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Solitary fibrous tumor of the liver (SFTL) is an exceptionally rare mesenchymal tumor, with only 117 cases reported in the literature. While most SFTs are benign, some exhibit malignant behavior, including local recurrence and metastasis. This report presents two cases of SFTL with systemic metastases, both involving prior intracranial tumors. The first case, a 52-year-old woman, discovered a liver mass incidentally during a routine physical exam. Subsequent investigations revealed potential bone metastasis, and biopsy confirmed SFT. She received two TACE procedures, anlotinib targeted therapy, and radiotherapy for the iliac bone lesion, resulting in stable disease with reduction in lesion size. The second case, a 46-year-old man, presented with multiple liver, pelvic, and lung lesions following pelvic tumor resection, with pathology confirming SFT. He was treated with long-term anlotinib therapy, CyberKnife for hepatic, lung, and pelvic lesions, and radiofrequency ablation for hepatic lesions. Postoperative recovery was uneventful, with no tumor progression on follow-up. SFTL presents with atypical clinical and imaging features, and diagnosis requires pathological and genetic confirmation. Radical resection is preferred for solitary tumors, while comprehensive treatment, including surgery and long-term follow-up, is essential for cases with recurrence or metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Lo, Gao, Zhu, Sun and Li.)

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment., Methods: We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated., Results: We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway., Conclusions: Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Hepatocellular carcinoma (HCC) continues to play a substantial role in cancer-related morbidity and mortality, largely owing to its pronounced tumor heterogeneity and propensity for recurrence. This underscores the pressing need for in-depth examination of its highly malignant mechanisms. Annexin A5 (ANXA5), recognized as a hallmark tumor protein, has emerged as a focal point of interest because of its ambiguous function and mechanism in HCC prognosis. This study aimed to provide a comprehensive understanding of the role of ANXA5 in the malignant progression of human HCC cells by employing an integrative approach that combines conventional experimental methods with RNA sequencing., Methods: Differences in ANXA5 expression between HCC tissues and corresponding nontumor tissues were evaluated using immunofluorescence ( n  = 25). Correlation analysis was subsequently performed to assess the association between ANXA5 expression and clinicopathological features ( n  = 65). The role of ANXA5 in human HCC cell lines with ANXA5 gene knockout and overexpression was explored in vitro using migration and invasion assays and Ki-67 indices and in vivo based on node mice xenograft model. A tube formation assay using human umbilical vein endothelial cells (HUVECs) was conducted to demonstrate the angiogenic effects of ANXA5 in HCC. Single-cell and bulk RNA sequencing was used to further investigate the underlying mechanisms involved., Results: This study revealed that ANXA5 is highly expressed in patients with HCC and correlates with poor prognosis. Assays for migration, invasion, and proliferation based on ANXA5 gene knockout and overexpression systems in human HCC cell lines have demonstrated that ANXA5 enhances HCC malignancy in vitro and in vivo . Tube formation assays of HUVECs indicated that ANXA5 facilitates angiogenesis and recruits endothelial cells to HCC cells. Single-cell and bulk RNA sequencing data analysis further confirmed that ANXA5 expression in HCC is associated with hepatocyte metabolism, immune response activation, and various oncogenic signaling pathways., Conclusions: This study revealed a meaningful association between elevated ANXA5 expression in tumor tissues and an unfavorable prognosis in patients with HCC. In addition, ANXA5 promotes HCC malignancy by promoting invasion and angiogenesis. Thus, ANXA5 has emerged as a promising therapeutic target for HCC and has the potential to improve patient outcomes.

Objective: Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB., Design: We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models., Results: We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1 + T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1 + T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1 + T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1 + T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models., Conclusion: Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Portal vein tumour thrombus (PVTT) is the main pathway of HCC intrahepatic metastasis and is responsible for the poor prognosis of patients with HCC. However, the molecular mechanisms underlying PVTT vascular metastases have not been fully elucidated., Methods: NDRG1 expression was assessed by immunohistochemistry and immunoblotting in clinical specimens obtained from curative surgery. The functional relevance of NDRG1 was evaluated using sphere formation and animal models of tumorigenicity and metastasis. The relationship between NDRG1 and EpCAM was explored using molecular biological techniques., Results: NDRG1 protein was upregulated in HCC samples compared to non-tumorous tissues. Furthermore, NDRG1 expression was enhanced in the PVTT samples. Our functional study showed that NDRG1 was required for the self-renewal of tumour-initiating/cancer stem cells (CSCs). In addition, NDRG1 knockdown inhibited the proliferation and migration of PVTT-1 cells in vitro and in vivo. NDRG1 was found to stabilise the functional tumour-initiating cell marker EpCAM through protein-protein interactions and inhibition of EpCAM ubiquitination., Conclusion: Our findings suggest that NDRG1 enhances CSCs expansion, PVTT formation and growth capability through the regulation of EpCAM stability. NDRG1 may be a promising target for the treatment of patients with HCC and PVTT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing globally, and its prognosis has not improved substantially in recent years. Understanding the pathogenesis of ICC may provide a theoretical basis for its treatment. In this study, we investigated the effects and underlying mechanisms of fucosyltransferase 5 (FUT5) on the malignant progression of ICC., Methods: FUT5 expression in ICC samples and adjacent nontumor tissues was compared using quantitative real-time polymerase chain reaction and immunohistochemical assays. We performed cell counting kit-8, colony formation, and migration assays to determine whether FUT5 influenced the proliferation and mobility of ICC cells. Finally, mass spectrometry was performed to identify the glycoproteins regulated by FUT5., Results: FUT5 mRNA was significantly upregulated in most ICC samples compared with corresponding adjacent nontumor tissues. The ectopic expression of FUT5 promoted the proliferation and migration of ICC cells, whereas FUT5 knockdown significantly suppressed these cellular properties. Mechanistically, we demonstrated that FUT5 is essential for the synthesis and glycosylation of several proteins, including versican, β3 integrin, and cystatin 7, which may serve key roles in the precancer effects of FUT5., Conclusions: FUT5 is upregulated in ICC and promotes ICC development by promoting glycosylation of several proteins. Therefore, FUT5 may serve as a therapeutic target for the treatment of ICC., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people., Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer., Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint.", Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The heterogeneity of the tumour immune microenvironment (TIME), organized by various immune and stromal cells, is a major contributing factor of tumour metastasis, relapse and drug resistance 1-3 , but how different TIME subtypes are connected to the clinical relevance in liver cancer remains unclear. Here we performed single-cell RNA-sequencing (scRNA-seq) analysis of 189 samples collected from 124 patients and 8 mice with liver cancer. With more than 1 million cells analysed, we stratified patients into five TIME subtypes, including immune activation, immune suppression mediated by myeloid or stromal cells, immune exclusion and immune residence phenotypes. Different TIME subtypes were spatially organized and associated with chemokine networks and genomic features. Notably, tumour-associated neutrophil (TAN) populations enriched in the myeloid-cell-enriched subtype were associated with an unfavourable prognosis. Through in vitro induction of TANs and ex vivo analyses of patient TANs, we showed that CCL4 + TANs can recruit macrophages and that PD-L1 + TANs can suppress T cell cytotoxicity. Furthermore, scRNA-seq analysis of mouse neutrophil subsets revealed that they are largely conserved with those of humans. In vivo neutrophil depletion in mouse models attenuated tumour progression, confirming the pro-tumour phenotypes of TANs. With this detailed cellular heterogeneity landscape of liver cancer, our study illustrates diverse TIME subtypes, highlights immunosuppressive functions of TANs and sheds light on potential immunotherapies targeting TANs., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNα serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNα, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNα was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNα-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNα upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFNα, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNα-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNα/CX3CL1/CX3CR1 axis could inhibit surgical stress-induced HCC recurrence by attenuating postoperative immunosuppression., Significance: IFNα secreted by plasmacytoid dendritic cells drives postoperative immunosuppression and early recurrence of hepatocellular carcinoma, providing new biomarkers and therapeutic targets to improve patient outcomes after surgical resection., (©2022 American Association for Cancer Research.)

