Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

LncRNA THEMIS2-211, a tumor-originated circulating exosomal biomarker, promotes the growth and metastasis of hepatocellular carcinoma by functioning as a competing endogenous RNA.

Hepatocellular carcinoma (HCC) is a major challenge for human health. Finding reliable diagnostic biomarkers and therapeutic targets for HCC is highly desired in the clinic. Currently, circulating exosomal lncRNA is a promising biomarker for the diagnosis of cancer and lncRNA is also a potential target in cancer therapy. Here, the diagnostic value of a panel based on exosomal lncRNA THEMIS2-211 and PRKACA-202, superior to that of AFP, was identified for diagnosing human HCC. Besides, the performance of exosomal lncRNA THEMIS2-211 alone exceeds that of AFP in diagnosing early-stage HCC patients (stage I). Furthermore, lncRNA THEMIS2-211 is highly expressed in HCC tissues and correlated with the poor prognosis of HCC patients. LncRNA THEMIS2-211 is upregulated and localized in the cytoplasm of HCC cells. LncRNA THEMIS2-211 exerts its biological function as an oncogene that promotes the proliferation, migration, invasion, EMT of HCC cells by physically interacting with miR-940 and therefore promoting SPOCK1 expressions. Rescue assays show the regulation of SPOCK1 by lncRNA THEMIS2-211 dependents on miR-940. The discovery of lncRNA THEMIS2-211 further illuminates the molecular pathogenesis of HCC and the THEMIS2-211/miR-940/SPOCK1 axis may act as a potential therapeutic target for HCC.

Interleukin 1 beta-induced chloride currents are important in osteoarthritis onset: an in vitro study.

Persistent hypotonic and inflammatory conditions in the joint cavity can lead to the loss of cartilage matrix and cell death, which are the important mechanisms of osteoarthritis (OA) onset. Previous studies have confirmed that the existence of a hypotonic environment is a red flag for inflammation, as hypotonic environment induces the opening of the chloride channel of the cell and promotes chloride ion efflux, which prompts the cell volume to increase. Chloride channels play an important role in the regulation of mineralization and chondrocyte death. Here, we reported that OA chondrocytes showed a significant increase of cell death rate and the imbalance of cartilage matrix catabolism. We found that the distribution of skeleton protein F-actin was disordered. In addition, the volume-sensitive chloride current of OA chondrocytes decreased significantly with the increase of the expression levels of inflammation-related proteins caspase-1, caspase-3, and NLRP3. Moreover, interleukin-1ß (IL-1ß) showed a potential to activate the chloride current of normal chondrocytes. These results indicate that IL-1ß-induced chloride channel opening in chondrocytes may be closely related to the occurrence of OA. This chloride channel opening process may therefore be a potential target for the treatment of OA.

Slit2 signaling contributes to cholestatic fibrosis in mice by activation of hepatic stellate cells.

Liver Cholestasis is a widespread disease of broad etiologies and ultimately results in fibrosis, which is still lacking effective therapeutic strategies. Activation of hepatic stellate cells (HSCs) is the key event of liver fibrosis. Here, we aimed to investigate the effect and mechanism of the Slit2 signaling in cholestasis-induced liver fibrosis. Our findings revealed that the serum levels and hepatic expression of Slit2 were significantly increased in patients with primary biliary cirrhosis (PBC). Additionally, Slit2-Tg mice were much more vulnerable to BDL-induced liver injury and fibrosis compared to WT control. Slit2 up-regulation by Slit2 recombinant protein induced proliferation, and inhibited apoptosis of human HSCs cell line LX-2 via p38 and ERK signaling pathway, resulting in the activation of HSCs. In contrast, Slit2 down-regulation by siRNA silencing inhibit the activation of HSCs. In conclusion, Slit2 is involved in the activation of HSCs and liver fibrogenesis, highlighting Slit2 as a potential therapeutic target for liver fibrosis.

Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker.

