The microbiome of lower respiratory tract and tumor tissue in lung cancer manifested as radiological ground-glass opacity.

Recent studies have confirmed the existence of microbiota in the lungs. The relationship between lung ground-glass opacity (GGO) and microbiota in the lung microenvironment is not clear. In this study, we investigated the microbial composition and diversity in bronchoalveolar lavage fluid (BALF) of diseased lung segments and paired contralateral healthy lung segments from 11 GGO patients. Furthermore, lung GGO and paired normal tissues of 26 GGO patients were explored whether there are microbial characteristics related to GGO. Compared with the control group, the community richness of GGO tissue and BALF of GGO lung segment (α-diversity) and overall microbiome difference (ß-diversity) had no significant difference. The microbiome composition of BALF of GGO segments is distinct from that of paired healthy lung segments [genus (Rothia), order (Lachnospiraceae), family (Lachnospiraceae), genus (Lachnospiraceae_NK4A136_group, Faecalibacterium), and species (Faecalibacterium prausnitzii, Bacteroides uniforms)]. GGO tissue and adjacent lung tissue had more significant differences at the levels of class, order, family, genus, and species level, and most of them are enriched in normal lung tissue. The area under the curve (AUC) using 10 genera-based biomarkers to predict GGO was 91.05% (95% CI: 81.93-100%). In conclusion, this study demonstrates there are significant differences in the lower respiratory tract and lung microbiome between GGO and the non-malignant control group through the BALF and lung tissues. Furthermore, some potential bacterial biomarkers showed good performance to predict GGO.

Simultaneous uniportal video-assisted thoracic surgery for pulmonary nodules and synchronous mediastinal lesions.

INTRODUCTION: Video-assisted thoracic surgery (VATS) has been widely accepted in the diagnosis and treatment of thoracic diseases for the past three decades due to its small incision, minimal trauma, and rapid recovery after surgery. A growing number of patients with concurrent pulmonary nodules and mediastinal lesions have been detected. Simultaneous ipsilateral resection of coexisting lesions is a preferred procedure. AIM: To introduce our technique and preliminary experience in performing uniportal video-assisted thoracic surgery (VATS) for the simultaneous resection of pulmonary and mediastinal lesions. MATERIAL AND METHODS: We retrospectively analysed 8 consecutive patients who underwent simultaneous uniportal VATS resection of coexisting lesions of the lung and mediastinum in our centre. The clinical data were recorded and analysed. RESULTS: A total of 8 patients were enrolled, and all patients successfully underwent surgery through a single incision; no perioperative deaths occurred. The average single incision length was 3.9 ±0.3 cm, the operative time was 102.3 ±54.4 min, and the bleeding volume was 27.5 ±17.9 ml. The thoracic drainage time was 3.0 ±2.3 days, with a mean volume of 390.6 ±361.3 ml. The length of postoperative hospital stay was 4.0 ±1.9 (range: 3-9) days. No serious complications were observed in the hospital or during postoperative follow-up. CONCLUSIONS: Uniportal VATS is feasible and safe for the simultaneous resection of pulmonary and mediastinal lesions in selected patients and offers cosmetically pleasing incisions and promising clinical application prospects.

Exploration of Prognostic Biomarkers for Lung Adenocarcinoma Through Bioinformatics Analysis.

With the development of computer technology, screening cancer biomarkers based on public databases has become a common research method. Here, an eight-gene prognostic model, which could be used to judge the prognosis of patients with lung adenocarcinoma (LUAD), was developed through bioinformatics methods. This study firstly used several gene datasets from GEO database to mine differentially expressed genes (DEGs) in LUAD tissue and healthy tissue via joint analysis. Later, enrichment analysis for the DEGs was performed, and it was found that the DEGs were mainly activated in pathways involved in extracellular matrix, cell adhesion, and leukocyte migration. Afterward, a TCGA cohort was used to perform univariate Cox, least absolute shrinkage and selection operator method, and multivariate Cox regression analyses for the DEGs, and a prognostic model consisting of eight genes (GPX3, TCN1, ASPM, PCP4, CAV2, S100P, COL1A1, and SPOK2) was established. Receiver operation characteristic (ROC) curve was then used to substantiate the diagnostic efficacy of the prognostic model. The survival significance of signature genes was verified through the GEPIA database, and the results exhibited that the risk coefficients of the eight genes were basically congruous with the effects of these genes on the prognosis in the GEPIA database, which suggested that the results were accurate. Finally, combined with clinical characteristics of patients, the diagnostic independence of the prognostic model was further validated through univariate and multivariate regression, and the results indicated that the model had independent prognostic value. The overall finding of the study manifested that the eight-gene prognostic model is closely related to the prognosis of LUAD patients, and can be used as an independent prognostic indicator. Additionally, the prognostic model in this study can help doctors make a better diagnosis in treatment and ultimately benefit LUAD patients.

Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer.

Nuclear factor erythroid-2-related factor-2 (NFE2L2/Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Both Kelch-like ECH-associated protein 1 (Keap1) mutations and Nrf2 mutations contribute to the activation of Nrf2 in non-small cell lung cancer (NSCLC). Nrf2 activity is associated with poor prognosis in NSCLC. Metabolic reprogramming represents a cancer hallmark. Increasing studies reveal that Nrf2 activation promotes metabolic reprogramming in cancer. In this review, we discuss the underlying mechanisms of Nrf2-mediated metabolic reprogramming and elucidate its role in NSCLC. Inhibition of Nrf2 can alter metabolic processes, thus suppress tumor growth, prevent metastasis, and increase sensitivity to chemotherapy in NSCLC. In conclusion, Nrf2 may serve as a therapeutic target for the treatment of NSCLC.

The diagnostic value of a seven-autoantibody panel and a nomogram with a scoring table for predicting the risk of non-small-cell lung cancer.

The early detection of non-small-cell lung cancer (NSCLC) remains a common concern. The aim of our study was to validate the diagnostic value of a seven-autoantibody (7-AAB) panel compared with radiological diagnosis for NSCLC. We constructed a nomogram and a scoring table based on the 7-AAB panel's result to predict the risk of NSCLC. We prospectively enrolled 268 patients who presented with radiological lesions and underwent both the 7-AAB panel test and pathological diagnosis by surgical resection. A comparison between the 7-AAB panel and radiological diagnosis was performed. A nomogram and a scoring table based on the 7-AAB panel's result to predict the risk of NSCLC were constructed and internally validated. The 7-AAB panel test had a specificity of 90.2% and a positive predictive value (PPV) of 92.7%, which were significantly higher than those of the radiological diagnosis. The 7-AAB panel also showed a preferable sensitivity in patients with early-stage disease. Seven factors, including the 7-AAB panel results, were integrated into the nomogram. For more convenient application, we formulated a scoring table based on the nomogram. The area under the receiver operating characteristic curve was 0.840 and 0.860 in the training group and validation group, respectively, which was higher than that using the 7-AAB panel or radiological diagnosis alone. This study reveals that our 7-AAB panel has clinical value in the diagnosis of NSCLC. The utility of our nomogram and the scoring table indicated that they have the potential to assist clinicians in avoiding unnecessary treatment or needless follow-up.

High Expression of Human AugminComplex Submit 3 Indicates Poor Prognosis and Associates with Tumor Progression in Hepatocellular Carcinoma.

The function of human augmin complex unit 3(Haus3), a component of the HAU augmin-like complex, in various cancers is not clear. This study aims to elucidate the clinical significance and the role of Haus3 in tumor progression of hepatocellular carcinoma (HCC). We analyzed the expression of Haus3 in 50 HCC patients from The Cancer Genome Atlas and 137 HCC patients in our hospital. Compared with adjacent normal tissue, Haus3 expression assessed by immunohistochemical staining was dramatically increased in tumor tissues. A high level of Haus3 expression was significantly correlated with large tumor size (p=0.025) and tumor multiplicity (p=0.004). Univariate and multivariate survival analysis showed thatexpression of Haus3 was an independent prognostic factor for overall survival ofHCCpatients. Western blot analysis showed that Haus3 regulated the phosphorylation of PLK1-T210 and activity of the Cdk1/cyclin B1 complex, indicating that Haus3 disrupted G2/M phase arrest. In immunofluorescence studies, expression of Haus3 correlated with the level ofα-tubulin and γ-tubulin. In summary, Haus3 plays a vital role in regulatingtheactivityof PLK2-T210 and Cdk1/cyclin B1 complex in G2/M phasetransition and the expression of tubulins to ensure normal mitotic progression. Our data suggest that Haus3 might be a promising prognostic biomarker and molecular target of HCC.