WW domain-containing E3 ubiquitin protein ligase1 (WWP1) is reported to be upregulated in many types of human cancers; however, its expression and function in intrahepatic cholangiocarcinoma (ICC) remain unknown. Here, in this study we investigated the expression pattern, clinical prognosis, tumor biological functions, and molecular mechanisms of WWP1 in ICC. The expression of WWP1 in patient tissues was detected by western blotting, immunohistochemistry (IHC), and immunofluorescence. CCK-8, colony formation, EdU, transwell, and xenograft models were used to explore the role of WWP1 in the proliferation and metastasis of ICC. Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, and immunofluorescence were performed to detect the potential mechanisms. Our study revealed that WWP1 was highly expressed in ICC, and high levels of WWP1 were associated with poor prognosis. Functionally, WWP1 overexpression enhanced the proliferation and metastasis of ICC cells and vice versa. Mechanistically, MYC could be enriched in the promoter region of WWP1 to facilitate its expression. Then, WWP1 targets Nedd4 family interacting protein1 (NDFIP1) and reduces NDFIP1 protein levels via ubiquitination. Downregulation of NDFIP1 in ICC cells rescued the effects of silenced WWP1 expression. WWP1 expression was also negatively correlated with the protein level of NDFIP1 in patient tissues. In conclusion, WWP1 upregulated by MYC promotes the progression of ICC via ubiquitination of NDFIP1, which reveals that WWP1 might be a potential therapeutic target for ICC., (© 2022. The Author(s).)

Plasmacytoid dendritic cells (pDCs) play immunosuppressive roles in the tumor microenvironment (TME). However, the molecular mechanisms underlying the recruitment and dysfunction of pDCs in the TME remain largely elusive, especially in hepatocellular carcinoma (HCC). In this study, we observed the accumulation of pDCs in the blood, tumor tissue, and ascitic fluid of HCC patients. A high density of tumor-infiltrating pDCs was correlated with poor prognosis in patients with HCC. Hypoxia-induced extracellular adenosine (eADO) significantly enhanced pDC recruitment into tumors via the adenosine A1 receptor (ADORA1). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transcriptionally upregulated the expression of the ectonucleotidases CD39 and CD73 in HCC cells, both of which are essential for the generation of eADO. Moreover, eADO-stimulated pDCs promoted the induction of regulatory T cells and suppressed proliferation and cytotoxicity of CD8 + T cells. Depletion of pDCs using a monoclonal antibody or an ADORA1 antagonist significantly improved antitumor immunity and suppressed HCC growth in the immunocompetent HCC mouse model. Thus, targeting pDC recruitment may serve as a potential adjuvant strategy for immunotherapies in HCC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancers, which is the most common malignant tumor worldwide. Polypeptide extract from scorpion venom (PESV) has been reported to inhibit NSCLC process. The present study aims to reveal the roles of PESV in NSCLC progression under hypoxia and the inner mechanism., Methods: The expression levels of circular RNA 0016760 (circ_0016760) and microRNA-29b (miR-29b) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was determined by western blot and immunohistochemistry assays. Cell migration, invasion, proliferation and tube formation were investigated by transwell, cell colony formation, 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide and tube formation assays. The impacts between PESV and circ_0016760 overexpression on tumor growth in vivo were investigated by in vivo tumor formation assay., Results: Circ_0016760 expression was dramatically upregulated in NSCLC tissues and cells, compared with adjacent lung tissues and cells, respectively. PESV treatment downregulated circ_0016760 expression. Circ_0016760 silencing or PESV treatment repressed cell migration, invasion, proliferation and tube formation under hypoxia in NSCLC cells. Circ_0016760 overexpression restored the effects of PESV treatment on NSCLC process under hypoxia. Additionally, circ_0016760 acted as a sponge of miR-29b, and miR-29b bound to HIF1A. Meanwhile, miR-29b inhibitor impaired the influences of circ_0016760 knockdown on NSCLC process under hypoxia. Further, ectopic circ_0016760 expression restrained the effects of PESV exposure on tumor formation in vivo., Conclusion: Circ_0016760 overexpression counteracted PESV-induced repression of NSCLC cell malignancy and angiogenesis under hypoxia through miR-29b/HIF1A axis., (© 2021. The Author(s).)

Hepatocellular carcinoma (HCC) is rising steadily in incidence, and more effective methods are needed for early detection and image-guided surgery. Glypican-3 (GPC3) is a cell surface biomarker that is overexpressed in early-stage cancer but not in cirrhosis. An IRDye800-labeled 12-mer amino acid sequence was identified, and specific binding to GPC3 was validated in vitro and in orthotopically implanted HCC tumors in vivo . Over 4-fold greater binding affinity and 2-fold faster kinetics were measured by comparison with previous GPC3 peptides. Photoacoustic images showed peak tumor uptake at 1.5 h post-injection and clearance within ∼24 h. Laparoscopic and whole-body fluorescence images showed strong intensity from tumor versus adjacent liver with about a 2-fold increase. Immunofluorescence staining of human liver specimens demonstrated specific binding to HCC versus cirrhosis with 79% sensitivity and 79% specificity, and normal liver with 81% sensitivity and 84% specificity. The near-infrared peptide is promising for early HCC detection in clinical trials.

