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Hepatocellular carcinoma (HCC) is a highly lethal cancer, and proteomic studies have shown increased protein diversity and abundance in HCC tissues, whereas the role of protein translation has not been extensively explored in HCC. Our research focused on key molecules in the translation process to identify a potential contributor in HCC. We discovered that EIF4G2, a crucial translation initiation factor, is significantly upregulated in HCC tissues and associated with poor prognosis. This study uniquely highlights the impact of EIF4G2 deletion, which suppresses tumor growth and metastasis both in vitro and in vivo . Furthermore, polysome analysis and nascent protein synthesis assays revealed EIF4G2's role in regulating protein translation, specifically identifying PLEKHA1 as a key translational product. This represents a novel mechanistic insight into HCC malignancy. RNA immunoprecipitation (RIP) and Dual-luciferase reporter assays further revealed that EIF4G2 facilitates PLEKHA1 translation via an IRES-dependent manner. Importantly, the synergistic effects of EIF4G2 depletion and PLEKHA1 reduction in inhibiting cell migration and invasion underscore the therapeutic potential of targeting this axis. This study not only advances our understanding of translational regulation in HCC but also identifies the EIF4G2-PLEKHA1 axis as a promising therapeutic target, offering new avenues for intervention in HCC treatment.

Hepatocellular carcinoma (HCC) is the sixed most common malignant tumor in the world. The study for HCC is mired in the predicament confronted with the difficulty of early diagnosis and high drug resistance, the survival rate of patients with HCC being low. Ferroptosis, an iron-dependent cell death, has been discovered in recent years as a cell death means with tremendous potential to fight against cancer. The in-depth researches for iron metabolism, lipid peroxidation and dysregulation of antioxidant defense have brought about tangible progress in the firmament of ferroptosis with more and more results showing close connections between ferroptosis and HCC. The potential role of ferroptosis has been widely used in chemotherapy, immunotherapy, radiotherapy, and nanotherapy, with the development of various new drugs significantly improving the prognosis of patients. Based on the characteristics and mechanisms of ferroptosis, this article further focuses on the main signaling pathways and promising treatments of HCC, envisioning that existing problems in regard with ferroptosis and HCC could be grappled with in the foreseeable future., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control., (© 2024. The Author(s).)

Forkhead box M1 (FOXM1) is a key regulator of mitosis and is identified as an oncogene involved in several kinds of human malignancies. However, how it induces carcinogenesis and related therapeutic approaches remains not fully understood. In this study, we aimed to identify a regulatory axis involving FOXM1 and its target gene DEP domain containing 1 (DEPDC1) and investigate their biological functions. FOXM1 bound to the promoter and transcriptionally induced DEPDC1 expression, in turn, DEPDC1 physically interacted with FOXM1, promoted its nuclear translocation, and reinforced its transcriptional activities. The FOXM1/DEPDC1 axis was indispensable for cancer cells, as evidenced by the fact that DEPDC1 rescued cell growth inhibition caused by FOXM1 knockdown, and silencing DEPDC1 efficiently attenuated tumor growth in a murine hepatocellular carcinoma model. Furthermore, strong positive associations between FOXM1/DEPDC1 axis and poor clinical outcome were observed in human hepatocellular carcinoma samples, further indicating their significance for hepatocarcinogenesis. Finally, we attempted to exploit immunotherapy approaches to target the FOXM1/DEPDC1 axis. Several HLA-A24:02-restricted T-cell epitopes targeting FOXM1 or DEPDC1 were identified through bioinformatic analysis. Then, T cell receptor (TCR)-engineered T cells targeting FOXM1 262-270 or DEPDC1 294-302 were successfully established and proved to efficiently eradicate tumor cells. Our findings highlight the significance of the FOXM1/DEPDC1 axis in the process of oncogenesis and indicate their potential as immunotherapy targets., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Hepatocellular carcinoma (HCC) seriously threatens human health, mostly developed from liver fibrosis or cirrhosis. Since diethylnitrosamine (DEN) and carbon tetrachloride (CCl 4 )-induced HCC mouse model almost recapitulates the characteristic of HCC with fibrosis and inflammation, it is taken as an essential tool to investigate the pathogenesis of HCC. However, a comprehensive understanding of the protein expression profile of this model is little. In this study, we performed proteomic analysis of this model to elucidate its proteomic characteristics. Compared with normal liver tissues, 432 differentially expressed proteins (DEPs) were identified in tumor tissues, among which 365 were up-regulated and 67 were down-regulated. Through Gene Ontology (GO) analysis, Ingenuity Pathway Analysis (IPA), protein-protein interaction networks (PPI) analysis and Gene-set enrichment analysis (GSEA) analysis of DEPs, we identified two distinguishing features of DEN and CCl 4 -induced HCC mouse model in protein expression, the upregulation of actin cytoskeleton and branched-chain amino acids metabolic reprogramming. In addition, matching DEPs from the mouse model to homologous proteins in the human HCC cohort revealed that the DEN and CCl 4 -induced HCC mouse model was relatively similar to the subtype of HCC with poor prognosis. Finally, combining clinical information from the HCC cohort, we screened seven proteins with prognostic significance, SMAD2, PTPN1, PCNA, MTHFD1L, MBOAT7, FABP5, and AGRN. Overall, we provided proteomic data of the DEN and CCl 4 -induced HCC mouse model and highlighted the important proteins and pathways in it, contributing to the rational application of this model in HCC research., (© 2024. The Author(s).)

Background/aims:  The S100 family contains more than 20 Ca2+-binding proteins that participate in numerous cellular biological processes. However, the prognostic value of individual S100s in hepatocellular carcinoma (HCC) remains unclear. Therefore, we comprehensively assessed the prognostic value of S100s in HCC., Materials and Methods:  The mRNA level of S100s in distinct types of cancer was analyzed through Oncomine. The clinical prognostic significance of each S100 was evaluated using Kaplan-Meier plotter and OncoLnc. The expression and mutation of S100s were determined through cBioPortal. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the functions and pathways of S100s., Results:  The analyses revealed that, relative to normal tissues, liver cancer tissues showed aberrant mRNA expression of most S100s. In the survival analysis with Kaplan-Meier plotter, elevated expression levels of S100PBP, S100A2, S100A7, S100A10, and S100A13 were related to shorter overall survival (OS), whereas increased S100A5 expression was associated with longer OS. Moreover, results obtained using OncoLnc showed that increased expression levels of S100P, S100PBP, S100A13, S100A11, S100A10, and S100A2 were related to shorter OS. Thus, S100PBP, S100A13, S100A10, and S100A2 exhibited the same prognostic trend in the 2 databases. However, all S100 member gene mutational changes had no considerable prognostic value in OS and disease-free survival of HCC patients., Conclusion:  Although the findings need to be further confirmed by experiments, they provide new evidence for the prognostic significance of the S100s in HCC.

Background: While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N 6 -methyladenosine (m 6 A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis., Methods: Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling., Results: METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s)., Conclusions: Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency., (© 2024. The Author(s).)

