Identification of growth differentiation factor 15 as a pro-fibrotic factor in mouse liver fibrosis progression.

The aim of this study was elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells (HSCs) of mice. We generated a GDF15-neutralizing antibody that can inhibit TGF-ß1-induced activation of the TGF-ß/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary HSCs from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-ß pathway was detected using dual-luciferase reporter and Western blotting assays. The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-ß pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary HSCs. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression. The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-ß signalling.

Intestinal tuberculosis with small bowel stricture and hemorrhage as the predominant manifestation: Three case reports.

BACKGROUND: Intestinal tuberculosis is a chronic disease caused by Mycobacterium tuberculosis that mainly affects the ileum and cecum. Small bowel tuberculosis, characterized by predominant involvement of the small intestine, is an extremely rare condition with highly atypical clinical presentations, making diagnosis even more challenging. CASE SUMMARY: We report three cases of small intestinal tuberculosis, two of the patients presented primarily with abdominal pain, and one presented with gastrointestinal bleeding. All patients underwent blood tests and imaging examinations. Small bowel endoscopy (SBE) revealed that the main lesions in these patients were intestinal stenosis or gastrointestinal bleeding caused by small intestinal ulcers. One patient ultimately underwent surgical treatment. Following a complex diagnostic process and comprehensive analysis, all patients were confirmed to have small intestinal tuberculosis and received standard antituberculosis treatment, leading to an improvement in their condition. CONCLUSION: Patients with SBTs present with nonspecific symptoms such as abdominal pain, weight loss, and occasional gastrointestinal bleeding. Accurate diagnosis requires a thorough evaluation of clinical symptoms and various tests to avoid misdiagnosis and complications.

[The effect of portal hypertension on prognosis in patients with decompensated liver cirrhosis].

OBJECTIVE: To evaluate the effect of portal hypertension on prognosis in patients with decompensated liver cirrhosis. METHODS: The clinical data of decompensated cirrhosis patients in our hospital, between 2003 and 2006, were retrospected and followed up. Model for end-stage liver disease (MELD) score and Child-Turcotte-Pugh (CTP) classification was calculated using the standard formula. Kaplan-Meier survival analysis was used to compare the mortality in subgroups ranked by the syndromes. Cox proportional hazards regression was used to evaluate the effect of the syndromes on prognosis. RESULTS: A cohort of 322 patients was admitted in this study at the end of the follow-up. The mortality of variceal bleeding, hepatic encephalopathy, a large volume ascites, spontaneous bacterial peritonitis, the type I and type II hepatorenal syndrome was 45.9%, 79.4%, 66.7%, 100%, 100% and 84.6% respectively. On the whole, the occurrence of all the syndromes was correlated with CTP classification and MELD score. Kaplan-Meier survival analysis showed that all of these syndromes, except for low to medium volume of ascites, significantly affected the survival rate (P<0.01). In Cox regression analysis, all the syndromes were the independent predictors of prognosis, the regression coefficient values of hepatic encephalopathy, spontaneous bacterial peritonitis, type I and type II hepatorenal syndrome, variceal bleeding and ascites were 0.973, 0.928, 0.935, 0.866, 0.464 and 0.369 respectively. CONCLUSIONS: The portal hypertensive syndromes have significant effect on the prognosis of the patients with decompensated cirrhosis, hepatic encephalopathy is the worst one.

Inhibition of PSMD4 blocks the tumorigenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high mortality and frequent recurrence. Although various therapies provide potential cure for HCC patients, unfortunately the five-year survival rate of advanced HCC remains dismal. It is critical to explore the pathogenesis of HCC and identify novel biomarkers for early HCC diagnosis. PSMD4 is a major receptor of the 26S proteasome involved in ubiquitindependent and proteasome-mediated protein degradation. In our study, PSMD4 was overexpressed in HCC tissues and cell lines determined by Northern blot, western blot and immunohistochemistry. The silencing of PSMD4 blocked cell proliferation and tumor growth, induced cell apoptosis and inhibited the proteasome activity. Western blot results showed that the knockdown of PSMD4 blocked the expression of cyclooxygenase 2 (COX2), phosphorylated Sarcoma tyrosine kinase (P-SRC) and Bcl-2, but improved the levels of p53 and Bax in HCC, lung cancer, colorectal cancer, breast cancer and endometrial cancer cell lines. Taken together, these findings indicated that the subunit of 26S proteasome PSMD4 exerts as an oncogene in HCC and other cancers via regulating the expression p53, Bcl-2 and Bax. These findings enriched the pathogenesis of HCC, and provided a new biomarker for cancers diagnosis and a new target for cancers therapy.