Intrahepatic cholangiocarcinoma (ICC) is highly heterogeneous. Here, the authors perform exome sequencing and bulk RNA sequencing on 73 tumor regions from 14 ICC patients to portray the multi-faceted intratumor heterogeneity (ITH) landscape of ICC. The authors show that ITH is highly concordant across genomic, transcriptomic, and immune levels. Comparison of these data to 8 published datasets reveals significantly higher degrees of ITH in ICC than hepatocellular carcinoma. Remarkably, the authors find that high-ITH tumors highly overlap with the IDH (isocitrate dehydrogenase)-mutant subgroup (IDH-SG), comprising of IDH-mutated tumors and IDH-like tumors, that is, those IDH-wildtype tumors that exhibit similar molecular profiles to the IDH-mutated ones. Furthermore, IDH-SG exhibits less T cell infiltration and lower T cell cytotoxicity, indicating a colder tumor microenvironment (TME). The higher ITH and colder TME of IDH-SG are successfully validated by single-cell RNA sequencing on 17 503 cells from 4 patients. Collectively, the study shows that IDH mutant subgroup status, rather than IDH mutation alone, is associated with ITH and the TME of ICC tumors. The results highlight that IDH-like patients may also benefit from IDH targeted therapies and provide important implications for the diagnosis and treatment of ICC., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Hepatocellular carcinoma (HCC) recurrence after liver transplantation remains a significant clinical problem. Ischemia-reperfusion injury (IRI) occurred inevitably at the early phase after liver transplantation (LT) spawns a significant risk of HCC recurrence. However, their linkage and IRI-derived risk factors for HCC recurrence remain exclusive. Understanding the mechanism of post-transplantation hepatic injury could provide new strategies to prevent the later event of HCC recurrence. We demonstrated that glutathione S-transferase A2 (GSTA2) expression was significantly associated with early phase hepatic and systemic injury and ROS level after liver transplantation. Early phase circulating GSTA2 ( EPC GSTA2) protein was a significant predictor of HCC recurrence and survival. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. Enhancement of GSTA2 could protect HCC cells against H 2 O 2 -induced cell death by compensating for the elevated ROS stress. We also demonstrated that GSTA2 played crucial roles in regulating the ROS-associated JNK and AKT signaling pathways and ROS metabolism in HCCs in responding to a dynamic ROS environment. Functionally, endogenous or exogenous upregulation of GSTA2 could promote HCC growth and invasion through activating the epithelial-mesenchymal-transition process. Targeted inhibition of GSTA2 could suppress HCC growth and metastasis. In conclusion, GSTA2 could be a novel prognostic and therapeutic target to combat HCC recurrence after liver transplantation., (© 2021. The Author(s).)

Objective: Due to the tumor immune microenvironment (TIME) complexity and cancer heterogeneity, the clinical outcomes of hepatocellular carcinoma (HCC) are barely elicited from the conventional treatment options, even from the promising anti-cancer immunotherapy. As a suppressive TIME-related marker, the role played by cyclooxygenase-2 (COX-2) in HCC TIME, and its potential effects on anti-cancer T cell immune response remains unknown. In our study, to investigate the COX-2-dependent immune regulation pathway, we verified that the macrophages phenotypes were correlated to COX-2/PGE2 expressions among HCC patients. A multi-cellular co-culture platform containing HCC cells, macrophages, and T cells were established to mimic HCC TIME in vitro and in animal model. M2 macrophage polarization and activated CD8 + T cells exhaustion were observed under high COX-2 levels in HCC cells, with further evaluation using CRISPR/Cas9-based PTGS2 knocking out and COX-2 blockade (celecoxib) treatment controls. PGE2, TGF-β, Granzyme B, and IFN-γ levels were testified by flow cytometry and ELISA to fully understand the mechanism of COX-2 suppressive effects on T cell-based anti-HCC responses. The activation of the TGF-β pathway evaluated by auto-western blot in T cells was confirmed which increased the level of phosphorylated Smad3, phosphorylated Samd2, and FoxP1, leading to T cell de-lymphotoxin. In conclusion, high COX-2-expressing HCC cell lines can induce anti-tumor abilities exhaustion in activated CD8 + T cell through M2 TAMs polarization and TGF beta pathway. COX-2 inhibitors may reduce the inhibitory effect on CD8 + T cells through regulating TAMs in TIME, thus enhance the T cell-based cytotoxicity and improve the prognosis of HCC patients., Competing Interests: None., (AJTR Copyright © 2021.)

Background: Hepatocellular carcinoma (HCC) recurrence is still threatening patient survival after liver transplantation (LT). The efficacy and safety of sorafenib in the setting of post-LT recurrence are still equivocal. This study aims to disclose the efficacy and safety profile of sorafenib in treating post-LT HCC recurrence., Materials and Methods: Electronic databases were searched to retrieve relevant publications suitable for inclusion. Data from 23 studies containing 411 patients were analyzed. The primary outcome of interest was 1-year survival rate after sorafenib treatment, and the secondary endpoints included median overall survival (OS), time to progression (TTP), treatment response, and adverse events., Results: Patients with HCC recurrence after LT treated with sorafenib achieved a 1-year survival rate of 56.8%, with a median OS of 12.8 months and a median TTP of 6.0 months. Univariate logistic regression analysis showed that male gender (P = .048), TTP (P = .021), median duration of sorafenib (P = .021), diarrhea (P = .027), fatigue (P = .044), and partial response (P = .026) were associated with a better 1-year survival rate. In addition, sorafenib exerted a significant superior effect on OS compared with best supportive care in the setting of untreatable post-LT HCC recurrence., Conclusions: Based on the results of this meta-analysis, sorafenib therapy seems to be safe and feasible and exhibits survival benefit in patients with post-LT HCC recurrence. However, prospective randomized controlled trials with larger sample sizes and more rigorous study design are required to confirm the efficacy of sorafenib.

Background: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people., Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2017 Edition) in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition (2019 Edition) was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years., Key Messages: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People's Republic of China in December 2019., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

The efficacy of adoptive cellular immunotherapy against cancer cells is limited due to the presence of immunosuppressive cells within the solid tumor microenvironment. The upregulation of certain coinhibitory receptors may lead to exhaustion of the immune effector cells. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune inhibitory receptor expressed by regulatory T cells and activated T cells and natural killer cells. The aim of this study was to determine the immunosuppressive effects of CD155/TIGIT signaling on CD8 T cells of adoptive cellular immunotherapy in hepatocellular carcinoma (HCC). Our studies found that CD155 was overexpressed in HCC, and CD155 HCC cells upregulated TIGIT on CD8 T cells, which decreased the secretion of interferon-γ, tumor necrosis factor-α, and interleukin-17A and increased that of interleukin-10 from the effector cells. However, TIGIT blockade or CD155-knockdown reversed the inhibitory effect of HCC cells on CD8 T-cell effector function. These results indicate that TIGIT can exert an immunosuppressive effect on CD8 T cells by modulating cytokine production through CD155, and is a promising target to optimize adoptive cellular immunotherapy against HCC.

