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Hepatitis B virus (HBV) infection is a major factor responsible for HBV+ hepatocellular carcinoma (HCC).An immunological classification of HBV+ HCC may provide both biological insights and clinical implications for this disease.Based on the enrichment of 23 immune signatures, we identified two immune-specific subtypes (Imm-H and Imm-L) of HBV+ HCC by unsupervised clustering. We showed that this subtyping method was reproducible and predictable by analyzing three different datasets.Compared to Imm-L, Imm-H displayed stronger immunity, more stromal components, lower tumor purity, lower stemness and intratumor heterogeneity, lower-level copy number alterations, higher global methylation level, and better overall and disease-free survival prognosis. Besides immune-related pathways, stromal pathways (ECM receptor interaction, focal adhesion, and regulation of actin cytoskeleton) and neuro-related pathways (neuroactive ligand-receptor interaction, and prion diseases) were more highly enriched in Imm-H than in Imm-L. We identified nine proteins differentially expressed between Imm-H and Imm-L, of which MYH11, PDCD4, Dvl3, and Syk were upregulated in Imm-H, while PCNA, Acetyl-a-Tubulin-Lys40, ER-α_pS118, Cyclin E2, and β-Catenin were upregulated in Imm-L.Our data suggest that "hot" tumors have a better prognosis than "cold" tumors in HBV+ HCC and that "hot" tumors respond better to immunotherapy.

Metabolic reprogramming is a hallmark of cancer, including hepatocellular carcinoma (HCC). However, its role in HCC remains to be elucidated. Herein, we identified GTP cyclohydrolase 1 (GCH1), the first rate-limiting enzyme in tetrahydrobiopterin (BH4) de novo biosynthesis, as a novel metabolic regulator of HCC. GCH1 was frequently down-regulated in HCC tissues and cell lines by promoter methylation. Low GCH1 expression was associated with larger tumor size, increased tumor number, and worse prognosis in two independent cohorts of HCC patients. Functionally, GCH1 silencing promoted HCC growth in vitro and in vivo, while GCH1 overexpression exerted an opposite effect. The metabolite BH4 inhibited HCC growth in vitro and in vivo. GCH1 silencing exerted its growth-promoting effect through directly inhibiting BH4 de novo biosynthesis. Mechanistically, GCH1 silencing activated ASK1/p38 signaling; pharmacological or genetic inhibition of ASK1 or p38 abolished GCH1 silencing-induced growth-promoting effect. Further mechanistic studies found that GCH1 silencing-induced BH4 reduction resulted in an increase of intracellular superoxide anion levels in a dose-dependent manner, which mediated the activation of ASK1/p38 signaling. Collectively, our study reveals that epigenetic silencing of GCH1 promotes HCC growth by activating superoxide anion-mediated ASK1/p38 signaling via inhibiting BH4 de novo biosynthesis, suggesting that targeting GCH1/BH4 pathway may be a promising therapeutic strategy to combat HCC.

Adenoid hypertrophy is a pathological hyperplasia of the adenoids, which may cause snoring and apnea, as well as impede breathing during sleep. The lateral cephalogram is commonly used by dentists to screen for adenoid hypertrophy, but it is tedious and time-consuming to measure the ratio of adenoid width to nasopharyngeal width for adenoid assessment. The purpose of this study was to develop a screening tool to automatically evaluate adenoid hypertrophy from lateral cephalograms using deep learning. We proposed the deep learning model VGG-Lite, using the largest data set (1,023 X-ray images) yet described to support the automatic detection of adenoid hypertrophy. We demonstrated that our model was able to automatically evaluate adenoid hypertrophy with a sensitivity of 0.898, a specificity of 0.882, positive predictive value of 0.880, negative predictive value of 0.900, and F1 score of 0.889. The comparison of model-only and expert-only detection performance showed that the fully automatic method (0.07 min) was about 522 times faster than the human expert (36.6 min). Comparison of human experts with or without deep learning assistance showed that model-assisted human experts spent an average of 23.3 min to evaluate adenoid hypertrophy using 100 radiographs, compared to an average of 36.6 min using an entirely manual procedure. We therefore concluded that deep learning could improve the accuracy, speed, and efficiency of evaluating adenoid hypertrophy from lateral cephalograms.

