Jianfei Tu

Regulatory T cells, especially ICOS + FOXP3 + regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival

Hepatocellular carcinoma (HCC) is a common malignant tumour, especially in Asia. Its prognosis is poor, and there are limited methods for predicting patient survival. This study was carried out to analyse the prognostic value of tumour-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in HCC patients. TILs were analysed in 57 randomly selected HCC patients. The prognostic effects of groups with high and low numbers were evaluated by the Kaplan-Meier and Cox model analyses. Although higher densities of CD3+, CD4+, and CD8+ cytotoxic lymphocytes (CTLs) as well as CD56+ NK cells and CD68+ macrophages were observed in peritumoural tissue, increased numbers of forkhead/winged helix transcription factor P3+ (FOXP3+) Tregs were found in intratumoural tissue. Additionally, regarding ICOS+ FOXP3+ Tregs, an increased prevalence in carcinoma was not only associated with the absolute number but also with the percentage of FOXP3+ cells. Higher Treg levels in tumour tissues indicated a worse prognosis, and the FOXP3+ Tregs/CD4+ T cells ratio was an independent prognostic factor for OS. Therefore, FOXP3+ Tregs, especially ICOS+ FOXP3+ Tregs, contribute to the immunosuppressive HCC microenvironment. High tumour-infiltrating Tregs are thought to be an unfavourable prognostic indicator of HCC.

Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer

Abstract Emerging evidence implicates an important role for myeloid‐derived suppressor cells (MDSCs) in tumor growth, angiogenesis and metastasis. However, limited knowledge is known about the function of MDSCs in response to chemotherapies. In this study, we find that drug‐resistant hepatocellular cancer (HCC) cells‐derived conditioned medium significantly enhances the expansion and immunosuppressive function of MDSCs compared to their parental sensitive cells, which is demonstrated by increased level of arginase, nitric oxide (NO), and reactive oxygen species (ROS). Next, we reveal that drug‐resistant HCC cells‐derived IL‐6 activated MDSCs, which is demonstrated by using an anti‐IL‐6 neutralizing antibody that caused a reduced MDSC immunosuppressive activity. More importantly, the depletion of MDSC via the administration of anti‐Gr‐1 antibody or the blockade of IL‐6 signaling sensitized 5‐FU‐resistant H22 hepatoma to chemotherapy in the immunocompetent C57BL/6N mice. In primary human HCC, IL‐6 expression levels strongly correlate with an MDSC phenotype and chemotherapy response in HCC patients. In conclusion, these results describe a role of IL‐6 in the drug resistance in HCC chemotherapy and suggest that MDSC‐targeting treatments may be potential therapeutic strategy for HCC chemoresistance. Graphical abstract Figure. No Caption available. HighlightsDrug‐resistant HCC cells‐derived IL‐6 enhances the expansion and activity of MDSCs;MDSC depletion or IL‐6 blockade enhances the therapeutic efficacy of chemotherapy;IL‐6 expression correlates with the markers of MDSCs and chemotherapy response.

Mast Cells Comprise the Major of Interleukin 17-Producing Cells and Predict a Poor Prognosis in Hepatocellular Carcinoma.

AbstractIL-17 and IL-17-producing cells have been found in many types of human cancers and murine models. However, the source of tumor-infiltrating IL-17 and IL-17-producing cells in HCC and the prognostic values remain poorly understood.A total of 57 HCC patients were enrolled in this study, and immunofluorescence double stain was used to evaluate the colocalization of CD3+ T cells, CD4+ T cells, CD56+ NK cells, CD20+ B cells, CD68+ Macrophages, and MCT+ mast cells with IL-17. The prognostic value of IL-17-producing cells was evaluated by Kaplan–Meier analysis and Cox regression model.MCT+ mast cells, but not other cells, were the predominant IL-17-producing cell type. Overall survival analysis revealed that the increasing intratumoral-infiltrated MCT+ mast cells were significantly associated with poor prognosis. Immunofluorescence double stain showed a positive correlation between the number of MCT+ mast cells and MCVs.These findings indicated the major IL-17-producing cells in HCC were MCT+ mast cells and these cells infiltration may promote tumor progression by angiogenesis. Increased MCT+ mast cells was associated with a poor prognosis, indicating therapy targeting MCT+ mast cells might be an effective strategy in controlling intratumor IL-17 infiltration and MCVs.