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c-Myb-regulated MEK/ERK signaling.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in hepatocellular carcinoma (HCC). Here, we reported a novel lncRNA, CTC-505O3 (lncRNA DRHC), that was downregulated in HCC and its low expression was associated with dismal survival. Gain-of-function studies indicated that it inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in HCC cell lines in vitro. lncRNA DRHC also inhibited tumorigenicity in vivo. In mechanistic experiments, GO analysis based on NGS indicated that MAPK signaling was most affected. The result was confirmed by Western blot and this effect was abolished either by MEK1/2 specific inhibitor Trametinib or ERK1/2 inhibitor SCH772984. In addition, differences in proliferation and invasion were abrogated by Trametinib. Moreover, we found that lncRNA DRHC interacted with MYBBP1A and modulated MEK/ERK signaling via c-Myb. Taken together, our findings indicate that the lncRNA DRHC play a key role in HCC progression and may serve as a novel therapeutic target.

Development of models to predict early post-transplant recurrence of hepatocellular carcinoma that also integrate the quality and characteristics of the liver graft: A national registry study in China.

BACKGROUND: Donor characteristics and graft quality were recently reported to play an important role in the recurrence of hepatocellular carcinoma after liver transplantation. Our aim was to establish a prognostic model by using both donor and recipient variables. METHODS: Data of 1,010 adult patients (training/validation: 2/1) undergoing primary liver transplantation for hepatocellular carcinoma were extracted from the China Liver Transplant Registry database and analyzed retrospectively. A multivariate competing risk regression model was developed and used to generate a nomogram predicting the likelihood of post-transplant hepatocellular carcinoma recurrence. RESULTS: Of 673 patients in the training cohort, 70 (10.4%) had hepatocellular carcinoma recurrence with a median recurrence time of 6 months (interquartile range: 4-25 months). Cold ischemia time was the only independent donor prognostic factor for predicting hepatocellular carcinoma recurrence (hazard ratio = 2.234, P = .007). The optimal cutoff value was 12 hours when patients were grouped according to cold ischemia time at 2-hour intervals. Integrating cold ischemia time into the Milan criteria (liver transplantation candidate selection criteria) improved the accuracy for predicting hepatocellular carcinoma recurrence in both training and validation sets (P < .05). A nomogram composed of cold ischemia time, tumor burden, differentiation, and α-fetoprotein level proved to be accurate and reliable in predicting the likelihood of 1-year hepatocellular carcinoma recurrence after liver transplantation. Additionally, donor anti-hepatitis B core antibody positivity, prolonged cold ischemia time, and anhepatic time were linked to the intrahepatic recurrence, whereas older donor age, prolonged donor warm ischemia time, cold ischemia time, and ABO incompatibility were relevant to the extrahepatic recurrence. CONCLUSION: The graft quality integrated models exhibited considerable predictive accuracy in early hepatocellular carcinoma recurrence risk assessment. The identification of donor risks can further help understand the mechanism of different patterns of recurrence.

Peroxiredoxins in inflammatory liver diseases and ischemic/reperfusion injury in liver transplantation.

Peroxiredoxins (Prxs) belong to the superfamily of thiol-dependent peroxidases, and remove reactive oxygen species (ROS) and other oxidative stress products. The expression and activity of Prxs can be substantially affected by stimuli from the microenvironment, and in turn regulate cytokine secretion in the context of inflammation in both peroxidase-dependent and -independent pathways. Prxs translocate to mitochondria and are hyperoxidized during acute liver damage, and attenuate intracellular ROS accumulation through their peroxidase activity. In particularly, Prx1 modulates the microenvironment in liver injuries by reducing adhesion molecule expression in vascular endothelial cells and inhibiting the inflammatory response and adhesion of macrophages. Prxs have potent prosurvival effects against ROS in ischemic/reperfusion (I/R) injury, but Prxs released from necrotic cells increase secretion of inflammatory cytokines by macrophages through TLR2 and 4 activation, which promotes cell death. Prxs can be used as biomarkers to evaluate I/R injury and predict graft survival in liver transplantation. Prxs are modulated in various types of chronic hepatitis and hepatosteatosis, and mediate disease progression. Alcohol administration increases oxidization and inactivation of Prxs in mice because of oxidative stress. In conclusion, Prxs are essential mediators and biomarkers in inflammatory liver diseases and I/R injury.

