Vacancy-Enhanced Sb-N4 Sites for the Oxygen Reduction Reaction and Zn-Air Battery.

With the advantages of a Fenton-inactive characteristic and unique p electrons that can hybridize with O2 molecules, p-block metal-based single-atom catalysts (SACs) for the oxygen reduction reaction (ORR) have tremendous potential. Nevertheless, their undesirable intrinsic activity caused by the closed d10 electronic configuration remains a major challenge. Herein, an Sb-based SAC featuring carbon vacancy-enhanced Sb-N4 active centers, corroborated by the results of high-angle annular dark-field scanning transmission electron microscopy and X-ray absorption fine structure, has been developed for an incredibly effective ORR. The obtained SbSA-N-C demonstrates a positive half-wave potential of 0.905 V and excellent structural stability in alkaline environments. Density functional theory calculations reveal that the carbon vacancies weaken the adsorption between Sb atoms and the OH* intermediate, thus promoting the ORR performance. Practically, the SbSA-N-C-based Zn-air batteries achieve impressive outcomes, such as a high power density of 181 mW cm-2, showing great potential in real-world applications.

Unusual Sabatier principle on high entropy alloy catalysts for hydrogen evolution reactions.

The Sabatier principle is widely explored in heterogeneous catalysis, graphically depicted in volcano plots. The most desirable activity is located at the peak of the volcano, and further advances in activity past this optimum are possible by designing a catalyst that circumvents the limitation entailed by the Sabatier principle. Herein, by density functional theory calculations, we discovered an unusual Sabatier principle on high entropy alloy (HEA) surface, distinguishing the "just right" (ΔGH* = 0 eV) in the Sabatier principle of hydrogen evolution reaction (HER). A new descriptor was proposed to design HEA catalysts for HER. As a proof-of-concept, the synthesized PtFeCoNiCu HEA catalyst endows a high catalytic performance for HER with an overpotential of 10.8 mV at -10 mA cm-2 and 4.6 times higher intrinsic activity over the state-of-the-art Pt/C. Moreover, the unusual Sabatier principle on HEA catalysts can be extended to other catalytic reactions.

DFT Study of N-modified Co3Mo3C Electrocatalyst with Separated Active Sites for Enhanced Ammonia Oxidation.

Since the facile oxidation of ammonia is one key for its utilization as a zero-carbon fuel in a direct ammonia fuel cell, developing the ammonia oxidation reaction (AOR) catalysts with cost-effective and higher activity is urgently required. However, the catalytic activity of AOR is limited by the scaling relationship of the intermediate adsorption. Based on the density functional theory, the N-modified Co3Mo3C with separated active sites of NH3 dehydrogenation and N-N coupling has been designed and investigated, which is a promising strategy to circumvent the scaling relationship, achieving improved AOR catalytic performance with a lower theoretical overpotential of 0.59 V under fast reaction kinetics condition. The calculation results show that the hollow site (Co-Mo-Mo and Co-Co-Mo) and Co site in N-modified Co3Mo3C play essential roles in NH3 dehydrogenation and N-N coupling, respectively. This work not only benefits for understanding the mechanism of AOR, but also provides a fundamental guidance for rational design of AOR catalysts.

Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity.

As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.

Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Tenofovir (TDF) and entecavir (ETV) are first-line treatments for patients with chronic hepatitis B virus (HBV) infection. However, the effect of TDF versus ETV on the prognosis of HBV-related hepatocellular carcinoma (HCC) has not been fully clarified yet. RESEARCH DESIGN AND METHODS: PubMed, Embase and Web of science were searched up to March, 2021. Meta-analyses were performed for overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) to assess the effect of TDF versus ETV on the prognosis of HBV-related HCC. RESULTS: A total of 10 studies comprising 4706 Asian patients were included. The pooled results revealed that TDF was associated with better OS (adjusted HR = 0.50, 95% CI: 0.40-0.62; I2 = 36.0%, p = 0.167) and better RFS/DFS (adjusted HR = 0.70, 95% CI: 0.55-0.89, I2 = 71.9%, p = 0.002) than ETV in treatment of HBV-related HCC. Subgroup analysis revealed that OS benefit from TDF was generally consistent, except for patients who underwent non-surgical treatment for HCC. Subgroup analysis also indicated that TDF reduces the risk of late recurrence (HR = 0.41, 95% CI: 0.18-0.0.93; I2 = 63.0%, p = 0.067) rather than early recurrence (HR = 0.99, 95% CI: 0.64-1.52; I2 = 61.3%, p = 0.076). CONCLUSIONS: Compared with ETV, TDF has the advantage of improving OS and reducing late recurrence of patients with HBV-related HCC patients who underwent resection.

