Publications by authors named "Chuan Shen"

72 Publications

Identification of the molecular targets and mechanisms of compound mylabris capsules for hepatocellular carcinoma treatment through network pharmacology and bioinformatics analysis.

J Ethnopharmacol 2021 Aug 29;276:114174. Epub 2021 Apr 29.

Department of Infectious Diseases, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, China. Electronic address:

Ethnopharmacological Relevance: Traditional Chinese herbal formulas have been proven to exert an inhibitory effect on tumor. Compound mylabris capsules (CMC) has been used for treating cancer, especially hepatocellular carcinoma (HCC), for years in China. However, its therapeutic mechanisms on HCC remain unclear.

Aim Of The Study: This research aimed to elucidate the molecular targets and mechanisms of CMC for treating HCC.

Materials And Methods: First, the bioactive ingredients and potential targets of CMC, as well as HCC-related targets were retrieved from publicly available databases. Next, the overlapped genes between potential targets of CMC and HCC-related targets were determined using bioinformatics analysis. Then, networks of ingredient-target and gene-pathway were constructed. Finally, cell experiments were carried out to examine the effects of CMC-medicated serum on HCC and validate the core molecular targets.

Results: In total, 151 bioactive ingredients and 255 potential targets of CMC were selected, 982 differentially expressed genes of HCC were identified. Among them, 34 overlapped genes were finally selected. In addition, 20 pathways and 429 GO terms were significantly enriched. Protein-protein interaction and gene-pathway networks indicated that Cyclin B1(CCNB1) and Cyclin Dependent Kinase 1(CDK1) were the core gene targets for the treatment of CMC on HCC. Moreover, in vitro studies showed that CMC-medicated serum significantly inhibited the viability of HepG cells. Furthermore, CMC downregulated CCNB1 and CDK1 expressions and induced G/M phase cell cycle arrest.

Conclusions: CMC plays a therapeutic role in HCC via multi-component, -target and -pathway mechanisms, in which CCNB1 and CDK1 may be the core molecular targets. This study indicates that the integration of network pharmacology and bioinformatics analysis, followed by experimental validation, can serves as an effective tool for studying the therapeutic mechanisms of traditional Chinese medicine.
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http://dx.doi.org/10.1016/j.jep.2021.114174DOI Listing
August 2021

High mortality associated with gram-negative bacterial bloodstream infection in liver transplant recipients undergoing immunosuppression reduction.

World J Gastroenterol 2020 Dec;26(45):7191-7203

Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.

Background: Immunosuppression is an important factor in the incidence of infections in transplant recipient. Few studies are available on the management of immunosuppression (IS) treatment in the liver transplant (LT) recipients complicated with infection. The aim of this study is to describe our experience in the management of IS treatment during bacterial bloodstream infection (BSI) in LT recipients and assess the effect of temporary IS withdrawal on 30 d mortality of recipients presenting with severe infection.

Aim: To assess the effect of temporary IS withdrawal on 30 d mortality of LT recipients presenting with severe infection.

Methods: A retrospective study was conducted with patients diagnosed with BSI after LT in the Department of Liver Surgery, Renji Hospital from January 1, 2016 through December 31, 2017. All recipients diagnosed with BSI after LT were included. Univariate and multivariate Cox regression analysis of risk factors for 30 d mortality was conducted in the LT recipients with Gram-negative bacterial (GNB) infection.

Results: Seventy-four episodes of BSI were identified in 70 LT recipients, including 45 episodes of Gram-positive bacterial (GPB) infections in 42 patients and 29 episodes of GNB infections in 28 patients. Overall, IS reduction (at least 50% dose reduction or cessation of one or more immunosuppressive agent) was made in 28 (41.2%) cases, specifically, in 5 (11.9%) cases with GPB infections and 23 (82.1%) cases with GNB infections. The 180 d all-cause mortality rate was 18.5% (13/70). The mortality rate in GNB group (39.3%, 11/28) was significantly higher than that in GPB group (4.8%, 2/42) ( = 0.001). All the deaths in GNB group were attributed to worsening infection secondary to IS withdrawal, but the deaths in GPB group were all due to graft-versus-host disease. GNB group was associated with significantly higher incidence of intra-abdominal infection, IS reduction, and complete IS withdrawal than GPB group ( < 0.05). Cox regression showed that rejection (adjusted hazard ratio 7.021, = 0.001) and complete IS withdrawal (adjusted hazard ratio 12.65, = 0.019) were independent risk factors for 30 d mortality in patients with GNB infections after LT.

Conclusion: IS reduction is more frequently associated with GNB infection than GPB infection in LT recipients. Complete IS withdrawal should be cautious due to increased risk of mortality in LT recipients complicated with BSI.

Is:
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http://dx.doi.org/10.3748/wjg.v26.i45.7191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723669PMC
December 2020

Design of a bandgap-engineered barrier-blocking HOT HgCdTe long-wavelength infrared avalanche photodiode.

Opt Express 2020 Oct;28(22):33556-33563

The performance of high-operating-temperature (HOT) longwavelength infrared (LWIR) HgCdTe avalanche photodiodes (APDs) is significantly limited by the increasing dark current related to temperature. In this paper, a novel barrier-blocking LWIR pBp-APD structure is proposed and studied, and the results show that the dark current of pBp-APD is significantly restricted compared with conventional APD without sacrificing the gain at high temperature. Furthermore, the reduction of avalanche dark current is found to be the key points of the significant suppression of dark current. The physical essence of this reduction is revealed to be the depletion of carriers in the absorption region, and the feasibility of the improved structure is further confirmed by the analysis of its energy band and electric field distribution. In addition, the reduction of gain-normalized dark current (GNDC) does not need to sacrifice the gain. The proposed LWIR pBp-APD paves the way for development of high operation temperature infrared APDs.
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http://dx.doi.org/10.1364/OE.408526DOI Listing
October 2020

Barley yellow dwarf virus-GAV-derived vsiRNAs are involved in the production of wheat leaf yellowing symptoms by targeting chlorophyll synthase.

