Association between dietary folate intake and severe abdominal aorta calcification in adults: A cross-sectional analysis of the national health and nutrition examination survey.

BACKGROUND: Prior studies have established a connection between folate intake and cardiovascular disease (CVD). Abdominal aortic calcification (AAC) has been introduced as a good predictor of CVD events, but no previous study has investigated the relationship between dietary folate intake and severe AAC. Therefore, the study aims to explore the association between dietary folate intake and severe AAC in the United States (US) middle-aged and elderly population. METHODS: This study employed cross-sectional data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to examine the relationship between dietary folate intake and severe AAC. Two 24-h dietary recall interviews were conducted to assess dietary folate intake and its sources, while a DXA scan was used to determine the AAC score. To analyze the association between dietary folate intake and severe AAC, a multivariable logistic regression model was applied, and a subgroup analysis was performed. RESULTS: Our analysis utilized data from 2640 participants aged 40 years and above, including 288 individuals diagnosed with severe AAC. After adjusting for confounding factors, we observed an inverted L-shaped association between folate intake and severe AAC. Upon further adjustment for specific confounding factors and covariates, the multivariable-adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the second, third, and fourth quartiles of folate intake, using the first quartile as the reference, were as follows: 1.24 (0.86-1.79), 0.86 (0.58-1.27), and 0.63 (0.41-0.97), respectively. Subgroup analysis results were consistent with the logistic regression models, indicating concordant findings. Moreover, no significant interaction was observed in the subgroup analyses. CONCLUSIONS: The study findings suggest an inverted L-shaped association between dietary folate intake and severe AAC. However, additional prospective investigations are necessary to explore the impact of dietary folate intake on severe AAC in patients.

U-Shaped Association between Serum Chloride Levels and In-Hospital Mortality in Patients with Congestive Heart Failure in Intensive Care Units.

Serum chloride level has clinical significance in the prognosis of heart failure. Little is known regarding the association between serum chloride levels and in-hospital mortality in patients with heart failure.This retrospective study used clinical data obtained from the Medical Information Mart for Intensive Care Database. The study cohort comprised patients who were categorized on the basis of their serum chloride levels, and the primary endpoint was in-hospital mortality. To assess the impact of serum chloride levels at the time of intensive care unit admission on in-hospital mortality, we used various statistical approaches, including multivariable logistic regression models, a generalized additive model, and a two-piecewise linear regression model. In addition, subgroup analysis was conducted to examine the robustness of the main findings.This study comprised 15,983 participants. When compared with the reference group (Q5), the groups with the highest (Q7) and lowest (Q1) blood chloride levels exhibited increased in-hospital mortality, with fully adjusted odds ratios (ORs) of 1.36 [95% confidence interval (CI): 1.08-1.71] and 1.25 (95% CI: 1-1.56), respectively. A U-shaped relationship was observed between blood chloride levels and in-hospital mortality, with the lowest risk observed at a threshold of 105.017 mmol/L. The effect sizes and corresponding CIs below and above the threshold were 0.969 (95% CI: 0.957-0.982) and 1.039 (95% CI: 1.002-1.076), respectively. Stratified analyses demonstrated the robustness of this correlation.The relationship between serum chloride levels and in-hospital mortality in patients with heart failure was U-shaped, with an inflection point of 105.017 mmol/L.

U-shaped association between serum calcium and in-hospital mortality in patients with congestive heart failure.