Identification of the most effective subgroup of advanced hepatocellular carcinoma from immune checkpoint blocker treatment: a meta-analysis.

Aims: This work was designed to identify the subgroup of advanced hepatocellular carcinoma (HCC) patients for whom treatments containing immune checkpoint blockers (ICBs) were most effective. Materials & methods: A meta-analysis was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs. Results: A total of 2228 patients from four randomized control trials were included. Treatments containing ICBs had better overall survival, progression-free survival and higher objective response rate over treatment without ICBs. Subgroup analysis revealed that treatments containing ICBs were highly effective in improving the overall survival of males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients. Conclusion: Treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Immune checkpoint blockers (ICBs) have significantly improved the prognosis of advanced cancers. However, some patients still cannot benefit from ICBs. The use of ICBs in the treatment of advanced hepatocellular carcinoma (HCC) started late. The subgroup of advanced HCC patients that will benefit most from treatments containing ICBs is still largely unknown. Therefore, a meta-analysis (meta-analysis is a statistical method used to compare or synthesize research results on the same scientific problem) was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs (ICBs alone or in combination with anti-VEGF agents). The results show that treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

The somatic mutational landscape and role of the ARID1A gene in hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Clarification of the somatic mutational landscape of important genes could reveal new therapeutic targets and facilitate individualized therapeutic approaches for HCC patients. The mutation and expression changes in the ARID1A gene in HCC remain controversial. Methods: First, cBioPortal was used to visualize genetic alterations and DNA copy number alterations (CNAs) in ARID1A. The relationships between ARID1A mutation status and HCC patient clinicopathological features and overall survival (OS) were also determined. Then, a meta-analysis was performed to evaluate the effect of ARID1A mutation or expression on the prognosis of HCC patients. Finally, the role of ARID1A in HCC progression was verified by in vitro experiments. Results: ARID1A mutation was detected in 9.35% (33/353) of sequenced HCC cases, and ARID1A mutation decreased ARID1A mRNA expression. Patients with ARID1A alterations presented worse OS than those without ARID1A alterations. Meta-analysis and human HCC tissue microarray (TMA) analysis revealed that HCC patients with low ARID1A expression had worse OS and relapse-free survival (RFS), and low ARID1A expression was negatively correlated with tumour size. Then, ARID1A gain-of-function and loss-of-function experiments demonstrated the tumour suppressor role of ARID1A in HCC in vitro. In terms of the mechanism, we found that ARID1A could inhibit HCC progression by regulating retinoblastoma-like 1 (RBL1) expression via the JNK/FOXO3 pathway. Conclusions: ARID1A can be considered a potential prognostic biomarker and candidate therapeutic target for HCC.

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response.

Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive. Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells' pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes' expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation. Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines. Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

The association of fatty liver and risk of hepatocellular carcinoma in HBV or HCV infected individuals: a systematic review and meta-analysis.

BACKGROUND: Fatty liver (FL) is reportedly a risk factor for hepatocellular carcinoma (HCC) in individuals affected with Hepatitis C (HCV) or B (HBV) virus. However, the results are contradictory, necessitating a meta-analysis. RESEARCH DESIGN AND METHODS: Sixteen relevant studies involving 88,618 individuals were retrieved from the Cochrane Library, PubMed, MEDLINE, Embase, and Scopus databases from their inception to 10 December 2022. The hazard ratios (HR) and 95% confidence intervals (CI) were analyzed. RESULTS: Liver biopsy-proven FL may be a significant risk factor for HCC in individuals affected with HBV (univariate analyses: HR = 3.13, 95% CI = 1.69-5.79; multivariate analyses: HR = 3.42, 95% CI = 0.83-14.09) as well as HCV (univariate analyses: HR = 1.64, 95% CI = 0.93-2.90; multivariate analyses: HR = 1.75, 95% CI = 1.02-3.00). However, the presence of FL confirmed using reasonable methods other than liver biopsy may not indicate a risk for HCC in HBV-infected individuals (univariate analyses: HR = 0.90, 95% CI = 0.44-1.81; multivariate analyses: HR = 0.69, 95% CI = 0.45-1.08). CONCLUSIONS: Biopsy-proven FL may be a significant risk factor for HCC in HCV/HBV-infected individuals. Thus, such individuals should receive suitable interventions to prevent HCC formation or at least attenuate the risk of HCC.