Aldolase A (ALDOA) promotes hepatocellular carcinoma (HCC) growth and is a potential therapeutic target. A previous study found an α-D-glucan (α-D-(1,6)-Glcp-α-D-(1,4)-Glcp, 10.0:1.0), named HDPS-4II, that could specifically inhibit ALDOA but its activity was not high enough. In this study, the derivatives of α-D-glucan binding to ALDOA were optimized using molecular docking, and its sulfated modification demonstrated the highest affinity with ALDOA among sulfated, carboxylated, and aminated derivatives. Sulfated HDPS-4II and dextrans with different molecular weights (1000 Da, 3000 Da, and 4000 Da) were prepared. Using MST assay, 3-O-sulfated HDPS-4II (SHDPS-4II) and 1000 Da dextran (SDextran1) showed higher affinities to ALDOA with K d of 1.83 μM and 85.04 μM, respectively. Furthermore, SHDPS-4II and SDextran1 markedly inhibited the proliferation of HCC cells both in vitro and in vivo by blocking ALDOA. These results demonstrate that sulfated modification of α-D-glucans could enhance their affinities with ALDOA and anti-HCC effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Radiofrequency ablation (RFA) is an important treatment strategy for patients with advanced hepatocellular carcinoma (HCC). However, its therapeutic effect is unsatisfactory and recurrence often occurs after RFA treatment. The octamer-binding transcription factor OCT1 is a novel tumour-promoting factor and an ideal target for HCC therapy., Objective: This study aimed to expand the understanding of HCC regulation by OCT1., Methods: The expression levels of the target genes were examined using qPCR. The inhibitory effects of a novel inhibitor of OCT1 (NIO-1) on HCC cells and OCT1 activation were examined using Chromatin immunoprecipitation or cell survival assays. RFA was performed in a subcutaneous tumour model of nude mice., Results: Patients with high OCT1 expression in the tumour tissue had a poor prognosis after RFA treatment (n = 81). The NIO-1 showed antitumor activity against HCC cells and downregulated the expression of the downstream genes of OCT1 in HCC cells, including those associated with cell proliferation (matrix metalloproteinase-3) and epithelial-mesenchymal transition-related factors (Snail, Twist, N-cadherin, and vimentin). In a subcutaneous murine model of HCC, NIO-1 enhanced the effect of RFA treatment on HCC tissues (n = 8 for NIO-1 and n = 10 for NIO-1 + RFA)., Conclusion: This study demonstrated the clinical importance of OCT1 expression in HCC for the first time. Our findings also revealed that NIO-1 aids RFA therapy by targeting OCT1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Many cancers harbor homologous recombination defects (HRDs). A HRD is a therapeutic target that is being successfully utilized in treatment of breast/ovarian cancer via synthetic lethality. However, canonical HRD caused by BRCAness mutations do not prevail in liver cancer. Here we report a subtype of HRD caused by the perturbation of a proteasome variant (CDW19S) in hepatitis B virus-bearing (HBV-bearing) cells. This amalgamate protein complex contained the 19S proteasome decorated with CRL4WDR70 ubiquitin ligase, and assembled at broken chromatin in a PSMD4Rpn10- and ATM-MDC1-RNF8-dependent manner. CDW19S promoted DNA end processing via segregated modules that promote nuclease activities of MRE11 and EXO1. Contrarily, a proteasomal component, ADRM1Rpn13, inhibited resection and was removed by CRL4WDR70-catalyzed ubiquitination upon commitment of extensive resection. HBx interfered with ADRM1Rpn13 degradation, leading to the imposition of ADRM1Rpn13-dependent resection barrier and consequent viral HRD subtype distinguishable from that caused by BRCA1 defect. Finally, we demonstrated that viral HRD in HBV-associated hepatocellular carcinoma can be exploited to restrict tumor progression. Our work clarifies the underlying mechanism of a virus-induced HRD subtype.

Objective: Abundant angiogenesis in hepatocellular carcinoma (HCC) is critical in its malignant course; however, its mechanism is incompletely understood. Meanwhile, the corresponding roles of PIK3R6 molecules in HCC have not been investigated. This study aims to explore the intrinsic mechanism of PIK3R6 and provide theoretical reference for the treatment of hepatocellular carcinoma., Methods: Differential expressions of PIK in ovarian cancer and normal ones were detected by Western blotting and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Analyze the relationship between the expression of PIK3R6 and patient prognosis through the TCGA database. Subsequently constructed corresponding stable cell lines, combined with transcriptome sequencing and several cell biology experiments, we explored the inner mechanism and clinical significance of PIK3R6., Results: By analyzing multiple cohorts, we found that high PIK3R6 expression in tumor tissues negatively correlates with patient prognosis. PIK3R6 could increase angiogenesis in HCC by boosting the activity of the STAT3 signalling pathway to hasten the malignant progression of the disease, according to corresponding cellular and molecular experimental studies. Then again, immunohistochemistry on a series of tissue chips confirmed the important clinical significance of PIK3R6-STAT3 regulatory axis., Couclusions: This study initially addressed the clinical significance of PIK3R6 and revealed its mechanism for promoting angiogenesis in hepatocellular carcinoma, providing a reliable working foundation for future in-depth research and clinical translation.

Objective: This study aimed to compare the short-term and long-term outcomes between robotic-assisted simultaneous resection and open surgery in patients with rectal cancer and liver metastases., Background: Open simultaneous resection of colorectal cancer and synchronous liver metastases is widely performed and the potential cure for eligible patients. However, the feasibility of robotic simultaneous resection of primary and secondary liver lesions has not been established as a treatment option for metastatic rectal cancer., Patients and Methods: A single-center randomized controlled trial was conducted at a hospital in China. Enrolling patients were aged from 18 to 75 years and diagnosed with surgically resectable metastatic rectal cancer (distal extension to ≤15 cm from the anal margin). Patients selected for simultaneous resection were randomly assigned to have robotic or open surgery at a 1:1 ratio. The primary endpoint was the incidence rate of complications within 30 days after surgery. Secondary endpoints were bladder, sexual function, 3-year disease-free survival, and overall survival., Results: A total of 171 patients were enrolled in this trial with 86 in the robotic group and 85 in the open group. As a result, patients in the robotic group demonstrated fewer complications within 30 days after surgery than those in the open group (31.4 vs. 57.6%, P =0.014) and no mortality seen in either group. Patients in the robotic group had less blood loss [mean (SD), 125.5 (38.3) vs. 211.6 (68.7) ml; P <0.001], faster bowel function recovery [mean (SD), 63.7 (27.4) vs. 93.8 (33.5) h P <0.001] and shorter hospital stay [mean (SD), 8.0 (2.2) vs. 10.7 (5.4) days; P <0.001] compared with those in the open group. The robotic group had a faster recovery of bladder and sexual function at 3 months after surgery than that of the open group. The 3-year disease-free survival rate (39.5 vs. 35.3%, P =0.739) and the 3-year overall survival rate (76.7 vs. 72.9%, P =0.712) were not statistically significant between the two groups., Conclusions: In our randomized clinical trial, robotic simultaneous resection treatment of patients with rectal cancer and liver metastases resulted in fewer surgical complications, and a faster recovery to those of open surgery. Oncological outcomes showed no significant difference between the two groups., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: This study aimed to examine glycolysis/gluconeogenesis-related genes in hepatocellular carcinoma (HCC) and evaluate their potential roles in HCC progression and immunotherapy response., Methods: Data analyzed in this study were collected from GSE14520, GSE76427, GSE174570, The Cancer Genome Atlas (TCGA), PXD006512, and GSE149614 datasets, metabolic pathways were collected from MSigDB database. Differentially expressed genes (DEGs) were identified between HCC and controls. Differentially expressed glycolysis/gluconeogenesis-related genes (candidate genes) were obtained and consensus clustering was performed based on the expression of candidate genes. Bioinformatics analysis was used to evaluate candidate genes and screen prognostic genes. Finally, the key results were tested in HCC patients., Results: Thirteen differentially expressed glycolysis/gluconeogenesis-related genes were validated in additional datasets. Consensus clustering analysis identified two distinct patient clusters (C1 and C2) with different prognoses and immune microenvironments. Immune score and tumor purity were significantly higher in C1 than in C2, and CD4+ memory activated T cell, Tfh, Tregs, and macrophage M0 were higher infiltrated in HCC and C1 group. The study also identified five intersecting DEGs from candidate genes in TCGA, GSE14520, and GSE141198 as prognostic genes, which had a protective role in HCC patient prognosis. Compared with the control group, the prognostic genes all showed decreased expression in HCC patients in RT-qPCR and Western blot analyses. Flow cytometry verified the abnormal infiltration level of immune cells in HCC patients., Conclusion: Results showed that glycolysis/gluconeogenesis-related genes were associated with patient prognosis, immune microenvironment, and response to immunotherapy in HCC. It suggests that the model based on five prognostic genes may valuable for predicting the prognosis and immunotherapy response of HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Aierken, Li, Chen, Ren and Wang.)