AIMS: Serum calcium level is widely used for evaluating disease severity, but its impact on clinical outcomes in patients with congestive heart failure (CHF) remains poorly understood. The aim of this study is to investigate the relationship between serum calcium levels and in-hospital mortality in CHF patients. METHODS AND RESULTS: We conducted a retrospective analysis utilizing clinical data from the Medical Information Mart for Intensive Care database, encompassing a cohort of 15 983 CHF patients. This cohort was stratified based on their serum calcium levels, with the primary objective being the determination of in-hospital mortality. To assess the impact of admission serum calcium levels on in-hospital mortality, we employed various statistical methodologies, including multivariable logistic regression models, a generalized additive model, a two-piecewise linear regression model, and subgroup analysis. Comparative analysis of the reference group (Q3) revealed increased in-hospital mortality in the first quintile (Q1, the group with the lowest blood calcium level) and the fifth quintile (Q5, the group with the highest blood calcium level), with fully adjusted odds ratios of 1.38 [95% confidence interval (CI): 1.13-1.68, P = 0.002] and 1.23 (95% CI: 1.01-1.5, P = 0.038), respectively. A U-shaped relationship was observed between serum calcium levels and in-hospital mortality, with the lowest risk occurring at a threshold of 8.35 mg/dL. The effect sizes and corresponding CIs below and above this threshold were 0.782 (95% CI: 0.667-0.915, P = 0.0023) and 1.147 (95% CI: 1.034-1.273, P = 0.0094), respectively. Stratified analyses confirmed the robustness of this correlation. CONCLUSIONS: Our study identifies a U-shaped association between serum calcium levels and in-hospital mortality in CHF patients, with a notable inflection point at 8.35 mg/dL. Further investigation through prospective, randomized, and controlled studies is warranted to validate the findings presented in this study.

Association between dietary calcium intake and severe abdominal aorta calcification among American adults: a cross-sectional analysis of the National Health and Nutrition Examination Survey.

BACKGROUND: Evidence regarding the relationship between dietary calcium intake and severe abdominal aortic calcification (AAC) is limited. Therefore, this study aimed to investigate the association between dietary calcium intake and severe AAC in American adults based on data from the National Health and Nutrition Examination Survey (NHANES). METHODS: The present cross-sectional study utilized data from the NHANES 2013-2014, a population-based dataset. Dietary calcium intake was assessed using two 24-h dietary recall interviews. Quantification of the AAC scores was accomplished utilizing the Kauppila score system, whereby severe AAC was defined as having an AAC score greater than 6. We used multivariable logistic regression models, a restricted cubic spline analysis, and a two-piecewise linear regression model to show the effect of calcium intake on severe AAC. RESULTS: Out of the 2640 individuals examined, 10.9% had severe AAC. Following the adjustment for confounding variables, an independent association was discovered between an augmented intake of dietary calcium and the incidence of severe AAC. When comparing individuals in the second quartile (Q2) of dietary calcium intake with those in the lowest quartile (Q1), a decrease in the occurrence of severe AAC was observed (odds ratio: 0.66; 95% confidence interval: 0.44-0.99). Furthermore, the relationship between dietary calcium intake and severe AAC demonstrated an L-shaped pattern, with an inflection point observed at 907.259 mg/day. Subgroup analyses revealed no significant interaction effects. CONCLUSION: The study revealed that the relationship between dietary calcium intake and severe AAC in American adults is L-shaped, with an inflection point of 907.259 mg/day. Further research is required to confirm this association.

Association Between Body Temperature and In-Hospital Mortality Among Congestive Heart Failure Patients with Diabetes in Intensive Care Unit: A Retrospective Cohort Study.

Body temperature (BT) has been utilized to assess patient outcomes across various diseases. However, the impact of BT on mortality in the intensive care unit (ICU) among patients with congestive heart failure (CHF) and diabetes mellitus (DM) remains unclear. We conducted a retrospective cohort study using data from the Medical Information Mart for Intensive Care (MIMIC)-IV data set. The primary outcome assessed was in-hospital mortality rates. BT was treated as a categorical variable in the analyses. The association between BT on ICU admission and in-hospital mortality was examined using multivariable logistic regression models, restricted cubic spline, and subgroup analysis. The cohort comprised 7063 patients with both DM and CHF (3135 females and 3928 males), with an average age of 71.5 ± 12.2 years. Comparative analysis of the reference group (Q4) revealed increased in-hospital mortality in Q6 and Q1 temperature groups, with fully adjusted odds ratios of 2.08 (95% confidence interval [CI]: 1.45-2.96) and 1.95 (95% CI: 1.35-2.79), respectively. Restricted cubic spline analysis demonstrated a U-shaped relationship between temperature on admission and mortality risk (p nonlinearity <0.001), with the nadir of risk observed at 36.8°C. The effect sizes and corresponding CIs below and above the threshold were 0.581 (95% CI: 0.434-0.777) and 1.674 (95% CI: 1.204-2.328), respectively. Stratified analyses further validated the robustness of this correlation. Our study establishes a nonlinear association between BT and in-hospital mortality in patients with both CHF and DM, with optimal suitable BT at 36.8°C. Further research is necessary to confirm this relationship.

