ASSOCIATE EDITORS Frank A. Anania, Atlanta, GA Jorge A. Bezerra, Cincinnati, OH Raymond T. Chung, Boston, MA Eithan Galun, Jerusalem, Israel Guadalupe Garcia-Tsao, New Haven, CT Stephen A. Harrison, Fort Sam Houston, TX Brett Lindenbach, New Haven, CT Jacquelyn Maher, San Francisco, CA Wajahat Mehal, New Haven, CT Lola M. Reid, Chapel Hill, NC Mario Strazzabosco, New Haven, CT Norah Terrault, San Francisco, CA Snorri S. Thorgeirsson, Bethesda, MD Michael Trauner, Vienna, Austria

Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

Incidence of hepatocellular carcinoma (HCC) is on the rise due to the prevalence of chronic hepatitis and cirrhosis. Although there are surgical and chemotherapy treatment avenues the mortality rate of HCC remains high. Immunotherapy is currently the new frontier of cancer treatment and the immunobiology of HCC is emerging as an area for further exploration. The tumor microenvironment coexists and interacts with various immune cells to sustain the growth of HCC. Thus, immunosuppressive cells play an important role in the anti-tumor immune response. This review will discuss the current concepts of immunosuppressive cells, including tumor-associated macrophages, marrow-derived suppressor cells, tumor-associated neutrophils, cancer-associated fibroblasts, and regulatory T cell interactions to actively promote tumorigenesis. It further elaborates on current treatment modalities and future areas of exploration.

/pdf/current-perspectives-on-the-immunosuppressive-tumor-4miibvlfu1.pdf

Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities.

Immunotherapy for hepatocellular carcinoma.

Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investigations revealed that TXNDC12 promoted metastasis through upregulation of the ZEB1-mediated epithelial-mesenchymal transition (EMT) process. We subsequently showed that TXNDC12 overexpression stimulated the nuclear translocation and activation of β-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with β-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and β-catenin as well as for TXNDC12-mediated β-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear β-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate β-catenin via protein-protein interaction and promote ZEB1-mediated EMT and HCC metastasis.

/pdf/txndc12-promotes-emt-and-metastasis-of-hepatocellular-3v7s451o0o.pdf

TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin.

Fibrinogen-like protein 1 (FGL1)—Lymphocyte activating gene 3 (LAG-3) pathway is a promising immunotherapeutic target and has synergistic effect with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1). However, the prognostic significance of FGL1-LAG-3 pathway and the correlation with PD-L1 in hepatocellular carcinoma (HCC) remain unknown. The levels of LAG-3, FGL1, PD-L1 and cytotoxic T (CD8+T) cells in 143 HCC patients were assessed by multiplex immunofluorescence. Associations between the marker’s expression and clinical significances were studied. We found FGL1 and LAG-3 densities were elevated while PD-L1 and CD8 were decreased in HCC tissues compared to adjacent normal liver tissues. High levels of FGL1 were strongly associated with high densities of LAG-3+cells but not PD-L1. CD8+ T cells densities had positive correlation with PD-L1 levels and negative association with FGL1 expression. Elevated densities of LAG-3+cells and low levels of CD8+ T cells were correlated with poor disease outcome. Moreover, LAG-3+cells deteriorated patient stratification based on the abundance of CD8+ T cells. Patients with positive PD-L1 expression on tumor cells (PD-L1 TC+) tended to have an improved survival than that with negative PD-L1 expression on tumor cells (PD-L1 TC−). Furthermore, PD-L1 TC− in combination with high densities of LAG-3+cells showed the worst prognosis, and PD-L1 TC+ patients with low densities of LAG-3+cells had the best prognosis. LAG-3, FGL1, PD-L1 and CD8 have distinct tissue distribution and relationships with each other. High levels of LAG-3+cells and CD8+ T cells represent unfavorable and favorable prognostic biomarkers for HCC respectively.

/pdf/expression-and-clinical-significance-of-lag-3-fgl1-pd-l1-and-1hcxoo3w5w.pdf

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis.

Nicotinamide (Nam) has recently been characterized as an agent for tissue regeneration due to the observed pro‑proliferation effects. However, the effect of Nam on liver regeneration remains undetermined. In the present study, the potency of Nam as a regimen to promote liver regeneration and restore liver function was evaluated following partial hepatectomy (PH) on C57BL/6 mice. Ki‑67 immunohistochemical and cell cycle analyses demonstrated that exogenous Nam supplementation promoted the proliferation of hepatocytes and accelerated the recovery of liver tissue. The addition of Nam protected liver function following PH, as evidenced by hematoxylin and eosin staining of liver tissue morphology and measurement of serum liver injury markers. Notably, immunoblotting results revealed that the expression and activity of NAD‑dependent protein deacetylase sirtuin‑1 (SIRT1) were significantly upregulated following treatment with Nam, suggesting that Nam may promote liver regeneration through activation of SIRT1. The present study demonstrated that Nam regulated the process of liver regeneration and improved liver function by activating SIRT1, suggesting that Nam has the potency to be used for promoting liver regeneration following surgical resection.

