 0.823 (95% CI: 0.788, 0.855). Specificity combined was 0.782 (95% CI: 0.708, 0.845). +LR combined was 3.777 (95% CI: 2.794, 5.107). -LR combined was 0.221 (95% CI: 0.180, 0.272). Diagnostic odds ratio combined was 18.347 (95% CI: 11.725, 28.708). The area under the curve was 0.8896. Conclusions: Serum vWF can be used as an effective and feasible method for noninvasive diagnosis of liver cirrhosis with portal hypertension. However, further studies are still needed to evaluate the severity of liver cirrhosis with portal hypertension.

Value of gamma-glutamyltranspeptidase-to-platelet ratio in diagnosis of hepatic fibrosis in patients with chronic hepatitis B.

AIM: To investigate the value of the gamma-glutamyltraspeptidase (GGT)-to-platelet (PLT) ratio (GPR) in the diagnosis of hepatic fibrosis in patients with chronic hepatitis B (CHB). METHODS: We included 390 untreated CHB patients in this study. The GPR, aspartate aminotransferase (AST)-to-PLT ratio index (APRI), and fibrosis-4 (FIB-4) of all patients were analysed to determine if these parameter were correlated with age, gender, medical history, liver function [total bilirubin (TBil), alanine aminotransferase (ALT), and AST], GGT, PLT count, or hepatic fibrosis stage. The GPR, APRI, and FIB-4, as well as the combination of the GPR and APRI or the GPR and FIB-4 were assessed in different cirrhosis stages using receiver operating characteristic (ROC) curve analysis to evaluate their value in diagnosing hepatic fibrosis in CHB patients. RESULTS: The GPR, APRI, and FIB-4 were not correlated with CHB patients' age, gender, or disease duration (P > 0.05), but all of these parameters were positively correlated with serum ALT, AST, GGT, and PLT count (P < 0.01). Additionally, the GPR, APRI, and FIB-4 were positively correlated with hepatic fibrosis (P < 0.01); the areas under the ROC curve for the GPR in F1, F2, F3, and F4 stages were 0.723, 0.741, 0.826, and 0.833, respectively, which were significantly higher than the respective values for the FIB-4 and APRI (F1: 0.581, 0.612; F2: 0.706, 0.711; F3: 0.73, 0.751; and F4: 0.799, 0.778). The respective diagnostic cut-off points for each stage were 0.402, 0.448, 0.548, and 0.833, respectively. The diagnostic sensitivity and specificity were, respectively, 88.8% and 87.5% in F1, 72.7% and 89.7% in F2, 81.3% and 98.6% in F3, and 80% and 97.4% in F4 when the GPR and APRI were connected in parallel; 86.6% and 90.2%, 78.4% and 96%, 78.6% and 97.4%, and 73.2% and 97.9%, respectively, when the GPR and APRI were connected in series; 80.2% and 89%, 65% and 89%, 70.3% and 98.5%, and 78.8% and 96.8%, respectively, when the GPR and FIB-4 were connected in parallel; and 83.6% and 87.9%, 76.8% and 96.6%, 72.7% and 98%, and 74.4% and 97.7%, respectively, when the GPR and FIB-4 were connected in series. CONCLUSION: The GPR, as a serum diagnostic index of liver fibrosis, is more accurate, sensitive, and easy to use than the FIB-4 and APRI, and the GPR can significantly improve the sensitivity and specificity of hepatic fibrosis diagnosis in CHB when combined with the FIB-4 or APRI.

Assessment of high-sensitivity C-reactive protein tests for the diagnosis of hepatocellular carcinoma in patients with hepatitis B-associated liver cirrhosis.

Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, with high morbidity and mortality. Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma and the majority (~80%) of hepatocellular carcinoma patients in China exhibit co-morbidity with HBV-associated liver cirrhosis. The goal of reliable early diagnostic and prognostic techniques for HBV-associated HCC remains unrealized. The aim of the present study was to explore the efficacy of serum high-sensitivity C-reactive protein (hs-CRP) tests in the early diagnosis of HCC in patients with HBV-associated liver cirrhosis. A cohort of 493 patients with HBV-associated liver disease was divided into three groups: Chronic HBV (CHB) group; liver cirrhosis without HCC (LC) group; and liver cirrhosis with HCC (HCC) group. A further 47 healthy individuals comprised the healthy control (CN) group. Comparative analyses of clinical symptoms, histopathology, ultrasound imagery, computed tomography, magnetic resonance imaging, biochemistry [α-fetoprotein (AFP) and liver function enzymes], and hs-CRP tests were conducted across these four groups. Immunohistochemical analysis showed that CRP is strongly expressed in HCC tumor tissue, but is not expressed elsewhere. Analyses of the correlations between serum hs-CRP levels and HCC clinical parameters indicated that there was no correlation between serum hs-CRP levels, tumor Edmondson grade, tumor-node-metastasis stage and AFP status. Serum hs-CRP and AFP levels were found to be significantly elevated in the HCC group compared to those in the LC, CHB and CN groups (P<0.01). Receiver operator characteristic analysis showed that measurement of serum hs-CRP could differentiate HCC from HBV-associated liver cirrhosis, as well as increase the accuracy of HCC diagnoses. Additionally, measurement of hs-CRP and AFP together improved diagnostic accuracy for HCC compared with either test alone. Serum hs-CRP could have potential as an effective diagnostic tool to complement AFP in diagnosing HCC and improving the identification of AFP-negative HCC in patients with HBV-associated liver cirrhosis. The present findings may facilitate the earlier diagnosis of hepatocellular carcinoma, permitting more effective treatment and a broader spectrum of treatment modalities for patients with advanced hepatic disease.