Background: The type of liver resection (anatomical resection, AR or non-anatomical resection, NAR) for colorectal liver metastases (CRLM) is subject to debate. The debate may persist because some prognostic factors, associated with aggressive tumor biological behavior, have been overlooked., Objective: Our study aimed to investigate the characteristics of patients who would benefit more from anatomical resection for CRLM., Methods: Seven hundred twenty-nine patients who underwent hepatic resection of CRLM were retrospectively collected from June 2012 to May 2019. Treatment effects between AR and NAR were compared in full subgroup analyses. Tumor relapse-free survival (RFS) was evaluated by a stratified log-rank test and summarized with the use of Kaplan-Meier and Cox proportional hazards methods., Results: Among 729 patients, 235 (32.2%) underwent AR and 494 (67.8%) underwent NAR. We showed favorable trends in RFS for AR compared with NAR in the patients with KRAS/NRAS/BRAF mutation (interaction P <0.001) or right-sidedness (interaction P <0.05). Patients who underwent AR had a markedly improved RFS compared with NAR in the cohorts of RAS/NRAS/BRAF mutation (median RFS 23.2 vs. 11.1 months, P <0.001) or right-sidedness (median RFS 31.6 vs. 11.5 months, P <0.001); upon the multivariable analyses, AR [gene mutation: hazard ratio (HR)=0.506, 95% CI=0.371-0.690, P <0.001; right-sidedness: HR=0.426, 95% CI=0.261-0.695, P =0.001) remained prognostic independently. In contrast, patients who underwent AR had a similar RFS compared with those who underwent NAR, in the cohorts of patients with gene wild-type tumors (median RFS 20.5 vs. 21.6 months, P =0.333). or left-sidedness (median RFS 15.8 vs. 19.5 months, P =0.294)., Conclusions: CRLM patients with gene mutation or right-sidedness can benefit more from AR rather than from NAR., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Primary tumour resection (PTR) is still a selection for patients with low tumour burden and good condition, especially with conversion therapy purpose for colorectal liver-limited metastases (CRLMs). The objective was to evaluate whether pre-PTR chemotherapy could improve progression-free survival (PFS) for patients with asymptomatic synchronous unresectable CRLMs., Patients and Methods: Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were chosen according to the RAS genotype. The primary end-point was PFS; secondary end-points included overall survival (OS), tumour response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity., Results: Three hundred and twenty patients were randomly assigned to arm A (160 patients) and arm B (160 patients). Patients in arm A had significantly improved the median PFS compared with arm B (10.5 versus 9.1 months; P = 0.013). Patients in arm A also had significantly better DCR (84.4% versus 75.0%; P = 0.037). The median OS (29.4 versus 27.2 months; P = 0.058), objective response rate (ORR) (53.1% versus 45.0%; P = 0.146) and liver metastases resection rate (21.9% versus 18.1%; P = 0.402) were not significantly different. The Clavien-Dindo 3-4 complications post PTR (4.5% versus 3.8%, P = 0.759) and the incidence of grade 3/4 chemotherapy events (42.2% versus 40.4%, P = 0.744) reached no statistical significance., Conclusions: For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Second primary malignancies (SPMs) after liver transplantation (LT) are becoming the leading causes of death in LT recipients. The purpose of this study was to explore prognostic factors for SPMs and to establish an overall survival nomogram., Methods: A retrospective analysis was conducted of data from the Surveillance, Epidemiology, and End Results (SEER) database on adult patients with primary hepatocellular carcinoma who had undergone LT between 2004 and 2015. Cox regression analysis was used to explore the independent prognostic factors for SPMs. Nomogram was constructed using R software to predict the overall survival at 2, 3, and 5 years. The concordance index, calibration curves, and decision curve analysis were used to evaluate the clinical prediction model., Results: Data from a total of 2078 patients were eligible, of whom 221 (10.64%) developed SPMs. A total of 221 patients were split into a training cohort (n=154) or a validation cohort (n=67) with a 7:3 ratio. The 3 most common SPMs were lung cancer, prostate cancer, and non-Hodgkin lymphoma. Age at initial diagnosis, marital status, year of diagnosis, T stage, and latency were the prognostic factors for SPMs. The C-index of the nomogram for overall survival in the training and validation cohorts were 0.713 and 0.729, respectively., Conclusions: We analyzed the clinical characteristics of SPMs and developed a precise prediction nomogram, with a good predictive performance. The nomogram we developed may help clinicians provide personalized decisions and clinical treatment for LT recipients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: DTL has been found to be related with multiple cancers. However, comprehensive analyses, which identify the prediction value of DTL in diagnosis, prognosis, immune infiltration and treatment, have rarely been reported so far., Methods: Combined with the data online databases, the gene expression, gene mutation, function enrichment and the correlations with the immunity status and clinical indexes of DTL were analyzed. Expression of DTL and the degree of immune cell infiltration were examined by immunofluorescence (IF) and immunohistochemistry (IHC) and analyzed by statistical analysis. Furthermore, the influences of DTL on the cell cycle, cell proliferation and apoptosis were detected by live cell imaging, IF and flow cytometric (FC) analysis. Genomic stability assays were conducted by chromosome slide preparation., Results: DTL was widely expressed in various cells and tissues, while it was overexpressed in tumor tissues except acute myeloid leukemia (LAML). Pan-cancer bioinformatics analysis showed that the expression of DTL was correlated with the prognosis, immunotherapy, and clinical indexes in various cancers. In addition, gene set enrichment analysis (GSEA) uncovered that DTL was enriched in oocyte meiosis, pyrimidine metabolism, the cell cycle, the G2M checkpoint, mTORC1 signaling and E2F targets. Furthermore, the overexpression of DTL, and its association with immune cell infiltration and clinical indexes in liver hepatocellular carcinoma (LIHC), bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD) were verified in our study. It was also verified that overexpression of DTL could regulate the cell cycle, promote cell proliferation and cause genomic instability in cultured cells, which may be the reason why DTL plays a role in the occurrence, progression and treatment of cancer., Conclusions: Collectively, this study suggested that DTL is of clinical value in the diagnosis, prognosis and treatment of various cancers, and may be a potential biomarker in certain cancers., (© 2023. The Author(s).)

Aims: Transient receptor potential canonical-6 (TRPC6) is a therapeutic target for hepatocellular carcinoma. The authors aimed to synthesize and determine whether indole-2-carboxamide derivatives have anti-hepatocellular carcinoma activities targeting TRPC6. Materials & methods: Molecular docking was carried out to design these derivatives. The top five compounds were synthesized for activity validation using microscale thermophoresis. Cell cytotoxicity, flow cytometry, western blotting and cell transfection were used to investigate the anti-hepatocellular carcinoma activities and mechanisms in vitro . Xenografts of nude mice were used for in vivo evaluation. Results: The indole-2-carboxamide derivative, BP3112, promoted apoptosis and G1-phase arrest in HCCs via inhibiting TRPC6, and dose-dependently inhibit tumor growth in vivo . Conclusion: BP3112 as a specific inhibitor of TRPC6 is a potential therapeutic agent for hepatocellular carcinoma.

