BZW2, CDT1 and IVD Act As Biomarkers for Predicting Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths globally. This study aimed to provide a comprehensive investigation to screen and identify biomarkers for predicting HCC. METHODS: Firstly, the bioinformatics technique was applied to screen potential HCC-related genes, and the relationships between BZW2, CDT1, IVD expression and survival rate and clinicopathological factors were assessed. Afterward, qRT-PCR, western blot and immunohistochemistry were employed to validate the expression of BZW2, CDT1, and IVD in clinical resected cancer specimens. Furthermore, in vitro assays, cell cycle, apoptosis, colony formation and scratch experiments were performed to detect the effects of si-BZW2, si-CDT1 and oe-IVD in HCC cells. In vivo experiments, tumor volume and weight were measured to assess the anti-tumor effect of si-BZW2, si-CDT1 and oe-IVD in HCCtumor- bearing mice. RESULTS: Bioinformatics analysis indicated that HCC patients with high expression of BZW2, CDT1 and low expression of IVD have a poor prognosis and unfavorable clinicopathological factors. Similarly, clinical sample analysis revealed that BZW2 and CDT1 expression were increased while IVD expression was decreased in HCC tissues. Meanwhile, in vitro experiments found that si-BZW2, si- CDT1 and oe-IVD promoted apoptosis and inhibited the colony formation and migration of HCC cells. As expected, in vivo experiments demonstrated that si-BZW2, si-CDT1 and oe-IVD could inhibit tumor growth. CONCLUSION: Increased BZW2, CDT1 levels, and decreased IVD levels could act as biomarkers for predicting HCC. Furthermore, targeting BZW2, CDT1, and IVD may offer a new approach to treat HCC.

miR-181b-5p Promotes the Progression of Cholangiocarcinoma by Targeting PARK2 via PTEN/PI3K/AKT Signaling Pathway.

This study combined with bioinformatics analysis and investigated the expression pattern of miR-181b-5p, as well as explored its role and mechanism in cholangiocarcinoma (CCA or CHOL). Several bioinformatics databases were used to analyze the expression of miR-181b and the enrichment of miR-181b in biological activities and biological pathways in CCA. The RT-qPCR analysis was used to examine the expression levels of miR-181b-5p. A receiver operation characteristics (ROC) curve analysis and the Kaplan-Meier survival assay were conducted to validate the diagnostic and prognostic implication of miR-181b-5p. Cell experiments were used to explore the possible functional role of miR-181b-5p in CCA progression. The bioinformatics assay was used to predict the target gene of miR-181b-5p and Western blot was used to confirm the related signaling pathway. The bioinformatics analysis results suggest that miR-181b-5p was highly expressed in cholangiocarcinoma and its expression was negatively related to PARK2 expression in CCA tissues. miR-181b-5p expression in the serum and tissues was upregulated and associated with lymph node metastasis and TNM stage. Increased expression of miR-181b-5p had relatively high diagnostic accuracy and showed poor prognosis in CCA patients. In addition, miR-181b-5p overexpression enhanced cell proliferation, migration, and invasion by targeting PARK2. Overexpression of miR-181b-5p activated the PI3K/AKT signaling pathway, while knockdown of miR-181b-5p suppressed the signaling pathway. Increased expression of miR-181b-5p in CCA may be a potential diagnostic or/and prognostic indicator for CCA patients. The present data indicated miR-181b-5p acted as an oncogene in CCA through promoting tumor cell proliferation, migration, and invasion of CCA via the PTEN/PI3K/AKT signaling pathway by targeting PARK2, which might be a promising therapeutic target or biomarker for CCA.

Type A aortic dissection in pregnant patients with fibrillin-1 gene mutations: Two case reports and a literature review.

In acute aortic dissection (AD) in pregnancy, increased cardiovascular stress due to pregnancy is an important factor leading to an emergent aortic event. It is rare but often results in a devastating event for both the pregnant patient and the foetus. Two cases of acute AD (Stanford type A) in pregnant females are presented in the present study. The patients were diagnosed via echocardiography, and the diagnosis was confirmed with computed tomography angiography prior to aortic surgery. Up to 50% of ADs in pregnancy occur in patients with fibrillin-1 (FBN1) gene mutations. The FBN1 gene was sequenced in both patients, and notable, novel pathogenic mutations of FBN1 were identified in both patients. A literature review was also performed on available diagnostic imaging and other measurements regarding AD during pregnancy. The authors suggest that the relevant content may have important clinical implications in raising disease awareness, arranging test rationally and choosing an intervention method.