Virol J 2020 10 21;17(1):158. Epub 2020 Oct 21.

State Key Laboratory of Crop Stress Biology for Arid Areas and College of Plant Protection, Northwest A&F University, Yangling, 712100, China.

Background: Wheat yellow dwarf virus disease is infected by barley yellow dwarf virus (BYDV), which causes leaf yellowing and dwarfing symptoms in wheat, thereby posing a serious threat to China's food production. The infection of plant viruses can produce large numbers of vsiRNAs, which can target host transcripts and cause symptom development. However, few studies have been conducted to explore the role played by vsiRNAs in the interaction between BYDV-GAV and host wheat plants.

Methods: In this study, small RNA sequencing was conducted to profile vsiRNAs in BYDV-GAV-infected wheat plants. The putative targets of vsiRNAs were predicted by the bioinformatics software psRNATarget. RT-qPCR and VIGS were employed to identify the function of selected target transcripts. To confirm the interaction between vsiRNA and the target, 5' RACE was performed to analyze the specific cleavage sites.

Results: From the sequencing data, we obtained a total of 11,384 detected vsiRNAs. The length distribution of these vsiRNAs was mostly 21 and 22 nt, and an A/U bias was observed at the 5' terminus. We also observed that the production region of vsiRNAs had no strand polarity. The vsiRNAs were predicted to target 23,719 wheat transcripts. GO and KEGG enrichment analysis demonstrated that these targets were mostly involved in cell components, catalytic activity and plant-pathogen interactions. The results of RT-qPCR analysis showed that most chloroplast-related genes were downregulated in BYDV-GAV-infected wheat plants. Silencing of a chlorophyll synthase gene caused leaf yellowing that was similar to the symptoms exhibited by BYDV-GAV-inoculated wheat plants. A vsiRNA from an overlapping region of BYDV-GAV MP and CP was observed to target chlorophyll synthase for gene silencing. Next, 5' RACE validated that vsiRNA8856 could cleave the chlorophyll synthase transcript in a sequence-specific manner.

Conclusions: This report is the first to demonstrate that BYDV-GAV-derived vsiRNAs can target wheat transcripts for symptom development, and the results of this study help to elucidate the molecular mechanisms underlying leaf yellowing after viral infection.
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http://dx.doi.org/10.1186/s12985-020-01434-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576850PMC
October 2020

"Malignant" Liver Cysts Cause Liver Failure and Recurrence.

Gastroenterology 2021 May 9;160(6):e7-e9. Epub 2020 Oct 9.

Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Road, Shanghai 200127, China. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.09.049DOI Listing
May 2021

Activator of thyroid and retinoid receptor increases sorafenib resistance in hepatocellular carcinoma by facilitating the Warburg effect.

Cancer Sci 2020 Jun;111(6):2028-2040

Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China.

Sorafenib resistance is a major challenge in the therapy for advanced hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of HCC resistance to sorafenib remain unclear. Activator of thyroid and retinoid receptor (ACTR, also known as SRC-3), overexpressed in HCC patients, plays an important oncogenic role in HCC; however, the link between ACTR and sorafenib resistance in HCC is unknown. Our study demonstrated that ACTR was one of the most upregulated genes in sorafenib-resistant HCC xenografts. ACTR increases sorafenib resistance through regulation of the Warburg effect. ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo. Mechanistically, ACTR knockout or knockdown decreases the expression of glycolytic enzymes. In HCC patients, ACTR expression is positively correlated with glycolytic gene expression and is associated with poorer outcome. Furthermore, ACTR interacts with the central regulator of the Warburg effect, c-Myc, and promotes its recruitment to glycolytic gene promoters. Our findings provide new clues regarding the role of ACTR as a prospective sensitizing target for sorafenib therapy in HCC.
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http://dx.doi.org/10.1111/cas.14412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293092PMC
June 2020

Farnesoid X Receptor Activation Protects Liver From Ischemia/Reperfusion Injury by Up-Regulating Small Heterodimer Partner in Kupffer Cells.

Hepatol Commun 2020 Apr 13;4(4):540-554. Epub 2020 Feb 13.

Department of Surgery David Geffen School of Medicine University of California Los Angles Los Angeles CA.

Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild-type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow-derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor α but higher interleukin-10 expressions following toll-like receptor stimulation. FXR-targeted gene small heterodimer partner () was critical for the regulation of KC response by GW4064. , the depletion of KCs but not cluster of differentiation (CD) 11b cells or knockdown of diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up-regulating in KCs to inhibit the liver proinflammatory response.
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http://dx.doi.org/10.1002/hep4.1478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109340PMC
April 2020

NLRP3 inflammasome and related cytokines reflect the immune status of patients with HBV-ACLF.

Mol Immunol 2020 04 10;120:179-186. Epub 2020 Mar 10.

Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address:

Background: The NLRP3 inflammasome has been suggested to play a crucial role in host antiviral defense, including against hepatitis B virus (HBV) infection. In the present study, we measured expression of NLRP3 and its related cytokines in patients with different stages of HBV-related acute-on-chronic liver failure (HBV-ACLF), a pattern of end-stage liver disease that occurs frequently in patients with chronic HBV (CHB) infection or HBV-related cirrhosis.

