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Polo-like kinase 1,a new therapeutic target in hepatocellular carcinoma

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World Journal of Gastroenterology 2012年第27期18卷 3527-3536页

作者： Wei Chuen Mok Shanthi Wasser Theresa Tan seng gee lim Institute of Molecular and Cell Biology Agency for ScienceTechnology and ResearchSingapore 138673Singapore Department of Biochemistry Yong Loo Lin School of MedicineNational University of SingaporeSingapore 117597Singapore Department of Gastroenterology and Hepatology Yong Loo Lin School of MedicineNational University Health SystemSingapore 117597Singapore Department of Medicine National University of SingaporeSingapore 119074Singapore

AIM： To investigate the role of polo-like kinase 1 （PLK1） as a therapeutic target for hepatocellular carcinoma （HCC）. METHODS： PLK1 gene expression was evaluated in HCC tissue and HCC cell lines. Gene knockdown with short-interfering RNA （siRNA） was used to study PLK1 gene and protein expression using real-time reverse transcription polymerase chain reaction （RT-PCR） and Western blotting, and cell proliferation using 3-（4,5-dim ethylthiazol-2-yl）-5-（3-carboxymethoxyphenyl）-2（4-sulf ophenyl）-2H-tetrazolium （MTS） and bromodeoxyuridine （BrdU） assays. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick end label- ing （TUNEL） assay, and caspase-inhibition assay. Huh-7 cells were transplanted into nude mice and co-cultured with PLK1 siRNA or control siRNA, and tumor progres- sion was compared with controls. RESULTS： RT-PCR showed that PLK1 was overexpre- ssed 12-fold in tumor samples compared with controls, and also was overexpressed in Huh-7 cells, siRNA against PLK1 showed a reduction in PLK1 gene and protein expression of up to 96% in Huh-7 cells, and a reduction in cell proliferation by 68% and 92% in MTS and BrdU cell proliferation assays, respectively. There was a 3-fold increase in apoptosis events, and TUNEL staining and caspase-3 assays suggested that this was caspase-independent. The pan-caspase inhibitor Z-VAD-FMK was unable to rescue the apoptotic cells. Immnofluorescence co-localized endonuclease-G to fragmented chromosomes, implicating it in apoptosis. Huh-7 cells transplanted subcutaneously into nude mice showed tumor regression in siPLKl-treated mice, but not in controls. CONCLUSION： Knockdown of PLK1 overexpression in HCC was shown to be a potential therapeutic target, leading to apoptosis through the endonuclease-G path- way.

关键词： RNA Polo-like kinase 1 Apoptosis Endonu-clease G Forkhead box transcription factors Nude mice

Percutaneous paraumbilical embolization as an unconventional and successful treatment for bleeding jejunal varices

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World Journal of Gastroenterology 2009年第30期15卷 3823-3826页

作者： Lee-Guan lim Yin-Mei Lee Lenny Tan Stephen Chang seng-gee lim Department of Gastroenterology and Hepatology National University HospitalSingapore 119074Singapore Department of Diagnostic Radiology National University HospitalSingapore 119074Singapore Department of Surgery National University HospitalSingapore 119074Singapore

A 48-year-old Indian male with alcoholic liver cirrhosis was admitted after being found unresponsive. He was hypotensive and had hematochezia. Esophagogastroduodenoscopy (EGD) showed small esophageal varices and a clean-based duodenal ulcer. He continued to have hematochezia and anemia despite blood transfusions. Colonoscopy was normal. Repeat EGD did not reveal any source of recent bleed. Twelve days after admission, his hematochezia ceased. He refused further investigation and was discharged two days later. He presented one week after discharge with hematochezia. EGD showed non-bleeding Grade 1 esophageal varices and a clean-based duodenal ulcer. Colonoscopy was normal. Abdominal computed tomography (CT) showed liver cirrhosis with mild ascites, paraumbilical varices, and splenomegaly. He had multiple episodes of hematochezia, requiring repeated blood transfusions. Capsule endoscopy identified the bleeding site in the jejunum. Concurrently, CT angiography showed paraumbilical varices inseparable from a loop of small bowel, which had herniated through an umbilical hernia. The lumen of this loop of small bowel opacified in the delayed phase, which suggested variceal bleeding into the small bowel. Portal vein thrombosis was present. As he had severe coagulopathy and extensive paraumbilical varices, surgery was of high risk. He was not suitable for transjugular intrahepatic porto-systemic shunt as he had portal vein thrombosis. Percutaneous paraumbilical embolization via caput medusa was performed on day 9 of hospitalization. Following the embolization, the hematochezia stopped. However, he defaulted subsequent follow-up.