Prediction of long-term survival rates in patients undergoing curative resection for solitary hepatocellular carcinoma.

The present study developed a novel laboratory-based algorithm to predict long-term survival rates in patients undergoing curative resection for solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The present study included 426 patients with solitary HBV-related HCC who underwent surgery for primary tumors at a single center between 2003 and 2012. Demographic characteristics, laboratory analysis, clinical pathology and immunohistochemistry of topoisomerase II-a and Ki67 were analyzed. A simple prognostic risk calculator was developed using regression coefficients from multivariate models. A prognostic risk calculator incorporating tumor encapsulation, neutrophil-to-lymphocyte ratio, vascular invasion, α-fetoprotein level, Edmondson-Steiner classification, Topo II-α, prognostic nutritional index and Child-Pugh grade was constructed. The prognostic model demonstrated good discrimination with a C-index prior to adjustment of 0.81 (95% confidence interval: 0.78-0.84) and a bootstrap-corrected C-index of 0.81. Kaplan-Meier curves demonstrated that the probabilities of overall survival rates in the low-risk group were increased compared with those in the high-risk group. The areas under the receiver operating characteristic curve using the method were greater compared with those under the 7th Tumor-Node-Metastasis system and Cancer of the Liver Italian Program scoring system [0.83 vs. 0.62 and 0.77 (P<0.001), respectively]. The simple prognostic model of the present study accurately predicted survival rates in patients. Such a prognostic risk calculator for staging patients undergoing curative resection for solitary HBV-related HCC facilitates clinical surveillance and therapy.

Targeted therapy of multiple liver metastases after resected solitary gastric metastasis and primary pulmonary adenocarcinoma.

Gastric metastases from lung adenocarcinoma are rare and usually asymptomatic. A 61-year-old woman was referred to our department because of a right lower pulmonary mass found on a chest X-ray film in August 2012. Right lower lobectomy was performed for pulmonary adenocarcinoma. Four months later, she developed epigastric discomfort. A fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) scan showed a malignancy at the cardias of the stomach. A biopsy diagnosed poorly differentiated carcinoma and a gastric carcinoma was suspected. She underwent a subtotal gastrectomy and part of esophagectomy. The histologic diagnosis was metastasis from the pulmonary adenocarcinoma. She visited us again for her increasing level of carcinoembryonic antigen (CEA) after two months. FDG-PET/CT showed multiple malignant lesions in her liver, considering metastases from pulmonary origin. As she harbored activating epidermal growth factor receptor (EGFR) mutation, she received erlotinib from April, 2013. She survives 4 years after the lung resection and is still on erotinib treatment with complete response. Although gastric metastasis from lung cancer is considered a late stage of the disease, a radical resection might provide survival in solitary metastasis. Moreover, systemic therapy was emphasized after local treatment in some late stage cases.

Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.

Liver ischemia and reperfusion (I/R) injury is characterized by defective liver autophagy accompanied by alterations to the endogenous defense system. Dihydromyricetin (DHM) is a natural flavonoid that demonstrates a wide range of physiological functions, and has been implicated as a regulator of autophagy. This study investigates the protective effects of DHM pretreatment on liver injury caused by ischemia/reperfusion (I/R) and elucidates the potential mechanism of DHM-mediated protection. Mice were subjected to 60 minutes of ischemia followed by 5 hours of reperfusion. DHM (100 mg/kg bw/day) or the vehicle was administered daily by gavage 7 days before ischemia and immediately before reperfusion. In this study, DHM markedly decreased serum aminotransferase activity and inhibited liver I/R -stimulated apoptosis. Moreover, DHM exerted hepatoprotective effects by upregulating mRNA levels of various essential autophagy-related genes including ATG5, ATG12, BECN1, and LC3. Autophagy inhibitor chloroquine or Atg5 knockdown blocked DHM -mediated elevation in liver function. Specifically, DHM significantly increased FOXO3a expression, and enhanced FOXO3a nuclear translocation and Ser588 phosphorylation modification. Importantly, the inhibition of FOXO3a with FOXO3a-siRNA in mice decreased DHM-induced autophagy-related genes and diminished the protective effects of DHM against liver I/R injury. In summary, these findings identify DHM as a novel hepatoprotective small molecule by elevating FOXO3a expression and nuclear translocation, stimulating autophagy-related genes and suppressing liver I/R-induced apoptosis, suggesting FOXO3a may have therapeutic value in liver cell protection in liver I/R injury.