Association between dietary zinc intake and Helicobacter pylori seropositivity in US adults: National Health and Nutrition Examination Survey.

Purpose: Helicobacter pylori infection is a well-established etiological factor for gastric inflammation and a significant risk factor for the development of gastric cancer. However, the precise relationship between dietary zinc intake and seropositivity for Helicobacter pylori remains uncertain. Methods: This cross-sectional observational study utilized data from the United States National Health and Nutrition Examination Survey conducted between 1999 and 2000. The study cohort comprised 2,884 adults aged 20 years or older who provided comprehensive 24-h dietary recall data. The presence of Helicobacter pylori infection was confirmed using serum analysis and lgG protein enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression models and generalized additive model (GAM) were employed to explore the potential association between dietary zinc intake and Helicobacter pylori seropositivity. Results: Additionally, subgroup analysis was performed to evaluate the robustness of the primary findings. Of the 1,281 participants, 47.8% were male and the average age was 49.5 years. In the fully adjusted model, a statistically significant inverse association between dietary zinc intake and Helicobacter pylori seropositivity was observed [quartile variable, Q4 vs. Q1, odds ratio (OR): 0.72, 95% confidence interval (CI): 0.57-0.91, p = 0.007]. Furthermore, the relationship between dietary zinc intake and Helicobacter pylori seropositivity exhibited an L-shaped pattern, indicating a saturation effect. The results of sensitivity analysis remained consistent and reliable. Conclusion: Therefore, this study suggests that higher dietary zinc intake may be associated with a lower prevalence of Helicobacter pylori seropositivity. Notably, this association follows an L-shaped pattern, with a threshold point estimated at 24.925 mg/day.

Association between dietary vitamin E intake and cognitive decline among old American: National Health and Nutrition Examination Survey.

PURPOSE: Numerous studies have reported that vitamin E plays a key role in nervous system development and neurotransmitter production. This study aimed to investigate changes in vitamin E intake in older adults with low cognitive performance using NHANES. METHODS: In this cross-sectional study, we examined a sample of 2255 American adults aged 60 and over between 2011 and 2014. We collected dietary data by averaging two recalls for dietary use to determine vitamin E intake. We assessed cognitive function using five tests and analyzed the association between these variables using a multivariate logistic regression model. RESULTS: A total of 2255 participants aged ≥ 60 years from the National Health and Nutrition Examination Survey (NHANES) for the 2011-2014 cycle were included in the analysis. Vitamin E intake was negatively associated with cognitive function. In the Z test, with each 1 mg/day increase in dietary intake of vitamin E, there was a 6% decrease in the correlation with cognitive impairment (OR = 0.94, 95% CI 0.91-0.97) in the fully fitted model (OR = 0.94, 95% CI 0.91-0.97). These findings remained consistent when analyzing the exposure as a categorical variable. In comparison to Q1, Q4 showed a 53% reduction in the incidence of cognitive impairment in the Z test (OR = 0.47, 95% CI 0.33-0.67).No significant statistical interaction between the variables was found. CONCLUSION: An increased dietary intake of vitamin E has been associated with decreased cognitive impairment in individuals over 60 years old. The dose-response curve showed an L-shaped association between dietary vitamin E intake and cognitive decline in US adults, with an inflection point of approximately 9.296 mg/day.

Efficacy and safety of Lenvatinib-based combination therapies for patients with unresectable hepatocellular carcinoma: a single center retrospective study.

Background: Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies. Methods: This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR). Results: Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE. Conclusion: Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.