Epidermal growth factor receptor-targeted immune magnetic liposomes capture circulating colorectal tumor cells efficiently.

AIM: To compare the capacity of newly developed epidermal growth factor receptor (EGFR)-targeted immune magnetic liposomes (EILs) vs epithelial cell adhesion molecule (EpCAM) immunomagnetic beads to capture colorectal circulating tumor cells (CTCs). METHODS: EILs were prepared using a two-step method, and the magnetic and surface characteristics were confirmed. The efficiency of capturing colorectal CTCs as well as the specificity were compared between EILs and EpCAM magnetic beads. RESULTS: The obtained EILs had a lipid nanoparticle structure similar to cell membrane. Improved binding with cancer cells was seen in EILs compared with the method of coupling nano/microspheres with antibody. The binding increased as the contact time extended. Compared with EpCAM immunomagnetic beads, EILs captured more CTCs in peripheral blood from colorectal cancer patients. The captured cells showed consistency with clinical diagnosis and pathology. Mutation analysis showed same results between captured CTCs and cancer tissues. CONCLUSION: EGFR antibody-coated magnetic liposomes show high efficiency and specificity in capturing colorectal CTCs.

Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression.

AIM: To determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression. METHODS: We detected expression of Smoc2 in HCC tissues and corresponding non-tumor liver (CNL) tissues using PCR, western blot, and immunohistochemistry methods. Subsequently, we down-regulated and up-regulated Smoc2 expression using siRNA and lentivirus transfection assay, respectively. Then, we identified the effect of Smoc2 on cell proliferation and cell cycle using CCK-8 and flow cytometry, respectively. The common cell growth signaling influenced by Smoc2 was detected by western blot assay. RESULTS: The expression of Smoc2 was significantly higher in HCC tissues compared with CNL tissues. Overexpression of Smoc2 promoted HCC cell proliferation and cell cycle progression. Down-regulation of Smoc2 led to inhibition of cell proliferation and cell cycle progression. Smoc2 had positive effect on ERK and AKT signaling. CONCLUSION: Smoc2 promotes the proliferation of HCC cells through accelerating cell cycle progression and might act as an anti-cancer therapeutic target in the future.

Tumor necrosis factor-alpha gene -308G > A polymorphism alters the risk of hepatocellular carcinoma in a Han Chinese population.

BACKGROUND: The aim of the present study was to evaluate the influence of tumor necrosis factor-alpha (TNF-α) -308 G > A polymorphism on hepatocellular carcinoma (HCC) risk. METHODS: The present case-control study was conducted in a Han Chinese population consisting of 753 HCC patients and 760 controls from May 2010 to March 2013. The -308 TNF-a promoter polymorphisms were detected. Conditional logistic regression was performed to analyze the association between TNF-α -308 G > A polymorphism and the risk of HCC, which were estimated by odds ratios (ORs) and their 95% confidence intervals (95% CIs). RESULTS: The genotypic frequencies in the cases were not similar to that of the controls, differences being statistically significant (P = 0.002). Using the GG genotype as the reference genotype, AA was significantly associated with increased risk of HCC (adjusted OR = 5.12, 95% CI = 2.31-7.82). Similarly, AG + AA genotype showed 5.59-fold increased HCC risk in a dominant model. Furthermore, we found A allele was significantly associated with increased risk of HCC, compared with G allele (OR = 4.18, 95% CI = 1.76-6.97). CONCLUSION: The present study showed that TNF-α -308 G > A polymorphism was associated with increased HCC risk in a Han Chinese population. Further prospective studies on large and different ethnic populations will be necessary to confirm our findings and elucidate the underlying molecular mechanism for the development of HCC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_199.