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Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

Society has been continuously changing and developing in various fields, the role and position of women have been increasingly altering and becoming important in society and in family. Korea and Vietnam have the same basic background in terms of Eastern culture and social context. These have strongly influenced gender conception and position. This article analyses the position and role of women in the two countries in the past and present. In order to conduct this research, we applied comparative cultural studies specifically, Affectual/ Consequential comparison, Parallel comparison, Synchronic and Diachronic comparison, Cross-cultural comparison and feminism perspective to highlight the similarities and differences in their position. The findings of the research disclose lots of similarities on the position of women in traditional and modern society as well as reveals no less differences in the assessment of women’s contributions to building and protecting the country, taking care of family and rearing children. Thus, the article will help the audience have a better understanding and knowledge of gender culture in the two countries., Dyskursy Młodych Andragogów/Adult Education Discourses, No. 23 (2022): DYSKURSY MŁODYCH ANDRAGOGÓW/ADULT EDUCATION DISCOURSES

Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23–dependent tumor necrosis factor–α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.

Cell-cell interactions between hepatocytes and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes hepatocyte (Hep) dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of NO. Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression.NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into neighboring hepatocytes to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. It's inhibitory action towards CcO specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo.Our findings provide a biochemical link between CYGB-absence in HSC and neighboring hepatocyte dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO.

Background and aims Antifibrotic therapy remains an unmet medical need in human chronic liver disease. We report the antifibrotic properties of cytoglobin (CYGB), a respiratory protein expressed in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis. Approach and results Cygb-deficient mice that had bile duct ligation-induced liver cholestasis or choline-deficient amino acid-defined diet-induced steatohepatitis significantly exacerbated liver damage, fibrosis, and reactive oxygen species (ROS) formation. All of these manifestations were attenuated in Cygb-overexpressing mice. We produced hexa histidine-tagged recombinant human CYGB (His-CYGB), traced its biodistribution, and assessed its function in HSCs or in mice with advanced liver cirrhosis using thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). In cultured HSCs, extracellular His-CYGB was endocytosed and accumulated in endosomes through a clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type 1 alpha 1 production and α-smooth muscle actin expression. Replacement the iron center of the heme group with cobalt nullified the effect of His-CYGB. In addition, His-CYGB induced interferon-β secretion by HSCs that partly contributed to its antifibrotic function. Momelotinib incompletely reversed the effect of His-CYGB. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis, and oxidative cell damage in mice administered TAA or DDC mice without adverse effects. RNA-sequencing analysis revealed the down-regulation of inflammation- and fibrosis-related genes and the up-regulation of antioxidant genes in both cell culture and liver tissues. The injected His-CYGB predominantly localized to HSCs but not to macrophages, suggesting specific targeting effects. His-CYGB exhibited no toxicity in chimeric mice with humanized livers. Conclusions His-CYGB could have antifibrotic clinical applications for human chronic liver diseases.