关键词： Embolization Jejunal varices Obscurebleed Capsule endoscopy Angiography

miR-106b-25/miR-17-92 clusters: Polycistrons with oncogenic roles in hepatocellular carcinoma

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World Journal of Gastroenterology 2014年第20期20卷 5962-5972页

作者： Weiqi Tan Yang Li seng-gee lim Theresa MC Tan Department of Biochemistry Yong Loo Lin School of Medicine National University of Singapore Singapore S117597 Singapore Department of Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore S117597 Singapore

MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational *** polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in *** has two other paralogs in the human genome,the miR-106b-25 cluster and the miR-106a-363 ***,the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families,namely the miR-17,the miR-92,the miR-18and the miR-19 ***-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular *** of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C *** targets of these microRNAs have been identified,and these targets are involved in tumor growth,cell survival and *** this review,we first describe the regulation of these clusters by c-Myc and E2F1,and how the members of these clusters inturn regulate E2F1 expression forming an auto-regulatory *** addition,the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.

关键词： miR-106b-25 cluster miR-17-92 cluster Hepatocellular carcinoma Liver cirrhosis MicroRNAs

Outcome of lamivudine-resistant hepatitis B virus is generally benign except in cirrhotics

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World Journal of Gastroenterology 2005年第28期11卷 4344-4350页

作者： Yock-Young Dan Chun-Tao Wai Yin-Mei Lee Dede Selamat Sutedja Bee-Leng Seer seng-gee lim Division of Gastroenterology National University Hospital Singapore

AIM： We set to determine factors that determine clinical severity after the development of resistance.METHODS： Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups： 13/35 （37%） were non-cirrhotics with normal pre-treatment ALT （Group IA）, 12/35 （34%） were non-cirrhotics with elevated pre-treatment ALT （Group IB）, and 10/35 （29%） were cirrhotics （Group II）. Patients were followed for a median of 98 wk （range 26-220） after the emergence of genotypic resistance.RESULTS： Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients （75%） developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score （in the cirrhotic group） were predictive of clinical resistance and correlated with peak ALT levels and CPT score.CONCLUSION： The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death （30%） with the development of lamivudine resistance.

关键词： Lamivudine resistance YMDD mutants Hepatitis B treatment Nucleoside analog

Chronic hepatitis C genotype 1 treatment roadmap for resource constrained settings

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World Journal of Gastroenterology 2015年第6期21卷 1972-1981页

作者： seng gee lim Department of Gastroenterology and Hepa-tology Department of Medicine National University Health System Yong Loo Lin School of Medicine National University of Singapore

AIM:To use existing hepatitis C virus(HCV)antiviral therapies as access to new treatments is ***:A Pub Med search for randomised control trials or meta-analysis related to response-guided therapy of HCV genotype 1 patients was undertaken using pegylated interferon and ribavirin(PR),boceprevir(B)and telaprevir(T)and lead-in where responseguided therapy at TW4(TW4),8(TW8),10(TW10),or12(TW12)based on HCVRNA(+)or HCVRNA(-).Studies presented at major conferences were also *** necessary,a post-hoc analysis was performed.A response-guided management roadmap was created based on sustained virological response(SVR).RESULTS:Starting with PR,those with HCVRNA(-)at TW4 have>86%SVR,while those are HCVRNA(+)have 34%-41.7%***(-)TW4 patients can have 24 wk PR if HCVRNA80%SVR,leading to the"80-80"***:Using a roadmap based on HCVRNA(-)at TW4 or TW8(the"80-80"rule),high SVR can be achieved,and guide the best choices for treatment,and also reduces drug exposure in poor responders.

关键词： Chronic hepatitis C hepatitis C virus RNA Sustaine

Alanine aminotransferase is an inadequate surrogate marker for detecting lamivudine resistance

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World Journal of Gastroenterology 2010年第37期16卷 4691-4696页

作者： Lee Guan lim Myat Oo Aung Bee Leng Seet Cindy Tan Yock Young Dan Yin Mei Lee Dede Selamat Sutedja Mark Fernandes Guan Huei Lee Evelyn Koay seng gee lim Department of Gastroenterology and Hepatology National University Health System Yong Yoo Lin School of Medicine National University of Singapore Department of Medicine National University Health System Yong Yoo Lin School of Medicine National University of Singapore Molecular Diagnostic Centre National University Health System Yong Yoo Lin School of Medicine National University of Singapore Investigative Medicine Unit National University Health System Yong Yoo Lin School of Medicine National University of Singapore