Annually, around 850 liver transplantation is performed in Beijing, China. Recently, the new coronavirus pneumonia (COVID-19) caused by 2019 novel coronavirus (2019-nCoV) has affected nearly 200 countries worldwide. 2019-nCov can cause severe lung disease, multiple-organ damage, and significant mortalities. Liver transplant recipients, because of long-term oral immunosuppressant effects, may be more susceptible to 2019-nCoV infection and have a worse prognosis than the general population. It is urgent to set up guidelines for the prevention, diagnosis, and treatment of COVID-19 in liver transplant recipients. In this article, we reviewed the clinical aspects of 2019-nCoV infection, characteristics of liver transplant recipients, immunosuppressant usage, and potential drug interactions to provide recommendations to clinical staff managing liver transplant recipients during the COVID-19 epidemic.

Introduction: hepatocellular carcinoma (HCC) recurrence after liver resection remains a major threat for patients' survival. Sorafenib is recommended as an adjuvant treatment for patients after a liver resection. The objective of this meta-analysis was to estimate the therapeutic value of sorafenib in patients who underwent a HCC resection., Materials and Methods: relevant reports were retrieved from electronic databases. All eligible studies were carefully reviewed and the required data were extracted. Outcome with regard to overall survival (OS), recurrence-free survival (RFS), recurrence rate, mortality rate, OS time (months) and RFS time (months) were analyzed., Results: nine trials were included. The results of the meta-analysis revealed that sorafenib did not exert a significant superior effect on OS (sorafenib as reference: hazard ratio [HR] = 2.15; 95% CI, 0.91-5.08, p = 0.80; control as reference: HR = 0.56; 95% CI, 0.31-1.02; p = 0.059), OS time in months (weighted mean differences [WMD] = 4.96; 95% CI, -1.21-11.13; p = 0.115) and RFS time in months (WMD = 7.58; 95% CI, -1.36-16.53; p = 0.097). Nevertheless, the use of sorafenib was associated with a significantly higher RFS (HR = 0.53; 95% CI, 0.31-0.90; p = 0.018), and a lower recurrence rate (risk ratio [RR] = 0.72; 95% CI, 0.60-0.86; p < 0.001) and mortality rate (RR = 0.74; 95% CI, 0.57-0.95; p = 0.20)., Conclusion: according to the present meta-analysis, sorafenib showed a significant benefit in RFS, recurrence rate and mortality rate. The effect of sorafenib for the prevention of HCC recurrence seems to be encouraging. However, more evidence is still needed before reaching a definitive conclusion.

Background: The mechanism underlying sorafenib resistance in hepatocellular carcinoma (HCC) remains unclear. Accumulating evidence suggests that tumor-initiating cells (TICs) are a pivotal driving force. Both CD44 and Hedgehog signaling play crucial roles in TIC properties in HCC. In this study, we explored the roles of CD44 and Hedgehog signaling in sorafenib resistance and evaluated the therapeutic effect of cotreatment with sorafenib and Hedgehog signaling inhibitors in HCC patient-derived organoid (PDO) models to improve treatment efficacy., Methods: We collected HCC specimens to establish PDO models. Cell viability and malignant transformation properties were investigated after treatment with different TIC-related inhibitors alone or in combination with sorafenib to evaluate the therapeutic effect in PDOs and cell lines by in vitro and in vivo experiments. Expression levels of Hedgehog signaling proteins and CD44 were monitored to reveal potential relationships., Results: We demonstrated that our HCC PDO models strongly maintained the histological features of the corresponding tumors and responded to drug treatment. Furthermore, CD44-positive HCC PDOs were obviously resistant to sorafenib, and sorafenib increased CD44 levels. A drug screen showed that compared with Notch, Hippo and Wnt signaling inhibitors, a Hedgehog signaling inhibitor (GANT61) potently suppressed HCC PDO cell viability. In addition, there was a highly synergistic effect in vitro and in vivo on the suppression of cell viability and malignant properties when sorafenib and GANT61 were added to CD44-positive HCC PDOs and cell lines, respectively. Furthermore, the upregulation of CD44 and Hedgehog signaling induced by sorafenib was reversed by GANT61., Conclusions: GANT61 significantly suppressed Hedgehog signaling to reverse sorafenib resistance in CD44-positive HCC. The combination of sorafenib and Hedgehog signaling inhibitors might be effective in HCC patients with high CD44 levels as a personalized-medicine approach.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with increasing incidence. Chemotherapy is required for HCC patients after receiving surgical resection. Serious off-target induced side effects and systemic toxicity limit the clinical utility of drugs. Targeting therapeutic nanomedicine is an innovative strategy for enhancing drug delivery efficiency and reducing side effects. Here, we successfully formulated nanocarriers to encapsulate sorafenib, an FDA approved drug for treatment of HCC. Sorafenib is encapsulated with an entrapment efficiency >80% over 20 days. The effective aqueous solubility is improved over 1900-fold. The release ratio in vitro is characterized by a half-life of T 1/2  = 22.7 h. The peak target-to-background ratio for nanocarrier uptake by tumor occurs at 24 h post-injection, and is significantly greater for the target peptide versus controls. Ex vivo biodistribution confirms the in vivo results. Tumor regression is significantly greater for the target peptide versus controls after 21 days of therapy. No acute toxicity is found by blood chemistry or necropsy. In summary, a peptide specific for GPC3 has been identified, and used to modify the surface of a nanocarrier that encapsulates sorafenib with high entrapment efficiency. Regression of HCC xenograft tumors showed promise for targeted drug delivery., (Copyright © 2019. Published by Elsevier B.V.)

Cancer metastasis has been demonstrated as it is the culmination of a cascade of priming steps. Increasing evidence has shown that tumor-derived molecular components (TDMCs) are known as extra cellular vesicle and nonvesicle factors and serve as versatile intercellular communication vehicles which can mediate signaling in the tumor microenvironment while creating the premetastatic niche. Noncoding RNAs (ncRNAs) as one of the TDMCs have been proved in participating in the formation of the premetastatic niche. Understanding the premetastatic niche formation mechanisms through TDMCs, especially ncRNAs may open a new avenue for cancer metastasis therapeutic strategies. In this review, recent findings regarding ncRNAs function were summarized, and then the interaction with the premetastatic niche formation was studied, which highlight the potential of using ncRNAs for cancer diagnosis and therapeutic effect.