BACKGROUND: Integrator complex subunit 6 (INTS6) was found to play a tumour suppressing role in certain types of solid tumours. In this study, we wanted to determine the expression level of INTS6 in hepatocellular carcinoma (HCC) and evaluate its clinical characteristics and mechanisms in HCC patients (Lui and Lu, European Journal of Cancer, 51:S94, 2015). METHODS: First, we used a microarray analysis to explore the mRNA expression levels in HCC and paired normal liver tissues; second, we used qRT-PCR to measure the INTS6 mRNA levels in a cohort of 50 HCC tissues and adjacent normal liver tissues; third, we used Western blot analyses to detect the INTS6 protein levels in 20 paired HCC and normal liver tissues; fourth, we used immunohistochemistry to determine the INTS6 expression levels in 70 archived paraffin-embedded HCC samples. Finally, we investigated the suppressive function of INTS6 in the Wnt pathway. RESULTS: Herein, according to the microarray data analysis, the expression levels of INTS6 were dramatically down-regulated in HCC tissues vs. those in normal liver tissues (p<0.05). qRT-PCR and Western blot analyses showed that the INTS6 mRNA and protein expression was significantly down-regulated in tumour tissues compared to the adjacent normal liver tissues (p<0.05). Immunohistochemical assays revealed that decreased INTS6 expression was present in 62.9% (44/70) of HCC patients. Correlation analyses showed that INTS6 expression was significantly correlated with serum alpha-fetoprotein levels (AFP, p =0.004), pathology grade (p =0.005), and tumour recurrence (p =0.04). Kaplan-Meier analysis revealed that patients with low INTS6 expression levels had shorter overall and disease-free survival rates than patients with high INTS6 expression levels (p =0.001 and p =0.001). Multivariate regression analysis indicated that INTS6 was an independent predictor of overall survival and disease-free survival rates. Mechanistically, INTS6 increased WIF-1 expression and then inhibited the Wnt/ß-catenin signalling pathway. CONCLUSION: The results of our study show that down-regulated INTS6 expression is associated with a poorer prognosis in HCC patients. This newly identified INTS6/WIF-1 axis indicates the molecular mechanism of HCC and may represent a therapeutic target in HCC patients.

Pseudogene integrator complex subunit 6 pseudogene 1 (INTS6P1) as a novel plasma-based biomarker for hepatocellular carcinoma screening.

In this study, we aimed to determine whether the pseudogene integrator complex subunit 6 pseudogene 1 (INTS6P1) in plasma could be used as a novel approach to screen for and detect hepatocellular carcinoma (HCC). We explored the clinical role of INTS6P1: First, the expression level of INTS6P1 was measured in a cohort of 33 HCC tissue samples and adjacent normal liver tissue, next, the INTS6P1 expression was detected in the culture medium and tumor cells in a cellular experiment, and last, the diagnostic performance of INTS6P1 was examined in an independent cohort of 100 people. The expression level of INTS6P1 was remarkably downregulated in the HCC tissues compared with that in the normal liver tissues (p = 0.0066). In plasma, the INTS6P1 levels were significantly decreased in HCC patients compared with non-HCC patients (p < 0.01). Additionally, we inferred that INTS6P1 might be a prospective biomarker for screening HCC patients in which the serum-AFP levels were lower than 20 ng/ml by the area under the curve-receiver operating characteristic (AUC-ROC) analysis (p < 0.05). Pseudogene INTS6P1 could be used as a novel HCC plasma-based biomarker and might improve the accuracy of HCC screening.

Short-term administration of steroids does not affect postoperative complications following liver resection: Evidence from a meta-analysis of randomized controlled trials.