Methods: A total of 75 subjects including 30 HBV-ACLF patients, 30 CHB patients, and 15 healthy controls (HCs) were enrolled. The NLRP3 inflammasome and its components (caspase-1, interleukin (IL)-1β, and IL-18) were measured in peripheral blood mononuclear cells (PBMCs), macrophages, and liver using flow cytometry, quantitative real-time polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry. The LPS was used to evaluate changes in NLRP3 and its related cytokines in CD14 monocytes which may reflect immune status. Cytokine expression was measured using RT-PCR.

Results: Patients with HBV-ACLF had lower NLRP3 inflammasome expression in peripheral CD14 monocytes, particularly in the middle-to-late stage, but higher expression in liver macrophages compared to CHB and HCs. Compared with H-LPS or L-LPS alone, L-LPS sequential H-LPS can significantly inhibit the expression of NLRP3 and its related cytokines.

Conclusion: Differential expression patterns of the NLRP3 inflammasome in the periphery and liver might be related to immune dysfunction and recruitment of monocytes to the injured liver during disease progression. Persistent systemic inflammation is likely a cause of compromised immune status in patients with HBV-ACLF.
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http://dx.doi.org/10.1016/j.molimm.2020.01.011DOI Listing
April 2020

MicroRNA-124a contributes to glucocorticoid resistance in acute-on-chronic liver failure by negatively regulating glucocorticoid receptor alpha.

Ann Hepatol 2020 Mar - Apr;19(2):214-221. Epub 2019 Oct 1.

Department of Infectious Disease, The Third Hospital of Hebei Medical University, No. 68 Xiangjiang Road, Shijiazhuang, China. Electronic address:

Introduction And Objectives: Glucocorticoid resistance frequently associating with inflammation, may severely compromise the therapeutic effect of glucocorticoids. In this study, we aimed to investigate the regulation of glucocorticoid resistance by microRNA-124a (miR-124a) in patients with acute-on-chronic liver failure (ACLF).

Materials And Methods: The miR-124a levels and glucocorticoid receptor alpha (GRα) expressions in peripheral blood monocytes and liver tissues were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot analyses in the following four groups: healthy controls (HC), moderate chronic hepatitis B (CHB) patients, hepatitis B virus-related ACLF (HBV-ACLF) patients, and alcohol-induced ACLF (A-ACLF) patients. In addition, the serum miR-124a levels and multiple biochemical indices were determined. The effects of miR-124a transfection on GRα expression were assayed by qRT-PCR and western blotting in U937 and HepG2 cells stimulated with lipopolysaccharide (LPS).

Results: Compared with the CHB patients and HC, the miR-124a levels in HBV-ACLF and A-ACLF patients increased, while GRα expressions decreased. No significant differences in miR-124a levels and GRα expressions were observed between the HBV-ACLF and A-ACLF patients. For the ACLF patients, miR-124a level was negatively related to GRα expression in monocytes and positively correlated with the inflammatory factors such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). In U937 and HepG2 cells, LPS stimulated miR-124a levels but inhibited GRα expressions; meanwhile, increasing miR-124a levels reduced GRα expressions, and inhibiting miR-124a levels increased GRα expressions.

Conclusions: This study provides evidence that GRα expression was negatively regulated by miR-124a, which primarily determines the extent of acquired glucocorticoid resistance in ACLF.
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http://dx.doi.org/10.1016/j.aohep.2019.08.007DOI Listing
February 2021

Effectiveness of tigecycline in the treatment of infections caused by carbapenem-resistant gram-negative bacteria in pediatric liver transplant recipients: A retrospective study.

Transpl Infect Dis 2020 Feb 1;22(1):e13199. Epub 2019 Nov 1.

Department of Liver Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.

Introduction: Tigecycline (TGC) is effective for the infections caused by carbapenem-resistant gram-negative bacteria (CRGNB) in adults, but it is not investigated systematically in children because of concern about adverse effects. This study aimed to analyze the effectiveness of TGC in treating CRGNB infections in children after receiving liver transplant.

Methods: The subjects in this retrospective study were pediatric liver transplant recipients treated with TGC for at least 3 days to fight microbiologically verified CRGNB infection after initial antibiotic failure during the period from January 2014 to May 2018. Clinical and microbiological outcomes were reviewed to evaluate the efficacy and safety of TGC.

Results: Of the 1177 pediatric liver transplant recipients, 13 patients were eligible for inclusion in this analysis. All the patients received TGC at dose of 2 mg/kg every 12 hours for a duration of 10.1 ± 5.1 days on average to treat CRGNB infections, including complicated intra-abdominal infection, ventilator-associated pneumonia, and bloodstream infection. The isolates included Klebsiella pneumoniae (69.2%, 9/13) and Acinetobacter baumannii (30.8%, 4/13). Clinical efficacy was achieved in 84.6% (11/13) and pathogen eradicated in 69.2% (9/13) of the patients. The overall mortality rate was 15.4% (2/13). No TGC-related serious adverse event was reported.

Conclusion: Tigecycline can be considered in combination antimicrobial regimen for treating CRGNB-related infections in pediatric liver transplant recipients.
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http://dx.doi.org/10.1111/tid.13199DOI Listing
February 2020

Metformin alleviates inflammatory response in non-alcoholic steatohepatitis by restraining signal transducer and activator of transcription 3-mediated autophagy inhibition in vitro and in vivo.

Biochem Biophys Res Commun 2019 05 29;513(1):64-72. Epub 2019 Mar 29.

