Previous research found tobacco smoking and solid fuel use for cooking to increase the risk of chronic liver disease mortality, but previous cohort studies have not investigated their independent and joint associations with liver cancer incidence in contemporary China. The China Kadoorie Biobank (CKB) study recruited 0.5 million adults aged 30-79 years from 10 areas across China during 2004-2008. Participants reported detailed smoking and fuel use information at baseline. After an 11.1-year median follow-up via electronic record linkage, we recorded 2,997 liver cancer cases. Overall, 29.4% participants were current smokers. Among those who cooked at least once per month, 48.8% always used solid fuels (i.e. coal or wood) for cooking. Tobacco smoking and solid fuel use for cooking were independently associated with increased risks of liver cancer, with HRs (95% CIs) of 1.28 (1.15-1.42) and 1.25 (1.03-1.52), respectively. The more cigarettes consumed each day, the earlier the age of starting smoking, or the longer duration of solid fuels exposure, the higher the risk (P_trend <0.001, =0.001, =0.018, respectively). Compared with never smokers who had always used clean fuels (i.e. gas or electricity), ever-smokers who had always used solid fuels for cooking had a 67% (95% CIs: 1.29-2.17) higher risk. Among Chinese adults, tobacco smoking and solid fuel use for cooking were independently associated with higher risk of liver cancer incidence. Stronger association was observed with higher number of daily cigarette consumption, the earlier age of starting smoking and longer duration of solid fuel use. This article is protected by copyright. All rights reserved.

Keywords: Liver cancer; Prospective cohort study; Solid fuel; Tobacco smoking.

Liver cancers, such as hepatocellular carcinoma (HCC), are a highly prevalent cause of cancer-related deaths. Current treatments to combat liver cancer are limited. (-)-Agelasidine A, a compound isolated from the methanol extract of Agelasnakamurai, a sesquiterpene guanidine derived from sea sponge, has antibacterial activity. We demonstrated its anticancer capabilities by researching the associated mechanism of (-)-agelasidine A in human liver cancer cells. We found that (-)-agelasidine A significantly reduced viability in Hep3B and HepG2 cells, and we determined that apoptosis was involved in the (-)-agelasidine A-induced Hep3B cell deaths. (-)-Agelasidine A activated caspases 9, 8, and 3, as well as PARP. This effect was reversed by caspase inhibitors, suggesting caspase-mediated apoptosis in the (-)-agelasidine A-treated Hep3B cells. Moreover, the reduced mitochondrial membrane potential (MMP) and the release of cytochrome c indicated that the (-)-agelasidine A-mediated mitochondrial apoptosis was mechanistic. (-)-Agelasidine A also increased apoptosis-associated proteins (DR4, DR5, FAS), which are related to extrinsic pathways. These events were accompanied by an increase in Bim and Bax, proteins that promote apoptosis, and a decrease in the antiapoptotic protein, Bcl-2. Furthermore, our results presented that (-)-agelasidine A treatment bridged the intrinsic and extrinsic apoptotic pathways. Western blot analysis of Hep3B cells treated with (-)-agelasidine A showed that endoplasmic reticulum (ER) stress-related proteins (GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, truncated ATF6, and CHOP) were upregulated. Moreover, 4-PBA, an ER stress inhibitor, could also abrogate (-)-agelasidine A-induced cell viability reduction, annexin V+ apoptosis, death receptor (DR4, DR5, FAS) expression, mitochondrial dysfunction, and cytochrome c release. In conclusion, by activating ER stress, (-)-agelasidine A induced the extrinsic and intrinsic apoptotic pathways of human HCC.

Keywords: (−)-agelasidine A; apoptosis; caspase; death receptor; endoplasmic reticulum stress; hepatocellular carcinoma (HCC); mitochondrial membrane potential.

Non-alcoholic fatty liver disease (NAFLD) has become an important etiology leading to liver cancer. NAFLD alters adaptive T cell immunity and has a profound influence on liver cancer development. However, it is unclear how NAFLD affects tumor antigen-specific T cell response. In this study, we generated a doxycycline-inducible MHC-I and -II antigen-expressing HCC cell line which allowed us to investigate tumor antigen-specific T cell response in two NAFLD mouse models. The system proved to be an effective and efficient way to study tumor antigen-specific T cells. Using this model, it was found that NAFLD impairs antigen-specific CD8⁺ T cell immunity against HCC. The effect was not due to reduced generation or intrinsic functional changes of tumor antigen-specific CD8⁺ T cells but caused by accumulated macrophages in the liver environment. The findings suggest that targeting macrophages in NAFLD-driven HCC may improve therapeutic outcomes.