The incidence and outcome of major complication following conventional TAE/TACE for hepatocellular carcinoma

Abstract To investigate the incidence and outcome of major complication following conventional transarterial embolization/chemoembolization (TAE/TACE) therapy for hepatocellular carcinoma (HCC). From May 2010 to May 2016, all patients with major complication following conventional TAE/TACE for HCC were included. Major complication was defined as admission to a hospital for therapy, an unplanned increase in the level of care, prolonged hospitalization, permanent adverse sequelae, or death after conventional TAE/TACE therapy by Society of Interventional Radiology. During the study period, a total of 2863 TAE/TACE procedures were performed among 1120 patients, and a total of 24 patients (21 male and 3 female) developed major complication with the incidence of 2.1% (24/1120) per patient and 0.84% (24/2863) per TAE/TACE procedure. The major complications were liver rupture (n = 6), liver abscess (n = 5), femoral artery pseudoaneurysm (n = 3), cholecystitis (n = 2), biloma (n = 2), pulmonary embolism (n = 2), and 1 each of the following: cerebral lipiodol embolism, tumor lysis syndrome, partial intestinal obstruction, gallbladder perforation. The mean interval from last TAE/TACE procedure to the diagnosis of major complication was 11.1 ± 7.7 days. The treatments of the complications were conservative treatment (n = 12), conservative treatment plus percutaneous drainage (n = 3), ultrasound-guided thrombin injection (n = 3), conservative treatment plus TAE (n = 2), and conservative treatment plus surgery (n = 2). Of the 24 patients, 20 patients were recovered, and remaining 4 patients were died of major complications; therefore, the mortality rate of major complication was 16.7% (4/24). Major complication following conventional TAE/TACE therapy is uncommon; the outcomes are benign of most major complications, but some are mortality.

MiR-155 and its functional variant rs767649 contribute to the susceptibility and survival of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks the fourth common cancer and the third common cause of cancer mortality among Chinese population. The development of hepatocellular carcinoma (HCC) were confirmed to be involved in complex interactions between environmental and genetic factors. MicroRNAs (miRNAs) have been found to play an important role in tumorigenesis and metastasis. Emerging evidence suggested that upregulation of miR-155, one of the best characterized miRNAs, could serve as a promising marker for the diagnosis and prognosis of many cancers, except for HCC. In current we tested the hypothesis that functional variant rs767649 located in the flanking region of miR-155 gene contributes to the development and survival of HCC. We identified that functional variant rs767649 in miR-155 regulation region was associated with risk and survival of HCC. The minor allele of rs767649 was significantly associated with an increased risk of HCC (OR=1.23, 95% CI=1.11-1.36, P = 7.97×10-5). The genotype TT of rs767649 was significantly associated with a 1.94 fold poor survival of HCC (HR=1.94, 95% CI=1.01-3.79), while 1.15 fold for genotype AT (HR=1.15, 95% CI=1.06-1.25). Results showed that miR-155 was highly overexpressed in HCC tissues, compared with the adjacent normal tissues (P<0.001). The allele T contributes to higher expression of miR-155 in both the HCC tissues and the adjacent non-tumor tissues (P< 0.01). Our findings suggested that miR-155 and its functional variant rs767649 might contribute to the increased risk and poor prognosis of HCC, highlighting the importance of miR-155 in the prevention and prognosis of HCC.