Department of Infection, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, China. Electronic address:

Autophagy is an intracellular recycling and degradation process for regulating cell survival and drug resistance. Non-alcoholic steatohepatitis (NASH) is becoming a widespread disease in developing countries. However, the role of autophagy in NASH has not yet been fully elucidated. The present study determined that signal transducer and activator of transcription 3 (STAT3), in the inflammation and autophagy regulation, was the key in the progression of NASH. In NASH mouse and cell models, STAT3 mRNA and protein expressions were significantly increased, while the induction of autophagy was radically decreased. Furthermore, the effects of metformin on STAT3 expression level and NASH inflammation were investigated. The current results showed that metformin activated autophagy and decreased the mRNA expressions of inflammatory cytokines, IL-1β, IL-6, and TNF-α via inhibition of the STAT3 mRNA and protein expression. The siRNA targeting STAT3 activated autophagy and inhibited the NASH inflammatory response by reducing the mRNA expressions of the inflammatory cytokines in vivo and in vitro. The correlation between autophagy and inflammation was also explored. Autophagy induced by metformin attenuated the inflammatory response. This phenomenon of inflammation reduction was partially restored by treatment with the autophagy inhibitor 3-methylindole (3-MA). In conclusion, this study demonstrated that metformin alleviated the inflammatory response in the liver and the hepatocyte of the NASH model via STAT3-mediated autophagy induction. This mechanism provides a strategy for targeting the NASH inflammatory response.
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http://dx.doi.org/10.1016/j.bbrc.2019.03.077DOI Listing
May 2019

The Clinical Outcomes After Intratympanic Gentamicin Injection to Treat Menière's Disease: A Meta-analysis.

Otol Neurotol 2019 04;40(4):419-429

Department of Otolaryngology Head and Neck Surgery, Lishui People's Hospital, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China.

Objectives: In recent decades, intratympanic gentamicin (ITG) has increasingly been used to treat intractable Menière's disease (MD). We performed a meta-analysis of pooled clinical outcomes, exploring whether ITG was effective and safe.

Data Sources: Cochrane Library database, Embase, and Medline.

Study Selection: We searched scientific and medical databases to March 2018 for articles evaluating clinical outcomes after ITG treatment of intractable MD according to the American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) guidelines.

Data Extraction: We performed a meta-analysis to evaluate treatment efficacy and safety. Quantitative and descriptive information of included RCTs was obtained.

Data Synthesis: We ultimately evaluated 49 of the initially retrieved 1,062 citations (the 49 articles included data from a total of 2,344 MD patients). In almost all studies, patients served as their own controls; "before-and-after" clinical outcomes were reported. The I metric was used to explore heterogeneity.

Conclusion: Overall, our results seem to provide the limited evidence about efficacy and toxicity effects of ITG. However, clinical outcomes require further confirmation; many included studies were poorly designed, less than 2 years for reporting results in MD are in the majority of patients. More long-term prospective follow-up, high-quality, large-scale, randomized controlled trials are needed to confirm that ITG is safe and effective when used to treat intractable MD.
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http://dx.doi.org/10.1097/MAO.0000000000002159DOI Listing
April 2019

Chronic active EBV infection associated with NK cell lymphoma and hemophagocytic lymphohistiocytosis in a 27-year-old woman: A case report.

Medicine (Baltimore) 2019 Jan;98(2):e14032

Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang.

Rationale: Chronic active Epstein-Barr virus infection (CAEBV) is a common infectious disease that often affects multiple organs or systems. However, it is liable to be neglected and misdiagnosed owing to its insidious onset, lack of specific findings in the early phase, and a general lack of awareness among clinicians. PATIENT CONCERNS:: a 27-year-old woman case has been described who was initially misdiagnosed as drug-induced liver injury due to onset presentation of mild splenomegaly, recurrent liver dysfunction, and disputable pathological evidence of liver biopsy.

Diagnoses: CAEBV complicated with natural killer (NK) cell lymphoma and hemophagocytic lymphohistiocytosis (HLH) was diagnosed by in situ hybridization of liver tissue section with EBV-encoded RNA -1 probe and flow cytometry of bone marrow.

Interventions: After admission, the patient received symptomatic treatment and antiviral therapy (combination of acyclovir and foscarnet sodium) as well as adjuvant treatment (thymosin alpha 1 and methylprednisolone); later, the patient received etoposide and dexamethasone for diagnosis of EBV associated HLH. Subsequently, the disease progressed to NK cell lymphoma and the patient received the revised EPOCH chemotherapy regimen [etoposide (100 mg/d, d1-5), dexamethasone (7.5 mg/d, d1-5; 5 mg/d, d6-14), cyclophosphamide (0.8 g/d, d1-2), and pegaspargase (3750 u/d, tid, d1-2)].

Outcomes: Although the patient received a series of therapies and other comprehensive measures, finally she died of gastrointestinal hemorrhage and multiple organ failure.

Lessons: Liver is one of the main target organs of EBV infection. In the clinical setting of unexplained fever and liver injury, it is necessary to be aware of CAEBV, as well as its fatal complication such as EBV associated NK cell lymphoma and HLH.
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http://dx.doi.org/10.1097/MD.0000000000014032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336602PMC
January 2019

Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone.

Skelet Muscle 2018 10 27;8(1):34. Epub 2018 Oct 27.

Research, Shire Pharmaceuticals, Lexington, MA, 02421, USA.

Background: Myostatin antagonists are being developed as therapies for Duchenne muscular dystrophy due to their strong hypertrophic effects on skeletal muscle. Engineered follistatin has the potential to combine the hypertrophy of myostatin antagonism with the anti-inflammatory and anti-fibrotic effects of activin A antagonism.

Methods: Engineered follistatin was administered to C57BL/6 mice for 4 weeks, and muscle mass and myofiber size was measured. In the mdx model, engineered follistatin was dosed for 12 weeks in two studies comparing to an Fc fusion of the activin IIB receptor or an anti-myostatin antibody. Functional measurements of grip strength and tetanic force were combined with tissue analysis for markers of necrosis, inflammation, and fibrosis to evaluate improvement in dystrophic pathology.