The aim of this study was to investigate the effects and mechanisms of hematopoietic-substrate-1-associated protein X-1 (HAX-1) on liver cancer cells. Information on HAX-1 from liver cancer patients was analyzed by the Cancer Genome Atlas (TCGA) program. Cell migration and invasion abilities were respectively tested by scratch assay and transwell assay. Tube formation assay was applied to detect angiogenesis protein and mRNA was determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. We found that the median month survival of HAX-1 overexpressing liver cancer patients was shorter than that of HAX-1 normal liver cancer patients. HAX-1 was overexpressed in liver cancer tissues and cells, and HAX-1 overexpression promoted the liver cancer cells growth, migration, and invasion, whereas silencing HAX-1 produced the opposite results. Inhibition of Akt by LY294002 reversed the migration and invasion abilities of liver cancer cells, and inhibited the ability of cells growth and angiogenesis. Silencing PIK3CA enhanced the inhibitory effects of HAX-1 silencing on the viability, migration, and invasion of liver cancer cells. HAX-1 affected liver cancer cells metastasis and angiogenesis by affecting Akt phosphorylation and FOXO3A expression.

Background: To investigate the effects of retrograde reperfusion on the intraoperative internal environment and hemodynamics in classic orthotopic liver transplantation (OLT)., Methods: Thirty patients were undergone classic OLT using retrograde reperfusion in our center. Blood sampling was done at different time points including: Before blood venting via the portal vein (PV), 10 mL of blood was collected from the inferior vena cava (T 0 ); During retrograde reperfusion through the inferior vena cava (IVC), 10 mL of blood was collected when the volume of blood venting reached 10 mL (T 1 ), 100 mL (T 2 ), and 200 mL (T 3 ), respectively. 5 mL of blood was analyzed using a NOVA-f-type Blood Gas Analyzer. The remaining 5 mL was measured to determine the level of IL-1β using an enzyme-linked immunosobent assay., Results: All operations were completed successfully, and postreperfusion syndrome (PRS) occurred in 6 patients (20%). The most notable findings were significant changes at T 1 , T 2 and T 3 , including pH value, PvO 2 , SvO 2 , BEecf, HCO 3 - , Lac, K + , Ca 2+ and IL-1β, compared with T 0 (P < 0.05). Yet their levels at T 3 were not back to the level at T 0 (P < 0.05)., Conclusion: This retrograde perfusion could eliminate some harmful metabolites inside the donor liver in time and reduce acid-base and electrolyte disorders as well as drastic hemodynamic fluctuations after recirculation during classic OLT.

Extrahepatic metastasis of hepatocellular carcinoma (HCC) may cause a diagnostic problem. All 195 cases of histologic and immunostained sections were reviewed retrospectively in one center. The expression of arginase-1 (Arg-1), hepatocyte paraffin-1 (HepPar-1), glypican-3 (GPC-3), and α-Fetoprotein (AFP) was evaluated. Eighty cases of metastatic tumors of the liver were also collected to verify their effectiveness. Totally 151 cases had previous history of HCC, in whom 49 had history of liver transplantation. Forty-four cases were diagnosed as metastatic HCC at initial presentation. The most common extrahepatic metastatic sites were bone (57%), followed by lung, lymph node, etc. Around 19 cases were positive for 1 marker, 22 were positive for 2 markers, 95 were positive for 3 markers, and 59 were positive for 4 markers. With the number of antibody increased in the panel, the negative cases decreased. The sensitivity of ARG, GPC-3, HepPar-1, and AFP was 82.6%, 89.2%, 83.6% and 53.8%, and the specificity was 98.3%, 94.8%, 96.2% and 100%, respectively. These data suggest that the panel of ARG-1, GPC-3, HepPar-1 and AFP has a high sensitivity and specificity to differentiate HCC from non-HCC. This study indicated that HCC should be considered when diagnosing metastasis of unclear origin. It is recommended to use the panel of ARG-1, GPC-3, HepPar-1 and AFP to differentiate HCC from non-HCC in extrahepatic metastasis, because of their sensitivity and specificity, especially in poorly differentiated lesions.

The effects of harmaline on the viability and apoptosis of human liver carcinoma were investigated in vitro . HepG2 cells were treated with harmaline (0-10 µM), and the proliferation and apoptosis of HepG2 cells were investigated using an MTT assay and flow cytometry, respectively. The protein expression of cellular tumor antigen p53 (p53), cyclin-dependent kinase inhibitor 1 (p21), tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand (FasL) and caspase-8 was subsequently measured using western blotting. In addition, an ELISA was used to analyze caspase-8/3 activity. Harmaline significantly increased p53, p21, Fas and FasL protein expression in HepG2 cells. Additionally, treatment with harmaline significantly increased the expression of caspase-8 and caspase-8/3 activity. The results from the present study suggest that harmaline suppresses the viability, but induces the apoptosis, of human liver carcinoma cells through upregulation of the p53/p21 and Fas/FasL signaling pathways.

Background: The aim of this study was to characterize the disorder of lipid metabolism in hepatocellular carcinoma (HCC). HCC is a worldwide disease. The research into the disorder of lipid metabolism in HCC is very limited. Study of lipid metabolism in liver cancer tissue may have the potential to provide new insight into HCC mechanisms., Methods: A lipidomics study of HCC based on Ultra high performance liquid chromatography-electronic spray ionization-QTOF mass spectrometer (UPLC-ESI-QTOF MS) and Matrix assisted laser desorption ionization-fourier transform ion cyclotron resonance mass spectrometer (MALDI-FTICR MS) was performed., Results: Triacylglycerols (TAGs) with the number of double bond (DB) > 2 (except 56:5 and 56:4 TAG) were significantly down-regulated; conversely, others (except 52:2 TAG) were greatly up-regulated in HCC tissues. Moreover, the more serious the disease was, the higher the saturated TAG concentration and the lower the polyunsaturated TAG concentration were in HCC tissues. The phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) were altered in a certain way. Sphingomyelin (SM) was up-regulated and ceramide (Cer) were down-regulated in HCC tissues., Conclusions: To our knowledge, this is the first such report showing a unique trend of TAG, PC, PE and PI. The use of polyunsaturated fatty acids, like eicosapentanoic and docosahexanoic acid, as supplementation, proposed for the treatment of Non-alcoholic steatohepatitis (NASH), may also be effective for the treatment of HCC., Competing Interests: The authors declare no conflict of interest.