The split-Hopkinson pressure bar (SHPB) and digital image correlation (DIC) techniques are combined to analyze the dynamic compressive failure process of coal samples, and the box fractal dimension is used to quantitatively analyze the dynamic changes in the coal sample cracks under impact load conditions with different loading rates. The experimental results show that the fractal dimension can quantitatively describe the evolution process of coal fractures under dynamic load. During the dynamic compression process, the evolution of the coal sample cracks presents distinct stages. In the crack propagation stage, the fractal dimension increases rapidly with the progress of loading, and in the crack widening stage, the fractal dimension increases slowly with the progress of loading. The initiation of the crack propagation phase of the coal samples gradually occurs more quickly with increasing loading rate; the initial cracks appear earlier. At the same loading time point, when the loading rate is greater, the fractal dimension of the cracks observed in the coal sample is greater.

Multiple mechanisms are involved in regulating hepatic ischemia‑reperfusion injury (IRI), in which Kupffer cells (KCs), which are liver‑resident macrophages, play critical roles by regulating inflammation and the immune response. Suberoylanilide hydroxamic acid (SAHA), a pan‑histone deacetylase inhibitor, has anti‑inflammatory effects and induces autophagy. To investigate whether SAHA ameliorates IRI and the mechanisms by which SAHA exerts its effects, an orthotopic liver transplantation (OLT) rat model was established after treatment with SAHA. The results showed that SAHA effectively ameliorated OLT‑induced IRI by reducing M1 polarization of KCs through inhibition of the AKT/glycogen synthase kinase (GSK)3β/NF‑κB signaling pathway. Furthermore, the present study found that SAHA upregulates autophagy 5 protein (ATG5)/LC3B in KCs through the AKT/mTOR signaling pathway and inhibition of autophagy by knockdown of ATG5 in KCs partly impaired the protective effect of SAHA on IR‑injured liver. Therefore, the current study demonstrated that SAHA reduces M1 polarization of KCs by inhibiting the AKT/GSK3β/NF‑κB pathway and upregulates autophagy in KCs through the AKT/mTOR signaling pathway, which both alleviate OLT‑induced IRI. The present study revealed that SAHA may be a novel treatment for the amelioration of OLT‑induced IRI.

Insufficient high-intensity focused ultrasound (HIFU) can promote the rapid progression of the residual tumor through the hypoxia inducible factor-2α +(HIF-2α)/vascular endothelial growth factor A (VEGFA)/ephrin type-A receptor 2 (EphA2) pathway. Although sorafenib has been shown to significantly improve the survival of patients with advanced liver cancer, the use of sorafenib in residual tumor tissues following HIFU has rarely been elucidated. Thus, this study aimed to investigate the potential adjuvant therapeutic effects of sorafenib following HIFU in order to reduce the relapse rate following insufficient HIFU.Xenograft tumors were established using nude mice injected with liver cancer cells. At approximately 4 weeks after the inoculation of the tumor cells (tumors reached 1.3-1.5 cm), all mice were randomly divided into 3 groups as follows: i) The control group (no treatment); ii) the HIFU-alone group, and iii) the combination group (HIFU + sorafenib), with 6 mice per group. The residual tumor volume was determined among the different treatment groups. The protein expression levels of HIF-2α, VEGFA and EphA2 were determined by immunohistochemistry and western blotting, and the mRNA levels were detected by RT-qPCR. The microvessel density (MVD) was calculated by CD31 immunohistochemistry staining.The results revealed that by comparing the control group, insufficient HIFU promoted HIF-2α, VEGFA and EphA2 expression (P0.05). Compared with the HIFU-alone group, the protein and mRNA levels of HIF-2α, VEGFA and EphA2 were markedly decreased in the group that received combined treatment with HIFU and sorafenib (P0.05). Similar results were obtained for MVD expression. Synergistic tumor growth inhibitory effects were also observed between the control group and HIFU group (P0.05).The findings of this study demonstrate that the expression of HIF-2α, VEGFA and EphA2 can be inhibited by sorafenib, and that sorafenib is likely to provide an effective adjunct treatment for patients with HCC following HIFU ablation.

