Search

Background: No effective drugs currently exist to cure Alzheimer's disease (AD) due to its complexity and the lack of understanding of the involved molecular signaling and pathways. The relationship between liver health and AD is now widely recognized. Still, molecular links and shared pathways between the liver and brain remain unclear, making the liver-brain axis in AD therapies a new area for exploration. However, bibliometric studies on this topic are lacking. Objective: This study aims to review the liver-brain axis in AD and identify future research hotspots and trends through bibliometric analysis. Methods: Articles and reviews related to AD and liver and its related diseases were searched in the Web of Science Core Collection (WoSCC) database up to 2024. Data were processed and visually analyzed using VOSviewer, CiteSpace, and Pajek. Results: We collected 1,777 articles on AD and liver and its related diseases from 2,517 institutions across 80 countries. Keyword cluster analysis identified 11 clusters, with 'insulin resistance,' 'amyloid-beta,' 'apolipoprotein-E,' 'oxidative stress,' and 'inflammation' appearing most frequently, and exhibiting strong total link strength. These results indicate that these topics have been the primary focus of research on the liver-brain axis in AD. Conclusions: This study is the first to comprehensively analyze the liver-brain axis in AD using bibliometric methods. The research results identify recent research frontiers and hotspots, aiding scholars in gaining a deeper understanding of the correlation between AD and the liver. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) gene aberration is detectable in >80% of cases with hepatocellular carcinoma (HCC). TERT reactivation is essential for cellular immortalization because it stabilizes telomere length, although the role of TERT in hepatocarcinogenesis remains unelucidated. To elucidate the significance of aberrant TERT expression in hepatocytes in inflammation‐associated hepatocarcinogenesis, we generated Alb‐Cre;TertTg mice, which overexpress TERT in the liver and examined their phenotype during chronic inflammation. Based on transcriptome data from the liver tissue of Alb‐Cre;TertTg mice, we examined the role of TERT in hepatocarcinogenesis in vitro. We also evaluated the relationship between TERT and cell‐cycle‐related molecules, including p21, in HCC samples. The liver tumor development rate was increased by TERT overexpression during chronic inflammation, especially in the absence of p53 function. Gene set enrichment analysis of liver tissues revealed that gene sets related to TNF‐NFκB signaling, cell cycle, and apoptosis were upregulated in Alb‐Cre;TertTg liver. A luciferase reporter assay and immunoprecipitation revealed that TERT interacted with NFκB p65 and enhanced NFκB promoter activity. On the other hand, TERT formed protein complexes with p21, cyclin A2, and cyclin E and promoted ubiquitin‐mediated degradation of p21, specifically in the G1 phase. In the clinical HCC samples, TERT was highly expressed but p21 was conversely downregulated, and TERT expression was associated with the upregulation of molecules related to the cell cycle. Taken together, the aberrant upregulation of TERT increased NFκB promoter activity and promoted cell cycle progression via p21 ubiquitination, leading to hepatocarcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Summary: Background: The incidence of hospitalisations related to acute‐on‐chronic liver failure (ACLF) is increasing. Liver transplantation (LT) remains the definitive treatment for the condition. Aim: To evaluate the influence of race and ethnicity on LT outcomes in ACLF. Methods: We conducted a retrospective analysis utilising LT data from the United Network for Organ Sharing (UNOS) database. White patients served as the control group and patients of other races were compared at each ACLF grade. The primary outcomes assessed were graft failure and all‐cause mortality. Results: Blacks exhibited a higher all‐cause mortality (Grade 1: aHR 1.36, 95% CI 1.18–1.57, p < 0.001; Grade 2: aHR 1.27, 95% CI 1.08–1.48, p = 0.003; Grade 3: aHR 1.19, 95% CI 1.04–1.37, p = 0.01) and graft failure (Grade 1: aHR 2.05, 95% CI 1.58–2.67, p < 0.001; Grade 2: aHR 1.91, 95% CI 1.43–2.54, p < 0.001; Grade 3: aHR 1.50, 95% CI 1.15–1.96, p = 0.002). Hispanics experienced a lower all‐cause mortality at grades 1 and 3 (Grade 1: aHR 0.83, 95% CI 0.72–0.96, p = 0.01; Grade 3: aHR 0.80, 95% CI 0.70–0.91, p < 0.001) and Asians with severe ACLF demonstrated decreased all‐cause mortality (Grade 3: aHR 0.55, 95% CI 0.42–0.73, p < 0.001). Conclusion: Black patients experienced the poorest outcomes and Hispanic and Asian patients demonstrated more favourable outcomes compared to Whites. [ABSTRACT FROM AUTHOR]

This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Metabolic dysfunction‐associated steatotic liver disease is a significant driver of the increasing global burden of chronic liver disease. This study aimed to describe the temporal trends and inequalities of liver complications related to metabolic dysfunction‐associated steatotic liver disease (LC‐MASLD) by geographical region, age and sex during 1990–2021.Global Burden of Diseases Study 2021 data were analysed to assess LC‐MASLD incidence, prevalence, mortality and disability‐adjusted life years (DALYs). Temporal trends during 1990–2021 were measured by ‘estimated annual percentage change’ (EAPC). Inequalities of LC‐MASLD burden across countries were evaluated by the slope index of inequality (SII) and the relative concentration index (RCI).During 1990–2021, LC‐MASLD rose annually by 0.73% in incidence and prevalence, 0.19% in mortality and 0.16% in DALYs. In 2021, the Middle East and North Africa had the highest incidence and prevalence and Andean and Central Latin America had the highest mortality and DALY rates. While LC‐MASLD incidence was earliest in the 15–19 age group, both prevalence and DALY rates peaked at 75–79 years for both sexes. Inequalities in mortality and DALYs by countries' socioeconomic development index increased during 1990–2021, demonstrated by a decline in SII from −0.09 to −0.56 per 100 000 for mortality and from 1.41 to −7.74 per 100 000 for DALYs. RCI demonstrated similar findings.The LC‐MASLD burden is increasing globally, especially in economically disadvantaged countries, with widening disease inequalities during 1990–2021. Effective prevention and subregional interventions are crucial, with a specific focus on resource optimisation for disadvantaged populations. [ABSTRACT FROM AUTHOR]

Background Method Results Conclusion Post‐hepatectomy liver failure is a major cause of mortality, where future liver remnant (FLR) is the key controllable factor. Recommended minimum FLR is influenced by quality of liver parenchyma. Historical research has often failed to include Māori and Pacific Island (PI) populations despite worse health outcomes. Liver analysis by ethnicity is one such example of this. The aims were to determine digital FLR for various anatomical hepatectomies, investigate any correlations between computed tomography (CT) hepatic textural analysis and body mass index (BMI); and assess the variance of these relationships for different ethnicities.One hundred and fifty‐one patients who underwent abdominal CT scans at Burwood Hospital, Christchurch were retrospectively analysed. Māori and PI patients were selectively recruited to represent New Zealand's diversity. Liver volumetry, segmental ratio, and intra‐hepatic fat deposits (IHFD) per ethnicity were examined.Median age of the cohort was 66 (19–95) and 75 (50%) were males. 68%, 23% and 9% patients identified as being European, Māori/PI and Asian, respectively. No statistically significant difference in volume or segment/total volume ratio were noted across different ethnicities. Obese patients had higher IHFD compared with overweight and normal BMI groups. When stratified across ethnic groups, higher IHFD were observed in Asian compared with Māori/PI populations, despite lower BMI.No significant variances in liver volumetry were found across different ethnic groups in New Zealand. However association between BMI and IHFD varied across different ethnic cohorts. Consequently, knowledge of liver volumetry is not enough; patient liver quality and ethnicity should considered for hepatic‐surgery planning. [ABSTRACT FROM AUTHOR]

The burden of senescent hepatocytes correlates with the severity of metabolic dysfunction–associated steatotic liver disease (MASLD), but the mechanisms driving senescence and how it exacerbates MASLD are poorly understood. Hepatocytes experience lipotoxicity and become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine whether the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA- Seq analysis of liver samples from human and murine cohorts with MASLD confirmed that hepatocyte populations in MASLD livers were depleted of Smo+ cells and enriched with senescent cells. When fed a choline-deficient, amino acid–restricted high-fat diet (CDA-HFD) to induce MASLD, Smo– mice had lower antioxidant markers and developed worse DNA damage, senescence, steatohepatitis, and fibrosis than did Smo+ mice. Sera and hepatocyte-conditioned medium from Smo– mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo– hepatocytes with TP reduced senescence and lipotoxicity, whereas inhibiting TP in Smo+ hepatocytes had the opposite effect and exacerbated hepatocyte senescence, steatohepatitis, and fibrosis in CDA-HFD–fed mice. We conclude that inhibition of Hedgehog signaling in hepatocytes promoted MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence. [ABSTRACT FROM AUTHOR]