Organ-like microenviroment and 3-dimensional (3D) cell culture conformations have been suggested as promising approaches to mimic in a micro-scale a whole organ cellular functions and interactions present in vivo. We have used this approach to examine biologic features of hepatocellular carcinoma (HCC) cells. In this study, we demonstrate that hepatocellular carcinoma (HCC) cells, fibroblasts, endothelial cells and extracellular matrix can generate organoid-like spheroids that enhanced numerous features of human HCC observed in vivo. We show that the addition of non-parenchymal cells such as fibroblast and endothelial cells is required for spheroid formation as well as the maintenance of the tissue-like structure. Furthermore, HCC cells cultured as spheroids with non-parenchymal cells express more neo-angiogenesis-related markers (VEGFR2, VEGF, HIF-α), tumor-related inflammatory factors (CXCR4, CXCL12, TNF-α) and molecules-related to induced epithelial-mesenchymal transition (TGFβ, Vimentin, MMP9) compared with organoids containing only HCC cells. These results demonstrate the importance of non-parenchymal cells in the cellular composition of HCC organoids. The novelty of the multicellular-based organotypic culture system strongly supports the integration of this approach in a high throughput approach to identified patient-specific HCC malignancy and accurate anti-tumor therapy screening after surgery.

Aim: The purpose of this study was to investigate which inflammation-based marker more accurately predict recurrence in patients receiving hepatectomy for hepatocellular carcinoma (HCC)., Methods: A total of 1020 patients was included. The impacts of clinical variables and inflammation-based markers on disease-free survival (DFS) were measured by Kaplan-Meier method. Selected potential prognostic factors were further analyzed in multivariate model. To reduce influences of selection bias and possible confounders, clinical characteristics of patients were balanced by propensity score matching (PSM)., Results: Of the 1020 patients, 881 (86.4%) were male and 323 (31.7%) received major hepatectomy. In multivariate analysis, cirrhosis (HR: 1.49), tumor size (HR: 1.32), tumor number (HR: 1.57), portal vein tumor thrombus (HR: 1.66), microvascular invasion (HR: 1.60), histological grade (HR: 1.82), operation time (HR: 1.50), alpha foetal protein (HR: 1.29), neutrophil to lymphocyte ratio (NLR) (HR: 1.38), and lymphocyte to monocyte ratio (LMR) (HR: 1.51) were independently predictive of DFS. After PSM, 258 and 213 pairs of patients were generated for LMR and NLR, respectively. LMR and NLR were still independent predictors of recurrence for HCC patients receiving hepatectomy., Conclusion: Both LMR and NLR might be preferable independent prognostic factors for DFS in HCC patients undergoing hepatectomy., (© 2017 Wiley Periodicals, Inc.)

Stem cell research has significantly evolved over the last few years, allowing the differentiation of pluripotent cells into almost any kind of lineage possible. Studies that focus on the liver have considerably taken a leap into this novel technology, and hepatocyte-like cells are being generated that are close to resembling actual hepatocytes both genotypically and phenotypically. The potential of this extends from disease models to bioengineering, and even also innovative therapies for end-stage liver disease. Nonetheless, too few attention has been given to the non-parenchymal cells which are also fundamental for normal liver function. This includes cholangiocytes, the cells of the biliary epithelium, without whose role in bile modification and metabolism would impair hepatocyte survival. Such can be observed in diseases that target them, so called cholangiopathies, for which there is much yet to study so as to improve therapeutical options. Protocols that describe the induction of human induced pluripotent stem cells into cholangiocytes are scarce, although progress is being achieved in this area as well. In order to give the current view on this emerging research field, and in hopes to motivate further advances, we present here a review on the known differentiation strategies with sight into future applications.

Background: Both iodine-125 implantation and transarterial chemoembolization (TACE) are feasible options for hepatocellular carcinoma (HCC). The aim of the research is to investigate whether iodine-125 implantation combined with TACE could improve the overall survival of patients with HCC of 3-5cm., Methods: 144 patients with HCC of 3-5cm who underwent iodine-125 implantation plus TACE and TACE alone were retrospectively enrolled in this study. To reduce the selection bias, 55 matched pairs of patients were generated by propensity score matching (PSM). Their overall survival was compared by the Kaplan-Meier method. Independent prognostic factors were identified by Cox proportional hazards regression model., Results: patients receiving iodine-125 implantation plus TACE have significantly better overall survival than patients receiving TACE alone (P<0.001). After PSM, treatment of iodine-125 plus TACE still provide better survival (1-year, 89.1% vs. 65.5%; 3-year, 51.0% vs. 7.4%; P<0.001). In multivariate analysis, BCLC stage, vascular invasion and treatment modality independently predicted the prognosis. No severe adverse events occurred in both groups., Conclusion: for HCC patients of 3-5cm for whom surgical intervention is not an option, iodine-125 implantation combined with TACE might be an effective and viable alternative to provide better overall survival., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Recent studies have demonstrated that transducin (beta)-like 1 X-linked receptor 1 (TBLR1) is involved in tumor progression. However, the exact role and clinical significance of TBLR1 in hepatocellular carcinoma (HCC) are poorly understood., Aim: In this study, we aimed to investigate the expression and clinical significance of TBLR1 in HCC., Methods: Quantitative polymerase chain reaction and immunohistochemical staining were performed to detect the expression levels of TBLR1 in HCC tissue and adjacent noncancerous tissue (ANT). The relationships between TBLR1 expression and clinicopathological factors were examined in this study. The effects of TBLR1 on epithelial-mesenchymal transition (EMT) of HCC cells were investigated in vitro., Results: The expression levels of TBLR1 were elevated in HCC cell lines. TBLR1 mRNA in HCC tissue was markedly higher (P < 0.001) than that in ANT. High expression of TBLR1 is closely related to serum alpha fetoprotein (P = 0.047), BCLC stage (P < 0.001), maximum size of tumors (P < 0.001), tumor embolus (P < 0.001), and histological grade (P < 0.001). The disease-free survival and overall survival of HCC patients with high expression of TBLR1 were significantly shorter. Furthermore, we found that EMT of HCC cells could be induced by up-regulating TBLR1 and be inhibited by down-regulating TBLR1. ICG-001, the inhibitor of Wnt/β-catenin signaling, could suppress induction of EMT mediated by TBLR1., Conclusions: Our finding suggested that TBLR1 is likely to be a potential prognostic indicator and therapeutic target for HCC and that TBLR1 may be implicated in EMT of HCC cells.

