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.
Hypervirulent variants of Klebsiella pneumoniae (hvKp) that cause invasive community-acquired pyogenic liver abscess (PLA) have emerged globally. Little is known about the virulence determinants associated with hvKp, except for the virulence genes rmpA/A2 and siderophores (iroBCD/iucABCD) carried by the pK2044-like large virulence plasmid. Here, we collected most recent clinical isolates of hvKp from PLA samples in China, and performed clinical, molecular, and genomic sequencing analyses. We found that 90.9% (40/44) of the pathogens causing PLA were K. pneumoniae. Among the 40 LA-Kp, K1 (62.5%), and K2 (17.5%) were the dominant serotypes, and ST23 (47.5%) was the major sequence type. S1-PFGE analyses demonstrated that although 77.5% (31/40) of the LA-Kp isolates harbored a single large virulence plasmid varied in size, 5 (12.5%) isolates had no plasmid and 4 (10%) had two or three plasmids. Whole genome sequencing and comparative analysis of 3 LA-Kp and 3 non-LA-Kp identified 133 genes present only in LA-Kp. Further, large scale screening of the 133 genes in 45 LA-Kp and 103 non-LA-Kp genome sequences from public databases identified 30 genes that were highly associated with LA-Kp, including iroBCD, iucABCD and rmpA/A2 and 21 new genes. Then, these 21 new genes were analyzed in 40 LA-Kp and 86 non-LA-Kp clinical isolates collected in this study by PCR, showing that new genes were present 80–100% among LA-Kp isolates while 2–11% in K. pneumoniae isolates from sputum and urine. Several of the 21 genes have been proposed as virulence factors in other bacteria, such as the gene encoding SAM-dependent methyltransferase and pagO which protects bacteria from phagocytosis. Taken together, these genes are likely new virulence factors contributing to the hypervirulence phenotype of hvKp, and may deepen our understanding of virulence mechanism of hvKp.
Background
Resistance to chemotherapeutic treatment is a common phenomenon in cancers, especially in hepatocellular carcinoma (HCC). The Hippo signaling pathway has been demonstrated to play a role in tumor initiation, development, and progression. However, little is known about its roles in the HCC chemoresistance.
Methods
In this study, real-time PCR and western blotting were used to identify the expression profile of key components of Hippo signaling pathway between chemoresistant and chemosensitive HCC cell lines.
In vitro
and
in vivo
loss- and gain-of-function studies were performed to reveal the effects and related mechanism of microRNA-590-5p/YAP1 axis in the chemoresistant phenotype of HCC cells.
Findings
We identified yes-associated protein 1 (YAP1) as the major dysregulated molecules in adriamycin (ADR)-resistant HCC cells. YAP1 was profoundly implicated in the chemoresistant phenotype of HCC cells. Furthermore, microRNA-590-5p was revealed as a functional modulator of YAP1. Importantly, YAP1-mediated chemoresistant phenotype was closely related to increased expression of stemness markers and ATP-binding cassette transporters. HCC patients with poor response to transarterial chemoembolization (TACE) treatment had higher protein level of YAP1 than that in the responsive patients.
Interpretation
The microRNA-590-5p/YAP axis plays an important role in the chemotherapeutic resistance of HCC cells, suggesting new adjuvant chemotherapeutic directions in HCC.
Fund
National Natural Science Foundation of China, Zhejiang Province Medical and Health Care Key Project, Experimental Animal Science and Technology Projects of Zhejiang Province, Public Welfare Technology Application Research Project of Lishui, Chinese Medicine Science and Technology Projects of Zhejiang Province.
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.
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.
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