Background and Purpose: Only limited therapeutic agents have been developed for non‐alcoholic steatohepatitis (NASH). Glabridin, a promising anti‐obesity candidate, has only limited druggability due to its low in vivo chemical stability and bioavailability. Therefore, we developed vutiglabridin (VUTI), which is based on a glabridin backbone, and investigated its mechanism of action in treating NASH in animal models. Experimental Approach: Anti‐NASH effects of VUTI were determined in in vitro fatty liver models, spheroids of primary human hepatocytes and L02 normal liver cell lines. To identify VUTI possible cellular target/s, biotin‐labelled VUTI was synthesized and underwent chemical proteomic analysis. Further, the evaluation of VUTI therapeutic efficacy was carried out using an amylin‐NASH and high‐fat (HF) diet‐induced obese (DIO) mouse models. This was carried out using transcriptomic, lipidomic and proteomic analyses of the livers from the amylin‐NASH mouse model. Key Results: VUTI treatment markedly reduces hepatic steatosis, fibrosis and inflammation by promoting lipid catabolism, activating autophagy and improving mitochondrial dysfunction, all of which are hallmarks of effective NASH treatment. The cellular target of VUTI was identified as paraoxonase 2 (PON2), a newly proposed protein target for the treatment of NASH, VUTI enhanced PON2 activity. The results using PON2 knockdown cells demonstrated that PON2 is important for VUTI‐ activation of autophagy, promoting mitochondrial function, decreasing oxidative stress and alleviating lipid accumulation under lipotoxic condition. Conclusion and Implications: Our data demonstrated that VUTI is a promising therapeutic for NASH. Targeting PON2 may be important for improving liver function in various immune‐metabolic diseases including NASH. [ABSTRACT FROM AUTHOR]

Background: The Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) Index, serves as an effective tool for evaluating body fat (BF) levels. This research seeks to clarify the association between the CUN-BAE Index and metabolic dysfunction-associated steatotic liver disease (MASLD) from a gender perspective. Methods: The study utilized data from a comprehensive health assessment initiative known as "Human Dock", involving 14,251 participants. MASLD was diagnosed using abdominal ultrasound, primarily evaluated based on the following sonographic features: hepatorenal echo contrast, vascular blurring, deep attenuation, liver brightness. First, we evaluated the association of MASLD with the CUN-BAE Index using multivariate logistic regression. Second, we visualized this association and estimated potential threshold effect points using the restricted cubic spline (RCS) regression model. Ultimately, we evaluated the ability of the CUN-BAE Index to detect MASLD through receiver operating characteristic (ROC) curves. Results: The female-to-male ratio was 1:1.08, with a MASLD prevalence rate of 17.59%. Following the adjustment for confounding variables, an increase of one unit in the CUN-BAE Index corresponded to a 14% increase in the risk of MASLD for males and an 18% increase for females. RCS analysis revealed an S-shaped relationship between MASLD prevalence and the CUN-BAE Index for both genders, with potential threshold effect points at approximately 30 in females and 15 in males. Beyond these threshold points, the prevalence of MASLD increased rapidly. Further subgroup analyses indicated significant differences in the relationship of the CUN-BAE Index with MASLD within age and body mass index (BMI) subgroups in females, with a stronger association observed in younger and non-obese female participants. Additionally, ROC analysis revealed that the CUN-BAE Index possesses a strong ability to distinguish MASLD in both genders, especially in females. Conclusions: This research is the first to identify a positive relationship between the CUN-BAE Index and MASLD. The CUN-BAE Index appears to be more suitable for early screening of MASLD in females. [ABSTRACT FROM AUTHOR]

Chronic inflammation triggers development of metabolic disease, and pulmonary tuberculosis (TB) generates chronic systemic inflammation. Whether TB induced-inflammation impacts metabolic organs and leads to metabolic disorder is ill defined. The liver is the master regulator of metabolism and to determine the impact of pulmonary TB on this organ we undertook an unbiased mRNA and protein analyses of the liver in mice with TB and reanalysed published data on human disease. Pulmonary TB led to upregulation of genes in the liver related to immune signalling and downregulation of genes encoding metabolic processes. In liver, IFN signalling pathway genes were upregulated and this was reflected in increased biochemical evidence of IFN signalling, including nuclear location of phosphorylated Stat-1 in hepatocytes. The liver also exhibited reduced expression of genes encoding the gluconeogenesis rate-limiting enzymes Pck1 and G6pc. Phosphorylation of CREB, a transcription factor controlling gluconeogenesis was drastically reduced in the livers of mice with pulmonary TB as was phosphorylation of other glucose metabolism-related kinases, including GSK3a, AMPK, and p42. In support of the upregulated IFN signalling being linked to the downregulated metabolic functions in the liver, we found suppression of gluconeogenic gene expression and reduced CREB phosphorylation in hepatocyte cell lines treated with interferons. The impact of reduced gluconeogenic gene expression in the liver was seen when infected mice were less able to convert pyruvate, a gluconeogenesis substrate, to the same extent as uninfected mice. Infected mice also showed evidence of reduced systemic and hepatic insulin sensitivity. Similarly, in humans with TB, we found that changes in a metabolite-based signature of insulin resistance correlates temporally with successful treatment of active TB and with progression to active TB following exposure. These data support the hypothesis that TB drives interferon-mediated alteration of hepatic metabolism resulting in reduced gluconeogenesis and drives systemic reduction of insulin sensitivity. Author summary: Tuberculosis (TB) is a worldwide disease with a substantial proportion of undiagnosed cases. Control of TB is mediated by a protective cellular immune response which is also chronic, inflammatory and systemic. Chronic inflammation can disrupt metabolism and compromise the organs key to maintaining health–such as the liver. The extent to which pulmonary TB can disrupt the metabolic function of the liver is ill defined. We have used a mouse model of pulmonary TB to examine the changes occurring in the liver when immunity is first being expressed in the lung. We found that pulmonary TB leads to upregulation of immune-related signalling pathways in liver cells and that TB infected mice have altered glucose metabolism. Reanalysing published metabolic data from humans, we find that a metabolic signature associated with insulin resistance separates those with TB from healthy subjects and alters with time to progression and resolution of TB, thereby indicating glucose metabolism disruption occurs during TB in humans. These data are important because we show that TB disrupts liver glucose metabolism, and this is critical to understanding the interplay between TB and metabolic disease. [ABSTRACT FROM AUTHOR]

Background: Cancer initiation has long been "unknowable" in biology and medicine. In 1987, however, Moore and our research group observed single hepatocytes and minifoci that were strongly positive for glutathione S‐transferase P‐form (GST‐P) in the rat liver as early as 2 to 3 days after initiation by diethylnitrosamine prior to the induction of GST‐P+ foci and nodules. The induction of GST‐P+ single hepatocytes, precursors of GST‐P+ foci and nodules, was considered genetic. But, the details of the induction mechanism have remained unclear despite various examinations over a long period. Methods: Male Sprague‐Dawley rats (aged 6 weeks) were fed a basal diet containing either benzyl isothiocyanate (BITC, 0.5% by wt) or 2‐acetylaminofluorene (AAF, 0.04%) adlibitum for appropriate time intervals. All animals were anesthetized and euthanized. The livers obtained were excised, cut into 3‐ to 4‐mm‐thick slices and fixed in cold acetone at 4 °C. The liver specimens were then sliced into 25‐µm‐thick sections in PBS using an automated microtome (Vibratome 1500 Sectioning System, Vibratome Products, NY, USA). Immunocytochemical staining was performed in free solution, and the results were examined via digital light microscopy (Coolscope, Nikon, Tokyo). Results: 3D analysis using a vibratome showed that GST‐P is rapidly excreted into the bile of the liver of animals in response to strong carcinogenic stress caused by promoters or initiators. "Rapid biliary excretion of GST‐P" was widely and commonly observed in all hepatocytes, GST‐P+ single hepatocytes, minifoci, foci and nodules under appropriate conditions. Surprisingly, on the basis of these key findings, a new mechanism of cancer initiation involving the transformation of hepatocytes into GST‐P+ single hepatocytes and minifoci in animal livers was identified. In addition, the initiation process was determined to be nongenetic because mutation is an invisible rare event. Conclusions: This short review describes several details about breakthrough findings on cancer initiation in rat livers, the application of 3D analysis to other cancers and the importance in the genetic analysis in malignant diseases. [ABSTRACT FROM AUTHOR]

