Folate metabolism is involved in the development and progression of various cancers. We investigated the association of single nucleotide polymorphisms (SNP) in folate-metabolising genes and their interactions with serum folate concentrations with overall survival (OS) and liver cancer-specific survival (LCSS) of newly diagnosed hepatocellular carcinoma (HCC) patients. We detected the genotypes of six SNP in three genes related to folate metabolism: methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HR) and 95 % CI. This analysis included 970 HCC patients with genotypes of six SNP, and 864 of them had serum folate measurements. During a median follow-up of 722 d, 393 deaths occurred, with 360 attributed to HCC. In the fully-adjusted models, the MTRR rs1801394 polymorphism was significantly associated with OS in additive (per G allele: HR = 0·84, 95 % CI: 0·71, 0·99), co-dominant (AG v. AA: HR = 0·77; 95 % CI: 0·62, 0·96) and dominant (AG + GG v. AA: HR = 0·78; 95 % CI: 0·63, 0·96) models. Carrying increasing numbers of protective alleles was linked to better LCSS (HR10–12 v. 2–6 = 0·70; 95 % CI: 0·49, 1·00) and OS (HR10–12 v. 2–6 = 0·67; 95 % CI: 0·47, 0·95). Furthermore, we observed significant interactions on both multiplicative and additive scales between serum folate levels and MTRR rs1801394 polymorphism. Carrying the variant G allele of the MTRR rs1801394 is associated with better HCC prognosis and may enhance the favourable association between higher serum folate levels and improved survival among HCC patients.

Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial–mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.

Recent development in immunotherapy for cancer treatment has substantiated to be more effective than most of the other treatments. Immunity is the first line of defence of the body; nevertheless, cancerous cells can manipulate immunity compartments to play several roles in tumour progression. Tumour-associated macrophages (TAMs), one of the most dominant components in the tumour microenvironment, are recognized as anti-tumour suppressors. Unfortunately, the complete behaviour of TAMs is still unclear and understudied. TAM density is directly correlated with the progression and poor prognosis of hepatocellular carcinoma (HCC), therefore studying TAMs from different points of view passing by all the factors that may affect its existence, polarization, functions and repolarization are of great importance. Different epigenetic regulations were reported to have a direct relation with both HCC and TAMs. Here, this review discusses different epigenetic regulations that can affect TAMs in HCC whether positively or negatively.

The benefits of branched-chain amino acid (BCAA) administration after hepatic intervention in patients with liver diseases remain unclear. We conducted a systematic review and meta-analysis to evaluate the effects of BCAA on patients undergoing hepatectomy, trans-arterial embolisation and radiofrequency ablation. Relevant randomised controlled trials (RCT) were obtained from PubMed, EMBASE and Cochrane Library databases. A meta-analysis was performed to calculate the pooled effect size by using random-effects models. The primary outcomes were survival and tumour recurrence. The secondary outcomes were hospital stay, nutrition status, biochemistry profile, complication rate of liver treatment and adverse effect of BCAA supplementation. In total, eleven RCT involving 750 patients were included. Our meta-analysis showed no significant difference in the rates of tumour recurrence and overall survival between the BCAA and control groups. However, the pooled estimate showed that BCAA supplementation in patients undergoing hepatic intervention significantly increased serum albumin (mean difference (MD): 0·11 g/dl, 95 % CI: 0·02, 0·20; 5 RCT) at 6 months and cholinesterase level (MD: 50·00 U/L, 95 % CI: 21·08, 78·92; 1 RCT) at 12 months and reduced ascites incidence (risk ratio: 0·39, 95 % CI: 0·21, 0·71; 4 RCT) at 12 months compared with the control group. Additionally, BCAA administration significantly increased body weight at 6 months and 12 months and increased arm circumference at 12 months. In conclusion, BCAA supplementation significantly improved the liver function, reduced the incidence of ascites and increased body weight and arm circumference. Thus, BCAA supplementation may beneficial for selected patients undergoing liver intervention.

Approximately 80 million people live with chronic hepatitis B virus (HBV) infection in the WHO Africa Region. The natural history of HBV infection in this population is poorly characterised, and may differ from patterns observed elsewhere due to differences in prevailing genotypes, environmental exposures, co-infections, and host genetics. Existing research is largely drawn from small, single-centre cohorts, with limited follow-up time. The Hepatitis B in Africa Collaborative Network (HEPSANET) was established in 2022 to harmonise the process of ongoing data collection, analysis, and dissemination from 13 collaborating HBV cohorts in eight African countries. Research priorities for the next 5 years were agreed upon through a modified Delphi survey prior to baseline data analysis being conducted. Baseline data on 4,173 participants with chronic HBV mono-infection were collected, of whom 38.3% were women and the median age was 34 years (interquartile range 28–42). In total, 81.3% of cases were identified through testing of asymptomatic individuals. HBeAg-positivity was seen in 9.6% of participants. Follow-up of HEPSANET participants will generate evidence to improve the diagnosis and management of HBV in this region.