/pdf/nicotinamide-induces-liver-regeneration-and-improves-liver-ui535foidb.pdf

Nicotinamide induces liver regeneration and improves liver function by activating SIRT1

AIMS
To explore the prevalence and potential facilitators and inhibitors of compassion fatigue and compassion satisfaction among Chinese palliative care nurses.


BACKGROUND
Nurses with compassion fatigue may suffer from health-related problems, causing decreased work efficiency and quality of care. Palliative care nurses are especially at risk of compassion fatigue due to close contact with terminal patients.


METHODS
A province-wide cross-sectional survey using convenience sampling was conducted among 318 palliative care nurses at 25 hospitals and healthcare institutions in Sichuan Province, China. Data were collected using demographic questionnaire and five scales: Professional Quality of Life Scale, General Self-Efficacy Scale, Perceived Social Support Scale, Simplified Coping Style Questionnaire, and Connor-Davison Resilience Scale. Data analyses including descriptive statistics, t-test, one-way ANOVA, simple linear regression, and multiple linear regression.


RESULTS
Mean scores (SD) for burnout, secondary traumatic stress, and compassion satisfaction were 25.42 (4.75), 26.08 (5.72), and 35.67 (5.77), respectively. Related factors predicted 40.30%, 27.10%, and 35.4% of the variance in the model of burnout, secondary traumatic stress, and compassion satisfaction, respectively (all P<0.001).


CONCLUSIONS
The levels of burnout and secondary traumatic stress among Chinese palliative care nurses were higher than those among other types of nurses. Social support, resilience, positive coping, family recognition of work, and income satisfaction are inhibitors of compassion fatigue among palliative care nurses. Implications for Nursing Management Nursing administrators and educators should consider providing effective and targeted strategies (e.g. ongoing training and psychological interventions) to decrease compassion fatigue among palliative care nurses based on the cultural and ethical settings.

Compassion fatigue and compassion satisfaction among Chinese palliative care nurses: A province-wide cross-sectional survey.

Background:
MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration.


Methods:
The Sprague–Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA.


Results:
Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle.


Conclusion:
Exosomal miR-10a might accelerate liver regeneration through downregulation of EphA4.


Key words: 
Cell Cycle; EphA4; Liver Regeneration; Microarray; miR-10a

Exosomal MicroRNA-10a Is Associated with Liver Regeneration in Rats through Downregulation of EphA4.

Immunotherapy's effect against hepatocellular carcinoma (HCC) is hampered by immunosuppressive mechanisms in the tumor microenvironment. We assessed the clinicopathologic and biologic relevance of OX40, a costimulatory molecular expressed by regulatory T cells (Tregs), in HCC. We analyzed the immunohistochemistry data of 316 patients treated at West China Hospital (WCH) and the RNA sequencing data of 370 patients in The Cancer Genome Atlas (TCGA) to determine the clinicopathologic significance of OX40 in HCC. We also assessed associations between OX40 and multiple immune-related markers. Using the TCGA data, we further characterized the transcriptome, immune cell functions, and mutation signature related to OX40. We found that OX40 expression was higher in HCC than in adjacent liver tissue. In the WCH set, 136 (43%) patients had high-OX40 expression, whereas in the TCGA set, 247 (67%) patients had high-OX40 expression as determined by the X-tile program. High-OX40 expression was associated with high serum alpha-fetoprotein level, vascular invasion, and shorter survival. The prognostic significance of OX40 was validated in additional cohorts. OX40 expression was also associated with CD8A, CD68, LAG3, TIM-3, and PD-1 expression. High-OX40 expression tumors were characterized by upregulated cytokines and exhaustion-specific markers. Analysis of the enrichment data of immune cell types indicated that OX40 expression was associated with the functions of macrophages, plasmacytoid dendritic cells, and co-inhibitory T cells. Finally, high-and low-OX40 expressions were associated with mutations in AKT/mTOR and Wnt/β-catenin signaling, respectively. These results indicate that high-OX40 expression represents the activation of multiple immunosuppressive pathways and provide a rationale for the therapeutic targeting OX40 in HCC patients.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1404214

OX40 expression in hepatocellular carcinoma is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis.

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Nicotinamide induces liver regeneration and improves liver function by activating SIRT1

Compassion fatigue and compassion satisfaction among Chinese palliative care nurses: A province-wide cross-sectional survey.

Exosomal MicroRNA-10a Is Associated with Liver Regeneration in Rats through Downregulation of EphA4.

OX40 expression in hepatocellular carcinoma is associated with a distinct immune microenvironment, specific mutation signature, and poor prognosis.