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Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir., Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development., Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment., Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Dong, Cao, Zhang, Zhao, Shang, Zhang, Ma, Xie, Gui, Zhang, Liu, Shang, Xie, Liu, Zhang, Wang, Zhao and China HepB Related Fibrosis Assessment Research Group.)

Ethnopharmacological Relevance: The traditional use of Prunella vulgaris is for the treatment of liver cancer in a few areas of China. At present, it is used primarily for the treatment of thyroid cancer, throat cancer, and lymphosarcoma among others. However, there are few current scientific reports regarding its use for the treatment of liver cancer. In this paper, the effective treatment for liver cancer is studied to provide an experimental basis for the application of Prunella vulgaris, which is related to preparations in the treatment of liver cancer., Aim of the Study: To study the anti-hepatocarcinoma effect of Prunella vulgaris total flavonoids and explores the possible molecular mechanism., Methods: The effects of Prunella vulgaris total flavonoids on the proliferation of SMMC-7721 cells were respected by RTCA analysis system. The tumor volume and weight were found in H22 tumor bearing mice. ELISA was used to observe the apoptosis and autophagy protein expressions in tumor tissue homogenate, along with the immune serum factor. Tumor tissue apoptosis was respected by the TUNEL method. And Bax, Bcl2, PI3K, Akt, mTOR, Beclin-1 and LC3-I/LC3-II expression were observed through Western blot. We also observed the expression of Beclin-1 and LC3-I/LC3-II through immunohistochemistry., Results: The total flavonoids of Prunella vulgaris inhibited the activity of SMMC-7721 cells, and reduced the tumor volume and weight in H22 tumor bearing mice. HE staining showed that the Prunella vulgaris total flavonoids inhibited liver metastasis of H22 tumor. The Prunella vulgaris total flavonoids significantly made the expressions of IL-6, TNF-α and IFN-γ immune factors increasing in the serum of tumor bearing mice, and the contents of caspase-3 and caspase-9 increase as well in tumor tissue homogenate. TUNEL showed that the mean density in the intervention group was significantly higher than that in the control group. P62 content in tumor tissue homogenate increased and ATG5 decreased after intervention. Immunohistochemistry showed Beclin-1 expression decreased and LC3-I/LC3-II increased in the tumor tissue. Western blot showed Bcl2, Beclin-1 expression decreased and Bax, PI3K, Akt, mTOR, LC3-I/LC3-II increased in the tumor tissue., Conclusion: Prunella vulgaris total flavonoids have an obvious anti-hepatocarcinoma effect, and the mechanism may be linked to the inhibition of autophagy and promotion of apoptosis in liver cancer cells. The inhibition of autophagy may be related to activation of the PI3K/Akt/mTOR pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To assess the validity of contrast-enhanced ultrasonic parametric perfusion imaging in the evaluation of antiangiogenic tumor treatment by using histology as the reference standard., Materials and Methods: H22 hepatoma-bearing mice were treated with thalidomide or placebo by intraperitoneal injection. Contrast-enhanced ultrasound was performed on day 8 after bolus injection of SonoVue. Three different parametric perfusion images were calculated based on the following parameters: area under the curve (AUC), maximum intensity (IMAX) and perfusion index (PI). A score from 1 to 5 (1 = low, 5 = excellent) was used for analysis of parametric perfusion images by two independent readers. Immunohistochemical analysis was performed for evaluation of microvascular density (MVD)., Results: Treatment with thalidomide resulted in a significant decrease in perfusion scores assigned to AUC, IMAX and PI parametric images as compared with control tumors (P < 0.001). Immunohistochemistry showed significant decreases of MVD in treated tumors as compared with control tumors (P = 0.002). MVD was positively correlated with the perfusion scores assigned to AUC parametric images (r = 0.568, P = 0.009), IMAX parametric images (r = 0.614, P = 0.004) and PI parametric images (r = 0.636, P = 0.003)., Conclusion: Contrast-enhanced ultrasonic parametric perfusion imaging provides a noninvasive tool to directly visualize tumor perfusion changes after antiangiogenic tumor treatment., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: The purpose of this study was to quantify tumor blood perfusion with contrast-enhanced gray-scale ultrasound in the evaluation of tumor response to chemotherapy., Materials and Methods: Mice bearing H22 hepatoma were treated with cisplatin or placebo by intraperitoneal injection. Contrast-enhanced gray-scale ultrasound was performed on day 8 after bolus injection of a lipid-based ultrasound contrast agent. Regions of interest within the tumor were analyzed offline to determine area under the curve, maximum intensity, perfusion index, mean transit time, time to peak, and quality of fit. Immediately after imaging, mice were euthanized, and tumor tissue was removed for fixation in 10% formalin solution. Microvascular density was measured after anti-CD34 staining., Results: The volume of treated tumors was significantly smaller than that of control tumors (p < 0.001). Treatment with cisplatin resulted in a significant decrease in perfusion index and maximum intensity compared with control tumors (p < 0.05). There were no significant differences between control and treated tumors (p > 0.05) with respect to area under the curve, mean transit time, and time to peak. The microvascular density of treated tumors was significantly lower than that of control tumors (p < 0.001)., Conclusion: Quantitative analysis of tumor blood perfusion with contrast-enhanced ultrasound can be used for noninvasive assessment of functional changes in tumors after chemotherapy.