In recent years, obesity is a growing pandemic in the world and has likely contributed to increasing the incidence of obesity-related diseases. Fat mass and obesity-associated gene (FTO) is the first gene discovered which has a close connection with fat. Recent studies suggested that FTO gene has played an important role in the molecular mechanisms of many diseases. Obesity is considered to be a hereditary disease and can evoke many kinds of diseases, including polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), cancer, etc., whose exact possible molecular mechanisms responsible for the effect of FTO on obesity and obesity-related diseases remain largely unknown. In this review, we comprehensively discuss the correlation between FTO gene and obesity, cancer, PCOS, T2DM, as well as the molecular mechanism involved in these diseases.

Hepatitis B virus (HBV) infection led to 66% liver deaths world-wide in year 2015. Thirty-seven per cent of these deaths were the result of chronic hepatitis B (CHB)-associated hepatocellular carcinoma (HCC). Although early diagnosis of HCC improves survival, early detection is rare. Methylation of HBV DNA including covalently closed circular DNA (cccDNA) is more often encountered in HCC cases than those in CHB and cirrhosis. Three typical CpG islands within the HBV genome are the common sites for methylation. The HBV cccDNA methylation affects the viral replication and protein expression in the course of infection and may associate with the disease pathogenesis and HCC development. We review the current findings in HBV DNA methylation that provide insights into its role in HCC diagnosis.

This retrospective study investigated the predictive value of the Controlling Nutritional Status (CONUT) score in patients with intermediate-stage hepatocellular carcinoma (HCC) who received transarterial chemoembolization (TACE). Nomograms were developed to predict progression-free and overall survival (PFS, OS). The medical data of 228 patients with HCC and treated with TACE were collected. The patients were apportioned to 2 groups according to CONUT score: low or high (<4, ≥4). Univariate and multivariate analyses were performed using Cox regression for OS and PFS. OS and PFS were estimated by the Kaplan-Meier curve and compared with the log-rank test. Nomograms were constructed to predict patient OS and PFS. The nomograms were evaluated for accuracy, discrimination, and efficiency. The cut-off value of CONUT score was 4. The higher the CONUT score, the worse the survival; Kaplan-Meier curves showed significant differences in OS and PFS between the low and high CONUT score groups (P = 0·033, 0·047). The nomograms including CONUT, based on the prognostic factors determined by the univariate and multivariate analyses, to predict survival in HCC after TACE were generated. The CONUT score is an important prognostic factor for both OS and PFS for patients with intermediate HCC who underwent TACE. The cut-off value of the CONUT score was 4. A high CONUT score suggests poor survival outcomes. Nomograms generated based on the CONUT score were good models to predict patient OS and PFS.

In recent years, a wealth of factors are associated with increased risk of developing non-alcoholic fatty liver disease (NAFLD) and NAFLD is now thought to increase the risk of multiple extra-hepatic diseases. The aim of this review is first to focus on the role of ageing and sex as key, poorly understood risk factors in the development and progression of NAFLD. Secondly, we aim to discuss the roles of white adipose tissue (WAT) and intestinal dysfunction, as producers of extra-hepatic factors known to further contribute to the pathogenesis of NAFLD. Finally, we aim to summarise the role of NAFLD as a multi-system disease affecting other organ systems beyond the liver. Both increased age and male sex increase the risk of NAFLD and this may be partly driven by alterations in the distribution and function of WAT. Similarly, changes in gut microbiota composition and intestinal function with ageing and chronic overnutrition are likely to contribute to the development of NAFLD both directly (i.e. by affecting hepatic function) and indirectly via exacerbating WAT dysfunction. Consequently, the presence of NAFLD significantly increases the risk of various extra-hepatic diseases including CVD, type 2 diabetes mellitus, chronic kidney disease and certain extra-hepatic cancers. Thus changes in WAT and intestinal function with ageing and chronic overnutrition contribute to the development of NAFLD – a multi-system disease that subsequently contributes to the development of other chronic cardiometabolic diseases.

