Liver Research最新文献

Acute-on-chronic liver failure (ACLF) can be cured by liver transplantation; however, perioperative complications still affect posttransplant outcomes. In recent years, early rehabilitation for critical illness, liver disease, and surgery have significantly improved organ reserve function, surgery tolerance, and postoperative quality of life. They could also be applied in the perioperative period of liver transplantation in patients with ACLF. Therefore, the Transplantation Immunology Committee of Branch of Organ Transplantation Physician of Chinese Medical Doctor Association, the Organ Transplant Committee of China Association Rehabilitation Medicine, and the Guangdong Medical Doctor Association of Organ Transplantation conducted a comprehensive review of rehabilitation in end-stage liver disease, critical illness and surgical patients by summarizing current evidence and best clinical practices and proposed a practice consensus on evaluation of cardiopulmonary and physical function, rehabilitation or physiotherapies, as well as the safety concerns in perioperative liver transplant recipients. It will be a valuable resource for hepatologists, transplant surgeons, and intensivists as they care for ACLF patients during transplantation.

As evolutionarily conserved signals, roof plate-specific spondins (R-spondins; RSPOs) are a family with four members (RSPO1–4) exerting distinctly different functions. RSPOs have five receptors and correlate with different signaling pathways through these receptors and then perform various functions. Moreover, their best-known molecular function is the capacity to enhance WNT signaling pathways, which play critical roles in several processes. A recent study shows that RSPOs not only potentiate the WNT/beta (β)-catenin signaling pathway but are also involved in the WNT/planar cell polarity signaling pathway. RSPOs influence liver homeostasis and the development of multiple liver diseases. RSPO1 increases cell proliferation, protects hepatocytes from injury, improves liver regenerative potential, and affects liver metabolic zonation. RSPO2 not only regulates proliferation-associated genes and promotes differentiation in the liver but also participates in liver fibrosis through the WNT/β-catenin signaling pathway. RSPO3 is a key determinant of proper liver function, such as promoting hepatocyte regeneration and maintaining liver zonation. RSPO3 is upregulated in liver fibrosis and livers of patients with non-alcoholic steatohepatitis. Besides, RSPO2 and RSPO3 are confirmed as oncogenes and involved in the occurrence of liver cancer. The role of RSPO4 in the liver remains unclear. In this review, the structural and biochemical properties of RSPOs and their receptors and their roles in liver homeostasis and disease are summarized.

Hepatocellular carcinoma (HCC), a typical inflammatory-related cancer, mainly occurs in patients with chronic liver diseases. Moreover, the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups. The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment (TME) into one with strong immunosuppression, facilitating the immune escape of HCC cells. Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes (e.g., proteins and nucleic acids) for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming, ultimately creating a tumor-friendly microenvironment. Characterized by several intrinsic attributes, such as good stability (bilayer-like structure) and high biocompatibility (cell secretion), exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs, thus effectively triggering the HCC cell elimination by the immune system. This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.

Objectives

The difficulties in the early detection consequent to the lack of sensitive biomarkers render patients with cholangiocarcinoma (CCA) to have poor outcomes. Recently, sensitive and specific volatile organic compounds (VOCs) were identified in several cancers. However, the VOC profiles in CCA are not well-studied. Thus, we investigated the VOC profiles in exhaled breath of CCA patients and controls.

Methods

We prospectively collected exhaled breath samples from 30 consecutive patients newly diagnosed with CCA and 30 controls who did not have CCA (seven had benign biliary strictures and 23 had other medical conditions). Exhaled VOCs were identified using gas chromatography mass spectrometry Triple Quadrupoles system. Analysis of the significant differences in VOCs between cases and controls was conducted using supervised multivariate regression analysis. Further validation was performed for these VOCs in another cohort of 18 CCA patients and 22 controls.

Results

Levels of six compounds were significantly different between CCA patients and controls, namely, acetone, isopropyl alcohol, dimethyl sulfide, 1,4-pentadiene, allyl methyl sulfide, and N,N-dimethylacetamide. Acetone and dimethyl sulfide were independently associated with CCA as demonstrated in the multivariate analysis. Using the cut-off value of 8.59 × 10⁷ arbitrary unit (AU), acetone had a sensitivity and specificity of 82.1% and 75.8%, respectively, with an area under the receiving operator curve (AUROC) of 0.85 for the CCA diagnosis. Acetone level was also significantly different between cases and controls in the validation cohort. Using the same cut-off value, the sensitivity, specificity, and AUROC was 59.1%, 66.7%, and 0.85, respectively.

Conclusion

Breath analysis may potentially be useful for CCA diagnosis. A cohort of patients with early-stage CCA in further studies is needed to confirm the ability of exhaled VOCs for the early detection of CCA.

Alcohol use disorder (AUD) is a worldwide problem for individuals of varying ages and backgrounds and is associated with the underlying cause of alcoholic liver disease, liver cirrhosis, liver cancer, or many other common diseases and health conditions. Existing treatments such as cognitive behavioral therapy (CBT) have been demonstrated as an evidence-based treatment to aid individuals struggling with AUD. However, these treatments have excessive costs and time demand with trained experts. In this paper, we examine the efficacy and long-term impacts of digitally delivered CBT and other online telehealth tools and apps for AUD patients. Results show the effectiveness in the ability of digitally delivered CBT to decrease alcohol use in AUD patients. The additional use of online technologies and smartphone apps for post-CBT care demonstrates that such computer-aided apps could have long-term effects when it is continually employed, which opens the door for AUD patients who were not seeking treatment elsewhere. Further longitudinal examination research is needed to evaluate the lasting effects in liver health and other chronic diseases associated with digitally delivered alcohol reduction for AUD patients.