Results: In wild-type and mdx mice, dose-dependent increases in muscle mass and quadriceps myofiber size were observed for engineered follistatin. In mdx, increases in grip strength and tetanic force were combined with improvements in muscle markers for necrosis, inflammation, and fibrosis. Improvements in dystrophic pathology were greater for engineered follistatin than the anti-myostatin antibody.

Conclusions: Engineered follistatin generated hypertrophy and anti-fibrotic effects in the mdx model.
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http://dx.doi.org/10.1186/s13395-018-0180-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204036PMC
October 2018

Partial Hepatectomy-Induced Upregulation of miR-1907 Accelerates Liver Regeneration by Activation Autophagy.

Biomed Res Int 2018 31;2018:3817057. Epub 2018 Jul 31.

Department of Liver Surgery, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.

Liver regeneration after partial hepatectomy (PH) is a highly orchestrated biological process in which synchronized hepatocyte proliferation is induced after massive liver mass loss. Hepatocyte proliferation could be regulated by multiple signals, such as miRNAs and autophagy, but underlying mechanism remains unclear. Here a functional miRNA during liver regeneration was identified and its underlying mechanism was delineated in vitro and in vivo. We found that miR-1907 was highly upregulated during liver regeneration after 2/3 PH at various timepoints. The level of miR-1907 was also increased in normal liver cell line treated with HGF at different concentrations. Functionally, miR-1907 enhanced hepatocyte proliferation in vitro and in vivo, and the liver/body weight ratio in miR-1907-overexpressed mice was significantly higher in comparison to the control mice after 2/3 PH. Forced expression of miR-1907 promoted autophagy activation of hepatocyte. Importantly, autophagy inhibition significantly attenuated miR-1907-induced hepatocyte proliferation and the liver/body weight ratio. Finally, GSK3, a suppressor of autophagy signaling, was identified as the direct target gene of miR-1907. Taken together, miR-1907 accelerates hepatocyte proliferation during liver regeneration by activating autophagy; thus pharmacological intervention regulating miR-1907/autophagy axis may be therapeutically beneficial in liver transplantation and liver failure by inducing liver regeneration.
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http://dx.doi.org/10.1155/2018/3817057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091409PMC
January 2019

Dual Effect of Hepatic Macrophages on Liver Ischemia and Reperfusion Injury during Liver Transplantation.

Immune Netw 2018 Jun 28;18(3):e24. Epub 2018 Jun 28.

Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.

Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.
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http://dx.doi.org/10.4110/in.2018.18.e24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026692PMC
June 2018

Protein Engineering on Human Recombinant Follistatin: Enhancing Pharmacokinetic Characteristics for Therapeutic Application.

J Pharmacol Exp Ther 2018 08 11;366(2):291-302. Epub 2018 May 11.

Departments of Discovery Therapeutics (C.S., A.I., D.L., B.P., B.S.-L., A.R., G.B., J.G., B.Z., M.M., C.P., A.W.N.), Bioanalytical and Biomarker Development (T.H.), Discovery Biology and Translational Research (K.P., R.C., Q.D., D.E.), Analytical Development (M.T., S.G.), and Drug Metabolism and Pharmacokinetics (H.R.), Shire, Lexington, Massachusetts (H.R.)

Follistatin (FS) is an important regulatory protein, a natural antagonist for transforming growth factor-β family members activin and myostatin. The diverse biologic roles of the activin and myostatin signaling pathways make FS a promising therapeutic target for treating human diseases exhibiting inflammation, fibrosis, and muscle disorders, such as Duchenne muscular dystrophy. However, rapid heparin-mediated hepatic clearance of FS limits its therapeutic potential. We targeted the heparin-binding loop of FS for site-directed mutagenesis to improve clearance parameters. By generating a series of FS variants with one, two, or three negative amino acid substitutions, we demonstrated a direct and proportional relationship between the degree of heparin-binding affinity in vitro and the exposure in vivo. The triple mutation K(76,81,82)E abolished heparin-binding affinity, resulting in ∼20-fold improved in vivo exposure. This triple mutant retains full functional activity and an antibody-like pharmacokinetic profile, and shows a superior developability profile in physical stability and cell productivity compared with FS variants, which substitute the entire heparin-binding loop with alternative sequences. Our surgical approach to mutagenesis should also reduce the immunogenicity risk. To further lower this risk, we introduced a novel glycosylation site into the heparin-binding loop. This hyperglycosylated variant showed a 10-fold improved exposure and decreased clearance in mice compared with an IgG1 Fc fusion protein containing the native FS sequence. Collectively, our data highlight the importance of improving pharmacokinetic properties by manipulating heparin-binding affinity and glycosylation content and provide a valuable guideline to design desirable therapeutic FS molecules.
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http://dx.doi.org/10.1124/jpet.118.248195DOI Listing
August 2018

miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect.

Onco Targets Ther 2018 23;11:1643-1653. Epub 2018 Mar 23.

Department of Infectious Diseases, Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.

Background: Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear.

Materials And Methods: Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR-342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice.

Results: In this study, we demonstrate that by directly targeting the 3'-UTR (3'-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo.

Conclusion: Our findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer.
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http://dx.doi.org/10.2147/OTT.S161586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870664PMC
March 2018

Reply to: "HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient".

J Hepatol 2018 04 4;68(4):849-851. Epub 2017 Nov 4.

Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai, China. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2017.10.029DOI Listing
April 2018

Primary hepatic angiosarcoma with spleen metastases in an adult woman: a case report and literature review.

Int J Clin Exp Pathol 2017 1;10(11):11211-11218. Epub 2017 Nov 1.

Department of Infectious Disease, The Third Affiliated Hospital of Hebei Medical University Shijiazhuang, China.