Background: Previous studies confirmed that most neoantigens predicted by algorithms do not work in clinical practice, and experimental validations remain indispensable for confirming immunogenic neoantigens. In this study, we identified the potential neoantigens with tetramer staining, and established the Co-HA system, a single-plasmid system coexpressing patient human leukocyte antigen (HLA) and antigen, to detect the immunogenicity of neoantigens and verify new dominant hepatocellular carcinoma (HCC) neoantigens., Methods: First, we enrolled 14 patients with HCC for next-generation sequencing for variation calling and predicting potential neoantigens. Then, the Co-HA system was established. To test the feasibility of the system, we constructed target cells coexpressing HLA-A*11:01 and the reported KRAS G12D neoantigen as well as specific T-cell receptor (TCR)-T cells. The specific cytotoxicity generated by this neoantigen was shown using the Co-HA system. Moreover, potential HCC-dominant neoantigens were screened out by tetramer staining and validated by the Co-HA system using methods including flow cytometry, enzyme-linked immunospot assay and ELISA. Finally, antitumor test in mouse mode and TCR sequencing were performed to further evaluate the dominant neoantigen., Results: First, 2875 somatic mutations in 14 patients with HCC were identified. The main base substitutions were C>T/G>A transitions, and the main mutational signatures were 4, 1 and 16. The high-frequency mutated genes included HMCN1 , TTN and TP53 . Then, 541 potential neoantigens were predicted. Importantly, 19 of the 23 potential neoantigens in tumor tissues also existed in portal vein tumor thrombi. Moreover, 37 predicted neoantigens restricted by HLA-A*11:01, HLA-A*24:02 or HLA-A*02:01 were performed by tetramer staining to screen out potential HCC-dominant neoantigens. HLA-A*24:02-restricted epitope 5'-FYAFSCYYDL-3' and HLA-A*02:01-restricted epitope 5'-WVWCMSPTI-3' demonstrated strong immunogenicity in HCC, as verified by the Co-HA system. Finally, the antitumor efficacy of 5'-FYAFSCYYDL-3'-specific T cells was verified in the B-NDG- B2m tm1 Fcrn tm1(mB2m) mouse and their specific TCRs were successfully identified., Conclusion: We found the dominant neoantigens with high immunogenicity in HCC, which were verified with the Co-HA system., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have transformed the treatment landscape of advanced hepatocellular carcinoma (HCC), but consistent responses are not observed in all patients, and prognostic biomarkers to guide treatment decisions are lacking. We aimed to evaluate the predictive value of PD-L1 expression in advanced HCC patients treated with PD-1/PD-L1 inhibitors., Methods: A comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Studies comparing the objective response rate (ORR) and/or disease control rate (DCR) based on the tumor PD-L1 status of HCC were included., Results: Eleven studies with 1,330 HCC patients treated with PD-1/PD-L1 inhibitors were included. Pooled odds ratio (OR) analysis demonstrated a significantly improved ORR in PD-L1-positive patients compared with PD-L1-negative patients (OR, 1.86, 95% CI, 1.35-2.55). Similar results were observed in the anti-PD-1 treatment (p < 0.001) and anti-PD-1/PD-L1 monotherapy (p < 0.001) subgroups. The pooled ORRs in the PD-L1-positive and PD-L1-negative groups were 26% (95% CI, 20%-32%) and 18% (95% CI, 13%-22%), respectively. For DCR, the pooled OR analysis showed no significant difference between PD-L1-positive patients and PD-L1-negative patients (66% [95% CI, 55%-76%] vs. 69% [95% CI, 62%-76%]; OR, 0.92, 95% CI, 0.59-1.44). The results were consistent across the drug target and combination treatment subgroups., Conclusion: Positive PD-L1 expression is associated with a better ORR in advanced HCC patients treated with anti-PD-1/PD-L1-based therapies. This feature can help to identify HCC patients who will benefit most from PD-1/PD-L1 inhibitors., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Large hepatocellular carcinoma (LHCC) is prone to short-term recurrence and poor long-term survival after hepatectomy, and there is still a lack of effective neoadjuvant treatments to improve recurrence-free survival (RFS) and overall survival (OS). We retrospectively analyzed the efficacy of preoperative transcatheter arterial chemoembolization (TACE) in solitary LHCC (≥5 cm)., Materials and Methods: A multicenter medical database was used to analyze preoperative TACE's effects on RFS, OS, and perioperative complications in patients with solitary LHCC who received surgical treatment from January 2005 to December 2015. The patients were divided into Group A (5.0-9.9 cm) and Group B (≥10 cm), with 10 cm as the critical value, and the effect of preoperative TACE on RFS, OS and perioperative complications was assessed in each subgroup., Results: In the overall population, patients with preoperative TACE had better RFS and OS than those without preoperative TACE. However, after stratifying the patients into the two HCC groups, preoperative TACE only improved the survival outcomes of patients with Group B (≥10 cm). Multivariate Cox-regression analysis showed that lack of preoperative TACE was an independent risk factor for RFS and OS in the overall population and in Group B but not in Group A., Conclusions: Preoperative TACE is beneficial for patients with solitary HCC (≥10 cm)., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Due to the high recurrence, the HCC prognosis remains poor. Yet, the biomarkers for predicting the recurrence of high-risk patients are currently lacking. We aimed to develop a signature to predict the recurrence of HCC based on NKG2D ligands., Methods: The multivariate Cox proportional hazards regression was used to select recurrence-related variables of NKG2D ligands in HCC patients from The Cancer Genome Atlas (TCGA). HCC patients from the OEP000321 dataset and Guilin cohort were used to validate the predictive signature. The mRNA expression of NKG2D ligands was measured by QRT-PCR. Immunohistochemistry analysis of HCC tissue microarray samples was used to identify the expression of NKG2D ligands., Results: In this study, NKG2D ligands expression in the mRNA and protein level was both abnormally expressed in HCC and associated with recurrence-free survival (RFS). Then, the recurrence-related variables of NKG2D ligands in HCC were selected by the multivariate Cox proportional hazards regression. Among the eight NKG2D ligands, MICA (HR = 1.347; 95% CI = 1.012-1.793; p = 0.041), ULBP3 (HR = 0.453; 95% CI = 0.231-0.889; p = 0.021) and ULBP5 (HR = 3.617; 95% CI = 1.819-7.194; p < 0.001) were significantly correlated with RFS in the TCGA-LIHC cohort. Then, the signature was constructed by the three NKG2D ligands. The predictive effectiveness of this signature was also validated in the OEP000321 dataset and Guilin cohort. Further, HCC patients were classified into low-risk and high-risk subgroups by the predictive score. Compared with the low-risk group, the high-risk group had poor RFS in both training and validation cohorts. Importantly, compared with the low-risk patients with the G1-G2 stage, the levels of infiltrated NK-activated cells and NKG2D expression were both lower in the high-risk patients., Conclusions: The signature based on MICA, ULBP3, and ULBP5 could predict HCC recurrence., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Patients with colorectal liver metastases (CRLM) who underwent hepatic resection after conversion therapy had a high recurrence rate of nearly 90%. Preoperative DEB-TACE has the potential to prevent postoperative recurrence which has not been elucidated. The objective of this study was to evaluate the safety and efficacy of preoperative DEB-TACE., Materials and Methods: Patients with CRLM who underwent liver resection from June 1, 2016, to June 30, 2021, were collected and those who received conversional hepatectomy were included in this study. Patients with preoperative DEB-TACE were propensity-score matched in a 1:1 ratio to patients without preoperative DEB-TACE. Short-term outcomes and recurrence-free survival (RFS) were compared between the two groups., Results: After PSM, 44 patients were included in each group. The toxicities of DEB-TACE were mild and could be managed by conservative treatment. Overall response rate (ORR) of conversion therapy (75.0% vs. 81.2%, p = 0.437) and postoperative complication of hepatic resection (27.3% vs. 20.5%, p = 0.453) were similar between the two groups. The median RFS of the DEB-TACE group (10.7 months, 95%CI: 6.6-14.8 months) was significantly longer than that of the control group (8.1 months, 95%CI: 3.4-12.8 months) (HR: 0.60, 95%CI: 0.37-0.95, p = 0.027)., Conclusions: In patients who became resectable after conversion therapy, preoperative DEB-TACE might be a safe option to achieve longer RFS., Key Points: • This is a propensity-score matching study comparing patients who underwent conversional hepatectomy with or without preoperative DEB-TACE. • The preoperative DEB-TACE was safe and with mild toxicities (without toxicities more than CTCAE grade 3). • The preoperative DEB-TACE significantly prolonged the RFS of those patients who underwent conversional hepatectomy (10.7 vs. 8.1 months, p = 0.027)., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy where tumorigenesis and metastasis are believed to be tied to the hallmarks of hypoxia and tumor microenvironment (TME)., Methods: In this study, to investigate the relationships among hypoxia, TME, and HCC prognosis, we collected two independent datasets from a public database (TCGA-LIHC for identification, GSE14520 for validation) and identified the hypoxia-related differentially expressed genes (DEGs) from the TCGA data, and the univariable Cox regression and lasso regression analyses were performed to construct the prognosis model. An HCC prognosis model with 4 hypoxiarelated DEGs ("NDRG1", "ENO1", "SERPINE1", "ANXA2") was constructed, and high- and low-risk groups of HCC were established by the median of the model risk score., Results: The survival analysis revealed significant differences between the two groups in both datasets, with the results of the AUC of the ROC curve of 1, 3, and 5 years in two datasets indicating the robustness of the prognosis model. Meanwhile, for the TCGA-LIHC data, the immune characteristics between the two groups revealed that the low-risk group presented higher levels of activated NK cells, monocytes, and M2 macrophages, and 7 immune checkpoint genes were found upregulated in the high-risk group. Additionally, the two groups have no difference in molecular characteristics (tumor mutational burden, TMB). The proportion of recurrence was higher in the high-risk group, and the correlation between the recurrence month and risk score was negative, indicating high-risk correlates with a short recurrence month., Conclusion: In summary, this study shows the association among hypoxic signals, TME, and HCC prognosis and may help reveal potential regulatory mechanisms between hypoxia, tumorigenesis, and metastasis in HCC. The hypoxia-related model demonstrated the potential to be a predictor and drug target of prognosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The purpose of this study was to report the efficacy and safety of no-touch radiofrequency ablation (NT-RFA) in the treatment of small hepatocellular carcinoma (HCC)., Methods: We systematically searched for eligible studies in PubMed, Embase and Cochrane library until June 1, 2022. Random effect model was applied to synthesize the pooled proportions of local tumor progression-free survival (LTP), recurrence-free survival (RFS) and overall survival (OS) respectively, as well as adverse events, for small HCC treated by NT-RFA., Results: Of the 10 included studies, 3 of them reported local tumor recurrence. One reported local tumor recurrence at 19 months (range, 12-24), and 2 studies had no tumor recurrence with 24-months of follow-up. The 1- and 2-year LTP pooled proportions were 99.3% (95%CI, 97.5-100) and 97.8% (95%CI, 94.6-99.6) respectively, and two studies reported a 3-year LTP rate of 96.4% (204/212, 36/37). The 1-yearRFS rates was 91.3% (95%CI, 84.1-98.4), 2-year was 86.4% (95%CI, 75.3-97.5). The 1-, 2- and 3- year OS rates were 92.4% (95%CI, 82.8-92.7), 84.1% (95%CI, 74.7-93.6) and 81.8% (116/181, 33/36) respectively, and only one study reported a 5-year OS rate of 47.0% (85/181). The ablative success rate of the HCC nodules was 96.6% (95%CI, 91.3-99.5) and the proportions of mild and severe adverse events following ablation were 18.3% (95%CI, 8.1-41.6) and 5.0%, respectively., Conclusion: NT-RFA provides safely very high rate of sustained local control for the treatment of HCC up to 5 cm., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Aim: The purpose of this study was to analyze the features of conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) in hepatic epithelioid hemangioendothelioma (HEHE)., Material and Methods: We retrospectively analyzed the US images (grayscale, color Doppler and CEUS) of the patients with histopathologically confirmed HEHE in our hospital from March 2015 to August 2021 who had underwent a US investigation., Results: A total of 13 patients were reported during the study period (seven men, aged from 23 to 62 years, with an average age of 40 years). The unifocal, multifocal, and diffuse lesions were 2, 9, and 2, respectively. Five patients (5/13) had liver involvement of both lobes, and eight (8/13) patients had only right lobe involvement. The maximum diameter of the lesions ranged from 1.9 to 7.0 cm. The grayscale US of HEHE mainly showed multiple hypoechoic lesions (n=9) near the capsule of the right lobe of the liver, with well-defined margins (n=7), accompanied by a hypoechoic halo (n=3) or capsule retraction (n=4) and calcification (n=8). Color Doppler US can detect blood flow in the lesion (n=8). CEUS was performed in five patients (5/13). The enhancement pattern of CEUS varied in the arterial phase, mainly including rim-like hyper-enhancement (n=2) and inhomogeneous hypo-enhancement (n=2), but was approximately the same in the portal venous phase and the late venous phase, both showing varying degrees of regression., Conclusions: The grayscale US and CEUS seem to provide some reference value for diagnosing HEHE.