Eimeria stiedae is one of the few eukaryotic pathogens that exclusively infect the liver and serves as a good model to study the host–pathogen interactions in this vital organ. In this study, we show that rabbits infected with E. stiedae develop severe but self‐healing cholangitis. RNA‐seq analysis of the liver gene expression landscapes over the long course of E. stiedae infection identified 912 differentially expressed genes (DEGs) in the prepatent period (794 up‐ and 118 downregulated genes), 2889 DEGs in the early oocyst shedding period (1870 up‐ and 1019 downregulated genes), 2859 DEGs in the peak oocyst shedding period (1923 up‐ and 936 downregulated genes), and 327 DEGs in the recovery period (164 up‐ and 163 downregulated genes). Combined with pathological observations, we identified dynamic changes in host–parasite interactions involving multiple pathways. They showed that E. stiedae infection induced full‐blown inflammatory, Th1 and Th17 immune responses at all time points. This was associated with the strong innate immune responses during the prepatent period, including increased Toll‐like and NOD‐like receptor signaling. Despite mounting several damage control and repair responses, such as PI3K‐Akt signaling, Ras signaling, and extracellular matrix‐receptor interactions, the liver underwent severe metabolic dysfunction, oxidative damage, and coagulopathy after patency and at peak infection, possibly as a result of suppressed peroxisome activities and downregulated PPAR signaling. These responses largely disappeared during late infection, suggesting that the liver self‐heals after severe cholangitis. These data provide new insights into host–pathogen interactions during Eimeria infection and improve our understanding of the pathogenesis of parasitic cholangitis. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Cirrhosis continues to be the most common cause of chronic liver disease‐related deaths globally, which puts significant strain on global health. This report aims to investigate the patterns of cirrhosis in China, the United States, India and worldwide from 1990 to 2019 through an epidemiological analysis of the disease utilizing data from the Global Burden of Disease Study (GBD) 2019 database.Download the GBD database's statistics on liver cirrhosis deaths and Disability‐Adjusted Life Years for the years 1990–2019 worldwide as well as for China, the United States and India. Utilize techniques like age–period–cohort interaction, decomposition analysis, study of health inequities, Joinpoint model and Bayesian Average Annual Percentage Change model to process the data.The main age group affected by cirrhosis disease, according to the results, is 50–69 years old. According to the Joinpoint model, there has been a negative worldwide Average Annual Percent Change (AAPC) in the burden of cirrhosis between 1990 and 2019. Only the USA's AAPC is positive out of the three nations that were evaluated (albeit its 95% confidence interval spans 0). These are China, India and the United States. Forecasting models indicate that the prevalence of cirrhosis will keep rising in the absence of government action. According to decomposition analysis, the main factors contributing to the rising burden of cirrhosis are population ageing and size, whereas changes in the disease's epidemiology slow the disease's growth. Research on health disparities indicates that, between 1990 and 2019, there was a downward trend in health disparities between various locations.Health organizations across different areas should take aggressive measures to address the worrisome prevalence of cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Lanping black-boned sheep (LPB) represent a distinctive mammalian species characterized by hyperpigmentation, resulting in black bone and muscle features, in contrast to their conventional counterparts exhibiting red muscle and white bone. The genetic basis underlying LPB hyperpigmentation has remained enigmatic. Methods: In this study, we conducted whole-genome sequencing of 100 LPB and 50 Lanping normal sheep (LPN), and integrated this data with 421 sequenced datasets from wild and domestic sheep, shedding light on the genetic backdrop and genomic variations associated with LPB. Furthermore, we performed comparative RNA-Seq analysis using liver sample to pinpoint genes implicated in the pigmentation process. We generated a comprehensive dataset comprising 97,944,357 SNPs from 571 sheep, facilitating an in-depth exploration of genetic factors. Results: Population genetic structure analysis revealed that the LPB breed traces its origin back to LPN, having evolved into a distinct breed. The integration of positively selected genes with differentially expressed genes identified two candidates, ERBB4 and ROR1, potentially linked to LPB hyperpigmentation. Comparative analysis of ERBB4 and ROR1 mRNA relative expression levels in liver, spleen, and kidney tissues of LPB, in comparison to Diqing sheep, revealed significant upregulation, except for ERBB4 in the liver. Gene expression heatmaps further underscored marked allelic frequency disparities in different populations. Conclusion: Our findings establish the evolutionary lineage of the LPB breed from LPN and underscore the involvement of ERBB4 and ROR1 genes in melanin synthesis. These results enhance our comprehension of the molecular basis of hyperpigmentation and contribute to a more comprehensive depiction of sheep diversity. [ABSTRACT FROM AUTHOR]

An 8-week feeding trial was conducted to investigate the effects of dietary fucoidan levels (0 mg/kg, 500 mg/kg, 1,000 mg/kg, 1,500 mg/kg, and 2,000 mg/kg) on the hepatic ultrastructure and the transcriptomic landscape within the liver tissue of common carp. The results revealed that the addition of 1,000 mg/kg fucoidan to the diet significantly altered the ultrastructure of hepatocytes. Notably, the quantities of lipid droplets, autolysosomes, enlarged mitochondria, and endoplasmic reticulum were increased in the hepatocytes. The liver transcriptome analysis revealed that DEGs were notably abundant in the 1,000-mg/kg fucoidan group in glucolipid metabolism signaling pathways, including eukaryotes and nicotinate and nicotinamide metabolism, steroid biosynthesis, and PPAR signaling pathways. The quantitative real-time PCR (qPCR) results showed an excellent agreement on those of RNA-seq for both up- and down-regulated genes (a total of 13 genes selected for validation). Furthermore, fucoidan significantly influenced hepatic glucolipid metabolism of common carp at the mRNA level. Notably, the inclusion of lower concentrations of fucoidan in the diet, specifically at 500 mg/kg and 1,000 mg/kg, was found to significantly enhance the expression of mRNA for genes involved in glycolysis, including hk, gk, and pk, as well as genes linked to lipogenesis, such as srebf1, fasn, elovl5, acsl3a, scd, fads2, and cyp24a1. Conversely, higher concentrations of dietary fucoidan, at 1,500 mg/kg and 2,000 mg/kg, were observed to markedly upregulate the mRNA expression of genes associated with gluconeogenesis, including pck1, pck2, gs, gsk3a, gsk3b, and g6pca.1, along with genes related to lipolysis, such as hadhb, acadl, ecil, acacba, cpt1, fabp1, and fabp3. In summary, varying levels of fucoidan intake appear to exert differential influences on the hepatic glucolipid metabolism of common carp, suggesting a complex dose-dependent regulatory mechanism. For the first time, this research has established that fucoidan possesses a pronounced regulatory influence on the hepatic glucolipid metabolism in fish. This discovery not only underscores its potential as an immunostimulant but also opens new avenues for its application as a feed additive, with implications for modulating the nutritional metabolism of aquatic species. [ABSTRACT FROM AUTHOR]

Background & Aims: To evaluate, if high frame rate (HiFR) contrast-enhanced ultrasound (CEUS) and external perfusion analysis (VueBox®)can give answers on liver tumour diagnostics. Methods: A multifrequency probe (C1-6 /Resona R9) and 1-2.4 ml ultrasound contrast medium were used for CEUS up to 5-6 min. Independent analysis of DICOM-CINE files was performed, correlated to follow-up, computed tomography, magnetic resonance imaging, or histopathology. Results: In 110 patients the difference between marginal peak enhancement (PE) of malignant and benign leasions was significant. In the peripheral area, the AUCs were lower in malignant lesions (144.8±139.3) than in benign lesions (123.6±119.8). The mean transit time (mTT) was shorter in malignant lesions in the center. In the liver parenchyma, however, the mTT was significantly longer in malignant lesions (141.6±107.9s) than in benign lesions (128.8±138.6 s). The rise time (RT) was significantly shorter central (66.5±30.9s) and peripheral (72.8±35.1s) in malignant lesions than in benign lesions (114.33±159.58s). The wash in rate (WiR) in benign lesions was 848.3±2,563.7 rU in the center. Wash-out rate (WoR) in the center, peripheral and in the liver parenchyma showed a significantly lower wash-out in the malignant lesions. Conclusions: HiFR CEUS with perfusion analysis enables the assessment of focal, diffuse and postinterventional liver changes. [ABSTRACT FROM AUTHOR]