Primary hepatic angiosarcoma (PHA) is a rare malignancy that carries a poor prognosis, accounting for less than 2% of all primary hepatic tumors. It is reported to be associated with chronic exposure to environmental carcinogens, but the majority of patients were still with unknown etiology. For patients with PHA often present with nonspecific symptoms and its rapid progression, accurate and early diagnosis is difficult and necessary. We described a 41-year old woman with no history of exposure to toxic chemicals having intermittent abdominal distention for 1 month. Imaging examinations showed multiple nodules with different sizes throughout markedly enlarged liver and spleen. Liver histology showed majority of necrotic lesions with foci of atypical cells, which displayed immunoreactivity for endothelial markers CD31, CD34 and FLi-1, supporting the diagnosis of angiosarcoma. She was finally diagnosed as PHA concomitant with spleen metastases through imaging technology combined with the histopathologically results. Then the patient showed a rapidly worsening clinical course. Finally the patient received liver transplantation and splenectomy. Unfortunately, the patient died of infection in 35 days after liver transplantation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965857PMC
November 2017

Nucleos(t)ide analogue interruption: Alternative approach to intrahepatic set point for spontaneous control of HBV replication?

J Hepatol 2018 03 6;68(3):609-610. Epub 2017 Oct 6.

Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology, Fudan University, Shanghai, China. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2017.09.026DOI Listing
March 2018

Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients.

J Hepatol 2017 Sep 21. Epub 2017 Sep 21.

Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China. Electronic address:

Background & Aims: In diagnostics, serum hepatitis B virus (HBV)-RNA levels are valuable when the HBV-DNA load in circulation is effectively suppressed by nucleos(t)ide analogue (NUC) therapy. This study aimed to determine the intrahepatic viral replication activity reflected in serum HBV-RNA and whether HBV-RNA contributes to liver histological changes in patients treated with NUC.

Methods: A cross-sectional set of serum and liver biopsy samples was obtained from patients treated with entecavir, who had undetectable levels of serum HBV-DNA. The correlations between serum HBV-RNA concentration and levels of peripheral and intrahepatic viral replicative forms, as well as histological scores, were analyzed. Quasispecies of serum HBV-RNA and intrahepatic viral replicative forms were examined by deep sequencing. HBV-RNA-positive hepatocytes were visualized by in situ hybridization.

Results: Serum HBV-RNA was detected in 35 of 47 patients (74.47%, 2.33-4.80logcopies/ml). These levels correlated not only with the intrahepatic HBV-RNA level and the ratio of intrahepatic HBV-RNA to covalently closed circular DNA (cccDNA), but also with the histological scores for grading and staging. Regarding quasispecies, serum HBV-RNA was dynamic and more genetically homogenous to simultaneously sampled intrahepatic HBV-RNA than to the cccDNA pool. In situ histology revealed that HBV-RNA-positive hepatocytes were clustered in foci, sporadically distributed across the lobules, and co-localized with hepatitis B surface antigen.

Conclusion: Serum HBV-RNA levels reflect intrahepatic viral transcriptional activity and are associated with liver histopathology in patients receiving NUC therapy. Our study sheds light on the nature of HBV-RNA in the pathogenesis of chronic HBV infection and has implications for the management of chronic hepatitis B during NUC therapy.

Lay Summary: Serum HBV-RNA levels are indicative of the intrahepatic transcriptional activity of covalently closed circular DNA and are associated with liver histological changes in patients with chronic B hepatitis who are receiving nucleos(t)ide analogue therapy.
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http://dx.doi.org/10.1016/j.jhep.2017.08.021DOI Listing
September 2017

Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting.

Braz J Infect Dis 2017 May - Jun;21(3):213-218. Epub 2017 Mar 27.

Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address:

Aims: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB).

Methods: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100mg daily), adefovir (ADV, 10mg daily), telbivudine (LDT, 600mg daily), entecavir (ETV, 0.5mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated.

Results: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p<0.001, Hazard Ratio (HR)=2.203), elevated alanine aminotransferase (ALT) levels (p<0.001, HR=2.049), and non-vertical transmission (p=0.006, HR=1.656) were predictors of HBeAg seroconversion.

Conclusion: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.
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http://dx.doi.org/10.1016/j.bjid.2017.03.001DOI Listing
October 2017

NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection.

Sci Rep 2017 03 7;7(1):88. Epub 2017 Mar 7.

Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.

Hepatitis B virus (HBV) infection is thought to be an immune-mediated liver disease. The mechanisms underlying natural killer (NK) cell group 2D receptor (NKG2D) that activates NK cells and participates in anti-HBV immunity and immunopathology has not been thoroughly elucidated. Peripheral NKG2D and IFN-γ NK cells frequencies and intrahepatic NKG2D and IFN-γ mRNA and protein expressions were determined in HBV-infected patients. Levels of NKG2D and IFN-γ mRNA and protein in NK cells, co-cultured with HBV-replicating HepG2 cells with or without NKG2D blockade, were analyzed. Serum and supernatant IFN-γ, TNF-α, perforin and granzyme B were measured. In results, peripheral NKG2D and IFN-γ NK cells frequencies, intrahepatic NKG2D and IFN-γ mRNA and protein levels, and serum IFN-γ, TNF-α, perforin and granzyme B levels were all highest in HBV-related acute-on-chronic liver failure group, followed by chronic hepatitis B and chronic HBV carrier groups. In vitro, NKG2D and IFN-γ mRNA and protein levels were higher in NK cells with IFN-α stimulation than without stimulation. Supernatant IFN-γ, TNF-α, perforin and granzyme B levels were increased under co-culture or IFN-α stimulating conditions, but were partially blocked by NKG2DmAb. In conclusion, NKG2D regulates immune inflammation and anti-viral response partly through activation of NK cells during HBV infection.
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http://dx.doi.org/10.1038/s41598-017-00221-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427972PMC
March 2017

Predictive Value of Serum IFN-γ inducible Protein-10 and IFN-γ/IL-4 Ratio for Liver Fibrosis Progression in CHB Patients.