NEAT1 upregulates TGF-β1 to induce hepatocellular carcinoma progression by sponging hsa-mir-139-5p

Increasing evidence has shown that the lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) play important roles in cell proliferation, migration, and invasion in various tumors. In our current study, we concentrated on the biological mechanisms of NEAT1 in hepatocellular carcinoma (HCC) development. It was found that NEAT1 was significantly increased in human HCC cell lines including Hep3B, LM3, MHCC97L, SK‐hep1, and HepG2 cells compared to the normal human liver cell line LO2. Meanwhile, we observed that hsa‐miR‐139‐5p was greatly decreased in HCC cells, which suggested a negative correlation between NEAT1 and hsa‐mir‐139‐5p. In addition, NEAT1 downregulation can restrain HCC cell growth, migration, and invasion. Consistently, overexpression of hsa‐mir‐139‐5p exerted a similar phenomenon. Dual‐luciferase reporter assay, RIP assay, and RNA pull‐down assay confirmed that NEAT1 can function as a ceRNA by sponging hsa‐mir‐139‐5p. In addition, TGF‐β1 was identified as a downstream target of hsa‐mir‐139‐5p and hsa‐mir‐139‐5p overexpression was able to suppress TGF‐β1 levels. Furthermore, it was indicated that TGF‐β1 inhibition can inhibit HCC cell growth, migration, and invasion ability. Taken these together, we speculated that NEAT1 can modulate TGF‐β1 expression by sponging hsa‐mir‐139‐5p in HCC. These data indicates that targeting the NEAT1/hsa‐mir‐139‐5p/TGF‐β1 axis could be a new strategy for HCC.

125 I brachytherapy of locally advanced non-small-cell lung cancer after one cycle of first-line chemotherapy：a comparison with best supportive care

Objectives The objective of this study was to assess the efficacy of computed tomography (CT)-guided 125I brachytherapy alone in improving the survival and quality of life of patients with unresectable locally advanced non-small-cell lung cancer (NSCLC) after one cycle of first-line chemotherapy. Patients and methods Sixteen patients with locally advanced NSCLC were treated with CT-guided 125I brachytherapy after one cycle of first-line chemotherapy (group A). Sixteen patients who received only best supportive care (group B) were matched up with the patients in group A. Primary end point included survival, and secondary end point included assessment of safety, effectiveness of CT-guided 125I brachytherapy, and improvement in the quality of life. Results The two groups were well balanced in terms of age, disease histology, tumor stage, tumor location, and performance status (P>0.05). The median follow-up time was 16 months (range, 3–30). The total tumor response rate was 75.0% in group A, which was significantly higher than that in group B (0.0%) (P<0.01). The median progression-free survival time was 4.80 months for patients in group A and 1.35 months for patients in group B (P<0.001). Kaplan–Meier survival analysis showed that the median survival time of group A was 9.4±0.3 months versus 8.4±0.1 months in group B (P=0.013). Tumor-related symptoms of patients were significantly relieved, and the quality of life was markedly improved in group A than in group B. Conclusion CT-guided 125I brachytherapy improved the survival of patients with locally advanced NSCLC and quality of life after one cycle of first-line chemotherapy compared with best supportive care.

Computed Tomography-Guided Radiofrequency Ablation Following Transcatheter Arterial Embolization in Treatment of Large Hepatic Hemangiomas

AbstractThe aim of the study was to evaluate the feasibility, safety, and efficacy of computed tomography (CT)-guided radiofrequency (RF) ablation combined with transcatheter arterial embolization (TAE) to treat large (≥10 cm) hepatic hemangiomas.We retrospectively reviewed our sequential experience with 15 large hepatic hemangiomas in 15 patients.The mean diameter of the 15 hemangiomas was 13.0 ± 2.2 cm (10.0–16.0 cm). RF ablation combined with TAE treatment was performed successfully in all patients. The mean diameter of the hemangiomas decreased from 13.0 ± 2.2 to 7.1 ± 2.0 cm (P < 0.001) after TAE treatment. Out of 15 hepatic hemangiomas, 14 (93.3%) showed no enhancement on CT or MRI indicating complete ablation after RF treatment. The mean diameter of the ablation zone decreased to 6.1 ± 2.0 cm 1 month after ablation and further decreased to 4.9 ± 1.6 cm 6 months after ablation. There were 6 complications related to the ablation in 4 patients. According to the Dindo–Clavien classification, all the complications were minor (Grade I).RF ablation combined with TAE is a safe and effective treatment for large hepatic hemangiomas. TAE can improve the disruption of lesion blood supply and reduce lesion size to facilitate subsequent RF ablation and reduce the risk of ablation-related complications.