Background As one of the speculated bisphenols to replace bisphenol A (BPA), bisphenol F (BPF), naturally present in mustard, is structurally similar to BPA and may have similar estrogenic activity, but information on its toxicity is very limited compared to BPA. Objective In order to support the toxicology study of BPF at Heath Canada, a GC–MS method based on solid-phase extraction (SPE) and derivatization was developed for analysis of BPF in liver samples. Methods Samples were treated with β-glucuronidase to convert BPF glucuronide to free BPF for analysis of total BPF. Results The method was validated for free BPF at different spiking levels, and recoveries ranged from 90–97.5% with RSDs from 0.11–5.54%. The method was also validated for glucuronide-conjugated BPF at different spiking levels of BPF mono-β-D-glucuronide: recoveries ranged from 72.3–93.3% with RSDs from 1.7–8.94%. The method was used to analyze 60 liver tissue samples from rats dosed with BPF at different levels in a toxicology study. Free and glucuronide-conjugated BPF were not detected in any of the control samples, which were not dosed with BPF (average method detection limit: 0.31 ng/g) but detected in all the other liver tissue samples with levels increasing at higher doses. The percentage of glucuronide-conjugated BPF in total BPF varied among the liver samples, from as low as 9.8% to as high as 77.9%, indicating the importance of analyzing biological samples for BPF in both free and conjugated forms for total exposure. Conclusion A GC–MS method based on solid-phase extraction (SPE) and derivatization was developed for analysis of both free and glucuronide-conjugated BPF in liver samples. This method was validated not only for free BPF, but also for mono-β-D-glucuronide-conjugated BPF for the first time to confirm the efficiency of the deconjugation procedure with enzyme. Highlights This method can be adapted and applied for analysis of free and glucuronide-conjugated BPF in other biological samples with appropriate validation in target sample matrixes. [ABSTRACT FROM AUTHOR]

Purpose: Iron absorption in sickle cell anemia (SCA) remains unclear and studies in adults with SCA are scarce. The aim of this study was to evaluate the iron absorption SCA adults and its association with iron status and hepcidin concentration. Methods: SCA patients (n = 13; SCAtotal) and control participants (n = 10) ingested an oral stable iron isotope (57Fe). Iron absorption was measured by inductively coupled plasma mass spectrometry (ICP-MS) 14 days after isotope administration. Patients with ≥ 1000 ng/mL serum ferritin were considered to present iron overload (IO) (SCAio+; n = 3) and others classified without IO (SCAio-; n = 10). Results: Iron absorption in the control group ranged from 0.3 to 26.5% (median = 0.9%), while it varied from 0.3 to 5.4% in SCAio+ (median = 0.5%) and from 0.3 to 64.2% in the SCAio- (median = 6.9%). Hepcidin median values were 14.1 ng/mL (3.0–31.9 ng/mL) in SCAio-, 6.2 ng/mL (3.3–7.8 ng/mL) in SCAio + and 6.2 ng/mL (0.6–9.3 ng/mL) in control. Iron absorption was associated with ferritin level (r = − 0.641; p = 0.018) and liver iron concentration (LIC; r = − 0.786; p = 0.036) in the SCAtotal group. Conclusion: Our data suggest that SCAio- individuals may be at risk of developing primary IO. Simultaneously, secondary IO may induce physiological adaptation, resulting in reduced iron absorption. Further studies evaluating intestinal iron absorption using larger sample sizes should be conducted to help establish a safe nutrition approach to be adopted and to ensure the security of food-fortifying public policies for these patients. Trial registration: This trial was registered at www.ensaiosclinicos.gov.br (Identifier RBR-4b7v8pt). [ABSTRACT FROM AUTHOR]

Consuming an unbalanced diet and being overweight represent a global health problem in young people and adults of both sexes, and may lead to metabolic syndrome. The diet-induced obesity (DIO) model in the C57BL/6J mouse substrain that mimics the gradual weight gain in humans consuming a "Western-type" (WD) diet is of great interest. This study aims to characterize this animal model, using high-frequency ultrasound imaging (HFUS) as a complementary tool to longitudinally monitor changes in the liver, heart and kidney. Long-term WD feeding increased mice body weight (BW), liver/BW ratio and body condition score (BCS), transaminases, glucose and insulin, and caused dyslipidemia and insulin resistance. Echocardiography revealed subtle cardiac remodeling in WD-fed mice, highlighting a significant age–diet interaction for some left ventricular morphofunctional parameters. Qualitative and parametric HFUS analyses of the liver in WD-fed mice showed a progressive increase in echogenicity and echotexture heterogeneity, and equal or higher brightness of the renal cortex. Furthermore, renal circulation was impaired in WD-fed female mice. The ultrasound and histopathological findings were concordant. Overall, HFUS can improve the translational value of preclinical DIO models through an integrated approach with conventional methods, enabling a comprehensive identification of early stages of diseases in vivo and non-invasively, according to the 3Rs. [ABSTRACT FROM AUTHOR]

This study focused on exploring the effects of SW033291, an inhibitor of 15-hydroxyprostaglandin dehydrogenase, on type 2 diabetes mellitus (T2DM) mice from a comprehensive perspective. Studies have demonstrated that SW033291 benefits tissue repair, organ function, and muscle mass in elderly mice. Our recent investigation initially reported the beneficial effect of SW033291 on T2DM progression. Herein, we used a T2DM mouse model induced by a high-fat diet and streptozotocin injection. Then, serum and liver metabolomics, as well as liver transcriptomic analyses, were performed to provide a systematic perspective of the SW033291-ameliorated T2DM. The results indicate SW033291 improved T2DM by regulating steroid hormone biosynthesis and linoleic/arachidonic acid metabolism. Furthermore, integrated transcriptomic and metabolomic analyses suggested that key genes and metabolites such as Cyp2c55, Cyp3a11, Cyp21a1, Myc, Gstm1, Gstm3, 9,10-dihydroxyoctadecenoic acid, 11-dehydrocorticosterone, and 12,13-dihydroxy-9Z-octadecenoic acid played crucial roles in these pathways. qPCR analysis validated the significant decreases in the hepatic gene expressions of Cyp2c55, Cyp3a11, Myc, Gstm1, and Gstm3 in the T2DM mice, which were reversed following SW033291 treatment. Meanwhile, the elevated mRNA level of Cyp21a1 in T2DM mice was decreased after SW033291 administration. Taken together, our findings suggest that SW033291 has promising potential in alleviating T2DM and could be a novel therapeutic candidate. [ABSTRACT FROM AUTHOR]

Research on liver-related conditions requires a robust and efficient method to purify viable hepatocytes, lymphocytes and all other liver resident cells, such as Kupffer or liver sinusoidal endothelial cells. Here we describe a novel purification method using liver enzymatic digestion, followed by a downstream optimized purification. Using this enzymatic digestion protocol, the resident liver cells as well as viable hepatocytes could be captured, compared to the classical mechanical liver disruption method. Moreover, single-cell RNA-sequencing demonstrated higher quality lymphocyte data in downstream analyses after the liver enzymatic digestion, allowing for studying of immunological responses or changes. In order to also understand the peripheral immune landscape, a protocol for lymphocyte purification from mouse systemic whole blood was optimized, allowing for efficient removal of red blood cells. The combination of microbeads and mRNA blockers allowed for a clean blood sample, enabling robust single-cell RNA-sequencing data. These two protocols for blood and liver provide important new methodologies for liver-related studies such as NASH, hepatitis virus infections or cancer research but also for immunology where high-quality cells are indispensable for further downstream assays. [ABSTRACT FROM AUTHOR]

Introduction: Significant hepatic steatosis affects the outcome of surgery when living donors are transplanted. The gold standard for diagnosing and evaluating hepatic steatosis is hepatic imaging-guided biopsy. Hepatic steatosis assessment using MR spectroscopy and the proton density fat fraction (MR-PDFF) method has produced positive findings. Objectives: Is to compare the pre-operative assessment of liver fat quantification using MRI-PDFF methods, a non-invasive method, with histopathology. Subjects and methods: A 42 potential donors were then operated surgically for liver transplantation, consequently, were available for the assessment of the efficiency and sensitivity of the radiological findings MRI-PDFF procedures and imaging-guided liver biopsy. This radiological workup of these donors was done through a period of 7 months. Results: In many liver transplantations centers, liver imaging-guided biopsy histopathological examination is the gold standard. The study examined the MR proton density fat fraction modality, a recently developed test for hepatic steatosis measurement. The findings indicate 86.8% sensitivity, 50% specificity, 94.2% PDV, 28.5% NPV, 83.3% accuracy, and 0.684 AUC. On analyzing the fat percent, we found that the recorded fat percent using liver imaging-guided biopsy ranges between 1 and 10% with a median of 3. On the other hand, the recorded fat percent using MRI ranged between 2 and 15% with a median of 5. Conclusion: The non-invasive magnetic resonance hepatic proton density fat fraction approach using IDEAL sequence is a reliable and accurate means of quantitatively evaluating hepatic steatosis with excellent sensitivity, specificity, and accuracy. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to systematically dissect the role of Scinderin (SCIN) in tumorigenesis. Methods: Bioinformatics techniques were employed based on cancer data from TCGA, ENCORI, HPA, GEPIA2, UALCAN, Kaplan-Meier plotter, TIMER, TISIDB, cBioPortal, HCCDB, GeneMANIA and LinkedOmics database. Experiments in vitro and in vivo were conducted to dissect the role of SCIN in liver hepatocellular carcinoma (LIHC). Results: Significantly differential expression of SCIN was found in nine types of cancers, including LIHC. Through pan-cancer analysis, the correlations between SCIN expression with prognosis and immune cell infiltration were proven, especially in LIHC, ovarian serous cystadenocarcinoma and lung adenocarcinoma. The highest frequency of alteration in SCIN (6.81%) was seen in patients with uterine corpus endometrial carcinoma, in which "mutation" was the predominant type, with a frequency of about 5.29%; meanwhile, S673F and S381Y were the two most frequent mutation sites. Furthermore, the abnormal expression of SCIN exhibited a strong relationship with immune cell subtypes, immune checkpoint genes, tumor mutation burden, microsatellite instability, neoantigen, molecular subtypes, mismatch repair signatures and DNA methyltransferase in different cancer types. Through comparative analysis, we discovered that SCIN was dramatically up-regulated in LIHC, and associated with poor survival. Experiments in vitro and in vivo suggested the knockdown of SCIN could suppress tumor cell proliferation and improve the survival rate partly in animal models. Conclusion: This study reveals SCIN may be a promising biomarker for prognosis and treatment in certain cancers, especially in LIHC. [ABSTRACT FROM AUTHOR]