Perioperative and long-term survival outcomes of laparoscopic versus open hepatectomy for BCLC stage A large hepatocellular carcinoma patients in difficult segments: A two-centre, propensity score matching analysis.

Background: The differences in short- and long-term outcome between laparoscopic liver resection (LLR) and open liver resection (OLR) for BCLC stage A large hepatocellular carcinoma (HCC) in difficult segments (I, IVa, VII, VIII) remain unclear. This PSM two-centre study aimed to compare perioperative and long-term survival outcomes of LLR with OLR for this HCC. Methods: HCC patients with BCLC stage A who underwent OLR or LLR in two medical centres were enrolled in the study. PSM analysis was performed to match patients between the LLR cohort and OLR cohort. Survival was analysed based on the Kaplan-Meier method. Independent risk factors were identified by Cox regression. Results: After PSM, 35 patients remained in the LLR cohort, and 84 remained in the OLR cohort. Patients in the LLR cohort had more intraoperative blood loss (p=0.036) and shorter hospital stays after surgery (p<0.001). The LLR cohort and OLR cohort had no difference in intraoperative blood transfusion, surgical margin or postoperative short-term outcomes. The OS and RFS were not significantly different between the two cohorts. The OS and RFS of these two cohorts were not different in the subgroup analysis. Surgical margin was identified as an independent risk factor for tumour recurrence. Conclusion: For BCLC stage A large HCC patients with lesions in difficult segments, LLR was feasible and had shorter hospital stay than OLR. In addition, a surgical margin ≥1 cm could significantly decrease the recurrence probability for large HCC located in different segments without compromising short-term outcomes.

High-throughput sequencing approach for the identification of lncRNA biomarkers in hepatocellular carcinoma and revealing the effect of ZFAS1/miR-150-5p on hepatocellular carcinoma progression.

Aims: To screen abnormal lncRNAs and diagnostic biomarkers in the progression of hepatocellular carcinoma through high-throughput sequencing and explore the underlying mechanisms of abnormal lncRNAs in the progression of hepatocellular carcinoma. Methods: The transcriptome sequencing was used to analyze the RNA expression profile and identify differentially expressed RNAs. Hub lncRNAs were screened by combining (WGCNA, ceRNA regulatory network, PPI, GO and KEGG analyses, Kaplan-Meier curve analysis, Cox analysis, risk model construction and qPCR). Thereafter, the correlation between the expression of hub lncRNAs and tumor clinicopathological parameters was analyzed, and the hub lncRNAs were analyzed by GSEA. Finally, the effects of hub RNAs on the proliferation, migration and invasion of HepG2 cells were investigated in vitro. Results: Compared with the control group, a total of 610 lncRNAs, 2,593 mRNAs and 26 miRNAs were screened in patients with hepatocellular carcinoma. Through miRNA target prediction and WGCNA, a ceRNA was constructed, comprising 324 nodes and 621 edges. Enrichment analysis showed that mRNAs in ceRNA were involved mainly in cancer development progression. Then, the ZFAS1/miR-150-5p interaction pair was screened out by Kaplan Meier curve analysis, Cox analysis and qPCR analysis. Its expression was related to tumor stage, TNM stage and patient age. ROC curve analysis showed that it has a good predictive value for the risk of hepatocellular carcinoma. GSEA showed that ZFAS1 was also enriched in the regulation of immune response, cell differentiation and proliferation. Loss-of-function experiments revealed that ZFAS1 inhibition could remarkably suppress HepG2 cell proliferation, migration and invasion in vitro. Bioinformatic analysis and luciferase reporter assays revealed that ZFAS1 directly interacted with miR-150-5p. Rescue experiments showed that a miR-150-5p inhibitor reversed the cell proliferation, migration and invasion functions of ZFAS1 knockdown in vitro. Conclusion: ZFAS1 is associated with the malignant status and prognosis of patients with hepatocellular carcinoma, and the ZFAS1/miR-150-5p axis is involved in hepatocellular carcinoma progression.

Development of preoperative prognostic models including radiological features for survival of singular nodular HCC patients.

