A bimetallic MOF-derived MnCo spinel oxide catalyst to enhance toluene catalytic degradation.

MnCo spinel oxide catalysts were successfully synthesized by the calcination of bimetallic Mn/Co-MOFs as sacrificial templates. The derived catalysts exhibited optimal catalytic activity, reusability and thermal stability for toluene oxidation, which was ascribed to their large specific surface area, higher number of octahedral metal ions and the weakest metal-oxygen bonds.

Necrotic Liver Lesion Resolution: Another Mode of Liver Regeneration.

The liver has the great ability to regenerate after partial resection or injury, and the mechanisms underlying liver regeneration have been extensively investigated. Interestingly, acute liver injuries triggered by various etiologies are associated with the formation of necrotic lesions, and such necrotic lesions are also rapidly resolved. However, how necrotic liver lesions are repaired has not been carefully investigated until recently. In this review, we briefly summarize the spatiotemporal process of necrotic liver lesion resolution in several liver injury models including immune-mediated liver injury and drug-induced liver injury. The roles of liver nonparenchymal cells and infiltrating immune cells in controlling necrotic liver lesion resolution are discussed, which may help identify potential therapies for acute liver injury and failure.

White matter microstructure alterations of the posterior limb of internal capsule in first-episode drug naive schizophrenia patients.

OBJECTIVES: Previous studies have shown that microstructural alterations in white matter (WM) could contribute to the symptom manifestation and support the dysconnectivity hypothesis in schizophrenia patients. These alterations were pervasive, non-specific, and reported inconsistently across the literature. This study aimed to specifically investigate the microstructure alterations of the posterior limb of the internal capsule (PLIC) in first-episode, drug-naive schizophrenia patients. Utilizing a multicompartmental biophysical model, we further explored the correlation between these alterations and syndrome scale scores. METHODS: Thirty-two individuals with first-episode, drug-naive schizophrenia (FES) and thirty demographically matched healthy controls were enrolled. High-resolution multi-shell diffusion MRI data were collected, followed by the application of a three-compartment Neurite Orientation Dispersion and Density Imaging (NODDI) model to scrutinize the alterations in white matter microstructure. Changes in sensory and motor fibers within the PLIC were specifically focused on. Additionally, the correlation between these pathological changes and scores on the Positive and Negative Syndrome Scale (PANSS) was investigated. RESULTS: The Neurite density index (NDI) in the left PLIC was significantly lower in FES patients compared to healthy individuals, and positively correlated with PANSS positive syndrome scores (r = 0.0379, p = 0.046). In the sensory component (left superior thalamic radiation within PLIC, STR_P), the NDI was significantly elevated (p < 0.0001). Conversely, the NDI in the motor component (left corticospinal tract within PLIC, CST_P) was reduced (p = 0.007) in FES patients compared to healthy individuals, and strongly correlated with PANSS positive syndrome scores (p < 0.020) and PANSS total scores (p < 0.045). Moreover, the NDI deviation of STR from total PLIC (fSTR_P) and NDI deviation in STR_P and CST_P compared to PLIC region (fPLIC) were significantly higher in FES patients than in healthy controls (p < 0.00001), with an area under the curve (AUC) of fPLIC reaching 0.872. CONCLUSION: The study's findings provided new insights into the discrepancy of white matter microstructure changes associated with the sensory and motor fibers in the PLIC region in FES patients. These results contribute to the growing body of evidence suggesting that WM microstructural alterations play a critical role in schizophrenia pathophysiology.

The Effect of Transverse Sinus Stenosis Caused by Arachnoid Granulation on Patients with Venous Pulsatile Tinnitus: A Multiphysics Interaction Simulation Investigation.

This study aimed to investigate the effect of the transverse sinus (TS) stenosis (TSS) position caused by arachnoid granulation on patients with venous pulsatile tinnitus (VPT) and to further identify the types of TSS that are of therapeutic significance for patients. Multiphysics interaction models of six patients with moderate TSS caused by arachnoid granulation and virtual stent placement in TSS were reconstructed, including three patients with TSS located in the middle segment of the TS (group 1) and three patients with TTS in the middle and proximal involvement segment of the TS (group 2). The transient multiphysics interaction simulation method was applied to elucidate the differences in biomechanical and acoustic parameters between the two groups. The results revealed that the blood flow pattern at the TS and sigmoid sinus junction was significantly changed depending on the stenosis position. Preoperative patients had increased blood flow in the TSS region and TSS downstream where the blood flow impacted the vessel wall. In group 1, the postoperative blood flow pattern, average wall pressure, vessel wall vibration, and sound pressure level of the three patients were comparable to the preoperative state. However, the postoperative blood flow velocity decreased in group 2. The postoperative average wall pressure, vessel wall vibration, and sound pressure level of the three patients were significantly improved compared with the preoperative state. Intravascular intervention therapy should be considered for patients with moderate TSS caused by arachnoid granulations in the middle and proximal involvement segment of the TS. TSS might not be considered the cause of VPT symptoms in patients with moderate TSS caused by arachnoid granulation in the middle segment of the TS.