Sci Rep 2017 01 9;7:40404. Epub 2017 Jan 9.

Department of Infectious Disease, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Noninvasive serum markers for assessment of liver fibrosis in chronic hepatitis B (CHB) patients have not been well-studied. The present study was to evaluate the predictive value of serum interferon gamma-inducible protein-10 (IP-10/CXCL10) and the interferon (IFN)-γ/interleukin (IL)-4 ratio for liver fibrosis progression in CHB patients. A total of 180 CHB patients were categorized into four groups: no fibrosis, mild fibrosis, moderate fibrosis, and severe fibrosis. Serum and intrahepatic levels of IP-10, IFN-γ, and IL-4 were examined, from which the IFN-γ/IL-4 ratio was calculated. We found that the serum IP-10 levels were positively correlated with the severity of liver fibrosis, whereas the IFN-γ/IL-4 ratio was negatively associated with the progression of hepatic fibrosis. Multivariate logistic regression analysis revealed that the serum IP-10 was an independent predictor for significant fibrosis. For predicting significant fibrosis, the IP-10 cut-off value of 300 ng/mL had a sensitivity of 92.7% and a specificity of 68.6%. When the IP-10 level was combined with the IFN-γ/IL-4 ratio, the specificity and positive predictive value were 93.8% and 94.6%, respectively; thus, the discriminatory ability was much improved. In conclusion, the serum IP-10 level and the IFN-γ/IL-4 ratio have great potential to predict significant fibrosis among CHB patients.
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http://dx.doi.org/10.1038/srep40404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220308PMC
January 2017

Circulating kidney injury molecule-1 is a novel diagnostic biomarker for renal dysfunction during long-term adefovir therapy in chronic hepatitis B.

Medicine (Baltimore) 2016 Nov;95(44):e5264

Department of Infectious Disease, The Third Affiliated Hospital of Hebei Medical University Department of Liver Disease, The Fifth Hospital of Shijiazhuang, Shijiazhuang, China.

The aim of this study was to evaluate serum kidney injury molecule-1 (KIM-1) as a new diagnostic marker of renal dysfunction in chronic hepatitis B (CHB) patients receiving long-term adefovir dipivoxil (ADV) treatment.We retrospectively enrolled 85 patients treated with ADV and 85 patients treated with entecavir (ETV) monotherapy, for at least 6 months. The 2 groups were matched for baseline age (± 5 years), sex, and estimated glomerular filtration rate (eGFR). Serum creatinine, cystatin C, and KIM-1 concentrations were measured, and eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin C equation, at baseline and last follow-up.eGFR decreased by 10-20% from baseline in 11/85 (14.1%) patients, 20-30% in 5/85 (5.9%), and ≥ 30% in 2/85 (2.4%) patients treated with ADV. Serum KIM-1 was more significantly increased after ADV treatment 86.53 (10.20-355.40) pg/mL than ETV treatment 61.54 (10.53-200.56) pg/mL (P < 0.01). Furthermore, serum KIM-1 was positively correlated with serum cystatin C (r = 0.47; P < 0.001) and negatively correlated with eGFR (r = -0.46; P < 0.001). The area under the receiver operating characteristic curve (AUC-ROC) of serum KIM-1 for identifying renal dysfunction in all enrolled patients was 0.94 (95% confidence interval [95% CI], 0.87 to 1.02; P < 0.001), while the AUC-ROC of serum creatinine was only 0.82 (95% CI, 0.60 to 1.03; P < 0.01).Serum KIM-1 is a promising new diagnostic biomarker of renal dysfunction during long-term ADV therapy for CHB patients.
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http://dx.doi.org/10.1097/MD.0000000000005264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591140PMC
November 2016

Expression of excision repair cross-complementation group 1 in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy.

J Cancer Res Ther 2016 Oct;12(Supplement):72-75

Department of Otolaryngology, The 6th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang, China.

Objective: The purpose of this study was to evaluate the expression of excision repair cross-complementation group 1 (ERCC1) in locoregionally advanced nasopharyngeal carcinoma (NPC) treated with cisplatin-based induction chemotherapy.

Methods: Eighty-five patients with locoregionally advanced NPC treated with cisplatin-based induction chemotherapy were included in this study. The expression level of ERCC1 protein in cancer tissues was detected by immunohistochemistry, and the expression level was divided into the high- and low-expression groups according to their expression level. The objective response rate (ORR) and the long-term disease control rate of two groups were compared between the two groups.

Results: The expression level of ERCC1 in NPC tissues was detected by immunohistochemistry. Forty-one cases had the high ERCC1 expression, and 44 cases had the low ERCC1 expression. The cases for complete response, partial response, stable disease, and progression disease were 1, 19, 21 in the ERCC1 high expression group and 3, 29, 12 for the ERCC1 low-expression group which indicated that the ORR in ERCC1 low group were significant higher than that of ERCC1 high expression group (P < 0.05). The 5-year overall survival, 5-year disease-free survival (DFS), and 5-year local recurrence-DFS were not statistical different between two group (P < 0.05); but the 5-year distant-DFS for ERCC1 low group were significant higher than ERCC1 high group (P < 0.05).

Conclusion: Cisplatin-induced short-term ORR was decreased in nasopharyngeal carcinoma patients with high ERCC1 expression, which increased the risk of metastasis.
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http://dx.doi.org/10.4103/0973-1482.191636DOI Listing
October 2016

Sirolimus and metformin synergistically inhibit hepatocellular carcinoma cell proliferation and improve long-term survival in patients with HCC related to hepatitis B virus induced cirrhosis after liver transplantation.