BACKGROUND: Early singular nodular hepatocellular carcinoma (HCC) is an ideal surgical indication in clinical practice. However, almost half of the patients have tumor recurrence, and there is no reliable prognostic prediction tool. Besides, it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it. It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus, to improve the outcomes of these patients. The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival (RFS) and overall survival (OS) in patients with singular nodular HCC by integrating the clinical data and radiological features. METHODS: We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern Hepatobiliary Surgery Hospital (EHBH). They all met the surgical indications and underwent radical resection. We randomly divided the patients into the training cohort (n =132) and the validation cohort (n = 79). We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS. By analyzing the receiver operating characteristic (ROC) curve, the discrimination accuracy of the models was compared with that of the traditional predictive models. RESULTS: Our RFS model was based on HBV-DNA score, cirrhosis, tumor diameter and tumor capsule in imaging. RFS nomogram had fine calibration and discrimination capabilities, with a C-index of 0.74 (95% CI: 0.68-0.80). The OS nomogram, based on cirrhosis, tumor diameter and tumor capsule in imaging, had fine calibration and discrimination capabilities, with a C-index of 0.81 (95% CI: 0.74-0.87). The area under the receiver operating characteristic curve (AUC) of our model was larger than that of traditional liver cancer staging system, Korea model and Nomograms in Hepatectomy Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma, indicating better discrimination capability. According to the models, we fitted the linear prediction equations. These results were validated in the validation cohort. CONCLUSIONS: Compared with previous radiography model, the new-developed predictive model was concise and applicable to predict the postoperative survival of patients with singular nodular HCC. Our models may preoperatively identify patients with high risk of recurrence. These patients may benefit from neoadjuvant therapy which may improve the patients' outcomes.

Circulating Tumor Cells Expressing Krüppel-Like Factor 8 and Vimentin as Predictors of Poor Prognosis in Pancreatic Cancer Patients.

BACKGROUND: Circulating tumor cells (CTCs) with an epithelial-mesenchymal transition phenotype in peripheral blood may be a useful marker of carcinomas with poor prognosis. The aim of this study was to determine the prognostic significance of CTCs expressing Krüppel-like factor 8 (KLF8) and vimentin in pancreatic cancer (PC). METHODS: CTCs were isolated by immunomagnetic separation from the peripheral blood of 40 PC patients before undergoing surgical resection. Immunocytochemistry was performed to identify KLF8+ and vimentin+ CTCs. The associations between CTCs and time to recurrence (TTR), clinicopathologic factors, and survival were assessed. Univariate and multivariate analyzes were performed to identify risk factors. RESULTS: Patients with CTCs (n = 30) had a higher relapse rate compared to those without (n = 10) (70.0% vs 20.0%; P < 0.01). The proportion of KLF8+/vimentin+ CTCs to total CTCs was inversely related to TTR (r = -0.646; P < 0.01); TTR was reduced in patients with > 50% of CTCs identified as KLF8+/vimentin+ (P < 0.01). Independent risk factors for recurrence were perineural invasion and > 50% KLF8+/vimentin+ CTCs (both P < 0.05). CONCLUSION: Poor prognosis can be predicted in PC patients when > 50% of CTCs are positive for KLF8 and vimentin.

Prediction of Patient Survival Following Hepatic Resection in Early-Stage Hepatocellular Carcinoma with Indexed Ratios of Aspartate Aminotransferase to Platelets: A Retrospective Cohort Study.