Keywords: Cancer; Immunology.

Background & aims: Accurate hepatocellular carcinoma (HCC) risk prediction facilitates appropriate surveillance strategy and reduces cancer mortality. We aimed to derive and validate novel machine learning models to predict HCC in a territory-wide cohort of patients with chronic viral hepatitis (CVH) using data from the Hospital Authority Data Collaboration Lab (HADCL).

Methods: This was a territory-wide, retrospective, observational, cohort study of patients with CVH in Hong Kong in 2000-2018 identified from HADCL based on viral markers, diagnosis codes, and antiviral treatment for chronic hepatitis B and/or C. The cohort was randomly split into training and validation cohorts in a 7:3 ratio. Five popular machine learning methods, namely, logistic regression, ridge regression, AdaBoost, decision tree, and random forest, were performed and compared to find the best prediction model.

Results: A total of 124,006 patients with CVH with complete data were included to build the models. In the training cohort (n = 86,804; 6,821 HCC), ridge regression (area under the receiver operating characteristic curve [AUROC] 0.842), decision tree (0.952), and random forest (0.992) performed the best. In the validation cohort (n = 37,202; 2,875 HCC), ridge regression (AUROC 0.844) and random forest (0.837) maintained their accuracy, which was significantly higher than those of HCC risk scores: CU-HCC (0.672), GAG-HCC (0.745), REACH-B (0.671), PAGE-B (0.748), and REAL-B (0.712) scores. The low cut-off (0.07) of HCC ridge score (HCC-RS) achieved 90.0% sensitivity and 98.6% negative predictive value (NPV) in the validation cohort. The high cut-off (0.15) of HCC-RS achieved high specificity (90.0%) and NPV (95.6%); 31.1% of patients remained indeterminate.

Conclusions: HCC-RS from the ridge regression machine learning model accurately predicted HCC in patients with CVH. These machine learning models may be developed as built-in functional keys or calculators in electronic health systems to reduce cancer mortality.

Lay summary: Novel machine learning models generated accurate risk scores for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. HCC ridge score was consistently more accurate than existing HCC risk scores. These models may be incorporated into electronic medical health systems to develop appropriate cancer surveillance strategies and reduce cancer death.

Keywords: ALT, alanine aminotransferase; APRI, aspartate transaminase-to-platelet ratio index; AUROC, area under the receiver operating characteristic curve; Antiviral treatment; CDARS, Clinical Data Analysis and Reporting System; CHB, chronic hepatitis B; CHC, chronic hepatitis C; CI, confidence intervals; CVH, chronic viral hepatitis; Cirrhosis; DM, diabetes mellitus; HADCL, Hospital Authority Data Collaboration Lab; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; ICD-9-CM, International Classification of Diseases, Ninth Revision Clinical Modification; Liver cancer; Mortality; NA, nucleos(t)ide analogue; RS, ridge score; WHO, World Health Organization; World Health Organization; aHR, adjusted hazard ratio; anti-HCV, antibody to hepatitis C virus.

The associating liver partition and portal vein ligation for a staged hepatectomy (ALPPS) procedure is an excellent treatment strategy for patients with advanced primary or metastatic liver cancer and small liver remnants. This report discusses the surgical management of a 51-year-old male who was diagnosed with stage IV rectal cancer with multiple heterogeneous hypoenhancing solid masses seen in both lobes of the liver consistent with metastatic disease. He completed six cycles of preoperative FOLFOX chemotherapy with Avastin. Follow-up imaging demonstrated a good response. A combined low anterior resection and two-stage hepatectomy with ALPPS were discussed with the patient who agreed to proceed with the plan. He underwent a combined open low anterior resection with colorectal anastomosis in addition to the first stage of ALPPS. The patient tolerated the procedure well, and the immediate postoperative period was uncomplicated. Volumetric assessment of the left hepatic lobe on postoperative day seven demonstrated 26.7% of the original liver volume. The decision was made to take the patient back to the operating room on postoperative day nine for completion of the ALPPS, which entailed a total right hepatectomy. He tolerated the procedure well and was discharged home on postoperative day 16. No complications from the surgical procedure were reported on subsequent follow-up visits.

Keywords: alpps; hepatobiliary surgery; liver volume; low anterior resection; rectal cancer.