LHBs can elevate the expression of MDR1 through HIF-1α in patients with CHB infection: a comparative proteomic study.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). To gain a better understanding of the pathogenesis of HBV infection, this study aimed to investigate the differentially expressed proteins (DEPs) in liver tissues from patients with chronic hepatitis B (CHB) infection. RESULTS: Seventy-one DEPs were identified. Overexpression of multi-drug resistance protein 1 (MDR1) was validated by RT-qPCR and western blot analyses. Moreover, its expression was increased at both the mRNA and protein levels in response to overexpression of HBV large surface protein (LHBs). Furthermore, screening of transcription factors suggested the possible involvement of hypoxia-inducible factor 1α (HIF-1α) in the interaction between LHBs and MDR1. The function of HIF-1α in the MDR1 activation was confirmed by EMSA and reporter gene analyses. MATERIALS AND METHODS: Liver samples from CHB patients and controls without HBV infection were collected and subjected to isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometric analysis. CONCLUSIONS: These results imply that LHBs, in association with HIF-1α, induces MDR1 overexpression, which may contribute to the pathogenic changes in CHB infection.

Combined detection of liver stiffness and C-reactive protein in patients with hepatitis B virus-related liver cirrhosis, with and without hepatocellular carcinoma.

The aim of the present study was to investigate the usefulness of combined detection of liver stiffness (LS) and serum C-reactive protein (CRP) level in patients with hepatitis B virus (HBV)-related liver cirrhosis (LC). A total of 156 cases of previously untreated patients with HBV-related LC were classified into the LC group [LC without hepatocellular carcinoma (HCC)] and the HCC group (LC with HCC). Comparative analyses of LS and serum CRP level were conducted between these two groups. LS values and serum CRP levels were found to be significantly higher in the HCC group compared with those in the LC group (P<0.01). The LS values and serum CRP levels were not significantly different between α-fetoprotein (AFP)-positive and -negative patients. A high LS value was a high-risk factor for HCC in patients with chronic hepatitis B. The CRP-positive rate was significantly higher in the HCC group compared with that in LC group in a subset of patients with high LS values (P<0.01). In conclusion, the combined detection of LS and serum CRP may complement the measurement of AFP in the diagnosis of HBV-related HCC, improve the identification of patients with AFP-negative HCC and help distinguish HCC from LC.

[Clinical significance of high-sensitivity C-reactive protein in development of chronic hepatitis B].

OBJECTIVE: To explore the clinical significance of high-sensitivity C-reactive protein (hsCRP) in the development of chronic hepatitis B (CHB). METHODS: A total of 182 patients with untreated CHB and 50 healthy individuals (controls) participated in the study. Correlation analysis was performed to determine the association of serum hs-CRP with the age,sex,medical history,serum hepatitis B virus (HBV) DNA, liver function parameters,liver stiffness measure (LSM) and hepatic fibrosis; in addition, correlation analysis was carried out for the associations of degree of liver damage with grade of hepatic fibrosis, LSM and the serum levels of hs-CRP. RESULTS: CHB patients showed significantly higher serum hs-CRP levels than healthy controls (2.38 ± 2.79 vs.0.78 ± 1.07; t =2.495, P < 0.05). Serum hs-CRP levels were significantly correlated with HBV DNA (r = 0.159), liver function parameters (total bilirubin, r = 0.271; alanine aminotransferase, r = 0.298; aspartate aminotransferase, r = 0.389), and LSM, r = 0.562) (all P < 0.05). The correlations with liver function (r = 0.340), LSM (r = 0.292) and hepatic fibrosis grade were positive (r = 0.434) (all P < 0.01). CONCLUSION: Serum hs-CRP levels in CHB patients can reflect degree of liver damage and of liver fibrosis.

