Congestive hepatopathy (CH) is a hepatic vascular disease that results in chronic liver congestion, which can lead to liver fibrosis. New uses of metformin have been discovered over the years. However, the function of metformin in congestive liver fibrosis is not yet fully understood. This study aimed to investigate the effect of metformin on liver fibrosis in a mouse model of CH. Partial ligation of the inferior vena cava (pIVCL) was used to establish a mouse model of liver congestion. Metformin (0.1%) was added to the daily drinking water of the animals, and the effect of metformin on liver tissue was studied after 6 weeks. Hepatic stellate cells (HSCs) were also stimulated with CoCl2 to investigate the inhibitory impact of metformin on the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) pathway. Metformin attenuated liver congestion; decreased the expression of collagen, fibronectin, α-smooth muscle actin (α-SMA), and HIF-1α; and ameliorated liver fibrosis in pIVCL mice. The proliferation and migration of HSCs were inhibited by metformin in vitro, which prevented α-SMA expression and restrained HSC activation. The expression levels of phosphorylated-mTOR, HIF-1α, and vascular endothelial growth factor were also decreased. Metformin inhibits CH-induced liver fibrosis. Functionally, this beneficial effect may be the result of inhibition of HSC activation and of the mTOR/HIF-1α signaling pathway.
Abstract BackgroundHepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignant tumors in the world, and its recurrence and mortality rate are still in high level. In recent years, more and more inhibitors against gene targets have been found to be beneficial to survival. However, the function of homo-sapiens histone H3 associated protein kinase (GSG2) in HCC has not been completely understood. MethodsThe expression of GSG2 in HCC tissues was detected by immunohistochemical staining. The lentivirus-mediated short hairpin RNA (shRNA) was used to knockdown GSG2 expression in HCC cell lines Hep3B2.1-7 and SK-HEP-1. Cell proliferation and colony formation were detected by MTT assay and colony formation assay, respectively, and flow cytometry assay was used to investigate the cell apoptosis in vitro . Mice xenograft model was constructed to detect the functions of GSG2 on tumor growth in vivo . Human Apoptosis Antibody Array was conducted to find the possible mechanism.ResultsGSG2 was overexpressed in HCC tissues compared with adjacent normal tissues, which was positively related to the tumor pathological stage. The knockdown of GSG2 has the functions of inhibiting the progression of HCC, including inhibiting cell proliferation and colony formation and promoting cell apoptosis. Compared with shCtrl group, the shGSG2 group expressed higher apoptotic genes such as caspase 3, caspase 8, Fas and FasL, while lower IGF1, Bcl2 and Bcl-w. ConclusionsOur study showed that knockdown of GSG2 suppresses the tumor growth in vitro and vivo . Therefore, GSG2 might play an oncogenic role in HCC.
Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE).129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety.A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78–1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed.Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies.ClinicalTrials.gov: NCT01387555
Hepatocellular carcinoma (HCC) is the main type of primary liver cancer and shows a heavy burden worldwide. Its recurrence and mortality rate are still uncontrolled by the usage of present treatments. More attention has been focused on exploring specific genes that play important roles in HCC procession, and the function of DEP domain containing 1B (DEPDC1B) in HCC has not been researched.