This study was to assess the changes in the haemodynamic parameters of the hepatic artery and vein in the diagnosis of liver metastases by contrast-enhanced ultrasound (CEUS). 52 patients with proven liver metastases (patient group) and 23 normal volunteers (control group) were recruited in this study. Each subject was administered an intravenous bolus injection of SonoVue (0.6 ml). The arrival time in the hepatic artery (AT HA), time to peak in the hepatic artery (TTP HA), peak intensity of the hepatic artery (PI HA), arrival time in the hepatic vein (AT HV), time to peak in the hepatic vein (TTP HV) and peak intensity of the hepatic vein (PI HV) were measured with the use of time-intensity curve software. The hepatic artery to vein transit time (HAVTT) was calculated as the difference between the arrival times in the hepatic artery and the hepatic vein. AT HA, TTP HA, AT HV, TTP HV and HAVTT in the patient group were significantly shorter than those of the control group (P<0.01). PI HA and PI HV in the patient group were significantly higher than those of the control group (P<0.01). These results suggest that CEUS assessment of changes in the haemodynamic parameters of the hepatic artery and vein help to diagnose liver metastases. This functional imaging technique may contribute to the early detection of micrometastases in the liver.

Integrin alpha 5 beta 1 and alpha 2 beta 1 are the major integrin receptors in human hepatocytes. However, in human hepatocellular carcinoma cells it was found that the expression of integrin alpha 5 beta 1 was decreased and another integrin alpha 6 beta 1 increased. In this study, the SMMC7721 human hepatocellular carcinoma cells cotransfected or singly transfected with integrin alpha 5 and/or beta 1 cDNAs were established, and designated alpha 5 beta 1.6-7721, alpha 5.3-7721, and beta 1.6-7721 cell lines, respectively. Transfection with cDNAs of integrin alpha 5 and beta 1 subunits resulted in the over expression of each integrin and modified biological properties, including a slowed growth rate, changes in the cell cycle from 15.5% of control cells in the G2/M phase to 12.1%, 9.6% and 9.4% in alpha 5.3-7721, beta 1.6-7721, alpha 5 beta 1.6-7721, respectively, and a decrease in the Cell Mitosis Index from 1.6 in controls to 0.96, 0.95, and 0.72, and 34%, 28% and 52% derived from colony forming ability, respectively. Tumorigenicity was also tested in nude mice with inoculation of cells subcutaneously. Tumor masses growing in nude mice following inoculation with beta 1.6-7721, and alpha 5 beta 1.6-7721 cells weighed only 52% or 31% those of control cells. These results indicated that deletion or low expression of integrin alpha 5 beta 1 may play an important role in the development of hepatocellular carcinoma. Therefore, induction of expression of the integrin alpha 5 beta 1 in malignant cells could be a potential means of treating hepatocellular carcinoma.