Hepatocellular carcinoma (HCC) is the most common liver cancer with a high rate of metastasis. However, the molecular mechanisms that drive metastasis remain unclear. We combined single-cell transcriptomic, proteomic, and chromatin accessibility data to investigate how heterogeneous phenotypes contribute to metastatic potential in five HCC cell lines. We confirmed that the prevalence of a mesenchymal state and levels of cell proliferation are linked to the metastatic potential. We also identified a rare hypoxic subtype that has a higher capacity for glycolysis and exhibits dormant, invasive, and malignant characteristics. This subtype has increased metastatic potential. We further identified a robust 14-gene panel representing this hypoxia signature and this hypoxia signature could serve as a prognostic index. Our data provide a valuable data resource, facilitate a deeper understanding of metastatic mechanisms, and may help diagnosis of metastatic potential in individual patients, thus supporting personalized medicine.

Keywords: Cell biology; Omics; Transcriptomics.

Studies have shown that the physical, psychological, and social problems of liver cancer patients are more serious than those of other cancer patients and their quality of life is significantly reduced. This may be related to the poor treatment effect of patients with advanced liver cancer. Patients often have adverse symptoms such as cancer pain, pleural effusion, and ascites, etc., which have a great impact on patients' psychology and recovery from illness. With the change of the medical model, it has become history to rely solely on drugs to care for patients with advanced liver cancer and comprehensive nursing intervention has become very important. Continuous nursing intervention focuses on individualized and full-hearted care, effectively alleviating patients' anxiety and fear and improving patients' environmental adaptability and psychological defense mechanisms. However, in the field of liver cancer, there is no detailed comparison between the efficacy of continuous nursing and traditional conventional nursing. This article applies the hidden Markov model, starts with medical data mining, and describes the process achieved by the application of this article and the analysis of the results obtained by the two nursing methods, which reflect the difference in curative effect evaluation, and it proves that continuous nursing has more advantages in the curative effect of patients with liver tumors.

Spent coffee grounds (SCGs), which constitute 75% of original coffee beans, represent an integral part of sustainability. Contamination by toxigenic fungi and their mycotoxins is a hazard that threatens food production. This investigation aimed to examine SCGs extract as antimycotic and anti-ochratoxigenic material. The SCGs were extracted in an eco-friendly way using isopropanol. Bioactive molecules of the extract were determined using the UPLC apparatus. The cytotoxicity on liver cancer cells (Hep-G2) showed moderate activity with selectivity compared with human healthy oral epithelial (OEC) cell lines but still lower than the positive control (Cisplatin). The antibacterial properties were examined against pathogenic strains, and the antifungal was examined against toxigenic fungi using two diffusion assays. Extract potency was investigated by two simulated models, a liquid medium and a food model. The results of the extract showed 15 phenolic acids and 8 flavonoids. Rosmarinic and syringic acids were the most abundant phenolic acids, while apigenin-7-glucoside, naringin, epicatechin, and catechin were the predominant flavonoids in the SCGs extract. The results reflected the degradation efficiency of the extract against the growth of Aspergillus strains. The SCGs recorded detoxification in liquid media for aflatoxins (AFs) and ochratoxin A (OCA). The incubation time of the extract within dough spiked with OCA was affected up to 2 h, where cooking was not affected. Therefore, SCGs in food products could be applied to reduce the mycotoxin contamination of raw materials to the acceptable regulated limits.

Keywords: aflatoxins; anti-mycotoxigenic; antifungal; cytotoxicity; degradation; detoxification; flavonoids; phenolic acids; simulated media; spent coffee grounds.

In order to improve the transfection efficiency of gene vectors and monitor the effect of gene therapy, this study prepared a drug delivery vector with dual functions. The thiourea reaction was used to synthesize polyethyleneimine (PEI, MW: 1.8 kDa) with superparamagnetic iron oxide nanoparticles (SPION) (PEI1800-SPION), and the lipid polycationic gene vector PEI1800-SPION loaded cationic liposome (LP-PEI1800-SPION) was further prepared by ethanol injection method. Agarose gel electrophoresis experiment, cytotoxicity experiment, and In-vitro gene silencing experiment were used to evaluate the vector and screen the optimal prescription of LP-PEI1800-SPION/siRNA. When the weight ratio of LP-PEI1800-SPION to siRNA is 20, the transfection efficiency of the nanoparticles was the highest, and the silencing efficiency of the target protein was the largest. The cytotoxicity of LP-PEI1800-SPION was low; when the concentration was in the range of 1-50 μg/mL, the survival rate of the four types of cells was above 80%. Prussian blue staining experiments and In-vitro MRI imaging experiments showed that cells had significant uptake and imaging capabilities for LP-PEI1800-SPION. In conclusion, the visualized polycationic lipid siRNA delivery vehicle (LP-PEI1800-SPION) was successfully prepared in this experiment, which provides a research basis for further theranostics of liver cancer.

Keywords: Gene silencing; Lipid polycation; Magnetic resonance imaging; Superparamagnetic iron oxide nanoparticles; siRNA.