Objectives The health-related quality of life (HRQoL) and utilities of patients with chronic hepatitis B (CHB) virus infection, including compensated cirrhosis (CC), decompensated cirrhosis (DC) and different stages of hepatocellular carcinoma (HCC), have not been well described in China. This study aimed to evaluate HRQoL and utilities and provide parameters for the economic evaluation of CHB-related diseases. Methods We conducted a multicentre cross-sectional and study to measure the HRQoL of patients with CHB, CC, DC and HCC using the Chinese short form (SF) 36 health survey V.2. The utilities were extracted based on the SF-six dimension scoring model. Multivariable regression analyses identified the effects on HRQoL. Results A total of 1071 patients (639 with CHB, 125 with CC, 85 with DC and 222 with HCC) were invited to complete the questionnaire. Physical HRQoL was not impaired in the CHB stage, while mental HRQoL was significantly impaired. Physical composite summary scores have a more significant decrease than mental composite summary scores at the advanced stages (CC, DC and HCC). The utility scores of CHB only, CC, DC and HCC were 0.773, 0.750, 0.683 and 0.640, respectively. The utility scores in the early, middle and terminal stages of HCC were 0.656, 0.635 and 0.615, respectively. Conclusion Slowing the progress of CHB-related diseases and providing psychological support early are the key points to improving the quality of life with the diseases. The utility values estimated in this study can provide a vital instrument for cost-effectiveness studies on CHB-related diseases.
Primary hepatic neuroendocrine tumors (PHNETs), a group of neuroendocrine neoplasms, are extremely rare. There are only few case reports about PHNETs in the literature. The lack of large samples and multicenter research results in poor diagnostic and therapeutic approaches.To discuss the clinical characteristics, diagnosis, and treatment of PHNETs and risk factors related to survival.We retrospectively analyzed the clinical data, imaging features, immunohistochemistry data, and treatment efficacy of 40 patients who were pathologically diagnosed with PHNETs and admitted to The First Affiliated Hospital of Zhengzhou University from January 1, 2014 to November 15, 2019. Finally, survival analysis was performed to identify the risk factors for survival.The main symptoms and signs included intermittent abdominal pain (19 patients, 47.5%) and bloating (8 patients, 20.0%). The positive rates of tested tumor markers were recorded as follows: Carbohydrate antigen 19-9 (CA19-9) (6 patients, 15.0%), CA72-4 (3 patients, 7.5%), carcinoembryonic antigen (7 patients, 17.5%), and alpha-fetoprotein (6 patients, 15.0%). Immunohistochemical staining results showed positivity for Syn in 38 (97.4%) of 39 patients, for chromogranin A in 17 (65.4%) of 26 patients, for CD56 in 35 (94.6%) of 37 patients, for AE1/AE3 in 28 (87.5%) of 32 patients, and for Ki-67 in all 40 (100.0%) patients. The overall survival rate was significantly related to the tumor grade, AE1/AE3, and Ki-67. No significant correlation was found between other parameters (age, gender, tumor number, tumor size, metastasis, and treatment) and overall survival.Higher grade, negative AE1/AE3, and higher Ki-67 are associated with a worse survival rate. Kinds of treatment and other parameters have no significant influence on overall survival.
Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed malignant tumors in the world. In recent years, more and more inhibitors against gene targets have been found to be beneficial to survival. However, the function of homo-sapiens histone H3 associated protein kinase (GSG2) in HCC has not been completely understood.The expression of GSG2 in HCC tissues was detected by immunohistochemical staining. The lentivirus-mediated short hairpin RNA (shRNA) was used to knockdown GSG2 expression in HCC cell lines Hep3B2.1-7 and SK-HEP-1. Cell proliferation and colony formation were detected by MTT assay and colony formation assay, respectively, and flow cytometry assay was used to investigate the cell apoptosis in vitro. Mice xenograft model was constructed to detect the functions of GSG2 on tumor growth in vivo. Human Apoptosis Antibody Array was conducted to find the possible mechanism.GSG2 was overexpressed in HCC tissues compared with adjacent normal tissues. The knockdown of GSG2 had the functions of inhibiting the progression of HCC, including inhibiting cell proliferation and colony formation and promoting cell apoptosis. Compared with shCtrl group, the shGSG2 group expressed higher apoptotic genes such as caspase 3, caspase 8, Fas and FasL, while lower IGF1, Bcl2 and Bcl-w.Our study showed that knockdown of GSG2 suppresses the tumor growth in vitro and vivo. Therefore, GSG2 might play an oncogenic role in HCC.
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