Background: Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction., Methods: First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results., Results: AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin-yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness., Conclusions: Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy., (© 2022. The Author(s).)

Lipid metabolic reprogramming is one of the hallmarks of hepatocarcinogenesis and development. Therefore, lipid-metabolism-related genes may be used as potential biomarkers for hepatocellular carcinoma (HCC). This study aimed to screen for genes with dysregulated expression related to lipid metabolism in HCC and explored the clinical value of these genes. We screened differentially expressed proteins between tumorous and adjacent nontumorous tissues of hepatitis B virus (HBV)-related HCC patients using a Nanoscale Liquid Chromatography-Tandem Mass Spectrometry platform and combined it with transcriptomic data of lipid-metabolism-related genes from the GEO and HPA databases to identify dysregulated genes that may be involved in lipid metabolic processes. The potential clinical values of these genes were explored by bioinformatics online analysis tools (GEPIA, cBioPortal, SurvivalMeth, and TIMER). The expression levels of the secreted protein (angiopoietin-like protein 6, ANGPTL6) in serum were analyzed by ELISA. The ability of serum ANGPTL6 to diagnose early HCC was assessed by ROC curves. The results showed that serum ANGPTL6 could effectively differentiate between HBV-related early HCC patients with normal serum alpha-fetoprotein (AFP) levels and the noncancer group (healthy participants and chronic hepatitis B patients) (AUC = 0.717, 95% CI: from 0.614 to 0.805). Serum ANGPTL6 can be used as a potential second-line biomarker to supplement serum AFP in the early diagnosis of HBV-related HCC.

Background: Current diagnostic markers for hepatocellular carcinoma are compromised and limited by their low sensitivity and speci- ficity. In this study, circulating microRNAs were utilized as a diagnostic tool to segregate hepatocellular carcinoma patients from healthy subjects., Methods: We analyzed 2 public datasets for differences in plasma microRNA expression profiles of hepatocellular carcinoma patients and healthy controls to identify biomarkers related to hepatocellular carcinoma. Plasma samples from hepatocellular carcinoma patients and control subjects were then collected for next-generation microRNA sequencing analysis. The differential microRNAs obtained from the above 3 parts were intersected to obtain microRNAs that were significantly different between the 2 groups. We then analyzed 58 specimens, which come from hepatocellular carcinoma and the control group, for validation through a quantitative polymerase chain reaction. The diagnostic value of these differentially expressed miRNAs was assessed by receiver operating characteristic curve analysis., Results: The levels of miR-206 and miR-222 were significantly higher (P &lt; .05) and the level of miR-126 was lower (P &lt; .05) in patients with hepatocellular carcinoma than in healthy subjects. Receiver operating characteristic analysis established a powerful diagnostic accuracy when miR-206, miR-222, and miR-126 were combined (area under curve = 0.887), which was similar to that of the markerα-fetoprotein (area under curve = 0.889). When the microRNAs were combined with α-fetoprotein, the accuracy of hepatocellular carci- noma diagnostic potential was further improved (area under curve = 0.989)., Conclusion: We identified 3 microRNAs significantly altered in the plasma of hepatocellular carcinoma patients and they can screen patients at risk of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Surgical resection is often only possible in the early stages of HCC and among those with limited cirrhosis. Radiofrequency ablation and Microwave ablation are 2 main types of percutaneous thermal ablation for the treatment of HCC. The efficacy and safety between these 2 therapy methods are still under a debate., Objective: To compare the efficacy and safety of Radiofrequency ablation and Microwave ablation in treating HCC., Methods: PubMed, EMBASE, the Cochrane databases and Web of Science were systematically searched. We included randomized controlled trials and cohort studies comparing the efficacy and safety of Radiofrequency ablation and Microwave ablation in HCC patients. Outcome measures on local tumor progression, complete ablation, disease-free survival, overall survival, or major complications were compared between the 2 groups. The random effect model was used when there was significant heterogeneity between studies, otherwise the fixed effect model was used., Results: A total of 33 studies, involving a total of 4589 patients were identified, which included studies comprised 7 RCTs, 24 retrospective observational trials, and 2 prospective observational trial. Microwave ablation had a lower local tumor progression than Radiofrequency ablation in cohort studies (OR = 0.78, 95% CI 0.64-0.96, P = .02). Complete ablation rate of Microwave ablation was higher than that of Radiofrequency ablation in cohort studies (OR = 1.54, 95% CI 1.05-2.25, P = .03). There was no significant difference in overall survival and disease-free survival between the 2 groups. Meta-analysis showed that there was no significant difference in the main complications between Microwave ablation and Radiofrequency ablation., Conclusions: Microwave ablation has higher complete ablation and lower local tumor progression than Radiofrequency ablation in the ablation treatment of HCC nodules. There was no significant difference in overall survival between the 2 therapy methods., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The extravasation capability of hepatocellular carcinoma (HCC) cells plays a vital role in distant metastasis. However, the underlying mechanism of extravasation in HCC lung metastasis remains largely unclear., Methods: The expression of ARHGEF37 in human HCC specimens and HCC cell lines was examined by quantitative RT-PCR, western blot, and immunohistochemistry (IHC) analyses. The biological roles and mechanisms of ARHGEF37/Cdc42 in promoting lung metastasis were investigated in vitro and in vivo using cell lines, patient samples, xenograft models., Results: In the current study, we found that Rho guanine nucleotide exchange factor 37 (ARHGEF37) was upregulated in human HCC samples and was associated with tumor invasiveness, pulmonary metastasis and poor prognosis. Overexpressing ARHGEF37 significantly enhanced the extravasation and metastatic capability of HCC cells via facilitating tumor cell adhesion to endothelial cells and trans-endothelial migration. Mechanistically, ARHGEF37 directly interacted with and activated Cdc42 to promote the invadopodia formation in HCC cells, which consequently disrupted the interaction between endothelial cells and pericytes. Importantly, treatment with ZCL278, a specific inhibitor of Cdc42, dramatically inhibited the attachment of ARHGEF37-overexpressing HCC cells to endothelial cells, and the adherence and extravasation in the lung alveoli, resulting in suppression of lung metastasis in mice., Conclusion: Our findings provide a new insight into the underlying mechanisms on the ARHGEF37 overexpression-mediated extravasation and pulmonary metastasis of HCC cells, and provided a potential therapeutic target for the prevention and treatment of HCC pulmonary metastasis., (© 2022. The Author(s).)