PURPOSE: To predict patient survival in early-stage hepatocellular carcinoma (HCC) following hepatic resection. We evaluated the prognostic potential of the aspartate aminotransferase to platelet ratio index (APRI) in order to use it to model a nomogram. PATIENTS AND METHODS: We randomized 901 early-stage HCC patients treated with hepatic resection at our center into training and validation cohorts that were followed from January 2009 to December 2012. X-tile software was used to establish the APRI cut-off threshold in the training cohort. The validation cohort was subsequently assessed to determine threshold value accuracy. Data generated from the multivariate analysis in the training cohort were used to design a prognostic nomogram. Decision curve analyses (DCA), concordance index values (C-index) and calibration curves were used to determine the performance of the nomogram. RESULTS: X-tile software revealed that the optimal APRI cut-off threshold in the training cohort that distinguished between patients with different prognoses was 0.9. We, therefore, validated its prognostic value. Multivariate analyses showed that poor overall survival was associated with APRI above 0.9, blood loss of more than 400 mL, liver cirrhosis, multiple tumors, tumor size greater than 5 cm, microvascular invasion and satellite lesions. When the independent risk factors were integrated into the prognostic nomogram, it performed well with accurate predictions. Indeed, the performance was better than comparative prognosticators (P<0.05 for all) with 0.752 as the C-index (95% CI: 0.706-0.798). These results were verified by the validation cohort. CONCLUSION: APRI was a noninvasive and accurate predictive indicator for patients with early-stage HCC. Following hepatic resection to treat early-stage HCC, individualized patient survival predictions can be aided by the nomogram based on APRI.

Impact of preoperative TACE on incidences of microvascular invasion and long-term post-hepatectomy survival in hepatocellular carcinoma patients: A propensity score matching analysis.

BACKGROUND: To study the influence of preoperative transcatheter arterial chemoembolization (TACE) on the incidence of microvascular invasion (MVI) and long-term survival outcomes in hepatocellular carcinoma (HCC) patients. METHODS: Between January 1, 2010 and December 1, 2014, consecutive HCC patients who underwent curative liver resection were enrolled in this study. Univariable and multivariable regression analyses were used to identify independent predictive factors of MVI. Propensity score matching (PSM) was used to compare the incidences of MVI and prognosis between patients who did and did not receive preoperative TACE. Factors associated with Disease-Free Survival (DFS) and Overall survival (OS) were identified using Cox regression analyses. RESULTS: Of 1624 patients, 590 received preoperative TACE. The incidence of MVI was significantly lower in patients with preoperative TACE than those without preoperative TACE (39.15% vs. 45.36%, p = 0.015). After PSM, the incidences of MVI were similar in the two groups (38.85% vs. 41.10%, p = 0.473). Multivariable regression analysis revealed preoperative TACE to have no impact on the incidence of MVI. Before PSM, survival of patients with preoperative TACE was significantly worse than those without preoperative TACE (p = 0.032 for DFS and p = 0.027 for OS). After PSM, the difference became insignificant (p = 0.465 for DFS and p = 0.307 for OS). After adjustment for other prognostic variables in the propensity-matched cohort, preoperative TACE was still found not to be associated with DFS and OS after HCC resection. Both before and after PSM, the prognosis of patients was not significantly different between the two groups for BCLC stages 0, A, and B. CONCLUSIONS: Preoperative TACE did not influence the incidence of MVI and prognosis of patients with HCC who underwent 'curative' liver resection.

NQO1 promotes an aggressive phenotype in hepatocellular carcinoma via amplifying ERK-NRF2 signaling.

Patients with hepatocellular carcinoma (HCC) are usually diagnosed at the later stages and have poor survival outcomes. New molecules are urgently needed for the prognostic predication and individual treatment. Our study showed that high levels of NQO1 expression frequently exist in HCC with an obvious cancer-specific pattern. Patients with NQO1-high tumors are significantly associated with poor survival outcomes and serve as independent predictors. Functional experiments showed that NQO1 promotes the growth and aggressiveness of HCC in both in vitro and in vivo models, and the underlying mechanism involved NQO1-derived amplification of ERK/p38-NRF2 signaling. Combined block of ERK and NRF2 signaling generated stronger growth inhibition compared with any single block, especially for HCC with high-NQO1. Therefore, NQO1 is a potential biomarker for HCC early diagnosis and prognosis prediction, and also attractive for cancer-specific targets for HCC treatment.

A High Preoperative Platelet-Lymphocyte Ratio Is a Negative Predictor of Survival After Liver Resection for Hepatitis B Virus-Related Hepatocellular Carcinoma: A Retrospective Study.