AIM: Although perioperative short-term administration of steroids can attenuate surgical stress response following liver resection, there is no consensus concerning the effect on postoperative complications. This study aims to use meta-analysis to quantitatively investigate the effect of perioperative short-term administration of steroids on postoperative complications following liver resection. METHODS: A systematic published work search was performed to detect randomized controlled trials (RCT) assessing the effect of perioperative short-term administration of steroids on outcomes following liver resection. Parameters of surgical stress, hospital stay and postoperative complications were analyzed. Two authors independently assessed study quality and extracted data. All data were analyzed using RevMan version 5 and meta-analyses were performed using a random-effects model. RESULTS: Five RCT published between 2001 and 2011 containing a total of 379 patients were eligible for final analysis. Serum total bilirubin, interleukin-6 and C-reactive protein were significantly lower in the steroid than in the control group on postoperative day 1 (P = 0.02, 0.004 and 0.02, respectively). There was no difference in duration of hospital stay between the steroid and control group (P = 0.37). The analysis of end-points including infective complications (odds ratio [OR], 0.95), wound complications (OR, 0.67), bile leakage (OR, 0.58) and overall complications (OR, 0.50) revealed no difference between steroid administration and no treatment. There was no postoperative death or adverse effect attributable to steroid treatment in all patients. CONCLUSION: On currently available evidence, short-term administration of steroids does not increase incidence of complications in patients undergoing liver resection.

Retinoic acid receptor-related receptor alpha (RORalpha) is a prognostic marker for hepatocellular carcinoma.

Retinoic acid receptor-related receptor alpha (RORalpha) has been proven to play a tumor suppressive role in certain types of solid tumors. However, the clinical characteristic of RORalpha has not been reported by far. This study investigated the expression of RORalpha in hepatocellular carcinoma (HCC) and evaluated its relationship with clinical parameters and prognosis in HCC patients. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot analyses were performed to detect RORalpha expression levels in 20 paired HCC and corresponding adjacent non-cancerous tissues. Immunohistochemistry was performed on 100 archived paraffin-embedded HCC samples. Statistical analyses evaluated the correlations between RORalpha expression and clinicopathological features. qRT-PCR showed that RORalpha mRNA expression was significantly down-regulated in tumors compared to the adjacent non-cancerous tissues, and Western blots found that RORalpha protein expression was also reduced in tumor tissues. Immunohistochemical assays revealed that decreased RORalpha expression was present in 65 % of HCC patients. Correlation analyses showed that RORalpha expression was significantly correlated with serum alpha fetoprotein (AFP, p = 0.005), pathology grade (p < 0.001), tumor recurrence (p = 0.008), and vascular invasion (p < 0.001). Kaplan-Meier analysis revealed that patients with low RORalpha expression levels had a shorter overall and disease-free survival than patients with high expression (p < 0.001 and p = 0.002, respectively). Multivariate regression analysis indicated that RORalpha was an independent predictor for overall survival and disease-free survival. In conclusion, the results of our study showed that down-regulated RORalpha expression was associated with poorer prognosis in HCC patients. RORalpha may be a new potential prognostic marker for HCC patients.

Integrated network pharmacology and metabolomics to dissect the mechanisms of naringin for treating cervical cancer.

INTRODUCTION: Cervical cancer is one of the malignant cancers with high mortality among women worldwide. Although vaccines and early detection have reduced cervical cancer mortality, it remains a malignancy with a high mortality rate in women. OBJECTIVE: We aimed to develop a novel integrated strategy that combines metabolomics with network pharmacology to explore the therapeutic mechanisms of naringin in cervical cancer. The mechanism of naringin intervention in cervical cancer was initially clarified by metabolomics and network pharmacology. METHODS: The method of LC-MS and network pharmacology for the detection and identification of potential biomarkers and the mechanisms of action of naringin was used. The metabolites were detected and identified based on ultra-high-performance liquid chromatography coupled with Quadrupole-Exactive Orbitrap MS (UHPLC-Q-Exactive Orbitrap MS) and followed by the network pharmacology analysis. RESULTS: In network pharmacology, naringin played a synergetic role through regulatory shared pathways, such as steroid hormone biosynthesis, sphingolipid signaling pathway and arachidonic acid metabolism, etc. Besides, the metabolomics analysis showed that 20 differential metabolites and 10 metabolic pathways were mainly involved in the therapeutic effect of naringin on cervical cancer. The result showed that naringin treatment for cervical cancer mainly occurs through the following metabolic pathways: amino acid metabolism and arachidonic acid metabolism. CONCLUSION: This work provided valuable information and a scientific basis for further studies of naringin in the treatment of cervical cancer.

Sodium cholate ameliorates nonalcoholic steatohepatitis by activation of FXR signaling.