Background: Circulating long non-coding RNAs (lncRNAs) have been demonstrated to serve as diagnostic or prognosis biomarkers for various disease. We aimed to elucidate the diagnostic efficacy of serum lncRNA SCARNA10 for the hepatocellular carcinoma (HCC)., Methods: In this study, a total of 182 patients with HCC, 105 patients with benign liver disease (BLD), and 149 healthy controls (HC) were enrolled. According to different classifications, the levels of serum SCARNA10 were assessed by quantitative real-time polymerase chain reaction (qPCR). The correlations between serum SCARNA10 and clinicopathological characteristics were further analyzed. The receiver operating characteristic (ROC) curve and area under curve (AUC) were utilized to estimate the diagnostic capacity of serum SCARNA10 and its combination with AFP for HCC., Results: The results demonstrated that the levels of serum SCARNA10 were significantly higher in HCC patients than in patients with BLD and healthy controls, and significantly increased in HCC patients with hepatitis B or C infection, or with liver cirrhosis. Furthermore, positive correlations were noted between serum SCARNA10 level and some clinicopathological characteristics, including tumor size, differentiation degrees, tumor stage, vascular invasion, tumor metastasis and complications. ROC analysis revealed that SCARNA10 had a significantly predictive value for HCC (Sensitivity = 0.70, Specificity = 0.77, and AUC = 0.82), the combination of SCARNA10 and AFP gained the higher sensitivity (AUC SCARNA10 + AFP  = 0.92 vs AUC AFP  = 0.83, p <  0.01). SCARNA10 retained significant diagnosis capabilities for AFP-negative HCC patients., Conclusions: In summary, lncRNA SCARNA10 may serve as a novel and non-invasive biomarker with relatively high sensitivity and specificity for HCC diagnosis., (© 2022. The Author(s).)

Abstract: Hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis with rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although discovered > 40 years ago, little attention has been paid to this pathogen from both scientific and public communities. However, effectively combating hepatitis D requires advanced scientific knowledge and joint efforts from multi-stakeholders. In this review, we emphasized the recent advances in HDV virology, epidemiology, clinical feature, treatment, and prevention. We not only highlighted the remaining challenges but also the opportunities that can move the field forward., (Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

The heavy metal cadmium (Cd) can induce damage in liver and liver cancer cells; however, the mechanism underlying its toxicity needs to be further verified in vivo. We daily administered CdCl 2 to adult male rats at different dosages via gavage for 12 weeks and established rat liver injury model and liver cancer model to study the dual role of Cd in rat liver. Increased exposure to Cd resulted in abnormal liver function indicators, pathological degeneration, rat liver cell necrosis, and proliferation of collagen fibres. Using immunohistochemistry, we found that the area of GST-P-positive precancerous liver lesions decreased in a dose-dependent manner. Real-time quantitative polymerase chain reaction, western blot, immunohistochemistry, and transmission electron microscopy revealed that Cd induced mitophagy, as well as mitophagy blockade, as evidenced by the downregulation of TOMM20 and upregulation of LC3II and P62 with increasing Cd dose. Next, the expression of PINK1/Parkin, a classic signalling pathway protein that regulates mitophagy, was examined. Cd was found to promote PINK1/Parkin expression, which was proportional to the Cd dose. In conclusion, Cd activates PINK1/Parkin-mediated mitophagy in a dose-dependent manner. Mitophagy blockade likely aggravates Cd toxicity, leading to the dual role of inducing liver injury and inhibiting the progression of early liver cancer., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Circular RNA hsa&#95;circ&#95;0088364 (circ&#95;0088364) is a contributory factor in the malignancy of hepatocellular carcinoma (HCC). We aimed to elaborate its role and competing endogenous RNA (ceRNA) mechanism in HCC cell growth and motility. Expression of circ&#95;0088364, microRNA (miR)-1270 and Collagen type IV alpha 1 chain (COL4A1) was measured by real-time quantitative PCR and Western blotting, and their relationships were determined by dual-luciferase reporter assay, RNA immunoprecipitation, biotinylated RNA pull-down, and Spearman's rank correlation analysis. Cellular programs were measured by cell counting kit-8 assay, flow cytometry and transwell assays, Western blotting, and xenograft experiment. Expression of circ&#95;0088364 and COL4A1 was upregulated, and miR-1270 was downregulated in HCC patients' tumors; moreover, there were linear correlations among circ&#95;0088364, miR-1270, and COL4A1 expression. Essentially, circ&#95;0088364 and COL4A1 were ceRNAs for miR-1270 via target binding. In function, silencing circ&#95;0088364 or upregulating miR-1270 could suppress cell proliferation, cell cycle entrance, transwell migration and invasion in Huh7 and HCCLM3 cells, as well as promote apoptosis rate. Moreover, above-mentioned effects were accompanied with reduced B-cell lymphoma (Bcl)-2, N-cadherin and Vimentin levels, and elevated Bcl-2-associated X protein (Bax) and E-cadherin levels. Contrarily, exhausting miR-1270 and restoring COL4A1 could severally abrogate the tumor-suppressive roles of circ&#95;0088364 knockdown and miR-1270 overexpression in HCC cells in vitro . I n vivo , silencing circ&#95;0088364 retarded xenograft tumor growth in nude mice induced by Huh7 cells by upregulating miR-1270 and downregulating COL4A1. Blocking circ&#95;0088364 suppressed HCC by inhibiting cell growth and motility via targeting miR-1270-COL4A1 axis.