AIM: To investigate the accuracy of serum alanine aminotransferase (ALT) in diagnosing lamivudine resistance and factors that contributed to abnormal serum ***: This was a retrospective study of chronic hepatitis B patients on lamivudine therapy who were followed for 3-mo with liver function tests and hepatitis B virus (HBV) DNA measurement. Lamivudine resistance was defined as HBV DNA ≥ 1 log from nadir on at least 2 occasions, confirmed by genotyping. Serum ALT levels in patients with lamivudine resistance were compared to serum ALT levels in those without lamivudine resistance. RESULTS: There were 111 patients with and 117 without lamivudine resistance. The area under the receiver operating characteristic of serum ALT to diagnose lamivudine resistance was 0.645 ± 0.037. Serum ALT > 42.5 U/L gave the best diagnostic accuracy with sensitivity = 61%, specificity = 60%, positive predictive value = 60%, negative predictive value = 61%, positive likelihood ratio = 1.53 and negative likelihood ratio = 0.65 for predicting lamivudine resistance, missing 39% of resistant patients. Using other serum ALT cutoffs, diagnostic accuracy was lower. By multivariate analysis, baseline abnormal serum ALT was associated with abnormal ALT during resistance (OR = 5.98, P = 0.003), and males were associated with serum ALT flares during resistance (OR = 8.9, P = 0.016). CONCLUSION: Serum ALT is inadequate for diagnosing lamivudine resistance and has implications where viral resistance testing is suboptimal and for reimbursement of rescue therapy.

关键词： Antiviral therapy Chronic hepatitis B Sensitivity Specificity YMDD mutants

Acute-on-chronic liver failure in a multi-ethnic Asian city:A comparison of patients identified by Asia-Pacific Association for the Study of the Liver and European Association for the Study of the Liver definitions

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World Journal of Hepatology 2017年第28期9卷 1133-1140页

作者： Anandraj Selva Rajoo seng-gee lim Wah Wah Phyo Thandar Tun Yock-Young Dan Yin-Mei Lee How-Cheng Low Kieron lim Poh-seng Tan Guan-Huei Lee Yong Loo Lin School of Medicine National University of SingaporeSingapore 119077Singapore Institute of Molecular and Cell Biology ASTARSingapore 138668Singapore Division of Gastroenterology and Hepatology Department of MedicineNational University HospitalSingapore 119228Singapore Department of Hepatology Mandalay General Hospital30th StChan Aye Tharsan TownshipMandalayMyanmar

AIM To explore the applicability of the Asia-Pacific Association for the Study of the Liver(APASL) and European Association for the Study of the Liver(EASL) guidelines for acute-on-chronic liver failure(ACLF) in profiling patients and determining the *** Patients admitted to a tertiary hospital in Singapore with acute decompensation of liver disease from January 2004to July 2014 are screened for ACLF according to the APASL and EASL criteria. The patients' data(including basic demographics, information about existing chronic liver disease, information about the acute decompensation, relevant laboratory values during admission, treatment, and outcome) are retrospectively analyzed to determine the background, precipitating factors and *** A total of 458 liver patients is analyzed, and 78 patients with ACLF are identified. Sixty-three patients(80.8%) meet the APASL criteria, 64 patients(82.1%) meet the EASL criteria, and 49 patients(62.8%) fulfilled both criteria. The most common causes of acute liver injury are bacterial infections(59.0%), hepatitis B flare(29.5%), and variceal bleeding(24.4%). The common aetiologies of the underlying chronic disease included hepatitis B(43.6%), alcoholic(20.5%) and cryptogenic(11.5%) liver disease. The overall mortality rate is 61.5%. Increased age, the number of organ failures(as per CLIF-SOFA score), peak creatinine, INR, and amylase levels are associated with increased mortality or the need for liver transplantation. 14.3% of patients undergo liver transplantation with a 100% 1-year survival rate. CONCLUSION Both APASL and EASL criteria have identified ACLF patients with high three-month mortality, but those who fulfill APASL criteria alone have a better survival.