Patients with liver cancer or space-occupying cysts suffer from malnutrition due to compression of gastric and digestive structures, liver and cancer-mediated dysmetabolism, and impaired nutrient absorption. As proportion of these patients requires removal of lesions through hepatic resection, it is important to evaluate the effects of malnutrition on post-hepatectomy outcomes. In our study approach, 2011–2017 National Inpatient Sample was used to isolate in-hospital hepatectomy cases, which were stratified using malnutrition (composite of malnutrition, sarcopenia and weight loss/cachexia). The malnutrition-absent controls were matched to cases using nearest neighbour propensity score matching method and compared with the following endpoints: mortality, length of stay, hospitalisation costs and postoperative complications. There were 2531 patients in total who underwent hepatectomy with matched number of controls from the database; following the match, malnutrition cohort (compared with controls) was more likely to experience in-hospital death (6·60 % v. 5·25 % P < 0·049, OR 1·27, 95 % CI 1·01, 1·61) and was more likely to have higher length of stay (18·10 d v. 9·32 d, P < 0·001) and hospitalisation costs ($278 780 v. $150 812, P < 0·001). In terms of postoperative complications, malnutrition cohort was more likely to experience bleeding (6·52 % v. 3·87 %, P < 0·001, OR 1·73, 95 % CI 1·34, 2·24), infection (6·64 % v. 2·49 %, P < 0·001, OR 2·79, 95 % CI 2·07, 3·74), wound complications (4·5 % v. 1·38 %, P < 0·001, OR 3·36, 95 % CI 2·29, 4·93) and respiratory failure (9·40 % v. 4·11 %, P < 0·001, OR 2·42, 95 % CI 1·91, 3·07). In multivariate analysis, malnutrition was associated with higher mortality (P < 0·028, adjusted OR 1·3, 95 % CI 1·03, 1·65). Thus, we conclude that malnutrition is a risk factor of postoperative mortality in patients undergoing hepatectomy.

Today, cancer is one of the leading causes of death worldwide. Lately, cytokine and chemokine imbalances have gained attention amongst different involved pathways in cancer development and attracted much consideration in cancer research. CXCL16, as a member of the CXC subgroup of chemokines, has been attributed to be responsible for immune cell infiltration into the tumour microenvironment. The aberrant expression of CXCL16 has been observed in various cancers. This chemokine has been shown to play a conflicting role in tumour development through inducing pro-inflammatory conditions. The infiltration of various immune and non-immune cells such as lymphocytes, cancer-associated fibroblasts and myeloid-derived suppressor cells by CXCL16 into the tumour microenvironment has complicated the tumour fate. Given this diverse role of CXCL16 in cancer, a better understanding of its function might build-up our knowledge about tumour biology. Hence, this study aimed to review the impact of CXCL16 in cancer and explored its therapeutic application. Consideration of these findings might provide opportunities to achieve novel approaches in cancer treatment and its prognosis.

The purpose of this study was to construct a glycyrrhetinic acid (GA)-mediated, breakable, intracellular, nanoscale drug-delivery carrier via amide and esterification reactions. The structures were identified by Fourier-transformed infrared (FTIR) and 1H-nuclear magnetic resonance (1H-NMR) spectrophotometry. The compatibility and safety of the carrier were evaluated using hemolysis and cytotoxicity tests. The GA-copolymer micelle was prepared using the solvent evaporation method. FTIR and 1H-NMR detection demonstrated the successful construction of the polymer. No hemolysis occurred in any concentration of polymer within 3 h, and the hemolysis rate was less than 5%. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) experimental results showed that the novel polymer reduced the cell survival rate and had significant cytotoxic effects. The blank nanoparticles were liquid with light blue opalescence. Transmission electron microscopy revealed that the empty micelles were uniform spheres, with an average size of 62 nm and a zeta potential of −13 mV. The novel GA-mediated polymeric carrier material developed here has the potential to effectively kill human SMMC-7721 cancer cells within 3 days when the dose is above 500 ug/mL.

Primary liver cancer is the third leading cause of cancer-related death worldwide. Most patients are diagnosed at late stages with poor prognosis; thus, identification of modifiable risk factors for primary prevention of liver cancer is urgently needed. The well-established risk factors of liver cancer include chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), heavy alcohol consumption, metabolic diseases such as obesity and diabetes, and aflatoxin exposure. However, a large proportion of cancer cases worldwide cannot be explained by current known risk factors. Dietary factors have been suspected as important, but dietary aetiology of liver cancer remains poorly understood. In this review, we summarised and evaluated the observational studies of diet including single nutrients, food and food groups, as well as dietary patterns with the risk of developing liver cancer. Although there are large knowledge gaps between diet and liver cancer risk, current epidemiological evidence supports an important role of diet in liver cancer development. For example, exposure to aflatoxin, heavy alcohol drinking and possibly dairy product (not including yogurt) intake increase, while intake of coffee, fish and tea, light-to-moderate alcohol drinking and several healthy dietary patterns (e.g. Alternative Healthy Eating Index) may decrease liver cancer risk. Future studies with large sample size and accurate diet measurement are warranted and need to consider issues such as the possible aetiological heterogeneity between liver cancer subtypes, the influence of chronic HBV or HCV infection, the high-risk populations (e.g. cirrhosis) and a potential interplay with host gut microbiota or genetic variations.