ShRNA knock-down of CXCR7 inhibits tumour invasion and metastasis in hepatocellular carcinoma after transcatheter arterial chemoembolization

To investigate the effects of lentiviral vector‐mediated shRNA suppressing CXCR7 on tumour invasion and metastasis in hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). HCCLM3 cell lines were cultured and assigned into the CXCR7‐shRNA, negative control (NC) and blank groups. The qRT‐PCR and Western blotting were applied to detect the mRNA and protein expressions of CXCR7, CXCR4 and MMP‐2 in HCCLM3 cells. Cell proliferation and invasion were evaluated by MTT and Transwell assays. A Buffalo rat model of HCC was established. Fifty model rats were divided into the CXCR7‐shRNA + TACE, CXCR7‐shRNA, TACE, NC and control groups. Immunohistochemistry was performed to detect the expressions of CXCR7, MMP‐2, vascular endothelial growth factor (VEGF) and intratumoral CD31‐positive vessel count in tumour tissues of mice. Compared with the blank and NC groups, the mRNA and protein expressions of CXCR7 and MMP‐2 were decreased in the CXCR7‐shRNA group. The cell proliferation and invasion rates of the CXCR7‐shRNA group were lower than the blank and NC groups. At the 4th week after TACE, tumour weight of the CXCR7‐shRNA + TACE group increased continuously. The CXCR7‐shRNA + TACE group showed longer survival time and smaller tumour sizes than other groups. Compared with other groups, the CXCR7‐shRNA + TACE and CXCR7‐shRNA groups had less number of lung metastatic nodules and lower expressions of CXCR7, MMP‐2, VEGF and CD31‐positive vessel count. CXCR7‐shRNA inhibits tumour invasion and metastasis to improve the efficacy of TACE in HCC by reducing the expressions of CXCR7, MMP‐2 and VEGF.

Association of blood pressure level with nonalcoholic fatty liver disease in nonhypertensive population: Normal is not the new normal.

AbstractThe functional crosstalk between nonalcoholic fatty liver disease (NAFLD) and hypertension has been reported by some literatures; however, in nonhypertensive individuals, there is no article describes the characteristic of NAFLD. In this study, we aimed to determine the strength of the association between NAFLD with normal blood pressure (BP) in nonhypertensive individuals. This cross-sectional study was conducted in the sixth Affiliated Hospital of Wenzhou Medical University, from October 2007 to December 2011. In brief, 24,200 subjects were enrolled to participate in the survey. Among those subjects, there were 5305 enrolled subjects, those with filling the diagnostic criteria for NAFLD (21.9%; 4803 males and 502 females). Nonhypertension was identified in 17,403 (71.9%; 8179 males and 9224 females). The PR% of NAFLD for the systolic blood pressure (SBP) in quartiles 1 to 4 was 10.83, 12.55, 20.38, and 19.97. SBP, diastolic blood pressure (DBP), sex, age, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, fasting plasma glucose, uric acid, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol are closely associated with the risk for NAFLD. SBP (odds ratio [OR]: 1.092, 95% confidence interval [CI]: 1.030–1.158; P < 0.05) and DBP (OR: 1.157, 95%CI: 1.094–1.223; P < 0.05) were found to be independent risk factors for NAFLD. Our analysis indicates that BP is significantly associated with NAFLD in nonhypertensive individuals; SBP and DBP are found to be independent risk factors for NAFLD.