The efficacy and safety of pemetrexed plus bevacizumab in previously treated patients with advanced non-squamous non-small cell lung cancer (ns-NSCLC).

Bevacizumab (Bev), a monoclonal antibody against vascular endothelial growth factor, when combined with standard first-line chemotherapy, shows impressive clinical benefit in advanced non-squamous non-small cell lung cancer (ns-NSCLC). Our study aims to investigate whether the addition of Bev to pemetrexed improves progression-free survival (PFS) in advanced ns-NSCLC patients after the failure of at least one prior chemotherapy regimens. Patients with locally advanced, recurrent, or metastatic ns-NSCLC, after failure of platinum-based therapy, with a performance status 0 to 2, were eligible. Patients received 500 mg/m(2) of pemetrexed intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone and Bev 7.5 mg/kg IV day 1 of a 21-day cycle until unacceptable toxicity, disease progression or the patient requested therapy discontinuation. The primary end point was PFS. Between December 2011 and October 2013, 33 patients were enrolled, with median age of 55 years and 36.4% men. Twenty-three patients (69.7%) had received two or more prior regimens, and 28 patients (84.8%) had received chemotherapy containing pemetrexed. The median number of the protocol regimens was 4. Median PFS was 4.37 months (95% CI 2.64-6.09 months). Median overall survival (OS) was 15.83 months (95% CI 10.52-21.15 months). Overall response rates were 6.45%. Disease control rate was 54.84%. No new safety signals were detected. No patient experienced drug-related deaths. The combination of Bev and pemetrexed every 21 days is effective in ns-NSCLC patients who failed of prior therapies with improved PFS. Toxicities are similar with historical data of these two agents and are tolerable. Our results may provide more a regimen containing Bev and pemetrexed for Chinese clinical practice in previously treated ns-NSCLC.

Mitofusin 2 protects hepatocyte mitochondrial function from damage induced by GCDCA.

Mitochondrial impairment is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Mitofusin 2 (Mfn2) regulates mitochondrial morphology and signaling and is involved in the development of numerous mitochondrial-related diseases; however, a functional role for Mfn2 in chronic liver cholestasis which is characterized by increased levels of toxic bile acids remain unknown. Therefore, the aims of this study were to evaluate the expression levels of Mfn2 in liver samples from patients with extrahepatic cholestasis and to investigate the role Mfn2 during bile acid induced injury in vitro. Endogenous Mfn2 expression decreased in patients with extrahepatic cholestasis. Glycochenodeoxycholic acid (GCDCA) is the main toxic component of bile acid in patients with extrahepatic cholestasis. In human normal hepatocyte cells (L02), Mfn2 plays an important role in GCDCA-induced mitochondrial damage and changes in mitochondrial morphology. In line with the mitochondrial dysfunction, the expression of Mfn2 decreased significantly under GCDCA treatment conditions. Moreover, the overexpression of Mfn2 effectively attenuated mitochondrial fragmentation and reversed the mitochondrial damage observed in GCDCA-treated L02 cells. Notably, a truncated Mfn2 mutant that lacked the normal C-terminal domain lost the capacity to induce mitochondrial fusion. Increasing the expression of truncated Mfn2 also had a protective effect against the hepatotoxicity of GCDCA. Taken together, these findings indicate that the loss of Mfn2 may play a crucial role the pathogenesis of the liver damage that is observed in patients with extrahepatic cholestasis. The findings also indicate that Mfn2 may directly regulate mitochondrial metabolism independently of its primary fusion function. Therapeutic approaches that target Mfn2 may have protective effects against hepatotoxic of bile acids during cholestasis.

Specific surface area of titanium dioxide (TiO2) particles influences cyto- and photo-toxicity.

The aim of this study is to examine how different specific surface areas of similar-sized titanium dioxide (TiO(2)) particles could influence both cytotoxicity and phototoxicity. TiO(2) particles of different specific surface areas were compared for their toxic effects on RAW264.7 cells in the absence and presence of UV light. From the results, TiO(2) particles with larger specific surface area were found to induce higher cyto- (UV absent) and photo-toxicity (UV activated) to cells after 24h incubation. The observed cytotoxicity from TiO(2) particles with larger surface area could be explained from their interactions with biomolecules. Upon photoactivation, a larger number of hydroxyl radicals were detected from TiO(2) particles with larger surface area, again suggesting a surface area dependent phototoxic effect. On the other hand, pre-adsorbing TiO(2) particles with extracellular proteins were found to decrease toxicity effects.