Background & aims: HBV infection initiates autoimmune responses, leading to autoantibody generation. This research explores the role of autoantibodies in HBV-related Acute-on-Chronic Liver Failure (ACLF), offering novel perspectives for clinical management. Method: We applied immunoprecipitation and iTRAQ techniques to screen for autoantibodies in serum from HBV-related cirrhosis patients and conducted detection with conformation-stabilizing ELISA in a cohort of 238 HBV-infected individuals and 49 health controls. Our results were validated in a retrospective cohort comprising 106 ACLF patients and further assessed through immunohistochemical analysis in liver tissues from an additional 10 ACLF cases. Results: Utilizing iTRAQ, we identified Argonaute1-3 autoantibodies (AGO-Abs) in this research. AGO2-Abs notably increased in cirrhosis, decompensation, and further in ACLF, unlike AGO1-Abs and AGO3-Abs. This reflects disease severity correlation. Logistic regression and COX models confirmed AGO2-Abs as independent prognostic indicators for decompensated liver cirrhosis (DLC) and ACLF. In the ROC analysis, AGO2-Abs showed significant diagnostic value for predicting 28- and 90-day mortality (AUROC = 0.853 and 0.854, respectively). Furthermore, combining AGO2-Abs with the Child-Pugh, MELD, and AARC scores significantly improved their predictive accuracy (P < 0.05). Kaplan-Meier analysis showed poorer survival for AGO2-Abs levels above 99.14mg/ml. These findings were supported by a retrospective validation cohort. Additionally, immunohistochemistry revealed band-like AGO2 expression in periportal liver areas, with AGO2-Abs levels correlating with total bilirubin, indicating a potential role in exacerbating liver damage through periportal functions. Conclusions: AGO2-Abs is a robust biomarker for predicting the mortality of patients with HBV-related ACLF. [ABSTRACT FROM AUTHOR]

Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone‐releasing hormone knockout (GHRH‐KO) female mice and their littermate controls. Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH‐KO mice, a well‐established model of enhanced longevity. While younger GHRH‐KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one‐third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH‐KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH‐KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH‐KO‐induced transcriptional changes. These findings provide the first evidence of disrupted ceramide metabolism in a long‐lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms influencing lifespan extension. [ABSTRACT FROM AUTHOR]

Background and Aims: The presence of steatosis in a donor liver and its relation to post‐transplantation outcomes are not well defined. This study evaluates the effect of the presence and severity of micro‐ and macro‐steatosis of a donor graft on post‐transplantation outcomes. Methods: The UNOS‐STAR registry (2005–2019) was used to select patients who received a liver transplant graft with hepatic steatosis. The study cohort was stratified by the presence of macro‐ or micro‐vesicular steatosis, and further stratified by histologic grade of steatosis. The primary endpoints of all‐cause mortality and graft failure were compared using sequential Cox regression analysis. Analysis of specific causes of mortality was further performed. Results: There were 9184 with no macro‐steatosis (control), 150 with grade 3 macro‐steatosis, 822 with grade 2 macro‐steatosis and 12 585 with grade 1 macro‐steatosis. There were 10 320 without micro‐steatosis (control), 478 with grade 3 micro‐steatosis, 1539 with grade 2 micro‐steatosis and 10 404 with grade 1 micro‐steatosis. There was no significant difference in all‐cause mortality or graft failure among recipients who received a donor organ with any evidence of macro‐ or micro‐steatosis, compared to those receiving non‐steatotic grafts. There was increased mortality due to cardiac arrest among recipients of a grade 2 macro‐steatosis donor organ. Conclusion: This study shows no significant difference in all‐cause mortality or graft failure among recipients who received a donor liver with any degree of micro‐ or macro‐steatosis. Further analysis identified increased mortality due to specific aetiologies among recipients receiving donor organs with varying grades of macro‐ and micro‐steatosis. [ABSTRACT FROM AUTHOR]

Aim/Introduction: Type 2 diabetes mellitus (T2DM) is one of the most frequent and widespread disease in the world.Obesity is the most significant predictor of T2DM, but the exact mechanism how obesity promotes T2DM remains unknown. Finding specific biomarkers to assist in diagnosing and treating patients with obese and T2DM is critical. Materials and Methods: We collected liver tissues from obesity patients with and without T2DM for proteomic sequencing and immunohistochemistry assay. Analysis Gene Ontology(GO) enrichment, Kyoto Encyclopedia of Genes and Genomes(KEGG), and protein interaction network (PPI) were performed on the parameters and data derived from the Tandem Mass Tags(TMT)-based proteomics analysis of liver tissues. Transcriptome data were downloaded from the Gene Expression Omnibus(GEO)website and genes that are deferentially expressed in both transcriptome and proteome were selected. Results: We identified 140 deferentially expressed proteins from proteomic sequencing. Six biomarkers were deferentially expressed in both proteome and transcriptome with consistent changes in direction. The protein–protein interaction (PPI) analysis suggested CMPK1, the expression with greatest difference, was the core protein among the six biomarkers. Immunohistochemistry validated CMPK1 was upregulated significantly in the liver tissues of T2DM patients. The correlation analysis revealed that the expression of CMPK1 was significantly associated with key molecules in T2DM-related pathways at both protein and transcriptome levels. Conclusion and Novelty: Our study showed CMPK1 was upregulated in the liver of T2DM patients and provides a possible new target for screening and diagnosing T2DM in patients with obese and a novel theoretical basis for the pathophysiological mechanism of obesity-related metabolic diseases. [ABSTRACT FROM AUTHOR]

Bile, a crucial fluid produced continuously by the liver, plays an essential role in digestion within the small intestine. Beyond its primary function in lipid digestion, bile also acts as a pathway for the elimination of various endogenous and exogenous substances. There have been limited studies focusing on interspecies differences. This study offers a comprehensive analysis of bile acid (BA) composition and its correlation with gene expression patterns across six different species, including mammals and poultry, through combining Liquid Chromatography-Mass Spectrometry (LC-MS) and transcriptome sequencing. The BA profiles revealed distinct metabolite clusters: D-glucuronic acid (GLCA) and glycochenodeoxycholic acid (GCDCA) were predominant in mammals, while taurolithocholic acid (TLCA) and T-alpha-MCA were prevalent in poultry, highlighting species-specific BA compositions. Differentially abundant metabolites, particularly GDCA, glycohyodeoxycholic acid (GHDCA) and taurodeoxycholic acid (TDCA) showed significant variations across species, with pigs showing the highest BA content. Transcriptome analysis of the liver and small intestine tissues of 56 cDNA libraries across the six species revealed distinct mRNA expression patterns. These patterns clustered samples into broad categories based on tissue type and phylogenetic relationships. Furthermore, the correlation between gene expression and BA content was examined, identifying the top 20 genes with significant associations. These genes potentially serve as biomarkers for BA regulation. [ABSTRACT FROM AUTHOR]

Bibliometric analysis of liver cancer research, particularly in immunotherapy, reveals crucial insights. The US leads in liver cancer mortality but ranks fifth globally. Scopus database analysis identified 2,349 papers, with the top 100 ranging from 127 to 4,959 citations. Notably, “Microenvironmental Regulation of Tumours Progression and Metastasis” in the Journal of Nature Medicine garnered the highest citations. Journals like the Journal of Hepatology, Hepatology, and Nature Reports Clinical Oncology contributed significantly. Understanding molecular mechanisms and prognostic indicators is paramount for advancing combination therapies.For better patient outcomes, research trends in liver cancer immunotherapy point to improved treatment protocols, knowledge of the tumor microenvironment, combining therapies, predicting disease course, international cooperation, sophisticated surgical techniques, early detection, oncolytic virotherapy, and patient-centered care. This research underscores immunotherapy’s pivotal role and encourages further exploration, offering valuable insights into liver cancer treatment trends. [ABSTRACT FROM AUTHOR]