Efficacy and security of tumor vaccines for hepatocellular carcinoma: a systemic review and meta-analysis of the last 2 decades.

BACKGROUND: Tumor vaccines for hepatocellular carcinoma (HCC) is an area of intense interest. Tremendous clinical trials have been conducted globally, but the efficacy and security of tumor vaccines are elusive. The aim of our study was to evaluate the efficacy and security of tumor vaccines. METHODS: All relevant studies were identified in PubMed, EMBASE, Web of science and Cochrane Library databases. Objective response rate (ORR), median overall survival (OS), or median progression-free survival (PFS) and 95% CI were meta-analyzed based on the random-effects model. The individual-level data of OS, PFS were pooled by conducting survival analysis. All observed adverse events were collected. RESULTS: 31 studies containing 35 eligible cohorts with 932 HCC patients were included. The pooled ORR were 7% (95% CI 3-14%), while ORR of dendritic cell (DC) vaccine (19%, 95% CI 11-29%) were highly significant than ORR of peptide vaccine (1%, 95% CI 0-5%). The pooled median OS and PFS were 13.67 months (95% CI 8.20-22.80) and 6.19 months (95% CI 2.97-12.91), respectively. The pooled median OS (DC vaccine: median OS = 21.77 months, 95% CI 18.33-25.86; Peptide vaccine: median OS = 10.08 months, 95% CI 5.23-19.44) and PFS (DC vaccine: median PFS = 11.01 months, 95% CI 5.25-23.09; Peptide vaccine: median PFS = 1.97 months, 95% CI 1.53-2.54) of DC vaccine were also longer than that of peptide vaccine. HBV-related HCC may acquire more benefits from tumor vaccines than HCV-related HCC. In almost all studies, the observed toxicities were moderate even tiny. CONCLUSIONS: Tumor vaccines for HCC, especially DC vaccine, are safe and worth exploring. More high-quality prospective studies are warranted.

Systemic immune-inflammation index predicts prognosis of cancer immunotherapy: systemic review and meta-analysis.

Objective: This meta-analysis was designed to explore the association between the systemic immune-inflammation index (SII) and the therapeutic effect of immune checkpoint inhibitors. Materials & methods: The authors retrieved relevant studies published before May 25, 2022. Hazard ratio (HR) with 95% CI was used to evaluate the relationship between SII and overall survival (OS) and progression-free survival (PFS). Results: 14 articles comprising 2721 patients were included in this study. The pooled results proved that high SII levels were closely related to poor prognosis in cancer patients receiving immune checkpoint inhibitors (OS HR = 2.40; 95% CI: 2.04-2.82; PFS HR = 1.57; 95% CI: 1.33-1.86) and that an SII value of 750 was appropriate as a cut-off value (OS HR = 2.20; 95% CI: 1.83-2.63; PFS HR = 1.54; 95% CI: 1.33-1.80). Conclusion: High SII levels (>750) may be an indicator of worse OS and PFS in cancer patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have substantially improved the prognosis of many patients with advanced cancer. However, some patients still do not benefit from ICIs. Therefore, determining indicators that can identify patients who may benefit from ICIs is essential. As a noninvasive, convenient and inexpensive clinical indicator, the systemic immune­inflammation index is expected to solve the aforementioned issue. Through this meta-analysis, the authors demonstrated that patients with cancers with high systemic immune­inflammation index levels had shorter survival and a smaller degree of clinical benefit after ICI treatment. Moreover, a systemic immune­inflammation index value of 750 is recommended to be the cut-off value for stratifying patients.

The causal relationship between white blood cell counts and hepatocellular carcinoma: a Mendelian randomization study.