Cigarette smoke is a known risk factor for urothelial carcinoma (UC). However, there is limited information about the distributions and effects of volatile organic compounds (VOCs) on smoking-related UC risk. With this hospital-based case-control study, we explored the associations between urinary levels of cotinine and VOC metabolites (acrylamide, 1,3-butadiene, and benzene) and the risk of UC. Urological examinations and pathological verifications were used to confirm the diagnoses of UC. All study participants provided smoking-related information via questionnaires and face-to-face interviews; they also provided urine samples for the measurement of VOC metabolites, cotinine, and 8-hydroxydeoxyguanosine (8-OHdG), which was used as an indicator of oxidative stress. We applied multiple logistic regression analysis to estimate the risk of UC, and we found that levels of urinary cotinine and 8-OHdG were higher in the UC group than in the control group. Furthermore, urinary levels of VOC metabolites, including N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine, N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine-3, trans,trans-muconic acid (t,t-MA), and S-phenylmercapturic acid (SPMA), increased with increasing levels of urinary cotinine. After adjusting for potential risk factors, dose–response relationships were observed between UC risk and urinary levels of AAMA, t,t-MA, SPMA, and 8-OHdG. Participants with high urinary levels of cotinine, AAMA, t,t-MA, SPMA, and 8-OHdG had risks of UC that were 3.5- to 6-fold higher than those of participants with lower levels. Future, large-scale investigations of the risks of UC should be explored, and repeated measurement of VOC metabolites should be assessed.

AIM To evaluate the prognostic value of the number of retrieved lymph nodes (LNs) and other prognostic factors for patients with distal cholangiocarcinomas, and to determine the optimal retrieved LNs cut-off number. METHODS The Surveillance, Epidemiology and End Results database was used to screen for patients with distal cholangiocarcinoma. Patients with different numbers of retrieved LNs were divided into three groups by the X-tile program. X-tile from Yale University is a useful tool for outcome-based cut-point optimization. The Kaplan-Meier method and Cox regression analysis were utilized for survival analysis. RESULTS A total of 449 patients with distal cholangiocarcinoma met the inclusion criteria. The Kaplan-Meier survival analysis for all patients and for N1 patients revealed no significant differences among patients with different retrieved LN counts in terms of overall and cancer-specific survival. In patients with node-negative distal cholangiocarcinoma, patients with four to nine retrieved LNs had a significantly better overall (P = 0.026) and cancer-specific survival (P = 0.039) than others. In the subsequent multivariate analysis, the number of retrieved LNs was evaluated to be independently associated with survival. Additionally, patients with four to nine retrieved LNs had a significantly lower overall mortality risk [hazard ratio (HR) = 0.39; 95% confidence interval (CI): 0.20-0.74] and cancer cause-specific mortality risk (HR = 0.32; 95%CI: 0.15-0.66) than other patients. Additionally, stratified survival analyses showed persistently better overall and cancer-specific survival when retrieving four to nine LNs in patients with any T stage of tumor, a tumor between 20 and 50 mm in diameter, or a poorly differentiated or undifferentiated tumor, and in patients who were ≤ 70-years-old. CONCLUSION The number of retrieved LNs was an important independent prognostic factor for patients with node-negative distal cholangiocarcinoma. Additionally, patients with four to nine retrieved LNs had better overall and cancer-specific survival rates than others, but the reason and mechanism were unclear. This conclusion should be validated in future studies.