A quantitative proteomics study on olfactomedin 4 in the development of gastric cancer.

Gastric cancer (GC) is now one of the most common malignancies with a relatively high incidence and high mortality rate. The prognosis is closely related to the degree of tumor metastasis. The mechanism of metastasis is still unclear. Proteomics analysis is a powerful tool to study and evaluate protein expression in tumor tissues. In the present study, we collected 15 gastric cancer and adjacent normal gastric tissues and used the isobaric tags for relative and absolute quantitation (iTRAQ) method to identify differentially expressed proteins. A total of 134 proteins were differentially expressed between the cancerous and non-cancerous samples. Azurocidin 1 (AZU1), CPVL, olfactomedin 4 (OLFM4) and Villin 1 (VIL1) were upregulated and confirmed by western blot analysis, real-time quantitative PCR and immunohistochemical analyses. These results were in accordance with iTRAQ. Furthermore, silencing the OLFM4 expression suppressed the migration, invasion and proliferation of the GC cells in vitro. The present study represents a successful application of the iTRAQ method in analyzing the expression levels of thousands of proteins. Overexpression of OLFM4 in gastric cancer may induce the development of gastric cancer. Overall, suppression of OLFM4 expression may be a promising strategy in the development of novel cancer therapeutic drugs.

C-reactive protein is a biomarker of AFP-negative HBV-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide and is associated with the high rates of morbidity and mortality. α-fetoprotein (AFP) is common used in diagnosis of HCC; however, a growing body of research is questioning the diagnostic power of AFP. There is, therefore, an urgent need to develop additional novel non-invasive techniques for the early diagnosis of HCC, particularly for patients with AFP-negative [AFP(-)] HCC. Accordingly, in the present study, we employed iTRAQ-based mass spectro-metry to analyze the plasma proteins of subjects with AFP(-) HBV-related HCC, AFP(+) HBV-related HCC and non-malignant cirrhosis. We identified 14 aberrantly expressed proteins specific to the HCC patients, including 10 upregulated and 4 downregulated proteins. We verified C-reactive protein (CRP) overexpression by ELISA and immunohistochemical staining of clinical samples. Per ROC curve analyses, CRP was positive in 73.3% of patients with HBV-related HCC, and CRP overexpression had significant diagnostic power for AFP(-) HBV-related HCC. Furthermore, we found that silencing CRP caused a >2-fold decease in HBV replication. Additionally, we determined that this reduction in HBV replication involved the interferon-signaling pathway. However, silencing CRP also promoted HCC invasion and migration in vitro. In conclusion, we demonstrated that CRP can serve as a diagnostic biomarker for AFP(-) HBV-related HCC.

[Diagnostic value of liver stiffness measurement combined with serum high-sensitivity C-reactive protein detection in HBV-related cirrhosis patients complicated with primary liver cancer].

OBJECTIVE: The aim of this study was to explore the diagnostic value of liver stiffness measurement combined with serum high-sensitivity C-reactive protein detection in HBV-related cirrhosis patients complicated with primary liver cancer. METHODS: A total of 156 previously untreated chronic hepatitis B-related cirrhosis patients and 50 healthy subjects were included in this study. The 156 patients were divided into two groups: those with primary liver cancer (67 cases) and without liver cancer (89 cases). The 50 healthy subjects were considered as normal control group. Liver stiffness measurement (LSM) was conducted and serum high-sensitivity C-reactive protein (CRP) level was assayed in all the 156 patients and 50 normal individuals, and their measurement values were statistically compared and analyzed. RESULTS: The LSM value was (39.72±29.05) kPa in the liver cancer patients, significantly higher than the (27.81±18.46) kPa in the cirrhosis alone patients and (4.25±0.74) kPa in the healthy controls (P<0.01 for both). Serum hs-CRP levels in the liver cancer patients was 5.81mg/L, significantly higher than 1.78 mg/L in the cirrhosis alone patients and 0.38mg/L in healthy controls, (P<0.01 for both). The higher the grade of LSM values was, the positive rate of CRP was higher in the cirrhosis patients complicated with primary liver cancer. In patients with LSM values ≥27.6 kPa, the serum CRP positive rate was 64.2% in patients with primary liver cancer, significantly higher than the 38.0% in patients with cirrhosis alone (P<0.01). In the 67 HBV-related cirrhosis patients complicated primary liver cancer, the LSM value and serum hs-CRP level in AFP-positive patients were (48.95±28.59) kPa and 4.91 mg/L, respectively, higher than those in the AFP-negative patients (28.64±26.83) kPa and 4.16 mg/L, but with a non-significant difference (P>0.05). CONCLUSION: Liver stiffness measurement combined with serum high-sensitivity C-reactive protein detection may have potential diagnostic implications as a marker of primary liver cancer occurrence in patients with HBV-related cirrhosis.