Excessive body weight may disrupt hepatic enzymes that may be aggravated by obesity-related comorbidities. The current case-control study was designed to evaluate the extent of liver enzyme alteration in obesity-related metabolic disorders. Obese females with BMI ≥ 30 suffering from metabolic disorders were grouped according to existing co-morbidity and their hepatic enzymes were compared with non-obese healthy females. The resultant data was subjected to analysis of variance and mean difference in liver enzymes were calculated at P = 0.05. Analysis of variance indicated that obese diabetic and obese hypertensive females had almost 96% and 67% increase in the concentration of gamma-glutamyl transferase than control, respectively (P<0.0001). The obese females suffering from diabetes and hypertension exhibited nearly 54% enhancement in alanine transaminase level (P<0.0001) and a 17% increase in aspartate aminotransferase concentration (P = 0.0028). Obesity along with infertility decline liver enzyme production and a 31% significant decline in aspartate aminotransferase was observed while other enzyme concentrations were not significantly altered. Regression analysis was performed on the resultant data to understand the association between liver enzyme alteration and the development of metabolic diseases. Regression analysis indicated that obese diabetic and obese diabetic hypertensive women had 20% production of normal liver enzymes and 80% enzymes produced abnormally. Obese hypertensive and obese infertile females had only 5% and 6% normal production of liver enzymes, respectively. This research leads to the conclusion that the ability of the liver to function normally is reduced in obesity-related diabetes and hypertension. This may be due to inflamed and injured liver and poses a serious threat to developing fatty liver disease and ultimately liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive. Methods: In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation. Results: Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis. Conclusions: Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL. [ABSTRACT FROM AUTHOR]

Previous research has demonstrated the impact of postoperative phosphate levels on liver regeneration and outcomes after liver resection surgeries, a potential predictor for regenerative success and liver failure. However, little is known about the association between low preoperative serum phosphate levels and outcomes in liver resections. We performed a retrospective analysis of liver resections performed at our institution. Patients were categorized based on preoperative phosphate levels (low versus normal). Our primary outcome measure was posthepatectomy liver failure. A total of 265 cases met the study criteria. 71 patients (26.7%) had low preoperative phosphate levels. The incidence of posthepatectomy liver failure was higher in the low preoperative phosphate group (19.2% versus 12.4%). However, after propensity score matching, rates of posthepatectomy liver failure were similar between low and normal preoperative phosphate cohorts (13% versus 14%, P = 0.83). Low preoperative phosphate levels were not associated with worse postoperative outcomes in this study. Further studies are warranted to investigate this association and its relevance as a clinical prognostic factor for postoperative liver failure. [ABSTRACT FROM AUTHOR]

For liver volumetry, manual tracing on computed tomography (CT) images is time-consuming and operator dependent. To overcome these disadvantages, several three-dimensional simulation software programs have been developed; however, their efficacy has not fully been evaluated. Three physicians performed liver volumetry on preoperative CT images on 30 patients who underwent formal right hepatectomy, using manual tracing volumetry and two simulation software programs, SYNAPSE and syngo.via. The future liver remnant (FLR) was calculated using each method of volumetry. The primary endpoint was reproducibility and secondary outcomes were calculation time and learning curve. The mean FLR was significantly lower for manual volumetry than for SYNAPSE or syngo.via; there was no significant difference in mean FLR between the two software-based methods. Reproducibility was lower for the manual method than for the software-based methods. Mean calculation time was shortest for SYNAPSE. For the two physicians unfamiliar with the software, no obvious learning curve was observed for using SYNAPSE, whereas learning curves were observed for using syngo.via. Liver volumetry was more reproducible and faster with three-dimensional simulation software, especially SYNAPSE software, than with the conventional manual tracing method. Software can help even inexperienced physicians learn quickly how to perform liver volumetry. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors. Patients and Methods: 12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq. Results: Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response. Conclusions: In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI. [ABSTRACT FROM AUTHOR]

Brominated flame retardants (BFRs), commonly found in consumer products, have been identified as potential hazards to liver function. While the individual effects of specific BFRs are somewhat understood, there is limited evidence on how mixtures of these chemicals, especially when influenced by demographic factors, interact to affect liver function. This study utilized data from 10,828 participants aged 12 and above from the National Health and Nutrition Examination Survey (2005–2016) to investigate the associations between BFRs (both individually and in combinations) and biomarkers of liver injury. The study focused on how age, gender, and body mass index (BMI) modify modulate these effects. Multivariate linear regression, restricted cubic spline function, weighted quantile sum (WQS) regression, and quantile g-computation (qgcomp) models were used to analyze the linear, non-linear, and joint associations between BFR levels and liver function parameters. We found positive associations between the mixed BFRs index and AST, ALT, GGT, ALP, and TBIL levels and a negative association with ALB levels. PBDE28, PBDE47, and PBB153 consistently contributed to the top weight in both the WQS and qgcomp models. Most critically, the study demonstrated that the relationship between co-exposure to BFRs and liver function parameters was modified by age, gender, and BMI. Therefore, our study highlights the importance of considering demographic diversity in assessing the risk of BFR-induced liver damage and supports the implementation of tailored preventive and intervention strategies. [ABSTRACT FROM AUTHOR]

Heat stress (HS) induces various physiological disorders in poultry, negatively impacting feed intake, feed efficiency, and growth performance. Considering the documented anti-stress and growth-promoting benefits of monochromatic green light in poultry, we aimed to investigate its effects on cyclic chronic HS-induced oxidative stress (OS) and inflammation in geese. We established three treatment groups—geese exposed to white light (W), white light with HS treatment (WH), and green light with HS treatment (GH)—treated over a six-week period with daily HS sessions. The results revealed that cyclic chronic HS induced liver OS and inflammation, leading to hepatocellular injury and reduced growth performance and feed intake. In comparison, the growth performance of geese under green light significantly improved. Additionally, liver index, serum, liver malondialdehyde (MDA), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-α (TNF-α) levels were reduced. Serum total antioxidant capacity (T-AOC), liver catalase (CAT), and superoxide dismutase (SOD) activity were enhanced, reducing hepatic OS and inflammation. Liver transcriptomic analysis indicated that green light alleviates cyclic chronic HS-induced liver injury and promotes geese growth performance by suppressing NF-κB pathway activation. [ABSTRACT FROM AUTHOR]

Excessive alcohol intake leads to significant physiological complications, particularly alcoholic liver diseases (ALD). The extent of liver damage caused by ethanol correlates with increased oxidative stress and accumulation of lipids in the hepatic tissue. In this study, we investigated the defense properties of the aqueous extract of Perilla frutescens Briton Var. acuta Kudo (PF) on hepatic injury in chronically ethanol-treated mice. The mice were orally administered the water extract from PF for 4 weeks with ethanol treatment (3 g/kg. P.O.). The level of malondialdehyde (MDA) in the liver tissues was determined. A substantial increase in MDA generation was detected in the livers of mice subjected to ethanol exposure, whereas the administration of PF markedly reduced MDA levels in hepatic tissues. Additionally, histological analysis of the liver tissue was performed. Histopathological investigation revealed a significant reduction in hepatocellular necrosis in the PF-treated group. This study demonstrated that the aqueous extract of Perilla frutescens Briton Var. acuta Kudo (PF) attenuated chronic ethanol-induced liver injury by augmenting the antioxidant capacity of mice. These results can be utilized for the development of high-value-added products using PF. [ABSTRACT FROM AUTHOR]

Background: Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth. Methods: The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression. Results: CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT). Conclusions: CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the acute and long-term effects of nandrolone decanoate (ND) on fractional synthetic rates (FSR). Methods: Male C57BL/6 mice were randomized into ND (n = 20) or sham (n = 20) groups. ND injections (10 g⋅kg-1⋅wk-1) started at 7 months of ages and continued for 6 wk. Ten animals from each group were randomly separated and examined 1 wk following drug cessation. The remaining animals were examined at 16 months of age. Animals were injected IP with 1.5 mL of deuterated water 24 h before euthanasia. The kidney, liver, heart, gastrocnemius, and soleus were extracted. Samples were analyzed for deuterated alanine enrichment in the bound protein and intracellular fraction by liquid chromatography tandem mass spectrometry to measure estimated FSR (fraction/day (F/D)) of mixed tissue. Results: One-way ANOVA, with treatment and age as fixed factors, indicated that kidney FSR was greater (P = 0.027) in ND (0.41 ± 0.02 F/D) than sham (0.36 ± 0.014F/D) and higher (P = 0.003) in young (0.42 ± 0.2 F/D) than old (0.35 ± 0.01 F/D). Liver and heart FSR values were greater (P ≤ 0.001) in young (0.79 ± 0.06 F/D and 0.13 ± 0.01 F/D, respectively) compared with old (0.40 ± 0.01 F/D and 0.09 ± 0.01 F/D, respectively), but not between ND and sham. Gastrocnemius FSR was (P ≤ 0.001) greater in young (0.06 ± 0.01 F/D) compared with old (0.03 ± 0.002 F/D), and greater (P = 0.006) in ND (0.05 ± 0.01 F/D) compared with sham (0.04 ± 0.003 F/D). Soleus FSR rates were greater (P = 0.050) in young (0.13 ± 0.01 F/D) compared with old (0.11 ± 0.003 F/D), but not between ND (0.12 ± 0.01 F/D) and sham (0.12 ± 0.01 F/D). Old animals who had received ND displayed elevated FSR in the gastrocnemius (P = 0.054) and soleus (P = 0.024). Conclusions: ND use in young adult animals appeared to maintain long-term elevations in FSR in muscle during aging. [ABSTRACT FROM AUTHOR]