// Kun He 1 , Xiwen Zhu 1 , Yan Liu 4 , Chunmu Miao 1 , Tao Wang 1 , Peizhi Li 1 , Lei Zhao 2 , Yaxi Chen 2 , Junhua Gong 1 , Can Cai 4 , Jinzheng Li 1 , Shengwei Li 1 , Xiong Z. Ruan 2, 3 , Jianping Gong 1 1 Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China 2 Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China 3 Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, United Kingdom 4 Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China Correspondence to: Jianping Gong, email: gongjianping11@126.com Shengwei Li, email: lishengwei11@163.com Keywords: NLRP3 inflammasome, Kupffer cell, non-alcoholic fatty liver disease, IL-1β Received: March 20, 2017 Accepted: April 17, 2017 Published: April 27, 2017 ABSTRACT NOD-like receptor (NLR) NLRP3 inflammasome activation has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It has been also shown that palmitic acid (PA) activates NLRP3 inflammasome and promotes interleukin-1β (IL-1β) secretion in Kupffer cells (KCs). However, the specific mechanism of the NLRP3 inflammasome activation is unclear. We studies the molecular mechanisms by investigating the roles of Thioredoxin-interacting protein (TXNIP) and NLRP3 on NAFLD development in patients, high-fat diet (HFD)-induced NAFL and methionine choline deficient (MCD) diet-induced NASH in wild type (WT), TXNIP −/− (thioredoxin-interacting protein) and NLRP3 −/− mice, and isolated KCs. We found that the expressions of NLRP3 and TXNIP in human liver tissues were higher in NASH group than in NAFL group. Furthermore, co-immunoprecipitation analyses show that activation of the TXNIP-NLRP3 inflammasome protein complex occurred in KCs of NASH WT mice rather than NAFL WT mice, thus suggesting that the formation and activation of this protein complex is mainly involved in the development of NASH. NLRP3 −/− mice exhibited less severe NASH than WT mice in MCD diet model, whereas TXNIP deficiency enhanced NLRP3 inflammasome activation and exacerbated liver injury. PA triggered the activation and co-localization of the NLRP3 inflammasome protein complex in KCs isolated from WT and TXNIP −/− but not NLRP3 −/− mice, and most of the complex co-localized with mitochondria of KCs following PA stimulation. Taken together, our novel findings indicate that TXNIP plays a protective and anti-inflammatory role in the development of NAFLD through binding and suppressing NLRP3.

Additional file 1. PVAT promotes destabilization of atherosclerotic plaque.

Background Perivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque. Methods We transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE−/−) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT. Results Ultrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in adipocytes under ER stress which would be suppressed by 4-PBA. In addition, ER stress enhanced NF-κB binding to the promoter of the mouse GM-CSF gene in adipocytes confirmed by Chromatin immunoprecipitation analyses. Conclusions Our findings demonstrate that ER stress in PVAT destabilizes atherosclerotic plaque, in part through increasing GM-CSF paracrine via transcription factor NF-κB. Electronic supplementary material The online version of this article (10.1186/s12967-018-1481-z) contains supplementary material, which is available to authorized users.

Rapid growth of residual tumors can occur as a result of their recurrence and progression. The present study aimed to investigate the expression of hypoxia inducible factor-2 subunit α (HIF-2α), vascular endothelial growth factor A (VEGFA), erythropoietin-producing hepatocellular A2 (EphA2) and angiogenesis in residual hepatocellular carcinoma (HCC), following treatment with high-intensity focused ultrasound (HIFU) ablation, in order to investigate the association between protein expression and tumor recurrence and growth. Athymic BALB/c (nu/nu) mice were subcutaneously inoculated with the HCC cell line HepG2, in order to create xenograft tumors. Approximately 30 days post-inoculation, eight mice were treated with HIFU, whereas eight mice received no treatment and acted as the control group. Residual tumor tissues were obtained from the experimental groups after one month. Levels of HIF-2α, VEGFA, EphA2 and cluster of differentiation 31 (CD31) expression was measured by immunohistochemical staining. CD31-positive vascular endothelial cells were counted to calculate microvascular density (MVD), and western blot analysis was performed to determine levels of HIF-2α, VEGFA, and EphA2 protein. It was found that the expression levels of HIF-2α, VEGFA, EphA2, and MVD proteins in residual HCC tissues were significantly higher than in the control group tissues (P

