Yuesi Zhong

Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells

During liver injury, bone marrow-derived mesenchymal stem cells (MSCs) can migrate and differentiate into hepatocytes. Hepatic stellate cell (SC) activation is a pivotal event in the development of liver fibrosis. Therefore, we hypothesized that SCs may play an important role in regulating MSC proliferation and differentiation through the paracrine signaling pathway. We demonstrate that MSCs and SCs both express hedgehog (Hh) pathway components, including its ligands, receptors, and target genes. Transwell co-cultures of SCs and MSCs showed that the SCs produced sonic hedgehog (Shh), which enhanced the proliferation and differentiation of MSCs. These findings demonstrate that SCs indirectly modulate the activity of MSCs in vitro via the Hh pathway, and provide a plausible explanation for the mechanisms of transplanted MSCs in the treatment of liver fibrosis.

Primary gastrointestinal stromal tumors: Current advances in diagnostic biomarkers, prognostic factors and management of its duodenal location

Gastrointestinal stromal tumors (GIST) constitute 1-3% of all gastrointestinal malignancies and is the most common mesenchymal tumor of the gastrointestinal tract. Although GIST were first described in the literature in the year 1941, important advances of kit mutation and tyrosine kinase inhibitors were not made to understand and manage GIST until the last decade. Here current advances in research of possible cellular origin, diagnostic biomarkers and prognostic factors of primary GIST are reviewed, and the management of primary duodenal GIST is focused on due to its specific location. It is possible that personalized assessment and therapy will turn out to be another milestone for primary GIST.

Key role of liver sinusoidal endothelial cells in liver fibrosis

Because of the prevalence of viral hepatitis and nonalcoholic fatty liver disease (NAFLD), liver fibrosis has become a very common disease in Asia and elsewhere in the world, constantly increasing the burden of care borne by society. Hepatic sinusoidal capillarization, characterized by gradually shrinking fenestrae on the surface of liver sinusoidal endothelial cells (LSECs) and the formation of an organized basement membrane, is an initial pathologic change associated with liver fibrosis. Basic and clinical studies have indicated that LSECs play a key role in hepatic sinusoidal capillarization by affecting various aspects of the development and progression of liver fibrosis. Reviewing studies on the effect of LSECs on liver fibrosis is essential to better understanding the pathogenesis of liver fibrosis and its mechanism of progression. Moreover, such a review will provide a theoretical basis for identifying new methods to promote the regression or even inhibition of fibrosis. This review will focus on structural and functional changes in LSECs during hepatic sinusoidal capillarization and the interaction between the micro-environment of the liver and the bodys immune system.

Delayed bronchobiliary fistula and cholangiolithiasis following percutaneous radio frequency ablation for hepatocellular carcinoma

Although percutaneous radio frequency ablation for hepatocellular carcinoma is a minimally invasive therapy, there are some complications reported; major complications include hemorrhage (0.477%), hepatic injuries (1.690%), and extrahepatic organ injuries (0.691%). We, for the first time, described a rare complication of delayed bronchobiliary fistula and cholangiolithiasis in common bile duct following radio frequency ablation and the salvage treatment in a patient with chronic hepatitis B virus infection. Surgeons should be aware of severe and rare complications before deciding the ablation area and when performing radio frequency ablation, and should be aware of the relevant salvage treatment.

Hepatitis B Virus Core Promoter A1762T/G1764A (TA)/T1753A/T1768A Mutations Contribute to Hepatocarcinogenesis by Deregulating Skp2 and P53

Background and AimHepatitis B virus core promoter (CP) mutations can increase risk of hepatocellular carcinoma. The CP region overlaps with the HBV X (HBx) gene, which has been associated with hepatocarcinogenesis. The cyclin kinase inhibitor P53 is an important regulator of cell cycle progression. We determined whether HBx mutants that result from mutations in the CP deregulate P53.MethodsA HBx combination (combo) mutant with changes in the CP region that corresponded to A1762T/G1764A (TA), T1753A, and T1768A was constructed and expressed in L-02 and Hep3B cells. The effects of CP mutations on expression and degradation of P53, and the effects on cell cycle progression and proliferation were analyzed.ResultsThe combo mutant decreased levels of P53 and increased cyclin D1 expression, accelerated P53 degradation in L-02 cells, accelerated cell cycle progression, and increased expression of S-phase kinase-associated protein 2 (Skp2) in L-02 and Hep3B cells. Silencing of Skp2 abrogated the effects of CP mutations on P53 expression. The kinetics of P53 expression correlated with changes in cell cycle distribution.ConclusionsThe HBx mutant with a combination of CP mutations can up-regulate Skp2, which then down-regulates P53 via ubiquitin-mediated proteasomal degradation, increasing the risk of hepatocellular carcinoma.