• Maternal copper deficiency induced growth retardation in offspring. • Maternal copper deficiency caused cardiac dysfunction and liver injury in offspring. • Autophagy is activated by copper deficiency in offspring. Maternal nutritional deficiencies during pregnancy result in birth defects and elevate the risk of cardiovascular diseases and metabolic diseases. Accumulating evidence suggests that deficiency of copper, a fundamental trace element involved in several pivotal physiological processes, promotes the onset of multiple diseases, notably heart and liver diseases. Yet, exploration into the effects of maternal copper deficiency (CuD) on offspring is still limited. In this study, we hypothesized that maternal CuD induced cardiomyopathy and liver injury in offspring through the activation of autophagy. We established a maternal CuD mouse model by feeding pregnant C57BL/6 mice with a CuD diet until the end of the experiment. Echocardiography, histological analysis, western blotting, and quantitative polymerase chain reaction were performed on offspring at postnatal day 14. We found that maternal CuD caused growth retardation and early postnatal death in the offspring. Furthermore, our results revealed that CuD induced cardiac systolic dysfunction, cardiac hypertrophy, hepatic steatosis, and liver injury. Moreover, higher expression of LC3 and lower expression of p62 were observed in the heart tissues and liver tissues of CuD mice compared with the control group, indicating that CuD induced autophagy activation. In conclusion, maternal CuD caused severely deleterious effects on the heart and liver of the offspring via activating autophagy. To explore the effect of dietary maternal CuD on offspring, we established an animal model by feeding pregnant mice with a CuD diet. We found that CuD caused cardiac systolic dysfunction and liver injury. Moreover, we presented the increased LC3 and decreased p62 in CuD mouse heart tissues and liver tissues. These results indicate that CuD causes systolic dysfunction and hepatic steatosis in offspring, which is associated with activation of autophagy. Abbreviations: CuA, copper adequate; CuD, copper deficiency. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of this study is to report the risk factors of severe statin induced liver injury (SILI). From the database of Shandong ADR Monitoring Center and Outpatients and inpatients in our hospital, SILI cases reported from 2013 to 2021 were extracted and screened. The diagnostic criteria of SILI, the inclusion and exclusion criteria of severe and general SILI were established separately. After the SILI cases were selected and confirmed, the socio-demographic and clinical characteristics were collected. Single factor chi-square test and multi-factor unconditional logistic regression analysis were used to analyze the influencing factors of severe SILI. From 1391 reported cases, 1211 met SILI diagnostic criteria, of which 157 were severe SILI and 964 were general SILI. Univariate analysis showed that age, drug combination, statin category were the influencing factors of severe SILI (p<0.1). Multivariate logistic analysis showed that drug combination and statin category were the influencing factors of severe SILI (p<0.05). Atorvastatin caused the most serious SILI, and its risk is 1.77 times higher than rosuvastatin. The serious SILI risk of drug combination was 2.08 times higher than statin alone. The patient with these factors should be monitored intensively during clinical treatment, to ensure their medication safety. [ABSTRACT FROM AUTHOR]

Sex inequities in liver transplantation (LT) have been documented in several, mostly USbased, studies. Our aim was to describe sex-related differences in access to LT in a system with short waiting times. All adult patients registered in the RETH-Spanish Liver Transplant Registry (2000--2022) for LT were included. Baseline demographics, presence of hepatocellular carcinoma, cause and severity of liver disease, time on the waiting list (WL), access to transplantation, and reasons for removal from the WL were assessed. 14,385 patients were analysed (77% men, 56.2 ± 8.7 years). Model for end-stage liver disease (MELD) score was reported for 5,475 patients (mean value: 16.6 ± 5.7). Women were less likely to receive a transplant than men (OR 0.78, 95% CI 0.63, 0.97) with a trend to a higher risk of exclusion for deterioration (HR 1.17, 95% CI 0.99, 1.38), despite similar disease severity. Women waited longer on the WL (198.6 ± 338.9 vs. 173.3 ± 285.5 days, p < 0.001). Recently, women's risk of dropout has reduced, concomitantly with shorter WL times. Even in countries with short waiting times, women are disadvantaged in LT. Policies directed at optimizing the whole LT network should be encouraged to guarantee a fair and equal access of all patients to this life saving resource. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is one of the most prescribed drugs for epilepsy. Extended use of VPA not only induces hepatotoxicity but also impairs the cognitive functions. Metformin has been reported to prevent epileptogenesis and enhance memory. To counter the VPA-induced adverse events, it is hypothesized that combination of sub-therapeutic dose of VPA with metformin may attenuate the toxicity stemming from the therapeutic dose of VPA. Pentylenetetrazole (PTZ)-induced kindling model of epilepsy in mice was used to assess the combined effects of sub-therapeutic dose of VPA (100 mg/kg) and metformin (200 mg/kg). The memory performance was analyzed by passive avoidance test, while alkaline comet assay was used to determine genotoxicity. Histopathological examination and serum biochemical analysis was performed to determine hepatotoxicity. Results showed that combination dose of VPA with metformin reduced seizure scores. VPA (300 mg/kg) administered as a single agent did not enhance memory impairment caused by PTZ, however, combination of sub-therapeutic dose of VPA with metformin enhanced memory function. Furthermore, in alkaline comet assay, combination therapy demonstrated reduced genotoxicity compared to the VPA 300 mg/kg. Histopathological examination of liver and analysis of serum hepatic enzymes revealed that combination therapy (VPA + metformin) reversed the toxicity as seen in case of PTZ or VPA (300 mg/kg) treated animals with no other treatment given. Based on the study data, it is concluded that the combination of sub-therapeutic dose of VPA with metformin might be used for epileptic seizures. This will prevent the hepatotoxicity and enhanced memory functions as compared to the VPA given as a single agent therapy. [ABSTRACT FROM AUTHOR]

The aqueous extract of Annona muricata L. leaves was thoroughly analyzed using the UPLC-MS/MS, in addition to a new approach of examination of the extract's impact on cancer of EAC(Ehrlich ascites carcinoma) in albino male mice. The aim was to investigate the diversity of the phytochemical constituents of the aqueous leaf capsule extract and their impacts on EAC as anticancer agents. The UPLC-ESI-MS/MS screening resulted in 410 tentatively identified metabolites. Among them, 384 compounds were tentatively identified in a previous study, besides a number of 26 compounds belonging to acetogenins, phenolics, flavonoids, alkaloids, and other miscellaneous compounds, which were exclusively identified in the aqueous extract of the leaf capsule. Interestingly, a new compound was tentatively characterized as galloyl-quinic acid-rutinoside. This study also demonstrated that treating EAC mice with an extract from A. muricata leaves significantly improved the abnormalities in the expression of pro-apoptotic (Bax and caspase-3) and anti-apoptotic (Bcl-2) genes. Furthermore, the extract showed good protection against induced Ehrlich hepatocarcinoma, according to the microscopical, histological, and immune-histochemical analyses of the liver tissues and tumor mass. [ABSTRACT FROM AUTHOR]

Since the 2000s, an increasing number of new psychoactive substances have appeared on the illicit drug market. β-Keto-arylcyclohexylamine compounds play important pharmacological roles in anesthesia; however, because these new psychoactive substances have rapidly increasing illicit recreational use, the lack of detailed toxicity data are of particular concern. Therefore, analysis of their metabolites can help forensic personnel provide references and suggestions on whether a suspect has taken an illicit new psychoactive β-keto-arylcyclohexylamine. The present study investigated the in vitro and in vivo metabolism and metabolites of three β-keto-arylcyclohexylamines: deschloro- N -ethyl-ketamine, fluoro- N -ethyl-ketamine and bromoketamine. In vitro and in vivo models were established using zebrafish and human liver microsomes for analysis of Phase I and Phase II metabolites by liquid chromatography–high-resolution mass spectrometry. Altogether, 49 metabolites were identified. The results were applied for the subject urine samples of known fluoro- N -ethyl-ketamine consumer screen analysis in forensic cases. Hydroxy-deschloro- N -ethyl-ketamine, hydroxy-fluoro- N -ethyl-ketamine and hydroxy-bromoketamine were recommended as potential biomarkers for documenting intake in clinical and forensic cases. [ABSTRACT FROM AUTHOR]

