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Background T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells were newly identified as the subsets of cluster of CD4+ T cells. As major components of human immune system, they were found in tumor microenvironment and reported to play vital roles in the progression of cancer. But their clinical significance in Hepatocellular carcinoma (HCC) was not elucidated. Thus, this research aimed to investigate their prognostic value in HCC. Materials and methods A total of 210 subjects (including 110 HCC patients, 50 chronic hepatitis patients and 50 healthy individuals) were enrolled in the research. Tfh, Tfr cells and Treg cells from peripheral blood were measured by flow cytometry. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of Tfr-Tfh Index (TTI) in early HCC and relapse status. Its further prognostic valve was assessed by Kaplan-Meier survival estimate and log rank tests. Results Tfh cells, Tfr cells, Treg cells and TTI were all higher in HCC patients than in chronic hepatitis patients and healthy control. TTI was found to have positive correlation with the load of HBV. The AUC of TTI for early HCC and relapse status was better than other clinical indices in HBV positive patients. An optimal cutoff point for the TTI stratified the HCC patients into high (>21.96) and low index (≤21.96) groups. High TTI was significantly correlated with recurrence. Univariate and multivariate analyses revealed TTI could be a predictor for recurrence. Moreover, it retained prognostic performance for patients with lower recurrence risk. Conclusion Our research showed that TTI could be a promising indicator for early recurrence in HCC patients with HBV infection.

Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma (HCC) and are associated with increased mortality due to this disease. Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC. However, most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding, and have limited efficacy against tumors with mutant or deficient p53. In the present study, we developed a novel MDM2 inhibitor (termed SP141) that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells. We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion, independent of p53. Mechanistically, SP141 directly binds the MDM2 protein and promotes MDM2 degradation. The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib. In addition, in orthotopic and patient-derived xenograft models, SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis, without any host toxicity. Furthermore, the inhibition of MDM2 by SP141 is essential for its anti-HCC activities. These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC. Keywords: CRISPR/Cas9, Hepatocellular carcinoma, MDM2, p53-independent, Patient-derived xenograft

Background & Aims Early recurrence of hepatocellular carcinoma (HCC) after curative resection is common. However, the association between genetic mechanisms and early HCC recurrence, especially in Chinese patients, remains largely unknown. Methods We performed whole-genome sequencing (49 cases), whole-exome sequencing (18 cases), and deep targeted sequencing (115 cases) on 182 primary HCC samples. Focusing on WNK2, we used Sanger sequencing and qPCR to evaluate all the coding exons and copy numbers of that gene in an additional 554 HCC samples. We also explored the functional effect and mechanism of WNK2 on tumor growth and metastasis. Results We identified 5 genes (WNK2, RUNX1T1, CTNNB1, TSC1, and TP53) harboring somatic mutations that correlated with early tumor recurrence after curative resection in 182 primary HCC samples. Focusing on WNK2, the overall somatic mutation and copy number loss occurred in 5.3% (39/736) and 27.2% (200/736), respectively, of the total 736 HCC samples. Both types of variation were associated with lower WNK2 protein levels, higher rates of early tumor recurrence, and shorter overall survival. Biofunctional investigations revealed a tumor-suppressor role of WNK2: its inactivation led to ERK1/2 signaling activation in HCC cells, tumor-associated macrophage infiltration, and tumor growth and metastasis. Conclusions Our results delineate genomic events that characterize Chinese HCCs and identify WNK2 as a driver of early HCC recurrence after curative resection. Lay summary We applied next-generation sequencing and conducted an in-depth genomic analysis of hepatocellular carcinomas from a Chinese patient cohort. The results delineate the genomic events that characterize hepatocellular carcinomas in Chinese patients and identify WNK2 as a driver associated with early tumor recurrence after curative resection.