CR6-interacting factor 1 inhibits invasiveness by suppressing TGF-ß-mediated epithelial-mesenchymal transition in hepatocellular carcinoma.

CR6-interacting factor 1 (CRIF1) regulates cell cycle progression and the DNA damage response. Here, we show that CRIF1 expression is decreased in hepatocellular carcinoma (HCC) tissues and positively correlates with patients' survival. In vitro, down-regulation of CRIF1 promotes HCC cell proliferation and invasiveness, while over-expression has the opposite effect. in vivo, CRIF1 knockdown enhances growth of HCC xenografts. Analysis of mRNA microarrays showed that CRIF1 knockdown activates genes involved in TGF-ß RI/Smad2/3 signaling, leading to epithelial-mesenchymal transition (EMT) and increased matrix metalloproteinase-3 (MMP3) expression. However, cell invasion and EMT are abrogated in HCC cells treated with SB525334, a specific TGF-ß RI inhibitor, which indicates the inhibitory effect of CRIF1 on HCC tumor growth is mediated by TGF-ß signaling. These results demonstrate that CRIF1 benefits patient survival by inhibiting HCC cell invasiveness through suppression of TGF-ß-mediated EMT and MMP3 expression. This suggests CRIF1 may serve as a novel target for inhibiting HCC metastasis.

A national report from China Liver Transplant Registry: steroid avoidance after liver transplantation for hepatocellular carcinoma.

OBJECTIVE: We aimed to evaluate the efficacy and safety of steroid-free immunosuppression after liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed HCC recipients without steroids after LT (SF group, n=368) based on the China Liver Transplant Registry (CLTR) database. These recipients were matched 1:2 with patients using steroids (S group, n=736) for the same period after LT for HCC, according to propensity scores. RESULTS: Multivariate analysis indicates that recipients with younger age [odds ratio (OR), 1.053; P=0.011], preoperative hepatitis B virus (HBV) DNA ≥1,000 copies/mL (OR, 2.597; P=0.004) and beyond Milan criteria (OR, 4.255; P<0.001) were identified as the risk factors associated with tumor recurrence in steroid avoidance recipients after LT. The patients fulfilling the Milan criteria in the SF group presented higher overall and tumor-free survival rates than those in the S group (P<0.05). Multivariate analysis revealed that recipient beyond Milan criteria was an independent prognostic factor for overall survival (OR, 1.690; P<0.001) and tumor-free survival (OR, 2.066; P<0.001). The incidences of new-onset diabetes mellitus (21.20%vs. 33.29%, P<0.001), new-onset hypertension (10.05%vs. 18.61%, P<0.001) and hyperlipidemia (4.08%vs. 7.20%, P=0.042) were significantly lower in the SF group. CONCLUSIONS: Steroid-free immunosuppression could be safe and feasible for HBV-related HCC patients in LT. Age, HBV DNA level and Milan criteria maybe risk factors associated with tumor recurrence in steroid avoidance recipients. Recipient beyond Milan criteria was an independent prognostic factor and recipient fulfilling Milan criteria can benefit the most from steroid-free immunosuppression.

A good prognostic predictor for liver transplantation recipients with benign end-stage liver cirrhosis.

BACKGROUND: Post-transplant model for predicting mortality (PMPM, calculated as -5.359+1.988Xln (serum creatinine [mg/dL])+1.089Xln (total bilirubin [mg/dL])) score has been proved to be a simple and accurate model for predicting the prognosis after liver transplantation (LT) in a single center study. Here we aim to verify this model in a large cohort of patients. METHODS: A total of 2727 patients undergoing LT with end-stage liver cirrhosis from January 2003 to December 2010 were included in this retrospective study. Data were collected from the China Liver Transplant Registry (CLTR). PMPM score was calculated at 24-h and 7-d following LT. According to the PMPM score at 24-h, all patients were divided into the low-risk group (PMPM score ≤-1.4, n=2509) and the high-risk group (PMPM score >-1.4, n=218). The area under receiver operator characteristic curve (AUROC) was calculated for evaluating the prognostic accuracy. RESULTS: The 1-, 3-, and 5-year patient survival rates in the low-risk group were significantly higher than those in the high-risk group (90.23%, 88.01%, and 86.03% vs 63.16%, 59.62%, and 56.43%, respectively, P<0.001). In the high-risk group, 131 patients had a decreased PMPM score (≤-1.4) at 7-d, and their cumulative survival rate was significantly higher than the other 87 patients with sustained high PMPM score (>-1.4) (P<0.001). For predicting 3-month mortality, PMPM score showed a much higher AUROC than post-transplant MELD score (P<0.05). CONCLUSION: PMPM score is a simple and effective tool to predict short-term mortality after liver transplantation in patients with benign liver diseases, and an indicator for prompt salvaging treatment as well.