Background. Both splenectomy (SP) and partial splenic embolization (PSE) are used to treat massive splenomegaly (MSM) secondary to hepatitis B-related liver cirrhosis (HB-LC). This retrospective case-control study was conducted to compare the effects of SP and PSE on these patients. Methods. From July 2004 to January 2012, patients with MSM secondary to HB-LC who underwent SP or PSE were 1 : 1 : 1 matched with similar nonsurgery patients, respectively. Intraoperative situation, hematological indices, liver function, HBV DNA level, HBeAg seroconversion rate, morbidity, and mortality at 6 months postoperatively were compared. Results. Operative time, estimated blood loss, blood transfusion rate, severe pain, postoperative stay, and portal vein thrombosis (PVT) rate in the PSE group were significantly superior to the SP group, although SP and PSE were similar in liver function improvement, HBV suppression, morbidity, and mortality at 6 months postoperatively, and SP even improved WBC and PLT counts higher than PSE. Conclusion. Both SP and PSE are effective in improving liver function, increasing WBC and PLT counts, and suppressing replication of HBV for MSM secondary to HB-LC. Although postoperative improvement in WBC and PLT counts by SP can be higher than PSE, PSE is simple and minimally invasive and has a lower incidence of PVT.

Background: Lysyl oxidase (LOX) is frequently overexpressed in a variety of malignancies and involved in tumor invasion and metastasis. Furthermore, it has been shown that LOX is closely related to vascular endothelial growth factor (VEGF)., Aims: In this study, we aimed to investigate the exact role of LOX and the correlation between LOX and VEGF in hepatocellular carcinoma (HCC)., Methods: The expression levels of LOX in HCC tissue and adjacent noncancerous tissue were evaluated by quantitative reverse transcription polymerase chain reaction and immunohistochemical analysis. The effect of LOX knockdown on cell proliferation, migration, and invasion was investigated in vitro. The role of LOX in the regulation of VEGF was further characterized in HCC cells that had been treated with transforming growth factor beta (TGF-β)., Results: Our study showed that LOX was up-regulated in HCC cell lines and tissue. HCC patients with elevated expression of LOX had relatively shorter disease-free survival and overall survival. Knockdown of LOX reduced the proliferation, migration, and invasion of HCC cells. Additionally, the expression level of LOX positively correlated with that of VEGF. After treatment with TGF-β, the levels of LOX and VEGF were both up-regulated in a dose-dependent manner. In the cells treated with siRNA of LOX, levels of VEGF and phosphorylated p38 were significantly decreased and could not be up-regulated by TGF-β. Inhibition of p38 MAPK signaling abrogated TGF-β-mediated up-regulation of VGEF but did not affect LOX expression., Conclusions: LOX appears to be a predictor of less favorable outcomes and may regulate the expression of VEGF via p38 MAPK signaling.

Background: A quantity of case-control studies have been performed to address the association between three cyclooxygenase-2(COX-2) polymorphisms (-1195G/A, -765G/C and +8473T/C) and the risk of hepatocellular carcinoma (HCC). However, previous research results are inconsistent. We conducted this meta-analysis to clarify the correlation between these COX-2 polymorphisms and HCC risk., Methods: The authors searched in PubMed, EMBASE, Google Scholar, CNKI and WanFang database for relevant articles up to April 28, 2014. The data were extracted by two independent reviewers. Odds ratios (ORs) and 95% confidence intervals were calculated., Results: A total of 8 studies consisting of 2182 cases and 3324 controls were included in this meta-analysis. For COX-2 polymorphism -1195G/A, an association with increased risk was observed under the heterogeneous, homozygous, dominant model. However, COX-2 polymorphisms (-765G/C and +8473T/C) were not related to HCC risk in this study. We also found a similar result in the subgroup analysis of Chinese population that -1195G/A polymorphism, instead of -765G/C or +8473T/C polymorphism, was correlated with the risk of HCC., Conclusions: Polymorphism -1195G/A of COX-2 might be associated with susceptibility to HCC, but no similar correlations were observed between polymorphisms (-765G/C and +8473T/C) and HCC risk. Further large and well-designed studies are required to validate this association.

Background/aims: To evaluate short-term outcomes and long-term survival after pancreaticoduodenectomy for malignancy in elderly Chinese patients (aged 70 years or older) compared with younger patients., Methodology: Between January 2005 and December 2013, 216 consecutive patients who underwent a PD with pancreatic cancer or periampullary cancers in our institution were recruited in this study. Sixty-eight patients aged 70 years or older when they underwent PD, while 148 patients younger than 70., Results: There were no significant differences in postoperative mortality (p = 0.104), overall morbidity (p = 0.057) and surgical complications (p = 0.200) between the elderly patients and the younger patients. Elderly patients had a significantly higher incidence of cardiac events (p = 0.008) and pneumonia (p = 0.041) postoperatively. The postoperative hospital stay in the older age group was significantly longer (p = 0.013). The overall survival did not differ between the two age groups both when patients with pancreatic cancer were analyzed (p = 0.836) and when patients with periampullary cancers were analyzed (p = 0.817)., Conclusions: Our results showed that pancreaticoduodenectomy for malignancy in Chinese patients over 70 years old could be performed safely. Age should not be considered as a contraindication to pancreaticoduodenectomy.