Background The venous thromboembolism, which may be caused by increased platelet activation, is a risk factor for tumor prognosis. We determined the platelet activation status for diagnosis and predicting postoperative prognosis of hepatocellular carcinoma. Methods We conducted a prospective study of 191 patients diagnosed with HCC at Zhongshan Hospital from April 2016 to July 2016 as well as 99 healthy people. The platelet activation status was assessed by 2 platelet markers, PAC-1 and CD62p, using flow cytometry. The patients were treated with TACE or resection and monitored for ≥6 months. The diagnostic value of marker-positive platelets was determined by the receiver operating characteristic curve and the postoperative value were analyzed using the Kaplan-Meier method and COX regression model. Results All the 3 groups with high levels of marker-positive platelets were likely to be diagnosed with HCC and the PAC-1+ percentage had the best efficacy. The univariate analysis showed that the levels of PAC-1+ and CD62p+ platelets was risker factors for poor postoperative prognosis after both TACE and resection. Moreover, the multivariate analysis revealed that the level of PAC-1+ platelets was an independent risk factor for poor prognosis. Conclusions The PAC-1+ percentage of platelets is a new indicator for diagnosis and predicting postoperative prognosis.

Long noncoding RNAs (lncRNAs) are implicated as novel drivers in hepatocellular carcinoma (HCC), but the underlying mechanisms of this relationship with hepatocarcinogenesis are unknown. We report a novel, liver-specific lncRNA LINC01093 that shows significant downregulation in HCC tissues. LINC01093 expression is inversely correlated with cancer embolus and HCC TNM stage and as a prognostic predictor for HCC patients. LINC01093 overexpression significantly suppresses HCC cell proliferation and metastasis in vitro and in vivo. Conversely, its knockdown promotes HCC progression. Mechanistic analyses indicate that LINC01093 directly binds insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), interfering with interaction between IGF2BP1 and glioma-associated oncogene homolog 1 (GLI1) mRNA. The result is degradation of GLI1 mRNA, further affecting expression of GLI1 downstream molecules involved in HCC progression. The liver-enriched lncRNA LINC01093 is a promising prognostic indicator for HCC patients, and the newly identified LINC01093-IGF2BP1-GLI1 axis shows potential for therapeutic targets in HCC.

Patients with Barcelona Clinic Liver Cancer (BCLC) 0+A are considered to have early-stage hepatocellular carcinoma (HCC). The albumin-bilirubin (ALBI) grade is a significant predictor of overall survival (OS) for HCC. However, data are lacking to support its significance for patients with early-HCC.We recruited 318 patients with early-HCC who underwent curative resection between January 2012 and August 2013. The Kaplan-Meier method and log-rank tests were used to compare OS of patients with different ALBI grades. Cox regression analysis was applied to evaluate ALBI grade as an independent predictor of OS.Early-HCC patients with ALBI grade II experienced significantly shorter OS (p0.001) and higher death rates. In the Child-Pugh (C-P) grade-A group, patients with ALBI grade I had a more favorable prognosis than those with grade II (p0.001), while the C-P grade did not distinguish patients with poor prognosis from the entire group. Cox regression analysis demonstrated that ALBI grade was the most significant independent predictor of OS, and the ALBI grade retained its clinical significance in low α-fetoprotein subgroup.ALBI grade predicted OS in patients with early-HCC. Reclassification of C-P grade according to ALBI grade might improve the management of HCC.

Summary Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8+ T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8+ T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC. The enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed potential immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8+ T cells. Our comprehensive picture of the HCC ecosystem provides deeper insights into immune evasion mechanisms associated with tumor relapse.

Hepatocellular carcinoma (HCC) has a high relapse rate and low 5-year survival rate. We generated > 20,000 full-length single-cell transcriptomes from 19 primary or relapsed HCC patients, determining unique features of the tumor microenvironment in relapsed as compared to primary HCC. Relapsed tumors have reduced regulatory T cells, and increased dendritic cells (DCs) and infiltrated CD8+ T cells. CD8+ T cells from relapsed tumors show group 2 innate lymphoid cell like state, with high naive, low cytotoxic and exhausted signals. The abundance of distinct DC subtypes is associated with good prognosis in primary or relapsed HCC, while FCN1+ monocytes are associated with poor prognosis only in relapsed HCC. Differentially expressed genes and interactions analyses reveal potential mechanisms driving immune evasion and tumor survival in relapsed and primary HCC. Together these results provide a compressive understanding of the ecosystem in primary and relapsed tumors, guiding future immune therapy strategies in HCC.