From driver genes to gene families: A computational analysis of oncogenic mutations and ubiquitination anomalies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a widespread primary liver cancer with a high fatality rate. Despite several genes with oncogenic effects in HCC have been identified, many remain undiscovered. In this study, we conducted a comprehensive computational analysis to explore the involvement of genes within the same families as known driver genes in HCC. Specifically, we expanded the concept beyond single-gene mutations to encompass gene families sharing homologous structures, integrating various omics data to comprehensively understand gene abnormalities in cancer. Our analysis identified 74 domains with an enriched mutation burden, 404 domain mutation hotspots, and 233 dysregulated driver genes. We observed that specific low-frequency somatic mutations may contribute to HCC occurrence, potentially overlooked by single-gene algorithms. Furthermore, we systematically analyzed how abnormalities in the ubiquitinated proteasome system (UPS) impact HCC, finding that abnormal genes in E3, E2, DUB families, and Degron genes often result in HCC by affecting the stability of oncogenic or tumor suppressor proteins. In conclusion, expanding the exploration of driver genes to include gene families with homologous structures emerges as a promising strategy for uncovering additional oncogenic alterations in HCC.

Tumor microenvironment characteristics association with clinical outcome in patients with resected intestinal-type gastric cancer.

BACKGROUND: Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. METHODS: TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. RESULTS: Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). CONCLUSIONS: Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.

Coordinated action of a gut-liver pathway drives alcohol detoxification and consumption.

Alcohol use disorder (AUD) affects millions of people worldwide, causing extensive morbidity and mortality with limited pharmacological treatments. The liver is considered as the principal site for the detoxification of ethanol metabolite, acetaldehyde (AcH), by aldehyde dehydrogenase 2 (ALDH2) and as a target for AUD treatment, however, our recent data indicate that the liver only plays a partial role in clearing systemic AcH. Here we show that a liver-gut axis, rather than liver alone, synergistically drives systemic AcH clearance and voluntary alcohol drinking. Mechanistically, we find that after ethanol intake, a substantial proportion of AcH generated in the liver is excreted via the bile into the gastrointestinal tract where AcH is further metabolized by gut ALDH2. Modulating bile flow significantly affects serum AcH level and drinking behaviour. Thus, combined targeting of liver and gut ALDH2, and manipulation of bile flow and secretion are potential therapeutic strategies to treat AUD.

Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets.

Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.

Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Acute depletion of BRG1 reveals its primary function as an activator of transcription.

The mammalian SWI/SNF-like BAF complexes play critical roles during animal development and pathological conditions. Previous gene deletion studies and characterization of human gene mutations implicate that the complexes both repress and activate a large number of genes. However, the direct function of the complexes in cells remains largely unclear due to the relatively long-term nature of gene deletion or natural mutation. Here we generate a mouse line by knocking in the auxin-inducible degron tag (AID) to the Smarca4 gene, which encodes BRG1, the essential ATPase subunit of the BAF complexes. We show that the tagged BRG1 can be efficiently depleted by osTIR1 expression and auxin treatment for 6 to 10 h in CD4 + T cells, hepatocytes, and fibroblasts isolated from the knock-in mice. The acute depletion of BRG1 leads to decreases in nascent RNAs and RNA polymerase II binding at a large number of genes, which are positively correlated with the loss of BRG1. Further, these changes are correlated with diminished accessibility at DNase I Hypersensitive Sites (DHSs) and p300 binding. The acute BRG1 depletion results in three major patterns of nucleosome shifts leading to narrower nucleosome spacing surrounding transcription factor motifs and at enhancers and transcription start sites (TSSs), which are correlated with loss of BRG1, decreased chromatin accessibility and decreased nascent RNAs. Acute depletion of BRG1 severely compromises the Trichostatin A (TSA) -induced histone acetylation, suggesting a substantial interplay between the chromatin remodeling activity of BRG1 and histone acetylation. Our data suggest BRG1 mainly plays a direct positive role in chromatin accessibility, RNAPII binding, and nascent RNA production by regulating nucleosome positioning and facilitating transcription factor binding to their target sites.

Machine learning and multi-omics data reveal driver gene-based molecular subtypes in hepatocellular carcinoma for precision treatment.