Non-alcoholic steatohepatitis (NASH) has become a major cause of liver transplantation and liver-associated death. The gut-liver axis is a potential therapy for NASH. Sodium cholate (SC) is a choleretic drug whose main component is bile acids and has anti-inflammatory, antifibrotic, and hepatoprotective effects. This study aimed to investigate whether SC exerts anti-NASH effects by the gut-liver axis. Mice were fed with an high-fat and high-cholesterol (HFHC) diet for 20 weeks to induce NASH. Mice were daily intragastric administrated with SC since the 11th week after initiation of HFHC feeding. The toxic effects of SC on normal hepatocytes were determined by CCK8 assay. The lipid accumulation in hepatocytes was virtualized by Oil Red O staining. The mRNA levels of genes were determined by real-time quantitative PCR assay. SC alleviated hepatic injury, abnormal cholesterol synthesis, and hepatic steatosis and improved serum lipid profile in NASH mice. In addition, SC decreased HFHC-induced hepatic inflammatory cell infiltration and collagen deposition. The target protein-protein interaction network was established through Cytoscape software, and NR1H4 [farnesoid x receptor (FXR)] was identified as a potential target gene for SC treatment in NASH mice. SC-activated hepatic FXR and inhibited CYP7A1 expression to reduce the levels of bile acid. In addition, high-dose SC attenuated the abnormal expression of cancer markers in NASH mouse liver. Finally, SC significantly increased the expression of FXR and FGF15 in NASH mouse intestine. Taken together, SC ameliorates steatosis, inflammation, and fibrosis in NASH mice by activating hepatic and intestinal FXR signaling so as to suppress the levels of bile acid in NASH mouse liver and intestine.

A technique of recipient portal venoplasty and cuff insertion for portal revascularization in orthotopic rat liver transplantation.

BACKGROUND: In addition to suprahepatic vena cava anastomosis in two-cuff rat liver transplantation, recipient portal vein revascularization is one of the most difficult procedures that must be performed, especially for beginners. MATERIALS AND METHODS: A total of 43 cases of liver transplantation were performed. Rats in Group 1 and Group 2 were subjected to transplant procedures that used the conventional and portal venoplasty techniques, respectively. The portal vein anastomosis duration, anhepatic phase length, portal vein surgical complications, and 1 wk post-transplant survival rates were recorded for each group. RESULTS: The portal revascularization duration was statistically significantly less for Group 2 versus Group 1 (1.50 ± 0.61 min and 4.32 ± 0.67 min, respectively, P < 0.05). The anhepatic phase length of Groups 1 and 2 were 21.79 ± 1.27 min and 18.55 ± 1.47 min, respectively (P < 0.05). No significant differences between the groups were observed in relation to either portal vein surgery complications or 1-week survival rates. CONCLUSIONS: The recipient portal venoplasty and cuff insertion technique is a safe and fast alternative surgical option for portal revascularization in two-cuff rat liver transplantations performed by a single trainee.

Clinical study on prevention of HBV re-infection by entecavir after liver transplantation.

PURPOSE: This aims to evaluate the effects of lamivudine (LAM) and entecavir (ETV) in preventing hepatitis B virus (HBV) re-infection after liver transplantation (LT). METHODS: A retrospective matched case-control method was used in this study. From June 2005 to May 2007, the patients who received LAM (100 mg qd) or ETV (0.5 mg qd) were chosen. The LAM and ETV groups were matched using a 3:1 ratio based on the factors, such as age, gender, LAM or ETV antiviral duration, primary disease, and HBV DNA levels at the initiation of antiviral therapy. Data on serum HBV markers, HBV DNA, and cumulative recurrence were collected. RESULTS: Two hundred and fifty-two patients were enrolled. The average duration of follow-up was 38.5 and 41.2 months (LAM and ETV groups) (p>0.05). Duration of pre-operative antiviral therapy was 30.3 and 25.8 d (LAM and ETV groups) (p>0.05). The HBV DNA level decreased from 3.89×10(6) to 5.31×10(5) copies/mL before LT in the LAM group, and decreased from 8.74×10(6) to 5.49×10(4) copies/mL in the ETV group (p<0.05). Eighteen patients in LAM group developed HBV re-infection and 0 in ETV group. CONCLUSION: ETV is superior to LAM for preventing HBV re-infection following LT.