Background

Dynactin (DCTN) can activate cytoplasmic dynein and drive intracellular organelle transport containing six family members (DCTN1 to DCTN6). The DCTN family has been studied as cancer-related genes or biomarkers in various cancers. Nevertheless, in hepatocellular carcinoma (HCC), the functions and prognostic roles of the DCTN family have been unexplored.

Methods

We evaluated the diagnostic and survival effects of DCTN subunits in HCC through bioinformatics analysis and validated the results of bioinformatics by our data to address this problem.

Results

The results of bioinformatics analysis found that DCTN2 was a significant prognostic factor in HCC, and high-level DCTN2 can predict poor patient survival in HCC. Cox regression analysis also suggested that DCTN2 (hazard ratio = 1.748, 95% confidence interval 1.190–2.568, P = 0.004) is an independent prognostic factor for patient survival. Western blot and quantitative reverse transcription-polymerase chain reaction assays confirmed that the protein and mRNA expression levels of DCTN2 were upregulated in HCC cell lines. The proliferation, invasion, and migration were decreased and cell apoptosis was enhanced after DCTN2 was knocked down in Huh7 and Hep3B cells. DCTN2 promoted the cell cycle progression through regulating the expression of cell cycle regulatory proteins cyclin-dependent kinase 4, Cyclin D1, and p21.

Conclusions

We propose that DCTN2 can serve as a prognostic marker for HCC. DCTN2 acts as an oncogene and promotes the cell cycle progression through the G1/S phase-related signaling pathway.

Background and aims

The sodium taurocholate co-transporting polypeptide (NTCP) is a functional receptor for the hepatitis B virus (HBV), and it is critical for bile acid homeostasis. Previous studies of the association between the S267F variant and chronic hepatitis B (CHB) have generated conflicting results. This study analyzed the correlation between the NTCP S267F variant and CHB susceptibility by using a large sample of participants classified by gender and age, and this study also analyzed the relationship between this variant and the level of serum total bile acids.

Methods

In total, 543 patients with CHB and 429 control subjects underwent S267F variant genotyping using SNaPshot technology. Logistic regression was utilized to evaluate any association of the NTCP S267F variant with CHB susceptibility.

Results

The S267F variant was inversely correlated with the risk of chronic HBV infection in both the dominant model (GG genotype vs. AG genotype: odds ratio (OR) = 0.46, 95% confidence interval (CI) 0.30–0.71, P < 0.001) and the allele model (G allele vs. A allele: OR = 0.50, 95% CI 0.33–0.76, P = 0.001), and this correlation was not affected by gender and age stratification. The carriers of the heterozygous NTCP variant exhibited higher total bile acids levels than the carriers of wild-type NTCP, regardless of whether they were control subjects or patients with CHB. Heterozygous carriers exhibited reduced hepatitis B e antigen (HBeAg)-positivity rates and had lower ALT, AST, and lg DNA concentrations compared with wild-type carriers in patients with CHB.

Conclusions

The S267F variant of NTCP is a protective factor that reduces the risk of chronic HBV infection and exhibits a higher total bile acids level. Patients with CHB who carry this variant may have a better prognosis than those carrying wild-type NTCP.

Background and aims

Alcoholic liver disease (ALD) is an important and growing cause for the development of chronic liver diseases in the world. Bile acid (BA) levels are increased in patients with ALD and dysregulation of BA homeostasis worsens ALD. BA synthesis is critically regulated by fibroblast growth factor (FGF)15 in mice and FGF19 in humans. FGF15/19 are mainly produced in the ileum and their main function is to suppress BA synthesis in the liver through the activation of fibroblast growth factor receptor 4 (FGFR4) on hepatocytes. The effects of intestine-specific Fgf15 deficiency on the development of ALD were determined in the current study.

Methods

Enterocyte-specific Fgf15 knockout mice (Fgf15^int−/−) and the established mouse model by chronic and binge ethanol feeding (NIAAA model) were adapted in this study.

Results

The Fgf15^int−/− mice had increased BA pool size, consistent with negative effects of FGF15-FGFR4 signaling on BA synthesis. There were not obviously physical and hepatic histological abnormalities presented in Fgf15^int−/− mice compared to wild-type mice. Following alcohol treatment, the Fgf15^int−/− mice exhibited a higher degree of liver injury, increased hepatic expression of Cd14, a receptor for lipopolysaccharide expressed in the liver, and increased hepatic lipid levels. We did not observe alterations in the levels of fibrosis in the liver or expression of genes involved in hepatic fibrosis, regardless of genotypes or following the alcohol treatment.

Conclusions

FGF15 may prevent hepatic steatosis in the development of ALD in mice, and maintaining FGF19/FGFR4 signaling may be critical in the prevention and/or treatment of ALD in humans in the future.

Immune checkpoint inhibitors are generally contraindicated for post-transplant patients. However, we report two patients with metastatic hepatocellular carcinoma (HCC) treated with camrelizumab (SHR-1210), an anti-programmed cell death 1 (PD-1) agent, after liver transplant. Before undergoing immunotherapy, both patients underwent liver allograft biopsy and obtained negative PD-L1 expression in tumor and liver graft specimens by immunohistochemistry. Then, camrelizumab (200 mg) was administered once every 3 weeks. During immunotherapy, the targeted therapy was continued, and the immunosuppression regimen was adjusted to a low-dose level. No graft rejection or other severe adverse reactions were observed. The disease remained stable (SD, mRECIST) for 3 months in one patient and 10 months in the other. Therefore, camrelizumab may have safety and potential benefits in advanced HCC after liver transplant.