Brake has a long engineering development history and has been widely applied on mechanical components from abstain from dynamic motion. There are many different types of brake mechanism, such as using tension cable, hydraulics and electronics. According to Automotive Research and Testing Center in Taiwan [1], electronics brake is becoming a very popular and is the main stream solution for brake mechanism. In addition, electronics brake using electromagnetic field for actuating power source has been widely developed in the recent years. However, brake system with smart fluid (i.e. Magneto-Rheological or Electro-Rheological Fluid) as brake mechanism has not been a common research development topic until recent year. The world’s first commercial MR fluid brake was invented by Lord Corp. [2] which was shown in Fig. 1. In 2003, Li, W. H and Du, H. has proposed an idea of applying electromagnetic as the source of excitation for the MR fluid brake [3]. However, a significant problem has been pointed out by the research suggesting that thermal effect is the major issue in preventing the MR fluid from performing the designed task. Evidently, heat is generated when the electric current passes through the coil of the electromagnetics.Copyright © 2016 by ASME

FcγRIIIa (CD16) is a low-affinity Fc receptor of IgG. As the idio-binding receptor of IgG Fc, it plays an important role in the antibody-dependent cellular cytotoxicity of natural killer cells. The aim of the present study was to investigate the distribution of Kupffer cells (KCs) and the expression of their surface receptor FcγRIIIa in hepatocellular carcinoma. Furthermore, we also aimed to observe the functional mechanism of FcγRIIIa. Immunohistochemical analysis was employed to study KCs and FcγRIIIa. In order to explore the role of FcγRIIIa in the growth of cancer cells, KCs and H22 tumor cells were co-cultured in different serum. The mRNA expression levels of tumor necrosis factor (TNF)-α and FcγRIIIa were analyzed by RT-qPCR; the TNF-α and FcγRIIIa protein expression levels were examined by enzyme‑linked immunosorbent assay and western blot analysis, respectively. Our results showed that the number of Kuppfer cells in cancerous tissues (21.6±7.8) was lower than those in para-cancerous (68.8±9.1) tissues and adjacent normal hepatic tissues (62.0±1.9) (P

Normal hepatocytes express connexin32 (Cx32), which forms gap junctions at cell‑cell contact areas. The aim of the present study was to investigate whether Cx32 mediates the cell death‑inducing effects of ultrasound microbubbles carrying the herpes simplex virus thymidine kinase (HSV‑TK) suicide gene against hepatocellular carcinoma cells in vitro and in vivo. HepG2 cells were exposed to different concentrations of trans‑retinoic acid (ATRA) in culture, to evaluate the intrinsic antitumor effect of ATRA. Detailed in‑vitro and in‑vivo investigations on the antitumor effects of ATRA via Cx32 mediation were performed, and the possible underlying mechanisms of action of the compound were then examined. The gene expression of HSV‑TK transfected by ultrasound wave irradiation in the HepG2 cells was quantified using reverse transcription‑quantitative polymerase chain reaction analysis. The effects on cell death were assessed using an MTT assay. The protein expression levels of Cx32 in ATRA‑untreated or ATRA‑treated tissues were quantified by immunohistochemical analysis and Western blot assays. The HSV‑TK gene was successfully transfected into the HepG2 cell using ultrasound wave irradiation, and was stably expressed. Compared with the other groups, the HSV‑TK gene group treated with ATRA exhibited an increased number of apoptotic cells (P