Background: This study is part of a larger research effort to explore the molecular mechanism of hepatocellular carcinoma, reduce drug resistance and seek new targets., Objective: The objective of this study is to investigate the effect and mechanism of fibroblast growth factor receptor inhibitor AZD4547 on Sorafenib-resistant hepatoma cells., Methods: First, we constructed a Sorafenib-resistant hepatoma cell line Huh7R. Different groups of Huh7R cells were treated with Sorafenib, AZD4547, Sorafenib combined with AZD4547, and normal saline. The cell viability was detected by Cell Counting Kit-8. Then Fibroblast growth factor receptor and Toll-like receptor 4 were detected by Western blot, as well as the LC3 II/I, Beclin1, and P62. In addition, we used the autophagy inhibitor 3-methyladenine to identify the mechanism of AZD4547 combined with Sorafenib for inducing Sorafenib-resistant hepatoma cell death., Results: We find that AZD4547 combined with Sorafenib significantly inhibited the viability of Sorafenib-resistant hepatoma cell Huh7R. As for its mechanism, AZD4547 was able to inhibit fibroblast growth factor receptor activity, promote autophagy and regulate immunity. AZD4547 increased LC3 II/I, Beclin1, and Toll-like receptor 4 proteins, and decreased P62 protein level in Huh7R cells significantly when given in combination with sorafenib. Furthermore, 3-methyladenine inhibited autophagy and reversed the killing effect of the combination of AZD4547 and Sorafenib on Huh7R cells., Conclusion: The inhibition of fibroblast growth factor receptor activity by AZD4547 can significantly enhance autophagy and immune response, as well as promote the death of Sorafenib-resistant hepatoma cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To develop a novel multi-contrast four-dimensional magnetic resonance imaging (MC-4D-MRI) technique that expands single image contrast 4D-MRI to a spectrum of native and synthetic image contrasts and to evaluate its feasibility in liver tumor patients., Methods and Materials: The MC-4D-MRI technique integrates multi-parametric MRI fusion, 4D-MRI, and deformable image registration (DIR) techniques. The fusion technique consists of native MRI as input, image pre-processing, fusion algorithm, adaptation, and fused multi-contrast MRI as output. Four-dimensional deformation vector fields (4D-DVF) were generated from an original T2/T1-w 4D-MRI by deforming end-of-inhalation (EOI) to nine other phase volumes via DIR. The 4D-DVF were applied to multi-contrast MRI to generate a spectrum of 4D-MRI in different image contrasts. The MC-4D-MRI technique was evaluated in five liver tumor patients on tumor contrast-to-noise ratio (CNR), internal target volume (ITV) contouring consistency, diaphragm motion range, and tumor motion trajectory; and in digital anthropomorphic phantoms on 4D-DIR introduced errors in tumor motion range, centroid location, extent, and volume., Results: MC-4D-MRI consisting of 4D-MRIs in native image contrasts (T1-w, T2-w, and T2/T1-w) and synthetic image contrasts, such as tumor-enhanced contrast (TEC) were generated in five liver tumor patients. Patient tumor CNR increased from 2.6 ± 1.8 in the T2/T1-w MRI, to -4.4 ± 2.4, 6.6 ± 3.0, and 9.6 ± 3.9 in the T1-w, T2-w, and TEC MRI, respectively. Patient ITV inter-observer mean Dice similarity coefficient (mDSC) increased from 0.65 ± 0.10 in the original T2/T1-w 4D-MRI, to 0.76 ± 0.14, 0.77 ± 0.12, and 0.86 ± 0.05 in the T1-w, T2-w, and TEC 4D-MRI, respectively. Patient diaphragm motion range absolute differences between the three new 4D-MRIs and original T2/T1-w 4D-MRI were 1.2 ± 1.3, 0.3 ± 0.7, and 0.5 ± 0.5 mm, respectively. Patient tumor displacement phase-averaged absolute differences between the three 4D-MRIs and the original 4D-MRI were 0.72 ± 0.33, 0.62 ± 0.54, and 0.74 ± 0.43 mm in the superior-inferior (SI) direction, and 0.59 ± 0.36, 0.51 ± 0.30, and 0.50 ± 0.24 mm in the anterior-posterior (AP) direction, respectively. In the digital phantoms, phase-averaged absolute tumor centroid shift caused by the 4D-DIR were at or below 0.5 mm in SI, AP, and left-right (LR) directions., Conclusion: We developed an MC-4D-MRI technique capable of expanding single image contrast 4D-MRI along a new dimension of image contrast. Initial evaluations in liver tumor patients showed enhancements in image contrast variety, tumor contrast, and ITV contouring consistencies using MC-4D-MRI. The technique might offer new perspectives on the image contrast of MRI and 4D-MRI in MR-guided radiotherapy., (© 2021 American Association of Physicists in Medicine.)

Liver cancer is one of the most common malignancies that is difficult to treat due to late diagnosis and chemo-resistance. In the present study, we developed and validated a cell based split nanoLuc biosensor to monitor the Apaf1-Apaf1 interactions in response to apoptosis-inducing drugs such as cisplatin. We showed that the activity of split nanoLuc is reconstituted only in response to apoptotic inducer, cisplatin and in a dose-dependent manner. Apaf1 mutants which were unable to oligomerize failed to recover nanoLuc activity while constitutively active variant increased the nanoLuc activity. Generation of Apaf1 knockout HepG2 and treatment with cisplatin showed dramatic reduction in cell death suggesting that cisplatin mainly targets liver cancer cells through apoptosis. As the natural products are potent sources of compounds for adjuvant therapy, we screened a collection of natural products and identified lentinan as an inducer of apoptosome formation, a key step for induction of apoptosis. Lentinan is a polysaccharide with antitumor, pro-apoptotic properties that functions with poorly understood mechanisms. Lentinan was shown to have cytotoxic effects with the IC 50 of 650 μM. Sub-lethal lentinan concentration doubled the nanoLuc activity when co-treated with cisplatin. We also showed that lentinan hugely reduced the dose of cisplatin to induce certain amount of death and that lentinan co-treatment with cisplatin enhanced the Apaf1 transcription in HepG2 cells while lentinan or cisplatin alone failed to alter the transcription. In addition, lentinan and cisplatin co-treatment induced mitochondrial depolarization. This suggested that lentinan combinatorial therapy with cisplatin engaged a different signalling pathway to kill the liver cancer cells and that adjuvant therapy with lentinan can reduce the dose of cisplatin and thus reduce the possibility of chemo-resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purposes: The purposes of this study were to assess the correlation between the plasma level of Hsp90α and the clinicopathological characteristics of patients with liver cancer and compare the diagnostic efficacy of Hsp90α, AFP, CEA, and CA199 in HCC., Experimental Design: A total of 200 individuals, including 140 patients with liver cancer or benign liver diseases and 60 healthy people, were enrolled for quantitative measurement of plasma Hsp90α by ELISA., Results: The plasma level of Hsp90α was significantly different between patients with liver cancer or benign liver diseases and healthy controls (P < 0.001). The sensitivity, specificity, and AUC (95% CI) of Hsp90α were 93.2%, 85.4%, and 0.931% (0.891-0.972%), respectively, when Hsp90α was applied to differentiate liver cancer patients and healthy controls. Significant positive correlations between the plasma Hsp90α level and clinicopathological characteristics such as the history of basic liver disease (P = 0.038), active stage of hepatitis (P = 0.039), Child-Pugh score (P < 0.001), size of focal liver lesions (P = 0.004), and extrahepatic metastasis (P < 0.001) were observed. AFP + Hsp90α was the best combination strategy for the auxiliary diagnosis of HCC, with a sensitivity of 95.7%, a specificity of 97.5%, and an AUC of 0.990 (0.976-1.000). The level of plasma Hsp90α decreased significantly (P < 0.001) after resection of tumor tissue., Conclusions: This study demonstrated that plasma Hsp90α levels are useful as a diagnostic biomarker in liver cancer and may predict the responses of patients with liver cancer to surgery. Some clinicopathological characteristics could affect the plasma Hsp90α levels., (© 2021. The Author(s).)

Background: Since it's a challenging task to precisely predict the prognosis of patients with hepatocellular carcinoma (HCC). We developed a nomogram based on a novel indicator GMWG [(Geometric Mean of gamma-glutamyltranspeptidase (GGT) and white blood cell (WBC)] and explored its potential in the prognosis for HCC patients., Methods: The patients enrolled in this study were randomly assigned to training and validation cohorts. And we performed the Least Absolute Shrinkage and Selection Operator proportional hazards model (LASSO Cox) model with clinical characteristics, serum indexes, and novel GMWG. Multivariate analysis was performed to build a nomogram. The performance of the nomogram was evaluated by C-index, the area under the receiver operating characteristic curve (AUC), and the calibration curve. Kaplan-Meier curves showed discrimination of the nomogram. Clinical utility was assessed by decision curve analysis (DCA). The discrimination ability of the nomogram was determined by the net reclassification index (NRI)., Results: The geometric mean of GGT and white WBC count (GMWG), neutrophil to lymphocyte ratio (NLR), and tumor size were significantly associated with the overall survival (OS). The variables above were used to develop the nomogram. The indexes of nomogram were 0.70 and 071 in the training or validation cohort, respectively. AUC of 1-, 3- and 5-year OS showed satisfactory accuracy as well. The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the overall survival (OS) and disease-free survival (DFS) showed significant differences between nomogram predictive low and high groups. DCA showed clinical utilities while NRI showed discrimination ability in both training or validation cohort., Conclusions: GMWG might be a potential prognostic indicator for patients with HCC. The nomogram containing GMWG also showed satisfaction prediction capacity., (© 2021. The Author(s).)

Objective: The objective of this study was to investigate the role of long noncoding RNAs small nucleolar RNA host gene 17 (SNHG17) in hepatocellular carcinoma (HCC)., Patients and Methods: Here, the expression level of SHNG17 was determined using reverse transcription quantitative PCR in tissue specimens and cell lines. The chi-squared test was used to analyze the associations between SNHG17 expression and clinical pathological factors in HCC patients. Kaplan-Meier and log-rank analyses were used to evaluate the prognosis of HCC patients, and proportional hazards model (Cox) regression was utilized for univariate and multivariate analyses. Knockdown of SNHG17 was achieved by transfection with si-SNHG17 in HepG2 and SNU-182 cells. Cell function was analyzed using CCK-8 assay, colony formation assay, Flow cytometry analysis and transwell assays., Results: Our data showed that SNHG17 expression was significantly upregulated in cancer regions of HCC compared with adjacent regions. Increased SNHG17 expression level was correlated with tumor size, TNM stage and poor survival prognosis in HCC patients. Further functional experiments indicated that inhibition of SNHG17 significantly inhibited HCC cell proliferation, migration and invasion, caused cell cycle G0/G1 phase arrest and apoptosis., Conclusions: In summary, our findings suggest that SNHG17 might function as novel therapeutic target for the treatment of HCC.