Exosomes derived from hepatocellular carcinoma (HCC) cells are nanovesicles and are involved in the occurrence and development of HCC, they also serve as important carriers and drug targets of nanodrug delivery systems. The external shape and internal structure of exosomes are important indexes of identification, and isolated intact morphology is crucial to biological function integrity. However, given their susceptibility to various influencing factors, the external shape and internal structure of exosomes derived from HCC cells remain incompletely studied. In this study, exosomes purified from HCC cells were isolated at different centrifugation speeds and examined via multiple electron microscopy (EM) techniques. The results demonstrate that exosomes possess a nearly spherical shape and bilipid membranous vesicle with a concave cavity structure containing electron-dense and coated vesicles, suggesting the possible existence of subpopulations of exosomes with specific functions. The exosomes isolated at ultracentrifugation (UC) speed (≥110,000×g) presented irregular and diverse external morphologies, indicating the effect on the integrity of the exosomes. Transforming growth factor signaling bioactive substances (TGF-β1, S100A8, and S100A9) can be found in exosomes by performing Western blotting, showing that the internal content is associated with metastasis of HCC. These findings show that EMelectron microscopy and UC speed can affect exosome characteristics, including external shape, internal structure, and content of bioactive substances. The electron-dense and coated vesicles that had been discovered in exosomes might become new additional morphological features, which could help to improve the interpretation of experimental results and widen our understanding of exosome morphology.

Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.

Nucleos(t)ide analogues (NAs) are widely used for antiviral therapy in patients with chronic hepatitis B (CHB), but real-world data on treatment patterns and long-term clinical outcomes are not always available. Using data from electronic medical records between January 2011 and December 2016 in Shanghai, China, we evaluated patient characteristics, treatment patterns and clinical outcomes in patients with CHB. There were 6688 patients in the study cohort. The incidences of cirrhosis and hepatocellular carcinoma (HCC) were 41.0‰ and 6.8‰ person-years, respectively. There were more cirrhosis and HCC cases among patients who had shorter NA treatment duration (<365 days), or who were less compliant (<80%). In addition, increased risk of cirrhosis and HCC was observed in patients who did not achieve hepatitis B surface antigen (HBsAg) loss/seroconversion. Moreover, patients with cirrhosis developed after antiviral treatments had a higher incidence of HCC (adjusted hazard ratio 15.86, 95% confidence interval 7.35–34.24). Good compliance with treatment and longer treatment duration significantly decreased the risk of developing cirrhosis and HCC. HBsAg loss seemed to be a protective factor for cirrhosis/HCC in NAs-treated patients with CHB, and cirrhosis was a confirmed risk factor for HCC development as expected.

Non-alcoholic fatty liver disease (NAFLD) is now a major public health concern with an estimated prevalence of 25–30% of adults in many countries. Strongly associated with obesity and the metabolic syndrome, the pathogenesis of NAFLD is dependent on complex interactions between genetic and environmental factors that are not completely understood. Weight loss through diet and lifestyle modification underpins clinical management; however, the roles of individual dietary nutrients (e.g. saturated and n-3 fatty acids; fructose, vitamin D, vitamin E) in the pathogenesis or treatment of NAFLD are only partially understood. Systems biology offers valuable interdisciplinary methods that are arguably ideal for application to the studying of chronic diseases such as NAFLD, and the roles of nutrition and diet in their molecular pathogenesis. Although present in silico models are incomplete, computational tools are rapidly evolving and human metabolism can now be simulated at the genome scale. This paper will review NAFLD and its pathogenesis, including the roles of genetics and nutrition in the development and progression of disease. In addition, the paper introduces the concept of systems biology and reviews recent work utilising genome-scale metabolic networks and developing multi-scale models of liver metabolism relevant to NAFLD. A future is envisioned where individual genetic, proteomic and metabolomic information can be integrated computationally with clinical data, yielding mechanistic insight into the pathogenesis of chronic diseases such as NAFLD, and informing personalised nutrition and stratified medicine approaches for improving prognosis.