BACKGROUND: Most of hepatocellular carcinoma (HCC) arises on the background of chronic inflammation. The presence of infiltrating inflammatory cells is associated with tumour initiation, progression and clinical response to treatment. The influence of white blood cell (WBC) subtype counts on HCC progression remains unclear. METHODS: In this study, we performed a Mendelian randomization (MR) study with the validation of two datasets. The summary data for WBC counts were extracted from a recent large GWAS of individuals of European ancestry. The GWAS data related to HCC were obtained from the UK Biobank (UKB). Univariable and multivariable MR analyses were used to identify risk factors genetically associated with HCC risks. RESULTS: In the discovery dataset, multivariable MR analysis revealed that sum basophil neutrophil counts had an independent causal effect on the occurrence of HCC, with the sum basophil neutrophil counts as follows: (OR = 0.437, P = 0.003, CI 0.252-0.757). Similarly, in the validation dataset, total basophil neutrophil counts were also been identified as an independent risk factor for HCC. The sum basophil neutrophil counts were as follows: (OR = 0.574, P = 0.021, CI 0.358-0.920). CONCLUSION: In the European population, genetically predicted lower total basophil neutrophil counts might be an independent risk factor for HCC.

Peripheral cytokine levels as novel predictors of survival in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

Background: Early identification of patients who will benefit from immune checkpoint inhibitors (ICIs) has recently become a hot issue in cancer immunotherapy. Peripheral cytokines are key regulators in the immune system that can induce the expression of immune checkpoint molecules; however, the association between peripheral cytokines and the efficiency of ICIs remains unclear. Methods: A systematic review was conducted in several public databases from inception through 3 February 2022 to identify studies investigating the association between peripheral cytokines (i.e., IL-1ß, IL-2, IL-2RA, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF-α, IFN-γ, and TGF-ß) and ICI treatment. Survival data, including overall survival (OS) and/or progression-free survival (PFS), were extracted, and meta-analyses were performed. Results: Twenty-four studies were included in this analysis. The pooled results demonstrated that the pretreatment peripheral levels of IL-6 (univariate analysis: HR = 2.53, 95% CI = 2.21-2.89, p < 0.00001; multivariate analysis: HR = 2.21, 95% CI = 1.67-2.93, p < 0.00001) and IL-8 (univariate analysis: HR = 2.17, 95% CI = 1.98-2.38, p < 0.00001; multivariate analysis: HR = 1.88, 95% CI= 1.70-2.07, p < 0.00001) were significantly associated with worse OS of cancer patients receiving ICI treatment in both univariate and multivariate analysis. However, high heterogeneity was found for IL-6, which might be attributed to region, cancer type, treatment method, sample source, and detection method. Conclusion: The peripheral level of IL-8 may be used as a prognostic marker to identify patients with inferior response to ICIs. More high-quality prospective studies are warranted to assess the predictive value of peripheral cytokines for ICI treatment.

Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies.

BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.

Role of Rab GTPases in Hepatocellular Carcinoma.

The Rab GTPase family contains almost 70 genes in the human genome and acts as the key regulator of intracellular membrane trafficking in human cells. The dysregulation of Rab GTPase has been shown to be associated with multiple human diseases, ranging from neurodegeneration, and infection to cancer. Rab GTPases not only play important roles in genome replication, morphogenesis and the release of hepatitis B virus (HBV) or hepatitis C virus (HCV), but also contribute to hepatitis-related hepatocarcinogenesis and hepatocellular carcinoma (HCC) progression. The alteration of Rab GTPase expression in HCC plays an important role in tumour cell proliferation, invasion and migration. Notably, the expression of Rab genes can be regulated by some noncoding RNAs, such as miRNAs and circRNAs. Thus, Rab GTPases can serve as promising rational and therapeutic targets for HCC treatments. In this review, we summarized recent advancements in this field focusing on Rab GTPases in HCC.

MOF-Derived Fe7 S8 Nanoparticles/N-Doped Carbon Nanofibers as an Ultra-Stable Anode for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have aroused wide concern due to their potential applications in large-scale energy-storage systems. In this work, a hybrid of Fe7 S8 nanoparticles/N-doped carbon nanofibers (Fe7 S8 /N-CNFs) is designed and synthesized via electrospinning. As an anode for SIBs, Fe7 S8 /N-CNFs exhibit a high reversible capacity of 649.9 mAh g-1 at 0.2 A g-1 after 100 cycles, and superior cycling stability for 2000 cycles at 1 A g-1 with only 0.00302% capacity decay per cycle. Such excellent performance originates from: i) Fe7 S8 nanoparticles (average diameter of 17 nm), which shorten the Na+ diffusion distance; ii) the unique 3D N-CNFs, which enhance the conductivity, alleviate the self-agglomeration and large volume change of Fe7 S8 nanoparticles, and offer numerous active sites for Na+ adsorption and paths for electrolyte diffusion. The fascinating structure and superior electrochemical properties of Fe7 S8 /N-CNFs shed light on developing high-performance SIBs anode materials.

RECK expression is associated with angiogenesis and immunogenic Tumor Microenvironment in Hepatocellular Carcinoma, and is a prognostic factor for better survival.

Angiogenesis and immunosuppression have been described as closely related processes that can occur in parallel. As an inhibitor of matrix metalloproteinase, whether the level of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in hepatocellular carcinoma (HCC) reflects a link between angiogenesis and immunosuppression is still unknown. We analyzed RNA expression, immune infiltration and survival of HCC from The Cancer Genome Atlas databases. Immune scores and stromal scores were calculated based on the ESTIMATE algorithm to quantify the immune and stromal components in HCC. The association between RECK and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high RECK expression was significantly better than that of patients with low RECK expression. High RECK expression was associated with high ESTIMATE Score, recruitment of more tumor-infiltrating lymphocytes, low tumor purity, and high PD-L1 expression. In addition, positive RECK expression was associated with a lower incidence of vascular invasion and recurrence, a lower level of alpha fetoprotein (AFP) and microvessel density and a better tumor differentiation. Multivariate analyses revealed that reduced RECK expression was an independent prognostic factor for recurrence and poor prognosis. In conclusion, high RECK expression reflects an immunogenic and hypovascularity status in HCC. RECK is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive anti-angiogenic therapy or immunotherapy.

Clinical Benefit of Antiviral Agents for Hepatocellular Carcinoma Patients With Low Preoperative HBV-DNA Loads Undergoing Curative Resection: A Meta-Analysis.

BACKGROUND AND AIMS: The clinical benefit of adjuvant antiviral therapy after curative therapy for HCC in patients with high preoperative HBV-DNA loads has been studied widely but that in patients with low preoperative HBV-DNA loads remains controversial. The purpose of this study was to determine the effect of antiviral treatment prophylaxis on HBV reactivation, overall survival (OS), and postoperative liver function in patients with low preoperative HBV-DNA levels undergoing curative resection. METHODS: A meta-analysis was conducted by searching Web of Science, PubMed, Embase, and Cochrane Library until May 2020. We used REVMAN for data analysis and completed the study under the PRISMA guidelines. RESULTS: Three randomized trials and seven cohort studies, comprising of 1,131 individuals, were included in the meta-analysis. Antiviral treatment significantly reduced the rate of HBV reactivation after curative treatment of HCC, with a pooled risk ratio of 0.12 (95% c.i. 0.07 to 0.21; P < 0.00001). The trials were consistently favorable for the antiviral group, with a pooled hazard ratio of 0.52 (95% c.i. 0.37 to 0.74; P = 0.0002) in respect of OS rate. However, by pooling the data from studies that reported ALT on the 30th day postoperatively, the result didn't reach statistical significance (mean difference -4.38, 95% c.i. -13.83 to 5.07; P = 0.36). The I² values of the heterogeneity test for the above three comparisons are zero. CONCLUSION: Antiviral therapy during curative resection is effective in reducing HBV reactivation and improving OS rate in HCC patients with low viral load.

Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: A systematic review with meta-analysis.

BACKGROUND AND AIM: The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS: A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS: Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION: Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.

Role of the E3 Ubiquitin Ligase TRIM4 in Predicting the Prognosis of Hepatocellular Carcinoma.

The E3 ubiquitin ligase TRIM4 has been reported to regulate the assembly of the antiviral signalling complex, induce mitochondrial aggregation and sensitize cells to H2O2-induced death. However, the relationship between TRIM4 and human malignancies, including hepatocellular carcinoma (HCC), is unclear. In this study, we detected the expression of TRIM4 in 134 pairs of HCC tissues and peritumoural tissues and investigated the association of TRIM4 expression with the prognosis of HCC. We found that the TRIM4 expression was much lower in HCC tissues than in peritumoural tissues and was significantly associated with vascular invasion, tumour capsule and Hong Kong Liver Cancer (HKLC) stage. Univariate and multivariate analyses revealed that the TRIM4 expression was an independent prognostic factor for overall survival (OS) and recurrence-free survival (RFS) in our HCC cohort. Patients with higher TRIM4 expression had a lower incidence of intrahepatic recurrence and a higher OS rate (p<0.001 and p<0.01, respectively). These results were further validated in another independent cohort of 200 HCC patients. In conclusion, the TRIM4 level in HCC tissues is an independent prognostic factor for HCC patients. Close clinical monitoring is recommended for patients with low TRIM4 expression.