Background: The combination of conventional transarterial chemoembolization (cTACE) and systemic therapy has the potential to treat chemotherapy-refractory unresectable colorectal liver metastases (CRLMs). This study aimed to compare survival after this combined treatment versus systemic chemotherapy alone., Methods: This single-centre RCT included patients with unresectable CRLMs that progressed after first-line treatment. Patients were randomized on a 1 : 1 basis to either systemic chemotherapy with or without cTACE, without further stratification. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall response rate, disease control rate, conversion rate to liver resection, overall survival, and adverse events., Results: Of 180 patients recruited, 168 were randomized. Eighty-five patients in arm A received systemic chemotherapy plus cTACE and 83 in arm B received systemic chemotherapy alone. Median PFS was longer in arm A than B (6.7 versus 3.8 months; hazard ratio (HR) 0.67, 95 per cent c.i. 0.49 to 0.91; P = 0.009), but did not translate into prolonged median overall survival (18.4 versus 14.8 months; HR = 0.92, 0.62 to 1.36; P = 0.669). Overall response rates (20 versus 22 per cent; P = 0.788) and conversion rate to liver resection (18 versus 16 per cent; P = 0.730) were no different between arms A and B. The disease control rate was higher in arm A than arm B (67 versus 51 per cent; P = 0.030). No adverse event higher than grade 3 according to the Common Terminology Criteria for Adverse Events was observed during treatment., Conclusion: Systemic chemotherapy plus cTACE is a safe option as second-line treatment for unresectable colorectal liver metastases, with a modest effect on PFS. Registration number: NCT03783559 (http://www.clinicaltrials.gov)., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has high morbidity and mortality rates. It is essential to search new biomarkers to improve the accuracy of early HCC diagnosis. Therefore, we evaluated the diagnostic value of prothrombin induced by vitamin K deficiency or antagonist- II (PIVKA-II) as a potential biomarker that complements α-fetoprotein (AFP) in HCC by detecting the serum PIVKA-II levels., Methods: Serum PIVKA-II levels were compared in 168 HCC patients, 150 benign liver disease patients and 153 healthy controls to investigate the PIVKA-II potential to be a HCC biomarker. Receiver operating characteristic curve (ROC) analysis was used to evaluate the value of PIVKA-II in the diagnosis of HCC and its complementary role of AFP. The correlation between serum PIVKA-II levels and clinicopathological characteristics was analyzed to study the value of PIVKA-II in assessing HCC progression and prognosis. Finally, the ability of PIVKA-II in assessing the surgical treatment effects of HCC was studied by comparing the pre- and post-operative serum PIVKA-II levels in 89 HCC patients., Results: Serum PIVKA-II levels in HCC patients were significantly higher than that in patients with benign liver disease and healthy controls. The PIVKA-II performance in the diagnosing HCC as an individual biomarker was remarkable. The combined detection of PIVKA-II and AFP improved the diagnostic efficiency of HCC. PIVKA-II retained significant diagnosis capabilities for AFP-negative HCC patients. Significant correlations were found between PIVKA-II expression levels and some clinicopathological characteristics, including tumor size, tumor stage, tumor metastasis, differentiation degree and complications. PIVKA-II expression obviously decreased after surgical resection., Conclusions: PIVKA-II is a promising serum biomarker for the HCC diagnosis that can be used as a supplement for AFP. The combined diagnosis of the two markers greatly improved the diagnostic efficiency of HCC. The PIVKA-II levels in HCC patients were widely associated with clinicopathological characteristics representing tumor cell dissemination and/or poor prognosis. PIVKA-II can be used to evaluate the curative effects of HCC resection.

Aldolase A (ALDOA) facilitated aerobic glycolysis in cancer cells is a potential target in the treatment of hepatocellular carcinoma (HCC). However, only few effective inhibitors of ALDOA have been reported until now. In this research, we found a polysaccharide called HDPS-4II from Holotrichia diomphalia Bates, which can specifically bind to ALDOA with a dissociation constant of 2.86 μM. HDPS-4II with a molecular weight of 19 kDa was a linear triple-helix glucan composed of ɑ-d-1,4-Glcp and ɑ-d-1,6-Glcp in a ratio of 1.0:10.0. HDPS-4II significantly inhibited aldolase enzyme activity, glycolysis, and further inhibited the expression of phosphorylated AMPKα in HCC cells. Through analyzing ALDOA-overexpressing and -knockdown cells, it was confirmed that ALDOA mediated the viability and glycolysis inhibition of HDPS-4II. Moreover, HDPS-4II administration markedly inhibited tumor growth in mice xenografted with HCCs. These findings suggest that HDPS-4II, as an ALDOA antagonist, is a promising remedy in the treatment and prevention of HCC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Ginseng is associated to the reduction of the risk of liver-cancer and some time is used as adjuvant therapy to treat liver-cancer, but its outcome remains uncertain. Hence, the present study aimed to determine the association between Ginseng consumption and liver-cancer., Methods: By a systematic-literature search up to Decamber-2019, 9-studies included 13,766 subjects, 9235 Ginseng consumer. Odds ratio (OR) with 95% confidence intervals (CIs) was determined comparing Ginseng consumption and liver-cancer relationship using the dichotomous method with a fixed-effect or random-effect models., Results: Subjects consuming Ginseng had a significantly lower risk of developing liver-cancer than those not consuming Ginseng (OR, 0.46; 95% CI, 0.40-0.52, p  < 0.001). Also, there was a significant relationship between Ginseng consumption as adjuvant-therapy and disease control rate (OR, 4.47; 95% CI, 2.41-8.28, p  < 0.001), Karnofsky Performance Scale (OR, 4.31; 95% CI, 1.80-10.36, p  = 0.001), response to chemotherapy rate (OR, 1.79; 95% CI, 1.05-3.02, p  = 0.03) and decline of leukocyte count (OR, 0.17; 95% CI, 0.07-0.42, p  < 0.001). However, there was no significant effect, but relatively favoring Ginseng consumption, between Ginseng consumption as adjuvant-therapy and one year survival rate (OR, 1.48; 95% CI, 0.78-2.81, p  = 0.23), two year survival rate (OR, 1.69; 95% CI, 0.87-3.25, p  = 0.12) gastrointestinal dysfunction (OR, 0.55; 95% CI, 0.17-1.79, p  = 0.32), and the hepatic dysfunction (OR, 1.15; 95% CI, 0.59-2.22, p  = 0.68)., Conclusions: Ginseng may have an independent relationship with reducing liver-cancer incidence when administrated to healthy subjects as a supplement and with reducing cancer-chemotherapy related outcomes risk when administrated with chemotherapy as adjuvant therapy.

Liver disease has been reported to associate with oral microbiota. This study aimed to identify the salivary microbial structure in liver disease patients and determine whether the disease progression influence the bacterial composition. 16S rDNA high-throughput sequencing and bioinformatic analysis were used to examine oral bacterial diversity in the different status of hepatitis patients including 6 patients with Hepatitis B (Y), 6 patients with Hepatitis B Cirrhosis (YY) and 6 patients with liver cancer (C), and 6 healthy controls (T). Phylogenetic analysis revealed that the genera of Streptococcus, Prevotella, Actinomyces, Veillonella and Neisseria are predominant genus in the saliva of Y, YY, C patients and T group. Lautropia, Abiotrophia and Veillonella were enriched in Y patients, while Treponema, Selenomonas and Oribacterium were also existed in YY patients. Haemophilus, Porphyromonas and Filifactor had high abundance in C patients. The genera of Moryella, Leptotrichia, Lactobacillus, Dialister, Serratia, Enterococcus and Actinobacillus were decreased in all patient samples compared with healthy control samples which may be used for treatment of liver disease. Diversity analyses showed decreased diversity of salivary bacterial communities was discovered in the progress of the liver disease. These findings identified the oral microbiota dysbiosis in liver disease, which may providing available information and possible diagnostic biomarkers for liver patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)