Although the ability of endogenous CD4(-)CD8(-) double negative (DN) T cells to suppress B cells has been documented, the extent to which ex vivo converted DN T cells suppress B cells activity is still being explored. The aim of this study was to determine whether and what extent ex vivo converted CD4(-)CD8(-) DN T cells suppress B cell activation and antibody production. We found that ex vivo converted DN T cells suppressed proliferation of activated B cells in a perforin and cell-cell contact dependent manner. In addition, ex vivo converted DN T cells significantly inhibited the production of IgG by stimulated B cells. This study provides evidence that ex vivo converted CD4(-)CD8(-) double negative T cells can down-regulate immune responses by suppressing B cell proliferation and IgG production, and supports efforts to develop ex vivo DN T cell therapies., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: OX40/OX40 ligand (OX40/OX40L) and programmed death-1/programmed death ligand-1 (PD-1/PD-L1) costimulatory signals play important roles in T cell-induced immune responses. The aim of this study was to investigate the roles of OX40/OX40L and PD-1/PD-L1 costimulatory pathways in mouse islet allograft rejection., Methods: Lentiviral vectors containing OX40L siRNA sequences and an adenovirus vector containing the PD-L1 gene were constructed. The streptozotocin-induced model of diabetes was established in C57BL/6 (H-2(b)) mice. Diabetic C57BL/6 mice were randomly allocated into five groups: group 1, untreated control; group 2, Ad-EGFP treatment; group 3, Ad-PD-L1 treatment; group 4, OX40L-RNAi-LV treatment; group 5, OX40L-RNAi-LV combined with Ad-PD-L1 treatment. Lentiviral vector and the adenovirus vector were injected, singly or combined, into the caudal vein one day before islet transplantation. The islets of DBA/2 (H-2(d)) mice were transplanted into the renal subcapsular space of the diabetic recipients. Recipient blood glucose and the survival time of the allografts were monitored. Antigen-specific mixed lymphocyte reaction was also evaluated., Results: The recombinant lentiviral RNA interference vector OX40L-RNAi-LV reduced OX40L protein expression by 70%. The recombinant adenovirus vector Ad-PD-L1 increased PD-L1 protein expression in vivo in C57BL/6 recipient mice. Combined OX40L-RNAi-LV/Ad-PD-L1 treatment induced a synergistic protective effect in pancreatic islet allografts. Allograft survival time in the combined treatment group was (92.27±9.65) days, not only longer than that of the control ((6.51±0.27) days) and Ad-EGFP groups ((7.09±0.13) days) (P < 0.01), but also significantly longer than that of Ad-PD-L1 and OX40L-RNAi-LV single treatment groups ((40.64±3.95) days and (55.14±5.48) days respectively, P < 0.01). The blood glucose concentration of recipient mice in the combined treatment group was also stable and kept within the normal range. Flow cytometry analysis showed that combined OX40L-RNAi-LV/Ad-PD-L1 treatment significantly decreased proliferation in an antigen-specific mixed lymphocyte reaction. After donor DBA/2 lymphocyte stimulation, 89.71% of lymphocytes from recipient combination treatment C57BL/6 mice were not split and proliferated. In contrast, after stimulation with third party Lewis rat lymphocytes, only 45.84% lymphocytes of C57BL/6 mice were not split and proliferated., Conclusions: This study demonstrates the successful construction of the recombinant lentivirus vector OX40L-RNAi-LV and adenovirus vector Ad-PD-L1 for the blockade of OX40/OX40L and activation of PD-1/PD-L1 costimulatory pathways simultaneously in pancreatic islet allografts in diabetic mice. Combination therapy with these two vectors resulted in inhibition of T cell activation, synergistically prolonging the survival time of pancreatic islet allografts.

We investigated the feasibility of the combined detection of HLA-A2/MAGE-A3 epitope-specific cytotoxic T lymphocytes (CTLs) and serum alpha-fetoprotein (AFP) for specific diagnosis of hepatocellular carcinoma (HCC). We detected the frequency of MAGE-A3 epitopes (p112-120, KVAELVHFL) in spontaneous CTLs in the peripheral blood of HCC patients, liver cirrhosis patients, and healthy subjects with HLA-A2/polypeptide complex (pentamer) detection technology. Eighty-five HCC cases, 38 liver cirrhosis cases, and 50 healthy cases who were HLA-A2-positive were selected from 175 HCC patients, 80 patients with liver cirrhosis, and 105 healthy volunteers, respectively. The frequency of HLA-A2-specific MAGE-A3(+) CTLs in the HCC group was significantly higher than that in the other groups. Combined detection of MAGE-A3(+) CTL frequency and serum AFP value had a higher specificity than either of the two indicators alone. The pentamer technique is helpful in distinguishing benign lesions and malignant lesions in the liver. Combined with serum AFP, it can improve the diagnosis performance for HCC, especially for AFP-negative cancer.

Unlabelled: MicroRNAs (miRNAs) play important roles in the posttranscriptional regulation of gene expression. Recent evidence has indicated the pathological relevance of miRNA dysregulation in hepatitis virus infection; however, the roles of microRNAs in the regulation of hepatitis B virus (HBV) expression are still largely unknown. In this study we identified that miR-373 was up-regulated in HBV-infected liver tissues and that the members of the miRs-371-372-373 (miRs-371-3) gene cluster were also significantly co-up-regulated in HBV-producing HepG2.2.15 cells. A positive in vivo association was identified between hepatic HBV DNA levels and the copy number variation of the miRs-371-3 gene cluster. The enhanced expression of miRs-372/373 stimulated the production of HBV proteins and HBV core-associated DNA in HepG2 cells transfected with 1.3×HBV. Further, nuclear factor I/B (NFIB) was identified to be a direct functional target of miRs-372/373 by in silico algorithms and this was subsequently confirmed by western blotting and luciferase reporter assays. Knockdown of NFIB by small interfering RNA (siRNA) promoted HBV expression, whereas rescue of NFIB attenuated the stimulation in the 1.3×HBV-transfected HepG2 cells., Conclusion: Our study revealed that miRNA (miRs-372/373) can promote HBV expression through a pathway involving the transcription factor (NFIB). This novel model provides new insights into the molecular basis in HBV and host interaction., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Objective: To detect protein expression of ERK(1), ERK(2), JNK(1), p38 and MEK(1), MEK(2) in human hepatocellular carcinoma and adjacent non-neoplastic liver., Methods: In 16 surgically resected hepatocellular carcinoma and para-carcinoma tissues, Western blotting was used to detect expression of ERK(1), ERK(2), JNK(1), p38 and MEK(1), MEK(2)., Results: In all cases, ERK(1), ERK(2), p38 expression in hepatocellular carcinoma was significantly higher than that in para-carcinoma: integral optic density (IOD) of ERK(1) was 300 +/- 98 in carcinoma and 98 +/- 48 in para-carcinoma tissues (t = 2.519, P < 0.01); IOD of ERK(2) was 587 +/- 83 in carcinoma and 232 +/- 96 in para-carcinoma tissues (t = 2.745, P < 0.01); IOD of p38 was 270 +/- 85 in carcinoma and 107 +/- 88 in para-carcinoma tissues (t = 2.491, P < 0.01). JNK(1) expression in hepatocellular carcinoma was significantly lower than that in para-carcinoma; IOD of JNK(1) was 111 +/- 93 in carcinoma and 292 +/- 109 in para-carcinoma tissues (t = 2.473, P < 0.01). Protein levels of MEK(1) and MEK(2) in carcinoma were significantly higher than in para-carcinoma. IOD of MEK(1) was 1 418 +/- 244 in carcinoma and 806 +/- 90 in para-carcinoma tissues (t = 2.546, P < 0.01). IOD of MEK(2) was 1 041 +/- 122 in carcinoma and 468 +/- 40 in para-carcinoma tissues (t = 2.861, P < 0.01)., Conclusions: ERK(1), ERK(2), MEK(1) and MEK(2) in the signal transduction pathway for cell proliferation are significantly overexpressed and the expression of JNK(1) is lower in hepatocellular carcinoma. Their unbalance is one of the important reasons for the over growth and infinite proliferation of the hepatocellular carcinoma cell. The p38 and JNK(1) may be activated by different pathway.