Serum high-sensitivity C-reactive protein are associated with HBV replication, liver damage and fibrosis in patients with chronic hepatitis B.

BACKGROUND/AIMS: The aim of this study was to explore the potential role of serum high-sensitivity C-reactive protein (hs-CRP) in the pathogenic process of chronic hepatitis B. METHODOLOGY: A total of 380 patients with chronic hepatitis B were included in this study. All patients received the concentrations of serum hs-CRP, Hepatitis B sero-markers, serum HBV-DNA loads, liver function parameters and liver stiffness were measured, and in which 172 patients undertaken liver biopsy and immunohistochemistry analysis. RESULTS: Serum hs-CRP concentration in patients with the chronic hepatitis B (2.38 ± 5.52) was significantly higher than healthy controls (0.60 ± 0.53), P < 0.05. The area under ROC curve in fibrosis S4 and S3 is 0.826 and 0.78. The sensitivity and specificity of hs-CRP for fibrosis S3 and S4 diagnosis were 81.8%, 80% and 73.4%, 76.2% respectively (cut off: 1.01 mg/ml, 1.11 mg/l). CONCLUSIONS: C-reactive Protein are associated with HBV replication, liver damage and fibrosis in patients with chronic hepatitis B, and serum High-sensitivity C-reactive Protein may be a marker for diagnosing significant fibrosis in patients with chronic hepatitis B, and can reflect the severity of liver damage.

The efficacy of lamivudine prophylaxis against hepatitis B reactivation in breast cancer patients undergoing chemotherapy: a meta-analysis.

BACKGROUND/PURPOSE: Lamivudine has been recommended as prophylaxis for the reactivation of hepatitis B virus (HBV) infection in patients undergoing chemotherapy. However, information on breast cancer patients in particular has been lacking. The purpose of this meta-analysis was to assess the overall efficacy of lamivudine prophylaxis compared to untreated patients with hepatitis B S-antigen (HBsAg) seropositive breast cancer who had undergone chemotherapy. METHODS: Studies that compared the efficacy of treatment with lamivudine prophylaxis versus no prophylaxis in HBsAg seropositive breast cancer patients were identified through Medline, Cochrane, and Embase databases. RESULTS: Six studies involving 499 patients were analyzed. The rates of HBV reactivation in patients with lamivudine prophylaxis were significantly lower than those with no prophylaxis (risk ratio [RR] = 0.23, 95% confidence interval [CI]: 0.13-0.39, p < 0.00001). Patients given lamivudine prophylaxis had significant reductions in the rates of hepatitis attributable to HBV compared with those not given treatment (RR = 0.20, 95% CI: 0.08-0.47, p = 0.002). The rates of moderate and severe hepatitis in patients with lamivudine prophylaxis were significantly lower compared with those patients who had not received prophylaxis (RR = 0.25, 95% CI: 0.10-0.62, p < 0.003; RR = 0.25, 95% CI: 0.10-0.59, p = 0.002). Patients given lamivudine prophylaxis had significantly fewer disruptions of chemotherapy (RR = 0.36, 95% CI: 0.21-0.64, p = 0.0004). There was no significant heterogeneity in the comparisons. CONCLUSION: Lamivudine prophylaxis in HBsAg seropositive breast cancer patients undergoing chemotherapy is effective in reducing HBV reactivation and HBV-associated morbidity and mortality.

Changes in glucose-6-phosphate dehydrogenase expression results in altered behavior of HBV-associated liver cancer cells.

Hepatocellular carcinoma (HCC) is regarded as a major global health care issue, and chronic hepatitis B virus (HBV) infection is considered to be involved in pathogenesis of HCC. To increase knowledge of HCC pathogenesis, as well as discover potential novel molecules for anti-cancer therapy, mass spectrometry and isobaric tag for relative and absolute quantitation (iTARQ) were employed. The differences between nine HBV-related HCC and adjacent non-HCC tissue specimens were studied. In total, 222 proteins were analyzed for differential expression in the two types of samples. Among these proteins, several were further confirmed by immunohistochemical, immunoblotting, and real-time RT-PCR analysis. RNA interference induced downregulation of glucose-6-phosphate dehydrogenase (G6PD) and decreased HBV replication by fivefold by the IFN pathway. Decreased G6PD expression resulted in decreased hepatoma cell migration and invasion in cell culture. In summary, the investigation provides new information on pathogenesis of HBV infection and suggests G6PD as a novel anti-HCC target. G6PD suppression may contribute to treatment strategies for inhibiting tumor progression.