Identification of prognostic immune cells and potential immune-related markers in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common and deadly tumors worldwide. Immunotherapy has emerged as a promising strategy for HCC treatment, and understanding the immune microenvironment of HCC provides a theoretical basis for identifying new immune targets. However, the roles of immune components and their regulatory mechanisms in HCC require further clarified. Methods: By analyzing HCC expression profiles from The Cancer Genome Atlas (TCGA) database, we depicted the proportion profile of immune cells for each sample using the software CIBERSORTx. Using R packages, we also characterized the distribution of differentially expressed genes (DEGs) in immune cells, calculated the correlation coefficient between immune cells and common DEGs, and analyzed their biology function by Gene-Ontology analysis. Results: We found that seven immune cell types were related to the overall survival of HCC patients, and identified 3,692 differentially expressed immune-related genes, predominantly functioning in nucleic acid processing and metabolism. Moreover, 14 DEGs were identified as common candidates related to immune cells and overall survival. Conclusions: Our study not only presents an overview of the immune features of the microenvironment of HCC, but also provides potential targets related to immune components.

[Preoperative neutrophil-lymphocyte ratio as a prognostic predictor after liver transplantation for hepatocellular carcinoma].

OBJECTIVE: To analyze the negative impact of preoperative neutrophil-lymphocyte ratio (NLR) on the tumor recurrence of hepatocellular carcinoma (HCC) after orthotopic liver transplantation. METHODS: The clinical data of HBV (hepatitis B virus)-associated HCC patients undergoing liver transplantation were retrospectively analyzed. Their clinical and pathological risk factors for tumor-free survival were evaluated by univariate analysis. The analysis of Cox multiple regression was performed to determine the parameters of predicting the HCC recurrence. NLR ≥ 2.5 was considered to be elevated. RESULTS: A total of 76 patients were identified. Among them, 37 had an elevated NLR. The 1, 3 and 5-year tumor-free survival rates were 69.2%, 52.7% and 50.9% respectively. The disease-free survival for patients with high NLR was significantly worse than that for those with normal NLR (1, 3, and 5 year survivals at 56.3%, 37.6% and 37.6% vs 81.1%, 66.9% and 63.3% respectively; P = 0.011). Univariate analysis of factors revealed that tumor size > 5 cm, tumor number > 3, vascular invasion, serum α-fetoprotein level ≥ 400 µg/L and NLR ≥ 2.5 were preoperative predictors of disease-free survival. Cox regression analysis showed that the presence of vascular invasion, tumor number > 3 and NLR ≥ 2.5 were independent prognostic factors of worse disease-free survival. CONCLUSION: An elevated NLR significantly increases the risk for tumor recurrence in HCC patients undergoing liver transplantation.

[Clinical analysis between "early" versus "late" liver retransplantation].

OBJECTIVE: To compare early and late orthotopic liver retransplantation (re-OLT) for patients with poor graft function after primary transplantation at our center and sum up our clinical experience in re-OLT. METHODS: The clinical data of 36 re-OLTs from January 2004 to July 2009 were analyzed retrospectively, consisting of the first group with 17 cases of early re-OLT and the second group with 19 cases of late re-OLT. The average ages were (45 ± 13) years and (48 ± 10) years, and the time intervals were (49 ± 54) days and (514 ± 342) days in early re-OLT group and late re-OLT group, respectively. RESULTS: Biliary tract complications were the main indications for early re-OLT and late re-OLT. Other common indications were vascular complications in early re-OLT and recurrence of primary diseases in late re-OLT. No significant differences were found between the groups with regard to the volume of bleeding during operation, cold ischemia time, operative duration and perioperative mortality except the MELD score. Outcome was fatal for 8 patients in early re-OLT and 10 patients in late re-OLT. Three deaths were due to severe sepsis-related disease, 3 deaths due to multiple organ failure in early re-OLT and 4 deaths due to severe sepsis-related disease, 3 deaths due to recurrence of HCC in late re-OLT. One and 2-year actuarial survival rates after re-OLT were 52.9% and 41.2%, respectively, for patients in early re-OLT, and 63.2% and 52.6%, respectively, for patients in late re-OLT. No significant differences were found regarding survival rates between the two groups (P > 0.05). CONCLUSIONS: The similar clinical results can be achieved in early and late re-OLT. Proper indications and optimal operation timing, experienced surgical procedures and effective perioperative anti-infection strategy contribute to the improvement of the overall survival rate of the patients after re-OLT.