关键词： Acute-on-chronic liver failure Survival Prognosis Liver decompensation Liver cirrhosis

Up-regulation of micro RNA-210 inhibits proliferation of hepatocellular carcinoma cells by targeting YES1

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World Journal of Gastroenterology 2015年第46期21卷 13030-13041页

作者： Weiqi Tan seng-gee lim Theresa MC Tan Department of Biochemistry Yong Loo Lin School of MedicineNational University of Singapore Department of Medicine Yong Loo Lin School of MedicineNational University of Singapore

AIM: To determine the expression of micro RNA-210(mi R-210) in hepatocellular carcinoma(HCC) and to examine its role using HCC ***: The expression of mi R-210 was determined in 21 pairs of HCC samples and the corresponding surrounding non-tumor tissues. The effects of mi R-210 on proliferation and cell cycle progression were examined using Hep G2 and Hu H7 cells. Overexpression and inhibition of mi R-210 was achieved by transfection of the cells with mi R-210 mimic or inhibitor. Luciferase reporter constructs were used to identify the mi R-210 interacting site on Yes1. Yes1 expression was examined after mi R-210 transfection,as well as in the HCC ***: mi R-210 was significantly up-regulated by 3.4 fold(P < 0.01) in the tumor samples. The over-expression of mi R-210 significantly reduced cell proliferation compared to the mock-treated cells(68.9% ± 7.4% and 53.6% ± 5.0%,P < 0.05 for the Hep G2 and Hu H7 cells respectively). Analysis of the Hu H7 cells transfected with mi R-210 mimic by flow cytometry showed that the cells took a longer time to reach the G2/M phase. The interaction between mi R-210 and the 3'UTR of the Yes1 transcript was confirmed using a luciferase reporter assay. Over-expression of mi R-210 reduced the expression of Yes1 protein in both Hu H7 and Hep G2 cells. Tumors with a greater than fourfold increase in the expression of mi R-210 showed consistently lower expressions of Yes1 in the *** nocodazole-treated cells with a significant G2/M cell population,Yes1 protein was significantly reduced and pre-inhibition of mi R-210 in Hu H7 cells was able to prevent the reduction of Yes1 protein expression. Knock-down of Yes1 by si RNA also led to reduced cell proliferation(70.8% ± 7.5%,P < 0.05 in the Hu H7 cells).CONCLUSION: Up-regulation of mi R-210 inhibits cell proliferation. Yes1 is a target of mi R-210 and affects cell proliferation in HCC.

关键词： Micro RNA-210 Hepatocellular carcinoma Proliferati

Risk factors for ribavirin treatment failure in Asian organ transplant recipients with chronic hepatitis E infection

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World Journal of Hepatology 2019年第6期11卷 553-561页

作者： En Xian Sarah Low Edhel Tripon Kieron lim Poh seng Tan How Cheng Low Yock Young Dan Yin Mei Lee Mark Muthiah Wai Mun Loo Calvin Jianyi Koh Wah Wah Phyo JunXiong Pang seng gee lim Guan-Huei Lee Department of Medicine Ng Teng Fong General HospitalNational University Health SystemSingapore 609606Singapore Centre for Liver Disease Management and Transplant of Medical City Manila 1605Philippines Mount Elizabeth Medical Centre Singapore 228510Singapore Division of Gastroenterology and Hepatology National University Health SystemSingapore 119228Singapore Department of Medicine National University of SingaporeSingapore 119077Singapore Centre for Infectious Disease Epidemiology and Research National University of SingaporeSingapore 117549Singapore Department of Medicine Yong Loo Lin School of MedicineNational University of SingaporeSingapore 119228Singapore

BACKGROUND Hepatitis E virus(HEV)infection is a cause of chronic hepatitis in immunosuppressed *** virologic response rates to a 12-wk course of ribavirin therapy were reported to be>70%in the *** study describes the outcome of HEV treatment in a transplant center in *** To study the outcome of ribavirin treatment in a series of chronic HEV patients,and the cause of treatment *** We studied all of the transplant recipients who were diagnosed with HEV infection between 2012 to *** outcome of therapy and virologic relapse are monitored for three years after the end of *** Ten transplant recipients(4 liver,5 kidney,and 1 bone marrow transplantation)with positive HEV RNA were *** patients received at least 12 wk of ribavirin therapy,and the remaining patient resolved after reducing immunosuppression *** subjects had prolonged viremia that lasted more than one year,despite continuous ribavirin *** ribavirin-treated patients(44.4%)had HEV RNA relapse after achieving a virologic response by the end of *** overall failure rate is 66.7%.Being a kidney transplant recipient is the strongest risk factor for not achieving an initial sustained virologic response(0/5 treated,Chi-Square test,P<0.05).The most common side effect of ribavirin is anemia(100%)(haemoglobin reduction of 3-6.2 g/dL).Seven patients required either a blood transfusion or erythropoietin *** The sustained virologic response rate of 12-wk ribavirin therapy for HEV infection in this Asian series was lower than *** transplant recipients had a higher rate of treatment failure due to higher immunosuppression requirements and adverse effects.

关键词： Toxicity Antiviral agents Hepatitis E virus Virus classification Systemic immunity Immune responses Persistent infection