Background Soluble programmed death-ligand 1 (sPD-L1) is associated with hepatocellular carcinoma (HCC) prognosis after resection or radiotherapy. However, its value in patients who received transcatheter arterial chemoembolization (TACE) remains unclear. The present study aimed to determine the prognostic significance of sPD-L1 in TACE subgroup. Methods 114 HCC patients with hepatitis B virus (HBV)-background who received TACE from 2012 to 2013 were recruited. sPD-L1 levels were determined by enzyme-linked immunosorbent assay. We evaluated prognoses according to mRESIST criteria and analyzed prognostic values by Cox regression and Kaplan-Meier analysis. We further evaluated correlations between sPD-L1 and systemic inflammation index (SII), soluble interleukin-2 receptor (sIL-2R), IL-10, hepatitis B virus (HBV)-DNA loads, and C-reactive protein. Results Significantly elevated sPD-L1 levels were found in patients who developed HCC progression (P = 0.002) and death (P Conclusions sPD-L1 level is a prognostic indicator of poor outcomes after TACE. High sPD-L1 indicated increased immune activation in an immunosuppressive environment that hindered anti-tumor response activity. Lowering sPD-L1 levels may provide a novel avenue for preventing HCC progression post-TACE. Legal entity responsible for the study The authors. Funding The National Natural Science Foundation of China (87172263 and 81572064) and Key Developing Disciplines of Shanghai Municipal Commission of Health and Family Planning (2015ZB0201). Disclosure All authors have declared no conflicts of interest.

Extracellular pH of solid tumor is generally acidic due to excessive glycolysis and poor perfusion. But whether acidic tumor microenvironment influenced the stromal cells infiltrating in tumor remains unknown. As the predominant progenitor of stromal cells in liver, the number of activated hepatic stellate cells (HSCs) was found positively correlated to the acidification level in the tumor tissues of HCC patients in our study. Whereas, in vitro acidic culture condition and in vivo co-implanting xenograft model were adopted to study the response of HSCs and its influence on HCC progression. HSCs were activated under acidic culture condition depending on the phosphorylation of cellular signal-regulated kinase (ERK). Acidity-activated HSCs promoted HCC metastasis in vitro and in vivo. Osteopontin (OPN) excretion from HSCs was increased under acidic condition and proved to promote the migration of HCC cells. Furthermore, the expression level of OPN was significantly associated with myofibroblasts and the combination of α-SMA with OPN was a powerful predictor for poor prognosis of HCC patients. Activation of HSCs in acidic tumor microenvironment represents a novel mechanism for HCC metastasis and provides a potential therapeutic strategy for HCC.

This brief studies the causal consensus problem of singular (descriptor) multi-agent systems with networked communication delays and agents described by general singular systems. For the studied systems, only the information of outputs are available through the network. An observer-based networked predictive control scheme is employed to compensate for the communication delays actively. Furthermore, based on the output feedback, observer and the networked predictive control scheme, a novel protocol is proposed in this paper. By using the tools of graph, algebra and singular system theory, the necessary and sufficient conditions are given for the existence of the proposed protocol to solve the considered consensus problem. The given conditions depend on not only the topologies of singular multi-agent systems but also the structure properties of each agent dynamics. Moreover, a consensus algorithm is proposed to design the novel observer-based predictive protocol. A numerical example demonstrates the effectiveness of compensation for networked delays using the provided consensus algorithm.

BACKGROUND: The prognostic role of diabetes mellitus (DM) coexisting with hepatocellular carcinoma (HCC) remains controversial. To clarify its impact on survival in HCC patients after curative treatments, a meta-analysis was performed. DATA SOURCES: Eligible studies were identified through multiple search strategies in the databases PubMed (MEDLINE), EMBASE, the Cochrane Library and ACP Journal Club between January 1950 and March 2010. Ten studies fulfilled the inclusion criteria, and data were aggregated comparing overall survival and recurrence-free survival in HCC patients according to DM status. RESULTS: The pooled hazard ratios (HRs) estimate for overall survival was 1.34 (95% CI, 1.18-1.51; P