Surgery and chemotherapy improve the prognosis of primary hepatic angiosarcoma: A retrospective study based on Propensity score matched survival analysis.

PURPOSE: Hepatic angiosarcoma(HAS) is rare and is the primary vascular-derived malignancy of the liver. Its clinical characteristics, therapeutic strategy management, and the outcome are unclear. METHODS: This is a retrospective study of patients from the SEER database. Survival analysis was performed by the Kaplan-Meier method. Univariate and multivariate Cox models were used to identify risk factors. Propensity Score Matching(PSM) analysis was used to remove confounding bias. The nomogram was constructed, and the performance was measured using the C-index. RESULTS: A total of 300 HAS patients diagnosed between 1975 and 2016 were identified for this study, with an estimated median cancer-specific survival(CSS) of 1 month. The median CSS was 6 months in both the surgery and chemotherapy groups. Age(HR = 1.5206, p = 0.0058), sex(HR = 1.3906, p = 0.0391), SEER stage(HR = 1.4426, p < 0.0001), surgery(HR = 0.4493, p = 0.0001) and chemotherapy(HR = 0.28161, p < 0.0001) are potential independent prognostic factors. Of these HAS patients, 29 received surgical treatment without chemotherapy, and 63 received chemotherapy without surgery. A 1:1 PSM was performed to select candidates from the surgery-only group and the chemotherapy-only group. The survival analysis showed that the median survival time was 3 months in the surgery-only cohort and 5 months in the chemotherapy-only cohort, and there was no statistical difference between the two groups. Finally, a nomogram was constructed, with a C-index of 0.754. CONCLUSIONS: HAS is uncommon and has a poor prognosis. It was found that age, sex, SEER stage, surgery, and chemotherapy were independent prognostic factors for patients. Both surgery and chemotherapy could significantly prolong the survival of patients, and there was no statistical difference between the prognosis of patients treated with chemotherapy alone and those treated with surgery alone.

CircRNA-Mediated Regulation of Angiogenesis: A New Chapter in Cancer Biology.

Angiogenesis is necessary for carcinoma progression and is regulated by a variety of pro- and anti-angiogenesis factors. CircRNAs are RNA molecules that do not have a 5'-cap or a 3'-polyA tail and are involved in a variety of biological functions. While circRNA-mediated regulation of tumor angiogenesis has received much attention, the detailed biological regulatory mechanism remains unclear. In this review, we investigated circRNAs in tumor angiogenesis from multiple perspectives, including its upstream and downstream factors. We believe that circRNAs have natural advantages and great potential for the diagnosis and treatment of tumors, which deserves further exploration.

Cleavage and polyadenylation-specific factor 3 induces cell cycle arrest via PI3K/Akt/GSK-3ß signaling pathways and predicts a negative prognosis in hepatocellular carcinoma.