研究グループは、肝臓に移行した腸内細菌叢の成分であるリポタイコ酸が、肝がん微小環境を変化させてがんの増殖進展を促進するSASP(Senescence-associated secretory phenotype、細胞老化随伴分泌現象)因子を老化肝星細胞から放出させるメカニズムを明らかにしました。がんの組織はがん細胞そのものだけでなく、線維芽細胞や免疫細胞など、様々な種類の細胞種が集まって「がん微小環境」を構成しています。進行したがん組織の微小環境ではがん細胞周囲の細胞ががんの増殖を助長していると考えられています。本グループは、脂肪肝を素地とする肝がん微小環境では、肝星細胞と呼ばれる線維芽細胞が細胞老化を引き起こしており、「細胞老化随伴分泌現象(SASP)」という様々な分泌因子を放出する現象が生じ、その分泌因子(SASP因子)ががんの増殖を促進することを以前から見出していました。しかしこれまでにSASP因子の放出メカニズムについては明らかにされていませんでした。本研究では高脂肪食摂取による肥満誘導性肝がんのマウスモデルを用い、老化肝星細胞の細胞膜上にガスダーミンDというタンパク質が酵素切断されて生じたN末端側の部分(以降GSDMD－Nと略記)が集合して形成される小孔を介して、SASP因子に含まれるサイトカインIL-1βとIL-33が細胞の外部に放出されることを明らかにしました。また、高脂肪食摂取マウスでは、腸管バリアが脆弱化しており、肝臓にグラム陽性腸内細菌の細胞壁成分であるリポタイコ酸が蓄積していました。さらに、蓄積したリポタイコ酸は老化肝星細胞にトル様受容体２(TLR2)を介した刺激を入れ続け、酵素切断で生じたGSDMD－Nによる細胞膜上の小孔形成とそれに続くIL-33やIL-1βの放出を促進していることもわかりました。老化肝星細胞から放出されたIL-33は、その受容体ST2が陽性の制御性T細胞(Treg細胞)に作用し、がんの増殖を促進させることがわかりました。また、GSDMD－NはヒトのNASH(Non-alcoholic steatohepatitis)肝がんの腫瘍部にある肝星細胞でもその存在が認められました。これらの結果から、ガスダーミンDによる小孔形成を阻害する薬剤は肝がんの予防や治療につながる可能性があります。, Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, ...

In vitro models of liver (patho)physiology, new technologies, and experimental approaches are progressing rapidly. Based on cell lines, induced pluripotent stem cells or primary cells derived from mouse or human liver as well as whole tissue (slices), such in vitro single- and multicellular models, including complex microfluidic organ-on-a-chip systems, provide tools to functionally understand mechanisms of liver health and disease. The International Society of Hepatic Sinusoidal Research commissioned this working group to review the currently available in vitro liver models and describe the advantages and disadvantages of each in the context of evaluating their use for the study of liver functionality, disease modeling, therapeutic discovery, and clinical applicability.

Brand loyalty has a crucial role in the business and wins the mind of the customers is the key mission of any brand. On the other hand, consumers use brands to express themselves, position and integrate the brand image into their own identity. Hence, this study aims to find out the relationship between brand credibility, self-brand connection, and brand identity to brand loyalty in the context of Apple's brand. The study is quantitative research, data is surveyed in a single time collected from a population. 420 questionnaires are distributed to young people who are studying and working in Ho Chi Minh City and they are the current Apple customers. The finding of the research was shown that there has a mediating role of self-brand connection and brand identity in the relationship between brand credibility and brand loyalty. Also, brand identity has a positive impact on a self-brand connection. The findings also implied to the managers must be aware to build up the brand of products, it could increase the brand loyalty of customers. The results were also contributed to the knowledge of self-congruity theory about the self-brand connection would affect the relationship. Keywords: Brand credibility, self-brand connection, brand identity, brand loyalty.

Most universities in Vietnam, especially the local ones, are struggling to implement the annual enrollment plan because their enrollment plans have not completed recently. What are the important factors affecting admissions results for local universities? On the basis of the theoretical model, the research has proposed, designed and tested the scale of factors affecting the decision to choose a local university in Vietnam. Through a survey of 412 students at local universities, the regression model showed that six groups of proposed factors influenced the decision on local university choice in Vietnam in descending order of impact as follows: Study Costs, Majors, Influence Group, Quality and Reputation, Facilities, Advertising and Operations. The research model explains 62.4% for the overall relationship of the above 6 groups of factors with the dependent variable, which is Decision of choosing local university in Vietnam.

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.

Cytoglobin (CYGB), discovered in hepatic stellate cells (HSCs), is known to possess a radical scavenger function, but its pathophysiological roles remain unclear. Here, for the first time, we generated a new transgenic (TG) mouse line in which both Cygb and mCherry reporter gene expression were under the control of the native Cygb gene promoter. We demonstrated that the expression of Cygb-mCherry was related to endogenous Cygb in adult tissues by tracing mCherry fluorescence together with DNA, mRNA, and protein analyses. Administration of a single dose (50 mg/kg) of thioacetamide (TAA) in Cygb-TG mice resulted in lower levels of alanine transaminase and oxidative stress than those in WT mice. After 10 weeks of TAA administration, Cygb-TG livers exhibited reduced neutrophil accumulation, cytokine expression and fibrosis but high levels of quiescent HSCs. Primary HSCs isolated from Cygb-TG mice (HSCCygb-TG) exhibited significantly decreased mRNA levels of α-smooth muscle actin (αSMA), collagen 1α1, and transforming growth factor β-3 after 4 days in culture relative to WT cells. HSCsCygb-TG were resistant to H2O2-induced αSMA expression. Thus, cell-specific overexpression of Cygb attenuates HSC activation and protects mice against TAA-induced liver fibrosis presumably by maintaining HSC quiescence. Cygb is a potential new target for antifibrotic approaches.

Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC who underwent lenvatinib (n = 24) or TACE (n = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased (p = 0.040) and levels of sCD40 (p = 0.014) and sTIM-3 (p &lt, 0.001) were increased at Week 1, while levels of sCD27 (p &lt, 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 (p = 0.028), sCD40 (p &lt, 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain&ndash, 3) (p &lt, 0.001), levels of sHVEM (soluble herpesvirus entry mediator) (p = 0.003), sTLR-2 (soluble Toll-like receptor 2) (p = 0.009), sCD80 (p = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) (p = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) (p = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) (p = 0.090), and sPD-L1 (soluble programmed death-ligand 1) (p = 0.070) also increased. The fold-changes in soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86 and sPD-1 (soluble programmed cell death domain&ndash, 1) with sPD-L1 were positively correlated in both the lenvatinib and TACE treatment groups. Our results suggest that there are some limited differences in immunomodulatory effects between anti-angiogenic agents and TACE. Further studies from multicenters may help to identify an effective combination therapy.

It is unclear whether tenofovir disoproxil fumarate and entecavir differ in their association with risk of hepatocellular carcinoma in patients with chronic hepatitis B, and previous meta-analyses have shown conflicting conclusions with substantial heterogeneity. We aimed to analyse the updated data and elucidate the source of heterogeneity.We searched PubMed, Embase, Web of Science, and the Cochrane library for relevant studies with time-to-event data for incident hepatocellular carcinoma occurring in patients with chronic hepatitis B who received tenofovir disoproxil fumarate or entecavir monotherapy with follow-up of at least 1 year. Studies published between Jan 1, 2006, and April 17, 2020, and abstracts from international conferences in 2018 and 2019 were included. We pooled covariate adjusted hazard ratios (HRs) for hepatocellular carcinoma using a random-effects model, assessed heterogeneity among included studies using the I31 studies involving 119 053 patients were analysed. The 5-year cumulative incidence of hepatocellular carcinoma was 5·97% (95% CI 5·81-6·13, 28 studies) for entecavir and 3·06% (2·86-3·26, 13 studies) for tenofovir disoproxil fumarate in studies with unmatched populations (p0·0001). For all eight studies matched by propensity score, the 5-year cumulative incidence was 3·44% (95% CI 3·08-3·80) for entecavir and 3·39% (2·94-3·83) for tenofovir disoproxil fumarate (p=0·87). Analysis of 14 comparative studies with covariate adjustment found that tenofovir disoproxil fumarate and entecavir had similar risk of hepatocellular carcinoma (primary outcome); adjusted HR 0·88, 95% CI 0·73-1·07; p=0·20), although heterogeneity was significant (IOur study found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident hepatocellular carcinoma. We suggest that treatment should be guided by patient tolerability and affordability rather than whether one drug is more effective than the other.Supported in part by E-DA Hospital (EDAHP 106008; EDAHP 103046).

Aims: Cytoglobin (CYGB) is a member of the mammalian globin family of respiratory proteins. Despite extensive research efforts, its physiological role remains largely unknown, but potential functions include reactive oxygen species (ROS) detoxification and signaling. Accumulating evidence suggests that ROS play a crucial role in podocyte detachment and apoptosis during diabetic kidney disease. This study aimed to explore the potential antioxidative renal role of CYGB both in vivo and in vitro. Results: Using a Cygb-deficient mouse model, we demonstrate a Cygb-dependent reduction in renal function, coinciding with a reduced number of podocytes. To specifically assess the putative antioxidative function of CYGB in podocytes, we first confirmed high endogenous CYGB expression levels in two human podocyte cell lines and subsequently generated short hairpin RNA-mediated stable CYGB knockdown podocyte models. CYGB-deficient podocytes displayed increased cell death and accumulation of ROS as assessed by 2 ' 7 '-dichlorodihydrofluorescein diacetate assays and the redox-sensitive probe roGFP2-Orp1. CYGB-deficient cells also exhibited an impaired cellular bioenergetic status. Consistently, analysis of the CYGB-dependent transcriptome identified dysregulation of multiple genes involved in redox balance, apoptosis, as well as in chronic kidney disease (CKD). Finally, genome-wide association studies and expression studies in nephropathy biopsies indicate an association of CYGB with CKD. Innovation: This study demonstrates a podocyte-related renal role of Cygb, confirms abundant CYGB expression in human podocyte cell lines, and describes for the first time an association between CYGB and CKD. Conclusion: Our results provide evidence for an antioxidative role of CYGB in podocytes.

In hepatocellular carcinoma (HCC), the clinical significance of soluble immune checkpoint protein levels as predictors of patient outcomes or therapeutic responses has yet to be defined. This study profiled the baseline levels of sixteen soluble checkpoint proteins and their changes following sorafenib treatment for HCC. Plasma samples were obtained from 53 patients with advanced HCC at baseline, week 1, 2 and 4 of sorafenib treatment and tested the concentrations of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays. Multivariate analysis showed high sBTLA levels at baseline were an independent predictor of poor overall survival (p = 0.038). BTLA was highly expressed in T cells and macrophages in peritumoral areas. At week 2, sCD27 levels were decreased compared to baseline. By contrast, the concentrations of most inhibitory proteins, including sBTLA, sLAG-3, sCTLA-4, sPD-1, sCD80, sCD86 and sPD-L1, had significantly increased. The fold-changes of soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86, sPD-1 with sPD-L1; and the fold-changes of sCTLA-4 with sBTLA or sPD-1 were positively correlated. sBTLA may be a good biomarker for predicting overall survival in HCC patients. Sorafenib treatment in patients with advanced HCC revealed dynamic changes of soluble checkpoint protein levels.

In the present paper, the synthesis of cobalt ferrite/reduced graphene oxide (Co2Fe2O4/rGO) composite and its use for the simultaneous determination of uric acid (UA), xanthine (XA), and hypoxanthine (HX) is demonstrated. Cobalt ferrite hollow spheres were synthesized by using the carbonaceous polysaccharide microspheres prepared from a D-glucose solution as templates, followed by calcination. The CoFe2O4/rGO composite was prepared with the ultrasound-assisted method. The obtained material was characterized by using X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, EDX elemental mapping, and nitrogen adsorption/desorption isotherms. The electrochemical behavior of UA, XA, and HX on the CoFe2O4/rGO-modified electrode was studied with cyclic voltammetry and differential pulse voltammetry (DPV). The modified electrode exhibits excellent electrocatalytic activity towards the oxidation of the three compounds. The calibration curves for UA, XA, and HX were obtained over the range of 2.0–10.0 μM from DPV. The limits of detection for UA, XA, and HX are 0.767, 0.650, and 0.506 μM, respectively. The modified electrode was applied to the simultaneous detection of UA, XA, and HX in human urine, and the results are consistent with those obtained from the high-performance liquid chromatography technique.