Generation of a human bone marrow-derived mesenchymal stem cell line expressing and secreting high levels of bioactive α-melanocyte-stimulating hormone

α-Melanocyte-stimulating hormone (α-MSH) functions as a mediator of inflammation and immunity; however, the short half-life and high dose needed limit the comprehensive clinical application of α-MSH. The aim of this study was to generate human bone marrow-derived mesenchymal stem cells (MSCs) that express and secrete high levels of bioactive α-MSH. MSCs were obtained from a normal donor and assessed for proliferation, surface markers, and adipogenic and osteogenic differentiation. A lentivirus-encoding α-MSH was constructed. MSCs were infected with this lentivirus-encoding α-MSH and assessed for stability and the expression and secretion of bioactive α-MSH. The cumulative MSC expansion rates pre- and post-lentivirus infection were not significantly different (P > 0.05). The MSCs remained stable after infection with the lentivirus-encoding α-MSH. The concentration of α-MSH in the supernatants of MSCs infected with the lentivirus-encoding α-MSH was 17.55 ng/ml (P < 0.001), and a melanin assay indicated that bioactive α-MSH was secreted from MSCs infected with the lentivirus-encoding α-MSH, with an optical absorbance at OD(405) of 0.886 (P < 0.001). These results suggested that MSCs were promising cell carriers for the expression and secretion of high levels of bioactive α-MSH.

Impaired phosphate and tension homologue deleted on chromosome 10 expression and its prognostic role in radical surgery for hepatocellular carcinoma with family aggregation resulting from hepatitis B and liver cirrhosis

This study aimed to retrospectively investigate the expression of the phosphate and tension homologue deleted on chromosome 10 (PTEN) protein and its prognostic role in hepatocellular carcinoma (HCC) with family aggregation resulting from hepatitis B and liver cirrhosis, which have not been established. Immunohistochemical analysis was performed to evaluate the PTEN protein expression in HCC and paired para-cancerous tissues from 79 patients with HCC caused by hepatitis B and liver cirrhosis. Of these cases, 34 represented HCC with family aggregation (HCCF group), and 45 represented HCC with no family aggregation (HCCN group). Follow-up data were collected for 3 months to 10 years and analysed for HCC recurrence, survival time and prognostic risk factors. The expression of the PTEN protein in the HCC tissue was dramatically lower in the HCCF group than in the HCCN group. The six-month, one-year and two-year overall recurrence (OR) rates of the HCCF group were significantly higher than those of the HCCN group. The one-year, two-year and five-year overall survival (OS) rates of the HCCF group were lower than those of the HCCN group. Impaired PTEN protein expression was an independent prognostic risk factor that was significantly correlated with OR and OS in HCC patients. Dramatically impaired PTEN protein expression in HCC patients with family aggregation resulting from hepatitis B and liver cirrhosis was correlated with OR and OS, and impaired PTEN expression was an independent risk factor for prognosis after radical surgery.

Associating liver partition and portal vein ligation for staged hepatectomy versus conventional two-stage hepatectomy: a systematic review and meta-analysis

BackgroundIt is generally accepted that an insufficient future liver remnant is a major limitation of large-scale hepatectomy for patients with primary hepatocellular carcinoma. Conventional two-stage hepatectomy (TSH) is commonly considered to accelerate future liver regeneration despite its low regeneration rate. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which is characterized by a rapid regeneration, has brought new opportunities.MethodsRelevant studies were identified by searching the selected databases up to September 2017. Then, a meta-analysis of regeneration efficiency, complication rate, R0 resection ratio, and short-term outcomes was performed.ResultsTen studies, comprising 719 patients, were included. The overall analysis showed that ALPPS was associated with a larger hyperplastic volume and a shorter time interval (P < 0.00001) than TSH. ALPPS also exhibited a higher completion rate for second-stage operations (odds ratio, OR 9.50; P < 0.0001) and a slightly higher rate of R0 resection (OR 1.90; P = 0.11). Interestingly, there was no significant difference in 90-day mortality between the two treatments (OR 1.44; P = 0.35).ConclusionsThese results indicate that compared with TSH, ALPPS possesses a stronger regenerative ability and better facilitates second-stage operations. However, the safety, patient outcomes, and patient selection for ALPPS require further study.