Oncotarget 2016 Sep;7(38):62647-62656

Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM). Kaplan-Meier and Log-rank tests were used to assess survival. Cell proliferation and tumor xenograft assays were performed to disclose the mechanisms underlying the sirolimus and metformin effects. The Sir+Met group showed significantly prolonged survival compared to the other groups. The most significant cytotoxicity was seen in the Sir+Met group, with significantly decreased levels of phosphorylated PI3K, AKT, AMPK, mTOR, 4EBP1 and S6K, compared with the other groups. In agreement, Sir+Met had the highest suppressive effect on tumor growth among all groups (P<0.01). In summary, Sir+Met treatment significantly prolonged survival, likely by suppressing cell proliferation. Therefore, this combination could represent a potential routine-regimen for patients post LT.
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http://dx.doi.org/10.18632/oncotarget.11591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308754PMC
September 2016

[Role of the Notch signaling pathway in development of acute liver failure in a mouse model].

Zhonghua Gan Zang Bing Za Zhi 2015 Oct;23(10):765-70

Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.

Objective: To investigate the role of the Notch signaling pathway, and the underlying mechanism, in development of acute liver failure (ALF) in a mouse model.

Methods: For in vivo analysis of the role of Notch signaling in ALF, a mouse model of ALF was generated by intraperitoneal injection of 3.0 g/kg D-galactosamine. Histological specimens were stained by hematoxylin-eosin, and then studied microscopically.Expression level of Jaggedl, Notchl, NICD, and Hes5 was measured by western blotting (for protein) and real time-PCR (for mRNA). The level of CD68 protein was detected by immunohistochemical staining. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-10, high mobility group box 1 (HMGB1) chromatin protein, and lipopolysaccharide (LPS) were measured by standard methods. For in vitro analysis of the molecular mechanism, the RAW264.7 macrophage cell line was cultured with LPS in the absence or presence of the Notch inhibitor DAPT, and the intracellular levels of Notch1, NICD, and Hes5 were measured by western blotting and real time-PCR and the extracellular levels of IL-10 and HMGB1 were detected in the supematant.

Results: Compared with unmodeled (normal control) mice, the ALF modeled mice showed higher levels of serum ALT (848.40+/-94.83 U/L vs. 38.99+/-9.63 U/L), AST (911.49+/-67.65 U/L vs. 55.28+/-7.50 U/L), HMGB1 (101.91+/-12.43 µg/L vs. 20.73+/-5.37 µg/L), 1L-10 (4 627.88+/-842.45 pg/mL vs. 1 064.92+/-238.46 pg/mL) and LPS (11.80+/-0.89 EU/mL vs. 0.58+/-0.12 EU/mL), as well as higher expression of Jagged1 (mRNA: 7.63+/-1.41 vs. 1.00+/-0.00; protein: 0.71+/-0.07 vs. 0.34+/-0.07), Notch1 (mRNA: 7.10+/-0.66 vs. 1.00+/-0.00; protein: 0.66+/-0.11 vs. 0.27+/-0.08), NICD (protein: 0.76+/-0.08 vs. 0.27+/-0.08), Hes5 (mRNA: 7.95+/-0.71 vs. 1.00+/-0.00; protein: 1.20+/-0.07 vs. 0.76+/-0.07), and CD68 (protein: 7 685.05+/-417.34 vs. 2 294.01+/-392.93) (all P<0.01). In vitro, LPS increased the extracellular levels of HMGB1 (7.44+/-0.63 vs. 0.21+/-0.05), IL-10 (315.19+/-79.13 vs. 59.19+/-23.30) and the intracellular expression of Notch1 (mRNA: 6.49+/-0.73 vs. 1.00+/-0.00), NICD (protein: 0.65+/-0.10 vs. 0.23+/-0.07), and Hes5 (mRNA: 7.30+/-0.85 vs. 1.00+/-0.00; protein: 0.96+/-0.10 vs. 0.54+/-0.07) (all P<0.01). DAPT treatment led to a decrease above the index serum levels of HMGB1 (6.22+/-0.71) and IL-10 (252.06+/-57.63), and of expression of Notch 1 (mRNA: 3.20+/-0.68), NICD (protein: 0.42+/-0.05), and Hes5 (mRNA: 4.72+/-0.67; protein: 0.84+/-0.09) (P<0.01 or <0.05).

Conclusion: The Notch signaling pathway may plan an important role in the development of ALF upon activation of the pathway in macrophages by LPS and leading to promoted secretion of HMGB 1 and IL-10, with a greater effect on the former.
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http://dx.doi.org/10.3760/cma.j.issn.1007-3418.2015.10.011DOI Listing
October 2015

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma.

Cancer Res 2015 Aug 11;75(15):3181-91. Epub 2015 Jun 11.

Department of Hepato-Bilio-Pancreatic Surgery, Shanghai Institute of Digestive Surgery, Rui Jin Hospital affiliated with Shanghai Jiaotong University, Shanghai, China.

Despite progress in the diagnostics and treatment of hepatocellular carcinoma (HCC), its prognosis remains poor. In this study, we globally assessed long noncoding RNAs (lncRNA) for contributions to HCC using publicly available microarray data, in vitro and in vivo assays. Here, we report that ZFAS1, encoding a lncRNA that is frequently amplified in HCC, is associated with intrahepatic and extrahepatic metastasis and poor prognosis of HCC. ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16. Conversely, ZFAS1 activated ZEB1, MMP14, and MMP16 expression, inhibiting these effects of miR-150. Our results establish a function for ZFAS1 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of HCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3721DOI Listing
August 2015