Predicting short-term survival after liver transplantation on eight score systems: a national report from China Liver Transplant Registry.

To compare the performance of eight score systems (MELD, uMELD, MELD-Na. iMELD, UKELD, MELD-AS, CTP, and mCTP) in predicting the post-transplant mortality, we analyzed the data of 6,014 adult cirrhotic patients who underwent liver transplantation between January 2003 and December 2010 from the China Liver Transplant Registry database. In hepatitis B virus (HBV) group, MELD, uMELD and MELD-AS showed good predictive accuracies at 3-month mortality after liver transplantation; by comparison with other five models, MELD presented the best ability in predicting 3-month, 6-month and 1-year mortality, showing a significantly better predictive ability than UKELD and iMELD. In hepatitis C virus and Alcohol groups, the predictive ability did not differ significantly between MELD and other models. Patient survivals in different MELD categories were of statistically significant difference. Among patients with MELD score >35, a new prognostic model based on serum creatinine, need for hemodialysis and moderate ascites could identify the sickest one. In conclusion, MELD is superior to other score systems in predicting short-term post-transplant survival in patients with HBV-related liver disease. Among patients with MELD score >35, a new prognostic model can identify the sickest patients who should be excluded from waiting list to prevent wasteful transplantation.

iRGD-Decorated Polymeric Nanoparticles for the Efficient Delivery of Vandetanib to Hepatocellular Carcinoma: Preparation and in Vitro and in Vivo Evaluation.

Molecularly targeted agents that are designed to target specific lesions have been proven effective as clinical cancer therapies; however, most currently available therapeutic agents are poorly water-soluble and require oral administration, thereby resulting in low bioavailability and a high risk of side effects due to dose intensification. The rational engineering of systemically injectable medicines that encapsulate such therapeutic payloads may revolutionize anticancer therapies and remains an under-explored area of drug development. Here, the injectable delivery of a nanomedicine complexed with an oral multitargeted kinase inhibitor, vandetanib (vanib), was explored using polymeric nanoparticles (NPs) to achieve the selective accumulation of drug payloads within tumor lesions. To demonstrate this concept, we used biodegradable amphiphilic block copolymer poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA) to nanoprecipitate this potent agent to form water-soluble NPs that are suitable for intravenous administration. NP-vanib induced cytotoxic activity by inhibiting the angiogenetic events mediated by VEGFR and EGFR kinases in tested cancer cells and inhibited the growth, tube formation and metastasis of HUVECs. The intravenously injection of NP-vanib into mice bearing HCC BEL-7402 xenografts more effectively inhibited the tumor than the oral administration of vanib. In addition, due to the modular design of these NPs, the drug-loaded particles can easily be decorated with iRGD, a tumor-homing and -penetrating peptide motif, which further improved the in vivo performance of these vanib-loaded NPs. Our results demonstrate that reformulating targeted therapeutic agents in NPs permits their systemic administration and thus significantly improves the potency of currently available, orally delivered agents.

Efficacy and Safety of a Steroid-Free Immunosuppressive Regimen after Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND/AIMS: We aimed to evaluate the efficacy and safety of an immunosuppressive regimen without steroids after liver transplantation (LT) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: Sixty-six HCC patients who underwent an immunosuppressive regimen without steroids after LT were enrolled in the steroid-free group. The preoperative characteristics and postoperative outcomes of these patients were compared with those of 132 HCC recipients who were placed on an immunosuppressive regimen using steroids (steroid group). The incidence of acute rejection, HBV recurrence, infection, and new-onset diabetes mellitus and the overall and tumor-free survival rates were compared between the two groups. RESULTS: Differences were not observed in the 1-year (83.3% vs 97.0%, p=0.067), 3-year (65.4% vs 75.8%, p=0.067) or 5-year (56.3% vs 70.7%, p=0.067) patient survival rates or in the 1-year (62.1% vs 72.7%, p=0.067), 3-year (49.8% vs 63.6%, p=0.067) or 5-year (48.6% vs 63.6%, p=0.067) tumor-free survival rates between the two groups, respectively. In the steroid-free group, the patients who fulfilled the Milan criteria had higher overall and tumor-free survival rates than those in the steroid group (p<0.001). The prevalence of HBV recurrence (3.0% vs 13.6%, p=0.02) was significantly lower in the steroid-free group compared with the steroid group. CONCLUSIONS: After LT, an immunosuppressive regimen without steroids could be a safe and feasible treatment for HBVrelated HCC patients, thus resulting in the reduction of HBV recurrence. Based on the observed survival rates, patients who fulfill the Milan criteria may derive benefits from teroidfree immunosuppression.

