Characteristics and prognostic significance of circRNA-100876 in patients with colorectal cancer.

OBJECTIVE: The purpose of this study was to explore the correlation between circRNA-100876 and the clinicopathological parameters of patients with colorectal cancer (Cc). PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) was applied to detect the circRNA-100876 expression in Cc tissues and cell lines. Overall survival analysis was carried out to explore the correlation between circRNA-100876 and the prognosis of Cc patients by Kaplan-Meier method and Log-rank method. Subsequently, Chi-square test was used to investigate the clinical significance of circRNA-100876 in the clinicopathological parameters of Cc patients. Moreover, the expression of circRNA-100876 was inhibited by small interfering RNAs (siRNAs) in loss-of-function assay. Finally, the invasion ability of Cc cells was determined by transwell assay. RESULTS: The results of this study manifested that circRNA-100876 was abnormally overexpressed in Cc tissues and cell lines, and the high expression of circRNA-100876 was clearly associated with the Clinical stage, T classification and Lymph node metastasis of Cc patients. Besides, Cc patients with high expression worsened overall survival. In addition, it was demonstrated that the inhibition of circRNA-100876 reduced the invasion ability of Cc cells. CONCLUSIONS: Acting as a tumor promoter, circRNA-100876 might be regarded as a new potential biomarker for the diagnosis and therapy of Cc.

Visfatin relieves myocardial ischemia-reperfusion injury through activation of PI3K/Akt/HSP70 signaling axis.

OBJECTIVE: Myocardial ischemia-reperfusion injury (MIRI) is the most common complication of ischemic cardiomyopathy, which severely affects the prognosis of patients. The purpose of this study was to investigate the protective effects of visfatin on the myocardium after ischemia-reperfusion (I/R) and its mechanism. MATERIALS AND METHODS: Sprague Dawley rats were used to construct the MIRI model and visfatin was administrated intraperitoneally in rats to determine the protective effect of visfatin on myocardium after I/R. In addition, visfatin was used to treat rat myocardial cell line H9c2 cells and detect its effect on H9c2 cells. The effect of visfatin on the PI3K/Akt/HSP70 signaling axis in H9c2 cells was also detected to determine the mechanism of the myocardial protection of visfatin. RESULTS: The damage of cardiomyocytes in MIRI rats pretreated with visfatin was significantly improved compared with untreated MIRI rats. Visfatin also reduced the level of inflammation and apoptosis of cardiomyocytes in MIRI rats, reduced myocardial injury markers, and improved cardiac function. In vitro, visfatin also reduced inflammatory and apoptotic factors in H9c2 cells. In addition, visfatin also promoted the activity of the PI3K/Akt signaling pathway and increased HSP70 expression in H9c2 cells. The inhibition of the PI3K/Akt signaling pathway was found to attenuate the promotion of HSP70 by visfatin. SiRNA-HSP70 also attenuated the protective effect of visfatin on H9c2 cells. CONCLUSIONS: Visfatin reduces the inflammation and apoptosis levels of myocardial cells through the PI3K/Akt/HSP70 signaling axis, thereby reducing I/R-induced myocardial injury.

Effect of lncRNA-BLACAT1 on drug resistance of non-small cell lung cancer cells in DDP chemotherapy by regulating cyclin D1 expression.

OBJECTIVE: The aim of this study was to investigate the effect of long non-coding ribonucleic acid (lncRNA)-bladder cancer associated transcript 1 (BLACAT1) on the drug resistance of non-small cell lung cancer (NSCLC) cells in cisplatin (DDP) chemotherapy by regulating the expression of Cyclin D1. MATERIALS AND METHODS: The analysis of the lncRNA expression profiles in 483 cases of NSCLC tissues and 347 cases of cancer-adjacent tissues in Gene Expression Omnibus (GEO) database revealed that lncRNA-BLACAT1 was differentially expressed in NSCLC and related to prognosis. In order to further study its mechanism of action on DDP-resistant cells, the expression level of lncRNA-BLACAT1 in normal human lung bronchial epithelial cell line BEAS-2B, NSCLC cell line A549, and DDP-resistant cell line A549 (A549/DDP) was detected by quantitative Polymerase Chain Reaction (qPCR). LncRNA-BLACAT1 small interfering RNA (siRNA) (si-BLACAT1) and lncRNA-BLACAT1 negative control (si-NC) were transfected into A549/DPP cells. Then, qPCR was carried out to detect the changes in the expression of lncRNA-BLACAT1 before and after transfection. Thereafter, cell cycle and cell growth rate were detected by flow cytometry and the cell growth curve. Besides, the changes in cell migration, cell apoptosis, and Cyclin D1 were detected via wound healing assay, flow cytometry, and Western blotting (WB). RESULTS: In GEO database, lncRNA-BLACAT1 was significantly overexpressed in NSCLC (p<0.05), and the prognosis of NSCLC in BLACAT1 low-expression group was better than that in the BLACAT1 high-expression group (p<0.0001). Compared with that in BEAS-2B cells, BLACAT messenger RNA (mRNA) was notably highly expressed in A549 cells (p<0.05), and compared with that in A549 cells, BLACAT1 mRNA in A549/DPP was significantly highly expressed in A549/DDP cells (p<0.05). Additionally, in comparison with that in the si-NC group, the content of lncRNA-BLACAT1 in si-BLACAT1 group was remarkably decreased (p<0.01). Moreover, flow cytometry detection of cell cycle revealed that compared with those in si-NC group, G0/G1 phase was markedly prolonged and S phase was shortened in si-BLACAT1 group. MTS assay manifested that the absorbance at 450 nm in si-BLACAT1 group was evidently decreased on the 3rd day compared with that in the si-NC group (p<0.05), and the difference between the two groups was the most significant on the 5th day (p<0.001). According to wound healing assay, compared with those in si-NC group, the distance between cells became larger, the cell migration ability was remarkably weakened (p<0.05), and cell apoptosis was prominently reduced in si-BLACAT1 group (p<0.05). WB results showed that compared with si-NC group, si-BLACAT1 group had significantly reduced Cyclin D1 (p<0.05) CONCLUSIONS: LncRNA-BLACAT1 regulates the expression of Cyclin D1, reduces the malignant phenotype of drug-resistant cells, and increases the sensitivity of lung cancer cells to DDP.

Long non-coding RNA BCAR4 accelerates cell proliferation and suppresses cell apoptosis in gastric cancer via regulating MAPK/ERK signaling.

OBJECTIVE: As the fourth most common malignant tumor with high mortality rate, gastric cancer (GC) seriously threatens people's health and life quality worldwide. The aim of this study was to explore the functional role of long non-coding RNA (lncRNA) BCAR4 in GC. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) assay was used to detect the expression level of lncRNA BCAR4 in GC cell lines and tissues. Subsequently, cell counting kit-8 (CCK-8) assay, colony formation assay, and flow cytometry were recruited to investigate the role of lncRNA BCAR4 in the proliferation and apoptosis of GC cells, respectively. Western blotting was used to detect the protein expression level of mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) in GC. Besides, tumor formation assay was applied to examine the ability of lncRNA BCAR4 in vivo. RESULTS: LncRNA BCAR4 was highly expressed in both GC tissues and cell lines. CCK-8 assay, colony formation assay, and flow cytometry results indicated that up-regulated lncRNA BCAR4 significantly promoted cell proliferation and suppressed cell apoptosis in GC. Besides, over-expression of lncRNA BCAR4 could activate the MAPK/ERK signaling pathways. Tumor xenograft formation assay demonstrated that over-expression of lncRNA BCAR4 promoted tumor formation in vivo. CONCLUSIONS: LncRNA BCAR4 was proved significantly up-regulated in GC. Over-expression of lncRNA BCAR4 promoted cell proliferation and suppressed cell apoptosis in vitro and promoted tumor formation in vivo. Besides, Western blotting revealed that lncRNA BCAR4 played an oncogenic role in GC via regulating MAPK/ERK signaling.

Microvesicle-containing miRNA-153-3p induces the apoptosis of proximal tubular epithelial cells and participates in renal interstitial fibrosis.

OBJECTIVE: To uncover the role of microvesicle-containing (MV-containing) miRNA-153-3p in inducing the apoptosis of proximal tubular epithelial cells and RIF (renal interstitial fibrosis), and its potential mechanism. MATERIALS AND METHODS: Mice were subjected to unilateral ureteral obstruction (UUO) to establish the in vivo RIF model. MVs were extracted from the obstructed kidney tissues of mice, to further isolate the RNAs. MiRNA-153-3p levels in RIF mice and MVs were determined. In vitro RIF model was constructed by TGF-ß1 induction in NRK-52E and NRK-49F cells. The regulatory effect of miRNA-153-3p on the apoptosis of tubular epithelial cells was examined. Subsequently, potential target gene of miRNA-153-3p was predicted and identified. Rescue experiments were finally carried out to uncover the role of miRNA-153-3p/Bcl-2 in influencing RIF. RESULTS: MiRNA-153-3p was upregulated in mice undergoing UUO, MVs extracted from obstructed kidney tissues of mice and TGF-ß1-induced NRK-52E and NRK-49F cells. The overexpression of miRNA-153-3p remarkably induced apoptosis in tubular epithelial cells. Bcl-2 was verified to be the target gene of miRNA-153-3p, and the Bcl-2 level was negatively regulated by miRNA-153-3p. Overexpression of Bcl-2 reversed the effect of miRNA-153-3p on inducing cell apoptosis. CONCLUSIONS: MV-containing miRNA-153-3p released by tubulointerstitial fibroblasts transmits to the proximal tubular epithelial cells via the damaged tubule basement membrane. It induces the apoptosis of proximal tubular epithelial cells by inhibiting Bcl-2 level and further aggravates RIF.

Regulatory effects of CCDC3 on proliferation, migration, invasion and EMT of human cervical cancer cells.

OBJECTIVE: To elucidate the potential effects of Coiled coil domain-containing 3 (CCDC3) on proliferative, migratory, invasive potentials and epithelial-mesenchymal transition (EMT) of human cervical cancer cells. MATERIALS AND METHODS: Protein and mRNA levels of CCDC3 in C33 and HeLa cells were determined by quantitative Real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. Proliferative capacity and clonality of C33 and HeLa cells transfected with sh-CCDC3 were evaluated by cell counting kit-8 (CCK-8) and colony formation assay, respectively. Transwell assay and wound healing assay were conducted to determine the invasive and migratory potentials of cervical cancer cells with CCDC3 knockdown. Protein expressions of EMT-related genes in C33 and HeLa cells with CCDC3 knockdown were determined by Western blot. RESULTS: Transfection of sh-CCDC3 in C33 and HeLa cells markedly inhibited CCDC3 expression compared with those transfected with sh-EGFP. CCDC3 knockdown remarkably attenuated proliferative, migratory and invasive capacities. Moreover, CCDC3 knockdown inhibited protein levels of EMT-related genes in C33 and HeLa cells. CONCLUSIONS: Low expression of CCDC3 attenuated proliferative, migratory, invasive potentials and EMT of cervical cancer cells. Hence, CCDC3 may be utilized as a novel therapeutic target for cervical cancer.

LncRNALUADT1 is overexpressed in colorectal cancer and its expression level is related to clinicopathology.

OBJECTIVE: LncRNAs participate in the proliferation, apoptosis, and invasion of colorectal cancer. We aimed at investigating the uncovered effect of lncRNALUADT1 on colorectal cancer. PATIENTS AND METHODS: The relative expression level of lncRNALUADT1 in tumor specimen was tested by Real-time quantitative PCR. The association of lncRNALUADT1 with clinical pathological data was analyzed by univariate, multivariate Cox and Kaplan-Meier curve. RESULTS: LncRNALUADT1 expression was up-regulated in colorectal cancer, and correlated with tumor size, metastasis, and TNM staging. Both univariate analysis and multivariate test indicated that lncRNALUADT1 high expression, TNM staging, and lymph node metastasis were closely related. Moreover, high expression of lncRNALUADT1 suggested the poor overall survival of patients. CONCLUSIONS: LncRNA LUADT1 might contribute to the development of colorectal cancer.

Trends in use of lymphadenectomy in surgery with curative intent for intrahepatic cholangiocarcinoma.

BACKGROUND: The role of routine lymph node dissection (LND) in the surgical treatment of intrahepatic cholangiocarcinoma (ICC) remains controversial. The objective of this study was to investigate the trends of LND use in the surgical treatment of ICC. METHODS: Patients undergoing curative intent resection for ICC in 2000-2015 were identified from an international multi-institutional database. Use of lymphadenectomy was evaluated over time and by geographical region (West versus East); LND use and final nodal status were analysed relative to AJCC T categories. RESULTS: Among the 1084 patients identified, half (535, 49·4 per cent) underwent concomitant hepatic resection and LND. Between 2000 and 2015, the proportion of patients undergoing LND for ICC nearly doubled: 44·4 per cent in 2000 versus 81·5 per cent in 2015 (P < 0·001). Use of LND increased over time among both Eastern and Western centres. The odds of LND was associated with the time period of surgery and the extent of the tumour/T status (referent T1a: OR 2·43 for T2, P = 0·001; OR 2·13 for T3, P = 0·016). Among the 535 patients who had LND, lymph node metastasis (LNM) was noted in 209 (39·1 per cent). Specifically, the incidence of LNM was 24 per cent in T1a disease, 22 per cent in T1b, 42·9 per cent in T2, 48 per cent in T3 and 66 per cent in T4 (P < 0·001). AJCC T3 and T4 categories, harvesting of six or more lymph nodes, and presence of satellite lesions were independently associated with LNM. CONCLUSION: The rate of LNM was high across all T categories, with one in five patients with T1 disease having nodal metastasis. The trend in increased use of LND suggests a growing adoption of AJCC recommendations in the treatment of ICC.

Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent.

BACKGROUND: The objective of this study was to investigate the characteristics, treatment and prognosis of early versus late recurrence of intrahepatic cholangiocarcinoma (ICC) after hepatic resection. METHODS: Patients who underwent resection with curative intent for ICC were identified from a multi-institutional database. Data on clinicopathological characteristics, initial operative details, timing and sites of recurrence, recurrence management and long-term outcomes were analysed. RESULTS: A total of 933 patients were included. With a median follow-up of 22 months, 685 patients (73·4 per cent) experienced recurrence of ICC; 406 of these (59·3 per cent) developed only intrahepatic disease recurrence. The optimal cutoff value to differentiate early (540 patients, 78·8 per cent) versus late (145, 21·2 per cent) recurrence was defined as 24 months. Patients with early recurrence had extrahepatic disease more often (44·1 per cent versus 28·3 per cent in those with late recurrence; P < 0·001), whereas late recurrence was more often only intrahepatic (71·7 per cent versus 55·9 per cent for early recurrence; P < 0·001). From time of recurrence, overall survival was worse among patients who had early versus late recurrence (median 10 versus 18 months respectively; P = 0·029). In multivariable analysis, tumour characteristics including tumour size, number of lesions and satellite lesions were associated with an increased risk of early intrahepatic recurrence. In contrast, only the presence of liver cirrhosis was independently associated with an increased likelihood of late intrahepatic recurrence (hazard ratio 1·99, 95 per cent c.i. 1·11 to 3·56; P = 0·019). CONCLUSION: Early and late recurrence after curative resection for ICC are associated with different risk factors and prognosis. Data on the timing of recurrence may inform decisions about the degree of postoperative surveillance, as well as help counsel patients with regard to their risk of recurrence.

Application value of procalcitonin in patients with central nervous system infection.

OBJECTIVE: To study the application value of procalcitonin (PCT) in patients with central nervous system (CNS) infection. PATIENTS AND METHODS: A total of 66 patients, including 24 patients with suppurative meningitis, 20 patients with viral meningitis and 22 patients with tuberculous meningitis, were enrolled. 20 patients admitted to the hospital due to epilepsy or headache without infection in the same period were enrolled as the control group. PCT, high-sensitivity C-reactive protein (Hs-CRP), high-sensitivity C-reactive protein (Hs-CRP), protein quantification, chloride and glucose in serum and cerebrospinal fluid, were collected. RESULTS: The serum PCT level in suppurative meningitis group was significantly higher than that in other three groups. The dynamic monitoring of suppurative meningitis group on admission, at 72 h and 1 week after treatment showed that the serum PCT level was significantly decreased. PCT levels in cerebrospinal fluid in suppurative meningitis group, viral meningitis group and tuberculous meningitis group were decreased successively, and the differences were statistically significant. The detection of PCT in cerebrospinal fluid was more valuable than serum PCT detection in distinguishing tuberculous meningitis from viral meningitis. Continuous monitoring of changes in PCT in cerebrospinal fluid showed that there was no statistically significant difference before and after treatment. PCT level in cerebrospinal fluid was positively correlated with the serum PCT, cerebrospinal fluid white blood cell (WBC), and protein content in cerebrospinal fluid. CONCLUSIONS: The dynamic changes of serum PCT in patients with suppurative meningitis can be used to evaluate the disease, guide the clinical medication, and monitor the prognosis.

Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice.

Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR), and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K) and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P) 12 were challenged with ovalbumin (OVA). Separate groups of mice (n=18/group) were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

Migration and invasion enhancer 1 (MIEN1) is overexpressed in breast cancer and is a potential new therapeutic molecular target.

Migration and invasion enhancer 1 (MIEN1) is a membrane-anchored protein that is highly expressed in various types of cancer, and is correlated with the PI3K/AKT pathway. The aim of this study was to investigate the expression of MIEN1 and its clinical pathological significance in breast cancer. We used immunohistochemical staining to examine the expression of MIEN1 in 40 samples of human breast cancer tissue and 10 samples taken from regions adjacent to normal breast tissue. The rate of detection of MIEN1 protein was 67.5%, which was significantly higher than that in adjacent non-cancerous breast tissue (0%, P < 0.05). The expression of MIEN1 correlated with age, World Health Organization grade, and lymph node metastasis, but not with tumor size or family history of cancer. Kaplan-Meier survival analysis showed that patients with positive MIEN1 protein expression had a lower overall survival rate than patients who did not express MIEN1. Downregulation of MIEN1 suppressed the expression of matrix metallopeptidase 9 by downregulating the expression of protein kinase B (also known as AKT) in breast cancer cells. Our results indicate that MIEN1 overexpression may facilitate migration and invasion in breast cancer, and MIEN1 is a potential molecular target for cancer chemotherapy.

Liver Transplantation for Biliary Rhabdomyosarcoma With Liver Metastasis: Report of One Case.

BACKGROUND: Liver transplantation in combination with chemotherapy in postoperative biliary rhabdomyosarcoma recurrence of children was evaluated. METHODS: An 8-year-old girl with biliary rhabdomyosarcoma underwent pancreatico-duodenectomy with postoperative vincristine (VCR), adriamycin (Act-D), and cyclophosphamide (CTX) (VAC chemotherapy) (VCR, 1 mg; Act-D, 0.7 mg; CTX, 1500 mg). Two years later, liver metastasis in the left and right lobes was found and was followed by VAC chemotherapy (CTX, 1800 mg; Act-D, 0.9 mg; VCR, 1.2 mg), with no change of the tumor size. One and a half years later, liver transplantation performed with postoperative pathology confirmed embryonal rhabdomyosarcoma recurrence and was followed by VAC chemotherapy (CTX, 1400 mg; Act-D, 0.7 mg; VCR, 1.9 mg) and immunosuppression treatment. RESULTS: The liver transplantation went well, with no major complications. At the time of this report, the patient had survived for 6 months, with a good quality of life and no tumor recurrence. CONCLUSIONS: For unresectable biliary rhabdomyosarcoma without extra-hepatic metastases, liver transplantation could be an effective treatment. Liver transplantation completely removes the tumor and reduces the long-term side effects of chemotherapy drugs.

Persistence of antibodies acquired by natural hepatitis E virus infection and effects of vaccination.

OBJECTIVE: Naturally acquired anti-hepatitis E virus (HEV) immunity can protect against new HEV infections. The aim of this study was to analyse the persistence of naturally acquired anti-HEV immunoglobulin (Ig) G and anti-HEV IgG concentrations after vaccination. METHODS: We examined the seropositivity rates of participants included in a phase 3 clinical efficacy trial (67 months' follow-up) for a HEV vaccine (Hecolin; Xiamen Innovax Biotech, China) and predicted long-term persistence using mixed-effect models. RESULTS: The analysis focused on 2242 baseline seropositive participants in a control group (placebo recipients) and 2031 baseline seropositive participants in an vaccine group (vaccine recipients) who received 1 to 3 doses of Hecolin. Naturally acquired anti-HEV IgG levels decreased steadily independent of the initial antibody level; 50% of the placebo recipients were expected to have undetectable antibody concentrations after 14.5 years. After immunization with Hecolin, the power-law model and the modified power-law model predicted that 82.1 and 99.4% of the participants, respectively, would remain seropositive for anti-HEV IgG for 30 years after vaccination. CONCLUSIONS: Whereas naturally acquired anti-HEV IgG levels decrease steadily, HEV vaccination induces long-lasting, high-level anti-HEV IgG concentrations.

Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice

Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR), and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K) and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P) 12 were challenged with ovalbumin (OVA). Separate groups of mice (n=18/group) were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

The role of ZNRF2 in the growth of non-small cell lung cancer.

OBJECTIVE: ZNRF2 belongs to ubiquitin ligases of the RING superfamily, and has been recently shown to be regulated by Akt to interact with a Mechanistic target of rapamycin (mTor). Nevertheless, a role of ZNRF2 in tumorigenesis, especially in non-small cell lung cancer (NSCLC), is unknown. Here, we assessed ZNRF2 expression in NSCLC. PATIENTS AND METHODS: We examined ZNRF2 levels by Western blot using NSCLC specimens, compared to the paired non-tumor controls. We also examined the effects of ZNRF2 on cell growth and cell survival in the presence of fluorouracil. RESULTS: We detected significant higher levels of ZNRF2 and mTor in NSCLC tissues, compared to the paired non-tumor controls. Moreover, ZNRF2 and mTor levels strongly correlated in NSCLC tissues. High ZNRF2 levels were correlated with poor prognosis of the NSCLC patients. In vitro, overexpression of ZNRF2 increased NSCLC cell growth and suppressed apoptotic cell death in the presence of Fluorouracil, while depletion of ZNRF2 decreased NSCLC cell growth and increased apoptotic cell death in the presence of fluorouracil. ZNRF2 appeared to augment mTor and its downstream targets CyclinD1 and CDK in NSCLC cells. CONCLUSIONS: ZNRF2 may be a promising target for treating NSCLC.

Bioinformatic analysis of RNA-seq data unveiled critical genes in rectal adenocarcinoma.

OBJECTIVE: RNA-seq data of rectal adenocarcinoma (READ) were analyzed with bioinformatics tools to unveil potential biomarkers in the disease. MATERIALS AND METHODS: RNA-seq data of READ were downloaded from The Cancer Genome Atlas (TCGA) database. Differential analysis was performed with package edgeR. False discovery rate (FDR) < 0.05 and |log2 (fold change)|>1 were set as cut-off values to screen out differentially expressed genes (DEGs). Gene coexpression network was constructed with package Ebcoexpress. Gene Ontology enrichment analysis was performed for the DEGs in the gene coexpression network with DAVID online tool. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was also performed for the genes with KOBASS 2.0. RESULTS: A total of 620 DEGs, 389 up-regulated genes, and 231 down-regulated genes, were identified from 163 READ samples and 9 normal controls. A gene coexpression network consisting of 71 DEGs and 253 edges were constructed. Genes were associated with ribosome and focal adhesion functions. Three modules were identified, in which genes were involved in muscle contraction, negative regulation of glial cell proliferation and extracellular matrix organization functions, respectively. Several critical hub genes were disclosed, such as RPS2, MMP1, MMP11 and FAM83H. Thirteen relevant small molecule drugs were identified, such as scriptaid and spaglumic acid. A total of 8 TFs and 5 miRNAs were acquired, such as MYC, NFY, STAT5A, miR-29, miR-200 and miR-19. CONCLUSIONS: Several critical genes and relevant drugs, TFs and miRNAs were revealed in READ. These findings could advance the understanding about the disease and benefit therapy development.

The FIB-4 score predicts postoperative short-term outcomes of hepatocellular carcinoma fulfilling the milan criteria.

BACKGROUND: The fibrosis score 4 (FIB-4) score is a useful tool to determine the degree of hepatic fibrosis. Liver fibrosis and cirrhosis are well-known predictors of postoperative complications after hepatectomy. This study examined the impact of FIB-4 on postoperative short-term outcomes of patients with hepatocellular carcinoma (HCC). METHODS: Three hundred and fifty patients undergoing hepatectomy for HCC between 2008 and 2013 were enrolled. The receiver operating characteristic (ROC) curve analysis was performed to determine the cutoff value of the FIB-4. Univariate and multivariate analysis was performed to identify the risk factors. The correlation of the preoperative FIB-4 value with clinicopathological parameters was examined. RESULTS: Postoperative complications were observed in 202 (57.7%) patients. The optimal cutoff value of the FIB-4 was set at 2.88 and 3.85 for postoperative complications and intraoperative blood loss respectively. It was also an independent prognostic factor for postoperative complications (hazard ratio [HR], 1.202; 95% CI, 1.076-1.344; P = 0.001) and intraoperative blood loss (HR, 1.196; 95% CI, 1.091-1.343; P < 0.001) by multivariate analysis. The FIB-4 was significantly correlated with age, liver function, coagulation function, blood loss, intraoperative blood transfusion (all P < 0.05). CONCLUSION: Preoperative FIB-4 is a useful index to predict postoperative outcomes in patients with HCC. The FIB-4 should be assessed routinely for hepatocellular carcinoma patients.

Cigarette smoking increases risk of early morbidity after hepatic resection in patients with hepatocellular carcinoma.

AIMS: Cigarette smoking is an important risk factor for the development of postoperative pulmonary complications after major surgical procedures. The objective of this study was to investigate whether preoperative smoking has any impact on early morbidity after liver resection for hepatocellular carcinoma (HCC). METHODS: Data of 425 consecutive patients undergoing partial hepatectomy for HCC was retrospectively reviewed. Smoking and drinking habits, biochemical tests, tumor status, operation data, and any postoperative complications occurring before discharge from the hospital were documented. The risk factors promoting postoperative complications were analyzed by univariate and multivariate methods. RESULTS: The overall morbidity rate was 40% (170 of 425). 166 patients were current smokers (39%). By multivariate analysis, liver cirrhosis (Risk Ratio (RR) 4.0, 95% confidence interval (CI) 2.0-8.0), smoking status (RR 3.0, 95% CI 1.7-5.1), PY of smoking (RR 1.3, 95% CI 1.1-1.9), preoperative platelet count (RR 1.6, 95% CI 1.4-2.0) and major hepatectomy (RR 1.4, 95% CI 1.1-1.8) were independent risk factors of postoperative morbidity (all p < 0.05). Liver failure, bile leakage, intractable ascites, chest and wound infection were more frequently occurred in smokers than non-smokers. Current smokers had higher postoperative morbidity than non- & former smokers in patients with normal liver and those with liver cirrhosis (p = 0.047 and p < 0.001, respectively). CONCLUSIONS: Cigarette smoking is an independent risk factor for the development of liver-related and infectious complications in patients undergoing partial hepatectomy for HCC, especially in those with liver cirrhosis.

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury.

Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-κB-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.