Objective: To evaluate the importance of preoperative blood platelet to lymphocyte ratio (PLR) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver surgery and to examine the connection with CD8+ lymph cell infiltration. Methods: Between 2009 and 2014, consecutive HCC patients who received curative liver surgery were included into this retrospective study. Baseline clinicopathological characteristics were analyzed to identify predictors of recurrence-free and overall patient survival rate after liver resection. The samples of all patients were under Tissue Microarray (TMA) construction and immunohistochemical staining for CD8+.The association of the number of CD8+T-cells in the cancer nests and peritumoral stroma with PLR level was analyzed. Results: A total of 1,174 HBV-related HCC patients who received a liver resection without any peri-operative adjuvant therapy were enrolled into this retrospective study. Univariate and Multivariate analysis using Cox regression model showed that PLR was an independent factor affecting recurrence and overall survivals. The optimal cutoff of PLR using the receiver operating characteristic curve was 150. There were 236 patients (20.1%) who had a PLR of 150 or more. The 5-year survival rate after liver resection was 71.8% in patients with a PLR of < 150 and it was 57.2% in those with a PLR of 150 or more (P < 0.001). Both 5-year recurrence-free and overall survival rates in liver cancer stage A patients at Barcelona Clinic with different PLR group were also significantly different (P = 0.007 for recurrence and P = 0.001 for overall survival). Similar results were also observed in stage B patients (P < 0.001 for recurrence and P = 0.033 for overall survival). To determine the association between PLR and the severity of liver inflammation, an immuno-histological examination using CD8+ staining was performed on the liver specimens of 1,174 patients. Compared with low PLR (<150) group, more CD8+T-cells were found in the peritumoral tissue in high PLR (≥ 150) group. Conclusions: PLR played as an independent factor for predicting the survival after hepatectomy for HCC patients. A high PLR was associated with an accumulation of CD8+ T-cells in the peritumoral stroma.

EYA4 serves as a prognostic biomarker in hepatocellular carcinoma and suppresses tumour angiogenesis and metastasis.

Eye absent homolog 4 (EYA4) has been demonstrated to be down-regulated in hepatocellular carcinoma (HCC), but its biological function and the mechanism in HCC angiogenesis and metastasis remain largely unknown. Herein, we showed that EYA4 expression was frequently low in HCC tissue samples compared with matched adjacent non-tumourous tissues. In the analysis of 302 HCC specimens, we revealed that decreased expression of EYA4 correlated with tumour differentiation status. Univariate and multivariate analyses identified EYA4 as an independent risk factor for recurrence-free survival (RFS) and overall survival (OS) among the 302 patients. Functional assays showed that forced expression of EYA4 suppressed HCC cell migration, invasion and capillary tube formation of endothelial cells in vitro, as well as in vivo tumour angiogenesis and metastasis in a mouse model. Furthermore, mechanism study exhibited that EYA4 could inhibit HCC angiogenesis and metastasis by inhibiting c-JUN/VEGFA pathway. Together, we provide proof that EYA4 is a novel tumour suppressor in HCC and a new prognostic biomarker and therapeutic target in HCC.

A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma.

BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.

MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN.

Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR-494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494-3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease.

IL-17A promotes the invasion-metastasis cascade via the AKT pathway in hepatocellular carcinoma.

We previously demonstrated that interleukin-17A (IL-17A) is associated with the progression of hepatocellular carcinoma (HCC). However, its role in the invasion-metastasis cascade of HCC and the efficacy of IL-17A-targeting therapeutics in HCC remain largely unknown. In this study, we found that IL-17A promoted intrahepatic and pulmonary metastasesis of HCC cells in an orthotopic implant model. Moreover, our results showed that IL-17A induced epithelial-mesenchymal transition (EMT) and promoted HCC cell colonization in vitro and in vivo, and the role of IL-17A in invasion-metastasis was dependent on activation of the AKT pathway. Remarkably, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis compared to sorafenib monotherapy. Additionally, the combination of intratumoral IL-17A+ cells and E-cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry. In conclusion, our studies reveal that IL-17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC.