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Purpose The programmed death protein 1 (PD-1) pathway is the critical mechanism in development of hepatocellular carcinoma (HCC). The present study analyzed the prognostic impact of pretransplant serum soluble PD-1 (sPD-1) concentration and α-FP–des-γ-carboxyprothrombin–tumor volume (ADV) score in patients with previously untreated HCC undergone liver transplantation (LT). Methods This retrospective single-center study enrolled 100 patients with HCC who underwent living donor LT from 2010 to 2016. Concentrations of sPD-1 were measured in stored serum samples. Results Receiver operating characteristic curve analysis of 2-year tumor recurrence resulted in an sPD-1 cutoff of 177.1 µg/mL, which was associated with higher rates of tumor recurrence (P = 0.022), but not with overall patient survival (P = 0.460). The derived cutoff for pretransplant ADV score was 5.4log, which was associated with higher tumor recurrence rate (P < 0.001) and lower overall patient survival rate (P < 0.001). Both sPD-1 of >177.1 µg/mL (hazard ratio [HR], 2.26; P = 0.020) and pretransplant ADV score of >5.4log (HR, 3.56; P < 0.001) were independent risk factors for posttransplant HCC recurrence. The combination of these 2 factors enabled the stratification of patients into 3 groups, with groups having 0, 1, and 2 risk factors differing significantly in the prognosis of tumor recurrence (P < 0.001) and overall patient survival (P = 0.006). Conclusion Both sPD-1 concentration and ADV score have prognostic impacts in patients who underwent LT for untreated HCCs. These factors, both individually and combined, can help in predicting posttransplant prognosis.

Cereblon (CRBN) has been shown to play an essential role in regulating inflammatory response and endoplasmic reticulum stress, thus mediating the development of various diseases. However, little is known about the roles of CRBN in chronic obstructive pulmonary disease (COPD) pathogenesis. We found that the protein levels of CRBN in lung homogenates from patients with COPD were lower than those from never smokers and smokers. The CRBN protein level was positively correlated with the forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). To investigate the role of CRBN in modulating elastase-induced emphysema, we used Crbn knockout (KO) mice. Elastase-induced emphysematous changes were significantly aggravated in Crbn KO mice. Neutrophil infiltration, lung cell injury, and protein leakage into the bronchoalveolar space were more severe in Crbn KO mice than in wild-type (WT) mice. Furthermore, Crbn KO resulted in the elevated release of neutrophilic chemokines and inflammatory cytokines in lung epithelial cells and macrophages. The transcriptional activity of nuclear factor-κB (NF-κB) was significantly increased in Crbn knocked-down cells. In conclusion, Crbn deficiency might be involved in the development of emphysema by enhancing NF-κB activation, suggesting that targeting CRBN might be an effective therapeutic approach for the treatment of COPD.

Pulmonary fibrosis is a progressive and lethal lung disease characterized by the proliferation and differentiation of lung fibroblasts and the accumulation of extracellular matrices. Since pulmonary fibrosis was reported to be associated with adenosine monophosphate-activated protein kinase (AMPK) activation, which is negatively regulated by cereblon (CRBN), we aimed to determine whether CRBN is involved in the development of pulmonary fibrosis. Therefore, we evaluated the role of CRBN in bleomycin (BLM)-induced pulmonary fibrosis in mice and in transforming growth factor-beta 1 (TGF-β1)-induced differentiation of human lung fibroblasts. BLM-induced fibrosis and the mRNA expression of collagen and fibronectin were increased in the lung tissues of wild-type (WT) mice; however, they were significantly suppressed in Crbn knockout (KO) mice. While the concentrations of TGF-β1/2 in bronchoalveolar lavage fluid were increased via BLM treatment, they were similar between BLM-treated WT and Crbn KO mice. Knockdown of CRBN suppressed TGF-β1-induced activation of small mothers against decapentaplegic 3 (SMAD3), and overexpression of CRBN increased it. TGF-β1-induced activation of SMAD3 increased α-smooth muscle actin (α-SMA) and collagen levels. CRBN was found to be colocalized with AMPKα1 in lung fibroblasts. CRBN overexpression inactivated AMPKα1. When cells were treated with metformin (an AMPK activator), the CRBN-induced activation of SMAD3 and upregulation of α-SMA and collagen expression were significantly suppressed, suggesting that increased TGF-β1-induced activation of SMAD3 via CRBN overexpression is associated with AMPKα1 inactivation. Taken together, these data suggest that CRBN is a profibrotic regulator and maybe a potential target for treating lung fibrosis., Lung disease: Putting the brakes on fibrosis Interventions that target a regulatory protein called cereblon could help reduce the damage inflicted on the lungs by idiopathic pulmonary fibrosis (IPF). This incurable and generally fatal condition is associated with the accumulation of scar tissue in the lungs, which leads to the gradual loss of respiratory function. Researchers led by Kyoung-Hee Lee at Seoul National University Hospital in South Korea have now identified cereblon as a potentially important contributor to this scarring process. They found that cereblon regulates a complex metabolic pathway that ultimately contributes to production of fibrosis-related proteins in a mouse model of IPF. Genetically modified animals that lacked the gene encoding cereblon showed reduced accumulation of these proteins in their lungs. These results suggest that cereblon-inhibiting agents could potentially control the progression of IPF and help preserve lung function.

Cereblon (CRBN), a negative modulator of AMP-activated protein kinase (AMPK), is highly expressed in the retina. We confirmed the expression of CRBN in ARPE-19 human retinal cells by Western blotting. We also demonstrated that CRBN knock-down (KD) could effectively downregulate IL-6 and MCP-1 protein and gene expression in LPS-stimulated ARPE-19 cells. Additionally, CRBN KD increased the phosphorylation of AMPK/acetyl-coenzyme A carboxylase (ACC) and the expression of heme oxygenase-1 (HO-1) in ARPE-19 cells. Furthermore, CRBN KD significantly reduced LPS-induced nuclear translocation of NF-κB p65 and activation of NF-κB promoter activity. However, these processes could be inactivated by compound C (inhibitor of AMPK) and zinc protoporphyrin-1 (ZnPP-1; inhibitor of HO-1). In conclusion, compound C and ZnPP-1 can rescue LPS-induced levels of proinflammatory cytokines (IL-6 and MCP-1) in CRBN KD ARPE-19 cells. Our data demonstrate that CRBN deficiency negatively regulates proinflammatory cytokines via the activation of AMPK/HO-1 in the retina.

Background Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population. Methods Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis. Results The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence. Conclusion Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval., Graphical Abstract

Cereblon (CRBN) has a pleiotropic role in important cellular processes and is a potential therapeutic target in several diseases, including mental retardation, cancer, and metabolic disorders. The role of CRBN in polymicrobial sepsis induced by cecal ligation and puncture (CLP) was investigated using CRBN-deficient (KO) mice. Survival following CLP was significantly higher in KO mice compared to wild-type (WT) controls (50% vs 0% at day 6 after CLP). The improved survival of KO mice was accompanied by reduced peripheral blood bacterial load and lung injury. Serum tumor necrosis factor (TNF)-α and high mobility group box 1 (HMGB1) concentrations were significantly lower in KO mice than in WT mice. Peritoneal macrophages from KO mice with CLP-induced septic mouse had higher levels of activation of AMPK and heme oxygenase-1 (HO-1). Forced expression of CRBN in macrophage of KO mice suppressed activation of 5′ adenosine monophosphate-activated protein kinase (AMPK) and HO-1 and augmented expression of TNF-α and HMGB1 as inhibition of AMPK by compound C. These studies demonstrate the contribution of CRBN expression to the pathogenesis of CLP-induced sepsis and peritoneal macrophage responses and suggest a novel therapeutic modality for polymicrobial sepsis.

Bioluminescence-induced proteinaceous photodynamic therapy enables cancer treatment by self-luminescent ROS generation., Despite the potential of photodynamic therapy (PDT), its comprehensive use in cancer treatment has not been achieved because of the nondegradable risks of photosensitizing drugs and limits of light penetration and instrumentation. Here, we present bioluminescence (BL)–induced proteinaceous PDT (BLiP-PDT), through the combination of luciferase and a reactive oxygen species (ROS)–generating protein (Luc-RGP), which is self-luminescent and degradable. After exposure to coelenterazine-h as a substrate for luciferase without external light irradiation, Luc-RGP fused with a small lead peptide–induced breast cancer cell death through the generation of BL-sensitive ROS in the plasma membrane. Even with extremely low light energy, BLiP-PDT exhibited targeted effects in primary breast cancer cells from patients and in in vivo tumor xenograft mouse models. These findings suggest that BLiP-PDT is immediately useful as a promising theranostic approach against various cancers.

Programmed death protein 1 (PD-1) pathway is one of the most critical mechanisms in tumor biology of hepatocellular carcinoma (HCC). The study aimed to assess the prognostic influence of pretransplant serum soluble PD-1 (sPD-1) in patients undergoing liver transplantation for treatment of HCC. Data from 229 patients with HCC who underwent living donor liver transplantation between January 2010 and December 2015 were retrospectively evaluated. Stored serum samples were used to measure sPD-1 concentrations. Overall survival (OS) and disease-free survival (DFS) rates were 94.3% and 74.5% at 1 year; 78.2% and 59.2% at 3 years; and 75.4% and 55.5% at 5 years, respectively. Prognostic analysis using pretransplant serum sPD-1 with a cut-off of 93.6 μg/mL (median value of the study cohort) did not have significant prognostic influence on OS (P = .69) and DFS (P = .26). Prognostic analysis using sPD-1 with a cut-off of 300 μg/mL showed similar OS (P = .46) and marginally lower DFS (P = .070). Combination of Milan criteria and sPD-1 with a cutoff of 300 μg/mL showed similar outcomes of OS and DFS in patients within and beyond Milan criteria. Multivariate analysis revealed that only Milan criteria was an independent prognostic for OS and DFS, but pretransplant sPD1 with a cut-off of 300 μg/mL did not become a prognostic factor. The results of this study demonstrate that pretransplant serum sPD-1 did not show significant influences on post-transplant outcomes in patients with HCC. Further large-scale, multicenter studies are necessary to clarify the role of serum sPD-1 in liver transplantation recipients.

The ITER thermal shield is actively cooled by 80 K pressurized helium gas. The helium coolant flows from the cold valve box to the cooling tubes on the TS panels via manifold piping. This paper describes the final design of thermal shield manifold. Pipe design to accommodate the thermal contraction considering interface with adjacent components and detailed design of support structure are presented. R&D for the pipe branch connection is carried out to find a feasible manufacturing method. Global structural behavior and structural integrity of the manifold including pipe supports are investigated by a finite element analysis based on ASME B31.3 code. Flow analyses are performed to check the flow distribution.

Crotamine is a peptide toxin found in the venom of the rattlesnake Crotalus durissus terrificus and has antiproliferative, antimicrobial, and antifungal activities. Herein, we show that crotamine dose-dependently induced macrophage phagocytic and cytostatic activity by the induction of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α). Moreover, the crotamineinduced expression of iNOS and TNF-α is mediated through the phosphorylation of p38 and the NF-κB signaling cascade in macrophages. Notably, pretreatment with SB203580 (a p38-specific inhibitor) or BAY 11-7082 (an NF-κB inhibitor) inhibited crotamine-induced NO production and macrophage phagocytic and cytotoxic activity. Our results show for the first time that crotamine stimulates macrophage phagocytic and cytostatic activity by induction of NO and TNF-α via the p38 and NF-κB signaling pathways and suggest that crotamine may be a useful therapeutic agent for the treatment of inflammatory disease. [BMB Reports 2016; 49(3): 185-190].

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Tussilagone, extracted from Tussilago farfara is an oriental medicine used for asthma and bronchitis. We investigated its mechanism of action, its inhibitory effects on lipopolysaccharide-induced inflammation in macrophages, and its impact on viability in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. Tussilagone suppressed the expression of the inflammatory mediators, nitric oxide and prostaglandin E2, and the inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and high-mobility group box 1 (HMGB1), in lipopolysaccharide-stimulated RAW 264.7 cells and peritoneal macrophages. Tussilagone also reduced the activation of the mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) involved in the activation of various inflammatory mediators in activated macrophages. Moreover, tussilagone administration (1 mg/kg and 10 mg/kg) produced decreased mortality and lung injury in CLP-activated septic mice. Augmented expression of cyclooxygenase (COX)-2 and TNF-α in pulmonary alveolar macrophages of septic mice were attenuated by tussilagone administration. Tussilagone also suppressed the induction of nitric oxide, prostaglandin E2, TNF-α and HMGB1 in the serum of the septic mice. Overall, tussilagone exhibited protective effects against inflammation and polymicrobial sepsis by suppressing inflammatory mediators possibly via the inhibition of NF-κB activation and the MAP kinase pathway. These results suggest the possible use of tussilagone for developing novel therapeutic modalities for sepsis and other inflammatory diseases.

Advanced glycation end products (AGEs) are harmful compounds generated by nonspecific glycation of proteins and lipids. The accumulation of AGEs is associated with various diseases, including breast cancer. AGEs have been shown to promote a breast cancer cell line by enhancing proliferation, invasion and migration. In this study, we investigated the effect and associated mechanism of AGEs on triple negative breast cancer cells. AGEs enhanced the proliferation, tumorigenicity, invasion and migration of primary breast cancer cells. AGEs also enhanced the RNA and protein expression of matrix metalloproteinase (MMP)-9 and its gelatinase activity. Enhanced MMP-9 expression was mediated by extracellular-signal regulated kinase (ERK) and nuclear factor kappa B (NF-κB) pathways. Moreover, inhibitors of ERK and NF-κB signaling attenuated the effect of AGEs on tumorigenicity, invasion and migration of primary breast cancer cells. Taken together, we suggest that AGEs directly promote primary breast cancer cells via the ERK and NF-κB pathway, which may lead to advanced therapeutic modalities of breast cancer.

Naringin, a flavanone glycoside extracted from various plants, has a wide range of pharmacological effects. In the present study, we investigated naringin's mechanism of action and its inhibitory effect on lipopolysaccharide-induced tumor necrosis factor-alpha and high-mobility group box 1 expression in macrophages, and on death in a cecal ligation and puncture induced mouse model of sepsis. Naringin increased heme oxygenase 1 expression in peritoneal macrophage cells through the activation of adenosine monophosphate-activated protein kinase, p38, and NF-E2-related factor 2. Inhibition of heme oxygenase 1 abrogated the naringin's inhibitory effect on high-mobility group box 1 expression and NF-kB activation in lipopolysaccharide-stimulated macrophages. Moreover, mice pretreated with naringin (200 mg/kg) exhibited decreased sepsis-induced mortality and lung injury, and alleviated lung pathological changes. However, the naringin's protective effects on sepsis-induced lung injury were eliminated by zinc protoporphyrin, a heme oxygenase 1 competitive inhibitor. These results revealed the mechanism underlying naringin's protective effect in inflammation and may be beneficial for the treatment of sepsis.

To support an efficient management of software verification and validation activities, much research has been conducted to predict defects in early phase. And defect prediction models have been proposed to predict defects. But the generality of the models has not been experimentally studied for other software system. In other words, most of prediction models were applied only to the same system that had been used to build the prediction models themselves. Therefore, we performed an experiment to explore generality of major prediction models. In the experiment, we applied three defects prediction models to three different systems. As a result, we cannot find their generality of defect prediction capability. The cause is analyzed to result from a different metric distribution between the systems.Keywords:Object-Oriented Metrics, Defects Prediction Model, Generality 1. 서 론 1) 소프트웨어 개발 초기 단계에 한정된 자원을 효율적으로 관리하기 위하여 소프트웨어 메트릭을 이용한 결함 예측 연구가 진행되고 있다[1-8]. 결함 예측 연구는 디자인 단계의 산출물을 대상으로 메트릭을 측정하여 결함이 발생할 가능성이 높은 클래스를 판단하는데 사용할 수 있다. 그리고 소프트웨어 산출물을 대상으로 결함 유무를 판단하기 위해서

Because most metricsin the literatures are described by a natural language, they can be interpreted in an ambigous manner. To cope with this problem, there are some researches to express based on Object Constraint Language(OCL). Because OCL has been proposed to describe structural constraintsfor Unified Modeling Language(UML) diagrams, it is difficult and awkward. In this paper, we propose Metric Description Language(MDL) which is a high level language to describe metrics. MDL supports a modular description of complex metrics, aggregation function, and automatic navigation between entities. Moreover, we develop MetriUs for describing metrics using MDL and supporting an automated computation for UML diagrams. In a case study, we have described a variety of existing metrics using MDL and found that MDL contributes to producing simpler expression of metrics than OCL.

We utilized a mice model of Parkinsonism: (1) to evaluate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity; and (2) to evaluate whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. A 2 × 3 experimental design (MPTP ×± Mn) was as follows: SS, MPTP(-) × Mn(-); SLMn, MPTP(-) × low Mn(+); SHMn, MPTP(-) × high Mn(+); MpS, MPTP(+) × Mn(-); MpLMn, MPTP(+) × low Mn(+); MpHMn, MPTP(+) × high Mn(+). We administered MPTP (30 mg/kg per day) to male C57BL/6 mice intraperitoneally, once a day for 5 days. Subsequently, mice were treated with either 2 or 8 mg/kg of MnCl2.4H2O intraperitoneally, once a day for 3 weeks. Blood and striatal Mn levels were elevated in the Mnexposed groups. The number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in the substantia nigra pars compacta were decreased significantly in the MPTP-exposed groups. The densities of TH-ir axon terminals in caudate-putamen (CPU) were significantly decreased in the MPTP-treated groups. However, Mn treatment did not affect MPTP neurotoxicity. The densities of glial fibrillary acidic protein (GFAP)-ir astrocytes in the CPU or globus pallidus were significantly increased in the MPTP-treated groups. Concentrations of dopamine in the striatum were decreased significantly in the MPTP-exposed groups only, but Mn had no effect.

Berberine (BBR) is one of the major alkaloids and has been reported to have a variety of pharmacologic effects, including inhibition of cell cycle progression. Here, we investigated the mechanisms of BBR protection of neuronal cells from cell death induced by the Parkinson’s disease-related neurotoxin 6-hydroxydopamine (6-OHDA). Pretreatment of SH-SY5Y cells with BBR significantly reduced 6-OHDAinduced generation of reactive oxygen species (ROS), caspase-3 activation, and subsequent cell death. BBR also upregulated heme oxygenase-1 (HO-1) expression, which conferred protection against 6-OHDA-induced dopaminergic neuron injury and besides, effect of BBR on HO-1 was reversed by siRNA-Nrf2. Furthermore, BBR induced PI3K/Akt and p38 activation, which are involved in the induction of Nrf2 expression and neuroprotection. These results suggest that BBR may be useful as a therapeutic agent for the treatment of dopaminergic neuronal diseases.

Although brain natriuretic peptide (BNP), a marker of cardiac dysfunction, has been known to predict postoperative mortality, little is known about the postoperative prognostic ability of BNP in liver transplantation (OLT) recipients. We aimed to determine whether intraoperative BNP level can predict 1-year all-cause mortality after OLT.We retrospectively investigated 525 OLT recipients. BNP and hemodynamic parameters were simultaneously measured 1 hour after induction of anesthesia. Cox regression analysis and receiver operating characteristic curve analysis were performed to determine clinical predictors and optimal cutoff values of post-OLT mortality.The 1-year all-cause mortality rate was 9.7% (51/525). Median BNP concentration was significantly higher in nonsurvivors than in survivors (114 vs 56 pg/mL, P.001). Significant factors in univariate Cox regression analysis were Child-Pugh score, model for end-stage liver disease (MELD) score, logBNP, hemoglobin, creatinine, heart rate, systolic pulmonary arterial pressure, and central venous pressure. In multivariate Cox regression analysis, independent predictors of posttransplant mortality were MELD score and logBNP. However, simultaneously measured hemodynamic parameters did not remain predictors. BNP levels greater than a cutoff of 136 pg/mL (specificity = 83.5%, negative predictive value = 93.6%) were associated with increased post-OLT mortality (log-rank test P.001).Intraoperative BNP level is an independent predictor of 1-year all-cause mortality after OLT with a high negative predictive value, suggesting that its measurement appears useful in identifying patients at low risk of post-OLT mortality.

Because most metrics in the literature are described by natural languages, they can be interpreted in an ambiguous manner, which can be an obstacle to consistent understanding of them. To cope with this problem, many works have been performed to clearly describe metrics using Object Constraint Language (OCL). Although OCL can help avoid the problems of ambiguous description, metrics described in OCL are awkward and difficult, which can lead to incorrect description of metrics. In this paper, we propose a description language, named Metric Description Language (MDL) for simple and clear description of software metrics. MDL supports a modular description of complex metrics, aggregation function, and automatic navigation between entities. Moreover, a tool, named MetriUs, has been developed for computing metrics expressed in MDL against UML diagrams. In a case study, we have described various existing metrics using MDL and found that MDL can describe metrics in simpler expressions than OCL.

Mast cells play a critical role in the effector phase of immediate hypersensitivity and allergic diseases. Scutellaria baicalensis is a widely used herb in traditional oriental medicine with anticancer, antiviral, antibacterial and anti-inflammatory properties. However, the roles of Scutellaria baicalensis in mast cell-mediated anaphylactic reactions have not fully been investigated. In this study, we examined the influences of the methanol extract of Scutellaria baicalensis (MESB) on compound 48/80- or anti-dinitrophenyl (DNP) IgE-induced anaphylaxis-like response in vivo. To further prove these in vivo results, the inhibitory effect of MESB on mast cell activation was evaluated, focusing on the histamine release from rat peritoneal mast cells (RPMC). MESB inhibited compound 48/80-induced systemic anaphylaxis-like reaction, plasma histamine release and ear swelling response in mice. MESB also attenuated passive systemic and cutaneous anaphylaxis evoked by anti-DNP IgE. In in vitro experiments, MESB dose-dependently reduced histamine release from RPMC activated by compound 48/80 or anti-DNP IgE. Moreover, compound 48/80-elicited calcium uptake was suppressed in a concentration-dependent manner of MESB. Furthermore, MESB transiently increased the level of intracellular cAMP. From these results, it is suggested that MESB possesses effective anti-anaphylactic activity.