The heterogeneity of Hepatocellular Carcinoma (HCC) poses a barrier to effective treatment. Stratifying highly heterogeneous HCC into molecular subtypes with similar features is crucial for personalized anti-tumor therapies. Although driver genes play pivotal roles in cancer progression, their potential in HCC subtyping has been largely overlooked. This study aims to utilize driver genes to construct HCC subtype models and unravel their molecular mechanisms. Utilizing a novel computational framework, we expanded the initially identified 96 driver genes to 1192 based on mutational aspects and an additional 233 considering driver dysregulation. These genes were subsequently employed as stratification markers for further analyses. A novel multi-omics subtype classification algorithm was developed, leveraging mutation and expression data of the identified stratification genes. This algorithm successfully categorized HCC into two distinct subtypes, CLASS A and CLASS B, demonstrating significant differences in survival outcomes. Integrating multi-omics and single-cell data unveiled substantial distinctions between these subtypes regarding transcriptomics, mutations, copy number variations, and epigenomics. Moreover, our prognostic model exhibited excellent predictive performance in training and external validation cohorts. Finally, a 10-gene classification model for these subtypes identified TTK as a promising therapeutic target with robust classification capabilities. This comprehensive study provides a novel perspective on HCC stratification, offering crucial insights for a deeper understanding of its pathogenesis and the development of promising treatment strategies.

Tinned: A symbolic library for response theory and high-order derivatives.

A symbolic C++ library-Tinned-has been developed for symbolic differentiation and manipulation in response theory. By recognizing different key building blocks in the density matrix-based (Thorvaldsen et al., J. Chem. Phys. 2008, 129, 214108) and coupled-cluster response theories, we have implemented their corresponding C++ symbolic classes, including but not limited to one- and two-electron operators, exchange-correlation energy and potential, and coupled-cluster operator. Formulas of response theory can be well expressed in terms of the symbolic classes in the library Tinned. Their high-order perturbation-strength derivatives can be straightforwardly computed and extracted afterwards for numerical evaluation. The library Tinned will greatly facilitate the development work of response theory and may lead to a unified framework for response theory at different levels of electronic structure theory.

The evolutionary novelty of insect defensins: from bacterial killing to toxin neutralization.

Insect host defense comprises two complementary dimensions, microbial killing-mediated resistance and microbial toxin neutralization-mediated resilience, both jointly providing protection against pathogen infections. Insect defensins are a class of effectors of innate immunity primarily responsible for resistance to Gram-positive bacteria. Here, we report a newly originated gene from an ancestral defensin via genetic deletion following gene duplication in Drosophila virilis, which confers an enhanced resilience to Gram-positive bacterial infection. This gene encodes an 18-mer arginine-rich peptide (termed DvirARP) with differences from its parent gene in its pattern of expression, structure and function. DvirARP specifically expresses in D. virilis female adults with a constitutive manner. It adopts a novel fold with a 310 helix and a two CXC motif-containing loop stabilized by two disulfide bridges. DvirARP exhibits no activity on the majority of microorganisms tested and only a weak activity against two Gram-positive bacteria. DvirARP knockout flies are viable and have no obvious defect in reproductivity but they are more susceptible to the DvirARP-resistant Staphylococcus aureus infection than the wild type files, which can be attributable to its ability in neutralization of the S. aureus secreted toxins. Phylogenetic distribution analysis reveals that DvirARP is restrictedly present in the Drosophila subgenus, but independent deletion variations also occur in defensins from the Sophophora subgenus, in support of the evolvability of this class of immune effectors. Our work illustrates for the first time how a duplicate resistance-mediated gene evolves an ability to increase the resilience of a subset of Drosophila species against bacterial infection.

CRISPR/Cas9-Based Functional Characterization of SfUGT50A15 Reveals Its Roles in the Resistance of Spodoptera frugiperda to Chlorantraniliprole, Emamectin Benzoate, and Benzoxazinoids.

UDP-glycosyltransferases (UGTs) are a diverse superfamily of enzymes. Insects utilize uridine diphosphate-glucose (UDP-glucose) as a glycosyl donor for glycosylation in vivo, involved in the glycosylation of lipophilic endosymbionts and xenobiotics, including phytotoxins. UGTs act as second-stage detoxification metabolizing enzymes, which are essential for the detoxification metabolism of insecticides and benzoxazine compounds. However, the UGT genes responsible for specific glycosylation functions in S. frugiperda are unclear at present. In this study, we utilized CRISPR/Cas9 to produce a SfUGT50A15-KO strain to explore its possible function in governing sensitivity to chemical insecticides or benzoxazinoids. The bioassay results suggested that the SfUGT50A15-KO strain was significantly more sensitive to chlorantraniliprole, emamectin benzoate, and benzoxazinoids than the wild-type strains. This finding suggests that the overexpression of the SfUGT50A15 gene may be linked to S. frugiperda resistance to pesticides (chlorantraniliprole and emamectin benzoate) as well as benzoxazinoids (BXDs).

Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China.

OBJECTIVE: This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients. METHODS: Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM. RESULTS: 33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years. CONCLUSION: Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.

Photothermal conditions and upwelling enhance very short-lived brominated halocarbons emissions in the western tropical Pacific Ocean.

Sea-to-air emissions of very short-lived brominated halocarbons (VSLBrHs) are known to contribute to 30 % of stratospheric and tropospheric ozone depletion. However, empirical data on their occurrence in open ocean are scarce, which makes it difficult to estimate the significant contribution of open ocean releases to the global budget of halocarbons. This study was conducted in 2022 to explore the spatial variations of VSLBrHs and their controlling factors in the western tropical Pacific Ocean (WTPO). The findings highlighted that high biological productivity and the resulting dissolved organic matter (DOM) as well as upwelling dynamics significantly influenced the distribution and production of VSLBrHs in seawater, with atmospheric levels primarily governed by oceanic emissions. Based on the simultaneous observation of seawater and atmospheric concentrations, the mean sea-to-air fluxes of CH2Br2, CHBr3, CHBrCl2, and CHBr2Cl were estimated to be 1.01, 6.65, 9.31, and 7.25 nmol m-2 d-1, respectively. Sea-to-air fluxes of these gases in the upwelling regions were 9.0, 4.6, 2.9, and 6.8 times those in the non-upwelling regions, respectively. Additionally, in-situ incubation experiments revealed that the enzymatic mediated biosynthesis pathways of VSLBrHs were enhanced under temperature and light-induced stress and in waters rich in humus-like substances. Therefore, we tentatively concluded that abundant photothermal conditions and the existence of upwelling in the WTPO made it a potential hotspot for the emission of VSLBrHs. This study offers critical insights into the environmental dynamics of VSLBrHs emissions and underscores the importance of regional oceanic conditions in influencing atmospheric greenhouse gas compositions.

Macrophages in necrotic liver lesion repair: opportunities for therapeutical applications.

Healthy livers contain 80% of body resident macrophages known as Kupffer cells. In diseased livers, the number of Kupffer cells usually drops but is compensated by infiltration of monocyte-derived macrophages, some of which can differentiate into Kupffer-like cells. Early studies suggest that Kupffer cells play important roles in both promoting liver injury and liver regeneration. Yet, the distinction between the functionalities of resident and infiltrating macrophages is not always made. By using more specific macrophage markers and targeted cell depletion and single-cell RNA sequencing, recent studies revealed several subsets of monocyte-derived macrophages that play important functions in inducing liver damage and inflammation as well as in liver repair and regeneration. In this review, we discuss the different roles that hepatic macrophages play in promoting necrotic liver lesion resolution and dead cell clearance, as well as the targeting of these cells as potential tools for the development of novel therapies for acute liver failure and acute-on-chronic liver failure.

Seawater flooding of calcareous soils: Implications for trace and alkaline metals mobility.

Developing management strategies to safeguard public health and environmental sustainability requires a comprehensive understanding of the solubility and mobility of trace and alkaline metals in the event of seawater flooding. This study investigated the effects of seawater flooding, along the duration of flooding, on the release of trace and alkaline metals (Mn, Fe, Cu, Zn, Ca, K, and Mg) in two calcareous soils (Krome and Biscayne) located in southern Florida. Seawater flooding experiments involved two soil types and four flooding durations (1, 7, 14, and 28 days) replicated three times. Freshwater flooding experiments were also conducted for comparison. After each flooding experiment, soil samples were collected at three depths (15, 30, and 45 cm), and analyzed for selected elements. Comparative analysis revealed significant releases of Mn, Fe, and Zn in both soils flooded by seawater compared to freshwater. In most cases, significant increments were evident as early as 1-day exposure to seawater flooding, which further increased with flooding duration. However, the impacts of seawater flooding had notable differences between the two soils. Seawater flooding in Krome soil for 28 days, resulted in higher Mn, Fe, and Zn contents by 58, 340, and 510% compared with freshwater flooding, while corresponding increases in Biscayne soil were 3.3, 130, and 180%, respectively. Comparable marginal increases in Cu content were observed for both soils. Similarly, seawater flooding increased K, Mg, and Na contents from single-day flooding. The interplay between soil type, column depth, flooding duration, and their interactions proved influential factors in determining Mn, Fe, Cu, and Zn releases, with peak levels typically observed on the 28th day of flooding and at bottom depths. Overall, these findings highlight the release of these elements, raising concerns about potential plant toxicity and groundwater or surface water contamination due to leaching and runoff.

Alcohol-associated liver cancer.

Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.