New-onset diabetes after liver transplantation: a national report from China Liver Transplant Registry.

BACKGROUND/AIMS: New-onset diabetes after transplantation (NODAT) is a serious complication of liver transplantation (LT). The present study aimed to investigate the risk factors of NODAT by a national survey using the China Liver Transplant Registry database. PATIENTS: A total of 10 204 non-pre-existing diabetic patients undergone primary LT between January 2000 and December 2013 were included. Risk factors were identified by logistic regression analysis. RESULTS: NODAT occurred in 24.3% of liver recipients with a median follow-up time of 2.6 years, and was associated with a significantly lower patient survival. NODAT increased not only diabetes related complications (e.g., infection, kidney failure) but also biliary stricture and cholangitis. NODAT patients who received hypoglycaemic treatment had a worse prognosis and a higher hepatocellular carcinoma recurrence compared with those without treatment. New-onset hyperglycaemia (<30 days) was the major predictor of NODAT. Other risk factors included cold ischaemia time >9 h, recipient age >50 years, body mass index >25 kg/m(2) , other hepatitis (mainly hepatitis C), post-transplant intensive care unit stay >15 days, cytomegalovirus infection and corticosteroid at discharge. CONCLUSIONS: The incidence of NODAT in China is similar to that in Western countries. However, the NODAT-related complications are more common and severer in China compared with those in Western countries. The major risk factors are different.

The phospholipase A2 activity of peroxiredoxin 6 promotes cancer cell death induced by tumor necrosis factor alpha in hepatocellular carcinoma.

In this study, we used proteomic profiling to compare hepatocellular carcinoma (HCC) and peri-tumoral tissues to identify potential tumor markers of HCC. We identified eight differentially expressed proteins (>3-fold), including Peroxiredoxin 6 (PRDX6). PRDX6 is a bifunctional enzyme with both peroxidase and calcium-independent phospholipase A2 (iPLA2) activity. We found that peri-tumoral tissues expressed higher levels of PRDX6 mRNA (n = 59, P = 0.018) and protein (n = 265, P < 0.001) than HCC tissues, and that decreased expression of PRDX6 in HCC tissues was an independent risk factor indicating a poor prognosis (n = 145, P = 0.007). Combining the examination of serum PRDX6 with α-fetoprotein improved the diagnostic sensitivity of tests for HCC compared to α-fetoprotein alone (85.0% vs 50.0%, n = 40). We found that PRDX6 induced S phase arrest in HCC cells and inhibited HCC tumorigenicity in mice injected with cancer cells. When treated with H2 O2 , PRDX6 inhibited apoptosis. When treated with tumor necrosis factor alpha (TNF-α), PRDX6 promoted apoptosis. Inhibition of iPLA2 activity of PRDX6 decreased the apoptosis induced by TNF-α. In conclusion, PRDX6 inhibited the carcinogenesis of HCC, and the iPLA2 activity of PRDX6 promoted cancer cell death induced by TNF-α. © 2015 Wiley Periodicals, Inc.

Coding-noncoding gene expression in intrahepatic cholangiocarcinoma.

Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in human cancers. However, the function of lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of intrahepatic cholangiocarcinoma (ICC). In the present study, we performed transcriptomic profiling of ICC and paired adjacent noncancerous tissues (N) by using lncRNA and messenger RNA (mRNA) microarrays. Quantitative real-time polymerase chain reaction was used to validate the microarray results. We tested for correlations between the expression levels of lncRNAs and target genes. Clinicopathologic characteristics and overall survival were compared using the t test and the Kaplan-Meier method, respectively. A total of 2773 lncRNAs were significantly upregulated in ICC tissues compared with the noncancerous tissues, whereas 2392 lncRNAs were downregulated. Bioinformatic analysis indicated that most of the genes were involved in carcinogenesis, hepatic system diseases, and signal transductions. Positive correlations were found between 4 lncRNA-mRNA pairs (RNA43085 and SULF1, RNA47504 and KDM8, RNA58630 and PCSK6, and RNA40057 and CYP2D6). When the clinicopathologic characteristics were accounted for, the cumulative overall survival rate was found to be associated with low expression levels of CYP2D6 (P = 0.005) and PCSK6 (P = 0.038). Patients with high expression levels of CYP2D6 and RNA40057 had a better prognosis (P = 0.014). Our results suggested that the lncRNA expression profiling in ICC tissues is profoundly different from that in noncancerous tissues. Thus, lncRNA may be a potential diagnostic and prognostic biomarker for ICC. Furthermore, the combined assessment of lncRNA and mRNA expressions might predict the survival of patients with ICC.

Donor PPARα Gene Polymorphisms Influence the Susceptibility to Glucose and Lipid Disorders in Liver Transplant Recipients: A Strobe-Compliant Observational Study.

Peroxisome proliferator-activated receptor α (PPARα) is an important regulator of glucose and lipid metabolism, and is predominantly expressed in the liver. We aimed to evaluate the effect of donor hepatic PPARα gene polymorphisms on the development of metabolic disorders following liver transplantation (LT).A total of 176 patients undergoing primary LT were included in this Review Board-approved study. Genomic DNA was extracted from fresh frozen donor liver tissues (biopsy specimens for pathological testing at surgery). Eight single nucleotide polymorphisms in the PPARα gene were chosen from either the HapMap CHB database or previous reports.The distribution of metabolic disorders differed significantly between the wild-type and variant genotypes of both the rs5767743 and rs5767700 loci (P < 0.05 for all). After an adjustment for other factors (body mass index and tacrolimus blood concentration), the rs5767743 genetic variant was found to be an independent protective factor (P = 0.005, odds ratio = 0.416 per C allele, 95% confidence interval  = 0.225-0.768). When compared with the wild-type genotype, the variant genotypes rs5767743 and rs5767700 correlated with significantly increased PPARα and CYP3A4 mRNA expression and lower tacrolimus trough concentration/dose ratios (P < 0.05 for all).Donor PPARα gene polymorphisms influence the susceptibility to metabolic disorders following LT and may also be associated with a fasten tacrolimus metabolism because of elevated CYP3A4 expression.

Chloride intracellular channel 1 participates in migration and invasion of hepatocellular carcinoma by targeting maspin.

BACKGROUND AND AIM: Our previous proteomic research found that chloride intracellular channel 1 (CLIC1) was upregulated in hepatocellular carcinoma (HCC) tissues with portal vein tumor thrombus. The present study aimed to determine the role of CLIC1 in HCC invasion. METHODS: Immunohistochemistry was used to explore protein expression of CLIC1 in 15 cirrhotic tissues and 69 pairs of HCC and paracarcinoma tissues. Small interfering RNA (siRNA) and plasmids were transfected into HepG2 and SMMC7721 cells, and the in vitro function of CLIC1 in these cells were assessed with cell counting kit-8 assays, cell apoptosis assays, scratch assays, and transwell assays. Microarray analysis was also performed to further explore the candidate genes related to CLIC1. RESULTS: Our results confirmed that upregulated CLIC1 expression was significantly correlated with vascular invasion (P = 0.034) in HCC tissues. Knockdown of CLIC1 decreased cell viability and the invasive potency of HepG2 cells, whereas CLIC1 overexpression resulted in an opposite effect in SMMC7721 cells. Microarray analysis identified 618 genes that were differentially expressed (fold change ≥ 2, P < 0.05) between HepG2 cells transfected with CLIC1 siRNA and the negative control. Further studies indicate that knockdown of CLIC1 increased maspin expression and reduced vascular endothelial growth factor (VEGF), matrixmetalloproteinase-2 (MMP2), MMP9, MMP11, and MMP12 expression. In contrast, overexpression of CLIC1 decreased maspin expression and increased VEGF, MMP2, MMP12, and MMP13 expression. CONCLUSIONS: CLIC1 protein expression is significantly correlated with vascular invasion, and the present study suggests a previously unknown mechanism of CLIC1-mediated control of HCC invasiveness by targeting maspin.