Background: Recent studies have shown that cleavage and polyadenylation-specific factor 3 (CPSF3) is a promising antitumor therapeutic target, but its potential role in hepatocellular carcinoma (HCC) has not been reported. Materials & methods: We explored the expression pattern of CPSF3 in HCC through bioinformatics analysis, quantitative polymerase chain reaction (qPCR) and western blot. The potential role of CPSF3 as a biomarker for HCC was evaluated by Kaplan-Meier analysis. Next, changes in HCC cell lines in the CPSF3 knockdown model group and the control group were assessed by Cell Counting Kit-8, clonal formation, flow cytometry and EdU staining. Western blot detected changes in protein levels of the PI3K/Akt/GSK-3ß axis of two HCC cell lines in the knockdown group and the control group. Results: The results showed that the transcription and protein levels of CPSF3 were significantly higher in HCC tissues than in adjacent normal tissues (p < 0.05). The HCC cohort with increased expression of CPSF3 is associated with advanced stage and differentiation and predicts poorer prognosis (p < 0.05). CPSF3 knockdown significantly inhibited proliferation and clone formation of HepG2 and SMMC-7721 cell lines. Flow cytometry analysis showed G1-S cell cycle arrest in the CPSF3 knockdown group, and the results of EdU staining were consistent with this. Compared with the control group, p-Akt and cyclin D1 were decreased, and GSK-3ß was increased in the knockdown group. Conclusion: CPSF3 may be a potential diagnostic biomarker and candidate therapeutic target for HCC.

The Outcome of Primary Hepatic Carcinoid Tumor: A Retrospective Study Based on Propensity Score Matched Survival Analysis.

BACKGROUND: Primary hepatic carcinoid tumor (PHCT) is rare and has unclear clinical characteristics and prognosis. METHODS: A retrospective study using data from the SEER database for patients diagnosed with PHCT used univariate and multivariate Cox models to screen for independent prognostic factors. The outcomes of patients in the surgical and nonsurgical groups were compared, and Propensity Score Matching (PSM) analysis was used to reduce confounder bias. RESULTS: A total of 186 PHCT patients were identified and the median survival was 65 (95% CI [43.287, 86.713]) months. Tumor size(HR = 2.493, 95% CI[1.222,5.083], p = 0.012), male(HR = 1.690, 95% CI[1.144,2.497], p = 0.008), age(HR = 2.583, 95% CI[1.697,3.930], p < 0.001), SEER stage(HR = 1.555, 95% CI[1.184,2.044], p = 0.002) and surgery(HR = 0.292, 95% CI[0.135,0.634], p = 0.002) were significantly correlated with patient prognosis. In multivariate analysis, sex(HR = 3.206, 95% CI[1.311,7.834], p = 0.011) and surgery(HR = 0.204, 95% CI[0.043,0.966], p = 0.0045) were independent predictors of patient prognosis. Females are potentially susceptible to PHCT but have a better prognosis. With consistent baseline data, surgical patients have a better prognosis. CONCLUSIONS: PHCT is uncommon and survival time is longer than that of other primary liver cancers. We found that none-surgery was potentially independent risk factors for poor prognosis.

Circulating microRNAs as novel diagnostic biomarkers and prognostic predictors for septic patients.

This study was to find out novel miRNAs whether could be used as diagnostic or prognostic biomarkers in sepsis. We used miRNAs microarray assays and further confirmed the levels of miRNAs in 151 septic patients' plasma. 56 miRNAs were up-regulated and 74 miRNAs down-regulated in septic patients compared with the healthy volunteers. But only miR-519c-5p and miR-3622b-3p were up-regulated in both septic and septic shock patients. The levels of miR-519c-5p and miR-3622b-3p were statistically higher in 151 septic patients than healthy controls on day 1. The AUC for miR-519c-5p was 0.79 (95% CI, 0.688-0.892, p = 0.001) in the diagnosis of sepsis, and the AUC for miR-3622b-3p 0.752 (95% CI, 0.622-0.881, p = 0.003). The AUC for the combination of these two miRNAs was 0.831 (95% CI, 0.74-0.923, p < 0.001). Besides, the AUC for miR-519c-5p was 0.597 (p = 0.043) in predicting 28-day mortality. MiR-519c-5p, miR-3622b-3p were novel biomarkers for diagnosing septic patients. High miR-519c-5p levels suggest a worse short-term prognosis. CLINICAL TRIAL REGISTRATION INFORMATION: Name of the registry: Diagnostic and prognostic value of circulating miRNA in patients with sepsis; Trial registration ID: ChiCTR-DDD-17013150; registered 30 October 2017; http://www.chictr.org.cn/edit.aspx?pid=22528&htm=4.