Machine learning (ML) has been successfully implemented for classification tasks (e.g., cancer diagnosis). ML performance for more challenging predictions is largely unexplored. This study's objective was to compare machine learning vs. expert-informed predictions for surgical outcome in patients undergoing major liver surgery. Single tertiary center data on preoperative parameters and postoperative complications for elective hepatic surgery patients were included (2008–2021). Expert-informed prediction models were established on 14 parameters identified by two expert liver surgeons to impact on postoperative outcome. ML models used all available preoperative patient variables (n = 62). Model performance was compared for predicting 3-month postoperative overall morbidity. Temporal validation and additional analysis in major liver resection patients were conducted. 889 patients included. Expert-informed models showed low average bias (2–5 CCI points) with high over/underprediction. ML models performed similarly: average prediction 5–10 points higher than observed CCI values with high variability (95% CI −30 to 50). No performance improvement for major liver surgery patients. No clinical relevance in the application of ML for predicting postoperative overall morbidity was found. Despite being a novel hype, ML has the potential for application in clinical practice. However, at this stage it does not replace established approaches of prediction modelling. [ABSTRACT FROM AUTHOR]

Iridovirus poses a substantial threat to global aquaculture due to its high mortality rate; however, the molecular mechanisms underpinning its pathogenesis are not well elucidated. Here, a multi-omics approach was applied to groupers infected with Singapore grouper iridovirus (SGIV), focusing on the roles of key metabolites. Results showed that SGIV induced obvious histopathological damage and changes in metabolic enzymes within the liver. Furthermore, SGIV significantly reduced the contents of lipid droplets, triglycerides, cholesterol, and lipoproteins. Metabolomic analysis indicated that the altered metabolites were enriched in 19 pathways, with a notable down-regulation of lipid metabolites such as glycerophosphates and alpha-linolenic acid (ALA), consistent with disturbed lipid homeostasis in the liver. Integration of transcriptomic and metabolomic data revealed that the top enriched pathways were related to cell growth and death and nucleotide, carbohydrate, amino acid, and lipid metabolism, supporting the conclusion that SGIV infection induced liver metabolic reprogramming. Further integrative transcriptomic and proteomic analysis indicated that SGIV infection activated crucial molecular events in a phagosome-immune depression-metabolism dysregulation-necrosis signaling cascade. Of note, integrative multi-omics analysis demonstrated the consumption of ALA and linoleic acid (LA) metabolites, and the accumulation of L-glutamic acid (GA), accompanied by alterations in immune, inflammation, and cell death-related genes. Further experimental data showed that ALA, but not GA, suppressed SGIV replication by activating antioxidant and anti-inflammatory responses in the host. Collectively, these findings provide a comprehensive resource for understanding host response dynamics during fish iridovirus infection and highlight the antiviral potential of ALA in the prevention and treatment of iridoviral diseases. [ABSTRACT FROM AUTHOR]

Purpose: Liver T1 mapping techniques typically require long breath holds or long scan time in free‐breathing, need correction for B1+ inhomogeneities and process composite (water and fat) signals. The purpose of this work is to accelerate the multi‐slice acquisition of liver water selective T1 (wT1) mapping in a single breath hold, improving the k‐space sampling efficiency. Methods: The proposed continuous inversion‐recovery (IR) Look‐Locker methodology combines a single‐shot gradient echo spiral readout, Dixon processing and a dictionary‐based analysis for liver wT1 mapping at 3 T. The sequence parameters were adapted to obtain short scan times. The influence of fat, B1+ inhomogeneities and TE on the estimation of T1 was first assessed using simulations. The proposed method was then validated in a phantom and in 10 volunteers, comparing it with MRS and the modified Look‐Locker inversion‐recovery (MOLLI) method. Finally, the clinical feasibility was investigated by comparing wT1 maps with clinical scans in nine patients. Results: The phantom results are in good agreement with MRS. The proposed method encodes the IR‐curve for the liver wT1 estimation, is minimally sensitive to B1+ inhomogeneities and acquires one slice in 1.2 s. The volunteer results confirmed the multi‐slice capability of the proposed method, acquiring nine slices in a breath hold of 11 s. The present work shows robustness to B1+ inhomogeneities (wT1,NoB1+=1.07wT1,B1+−45.63,R2=0.99), good repeatability (wT1,2°=1.0wT1,1°−2.14,R2=0.96) and is in better agreement with MRS (wT1=0.92wT1MRS+103.28,R2=0.38) than is MOLLI (wT1MOLLI=0.76wT1MRS+254.43,R2=0.44). The wT1 maps in patients captured diverse lesions, thus showing their clinical feasibility. Conclusion: A single‐shot spiral acquisition can be combined with a continuous IR Look‐Locker method to perform rapid repeatable multi‐slice liver water T1 mapping at a rate of 1.2 s per slice without a B1+ map. The proposed method is suitable for nine‐slice liver clinical applications acquired in a single breath hold of 11 s. [ABSTRACT FROM AUTHOR]

Background/Aim: Advancements in genetic analysis technologies have led to establishment of molecular classifications systems for primary liver cancers. The correlation between pathological morphology and genetic mutations in hepatocellular carcinoma (HCC) is becoming increasingly evident. To construct appropriate experimental models, it is crucial to select cell lines based on their morphology and genetic mutations. In this study, we conducted comprehensive genetic analyses of primary liver cancer cell lines and examined their correlations with morphology. Materials and Methods: Thirteen primary liver cancer cell lines established in our Department were investigated. Eleven cell lines were HCC cell lines, whereas 2 were combined hepatocellular-cholangiocarcinoma (CHC) cell line characteristics. Whole exome sequencing and fusion gene analyses were conducted using a next generation sequencing platform. We also examined correlations between cell mutations and morphological findings and conducted experiments to clarify the association between morphological findings and genetic alterations. Results: Mutations in TP53, HMCN1, PCLO, HYDIN, APOB, and EYS were found in 11, 5, 4, 4, 3, and 3 cell lines, respectively. CTNNB1 mutation was not identified in any cell line. The original tumor of four cell lines (KYN-1, KYN-2, KYN-3, and HAK-6) showed morphologically macrotrabecular massive patterns and these cell lines harbor TP53 mutations. Two cell lines (KYN-2 and KMCH-2) showed an extremely high tumor mutation burden. These two cell lines possess ultra-mutations associated with DNA repair and/or DNA polymerase. Conclusion: The study identified correlations between morphological findings and genetic mutations in several HCC cell lines. Cell lines with unique genetic mutations were found. This information will be a valuable tool for the selection of suitable experimental models in HCC research. [ABSTRACT FROM AUTHOR]

Background: Wailitst lost is an critical issue and we investigated the long-term effect of insufficient liver functional reserve at liver transplantation evaluation on waitlist outcomes in patients with hepatocellular carcinoma (HCC). Methods: Clinical data of patients with HCC waitlisted for liver transplantation were retrospectively collected from a single hospital cohort during the period from 2014 to 2021. Parameters of liver reserve, including cirrhosis, Child–Pugh grade, and Model for End-Stage Liver Disease (MELD) scores, were analyzed for patient survival, after adjustment for tumor factors. Results: Of 292 eligible patients, 94.2% had cirrhosis, 55.8% had Child–Pugh grade B or C, and the median MELD score was 13.2. The median follow-up time was 2.2 years, with a dropout rate of 62.7%. Eighty-nine candidates (30.5%) eventually received liver transplant, including 67 from live donors. The estimated 1-year mortality rate reached 40.6% in 203 patients who remained on the waitlist without receiving a transplant, of whom 143 died. Most deaths were attributed to liver failure (37.1%) and cancer death (35.7%). After we adjusted for tumor confounders, including alpha fetoprotein, primary HCC stage, tumor number at evaluation, and sequential cancer treatment before and while waiting, hazard ratios (HRs) for patient survival were 1.69 (95% confidence interval, 1.18–2.41) for cirrhotic stage B or C, 1.07 (1.04–1.10) for MELD scores, and 1.14 (1.04–1.25) for tumor size at transplant evaluation. Transplantation was a protective disease modifier with adjusted HR 0.22 (0.14–0.33). Conclusion: Insufficient liver functional reserve poses more risk than expected to liver transplant waitlist outcomes with HCC. [ABSTRACT FROM AUTHOR]