Publications by authors named "London Lucien Ooi"

63 Publications

Correlation of NUF2 Over-expression with Poorer Patient Survival in Multiple Cancers.

Cancer Res Treat 2021 Jan 4. Epub 2021 Jan 4.

Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore.

Purpose: NUF2 has been implicated in multiple cancers recently, suggesting NUF2 may play a role in the common tumorigenesis process. In this study, we aim to perform comprehensive meta-analysis of NUF2 expression in the cancer types included in the Cancer Genome Atlas (TCGA).

Materials And Methods: RNA-sequencing data in 31 cancer types in the TCGA data and 11 independent datasets were used to examine NUF2 expression. Silencing NUF2 using targeting shRNAs in hepatocellular carcinoma cell lines was used to evaluate NUF2's role in hepatocellular carcinoma (HCC) in vitro and in vivo.

Results: NUF2 up-regulation is significantly observed in 23 out of the 31 cancer types in the TCGA datasets and validated in 13 major cancer types using 11 independent datasets. NUF2 overexpression was clinically important as high NUF2 was significantly associated with tumor stages in eight different cancers. High NUF2 was also associated with significantly poorer patient overall survival and disease-free survival in eight and six cancers, respectively. We proceeded to validate NUF2 overexpression and its negative association with overall survival at the protein level in an independent cohort of 40 HCC patients. Compared to the non-targeting controls, NUF2 knockdown cells showed significantly reduced ability to grow, migrate into a scratch wound and invade the 8 μm porous membrane in vitro. Moreover, NUF2 knockdown cells also formed significantly smaller tumors than control cells in mouse xenograft assays in vivo.

Conclusion: NUF2 up-regulation is a common feature of many cancers. The prognostic potential and functional impact of NUF2 up-regulation warrant further studies.
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http://dx.doi.org/10.4143/crt.2020.466DOI Listing
January 2021

Comparison between long and short-term venous patencies after pancreatoduodenectomy or total pancreatectomy with portal/superior mesenteric vein resection stratified by reconstruction type.

PLoS One 2020 5;15(11):e0240737. Epub 2020 Nov 5.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore.

Background: Venous reconstruction has been recently demonstrated to be safe for tumours with invasion into portal vein and/or superior mesenteric vein. This study aims to compare the patency between various venous reconstructions.

Methods: This is retrospective study of 76 patients who underwent pancreaticoduodenectomy or total pancreatectomy with venous reconstruction from 2006 to 2018. Patient demographics, tumour histopathology, morbidity, mortality and patency were studied. Kaplan-Meier estimates were performed for primary venous patency.

Results: Sixty-two patients underwent pancreaticoduodenectomy and 14 underwent total pancreatectomy. Forty-seven, 19 and 10 patients underwent primary repair, end-to-end anastomosis and interposition graft respectively. Major morbidity (Clavien-Dindo >grade 2) and 30-day mortality were 14/76(18.4%) and 1/76(1.3%) respectively. There were 12(15.8%) venous occlusion including 4(5.3%) acute occlusions. Overall 6-month, 1-year and 2-year primary patency was 89.1%, 92.5% and 92.3% respectively. 1-year primary patency of primary repair was superior to end-to-end anastomosis and interposition graft (primary repair 100%, end-to-end anastomosis 81.8%, interposition graft 66.7%, p = 0.045). Pairwise comparison also demonstrated superior 1-year patency of primary repair (adjusted p = 0.037). There was no significant difference between the cumulative venous patency for each venous reconstruction method: primary repair 84±6%, end-to-end anastomosis 75±11% and interposition graft 76±15% (p = 0.561).

Conclusion: 1-year primary venous patency of primary repair is superior to end-to-end anastomosis and interposition graft.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240737PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644060PMC
December 2020

Impact of multidisciplinary tumour boards (MTB) on the clinicopathological characteristics and outcomes of resected colorectal liver metastases across time.

World J Surg Oncol 2020 Sep 3;18(1):237. Epub 2020 Sep 3.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Outram Rd, Singapore, 169856, Singapore.

Background: Resection of colorectal liver metastases (CLM) has been established as the standard of care. This study aims to compare the change in clinicopathological characteristics of patients who underwent curative resection of CLM across two time periods-2000 to 2010 (P1) and 2011 to 2016 (P2) and evaluate the prognostic impact of these characteristics on survival outcomes.

Methods: Patients who undergo liver resection for CLM at Singapore General Hospital from January 2000 to December 2016 were identified from a prospectively maintained database. The primary end point was overall survival.

Results: There were 183/318 (57.5%) patients and 135/318 (42.5%) patients in P1 and P2, respectively. There was a lower proportion of patients who had nodal metastases from primary colorectal cancer and clinical risk score (CRS) less than 3 in P2 when compared to P1. There was no difference in survival between both time periods. Independent predictors of survival for the cohort were CEA levels ≥ 200 ng/ml, primary tumour grade and lymph nodal status. Independent predictors of poor survival in P1 were poorly differentiated colorectal cancer and nodal metastases while in P2, independent predictors of poor survival were multiple liver metastases and nodal metastases.

Conclusion: Nodal metastases from primary colorectal cancer are an independent predictor of poor survival across time for resectable CLM. Although there is no difference in survival between the two time periods, patients with multiple liver metastases should be carefully considered prior to surgery as it is also an independent predictor of overall survival.
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http://dx.doi.org/10.1186/s12957-020-01984-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650267PMC
September 2020

Early Prediction of Post-hepatectomy Liver Failure in Patients Undergoing Major Hepatectomy Using a PHLF Prognostic Nomogram.

World J Surg 2020 Dec 28;44(12):4197-4206. Epub 2020 Aug 28.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 20 College Road, Singapore, 169856, Singapore.

Background: Liver resection (LR) is the main modality of treatment for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). Post-hepatectomy liver failure (PHLF) remains the most dreaded complication. We aim to create a prognostic score for early risk stratification of patients undergoing LR.

Methodology: Clinical and operative data of 472 patients between 2000 and 2016 with HCC or CRLM undergoing major hepatectomy were extracted and analysed from a prospectively maintained database. PHLF was defined using the 50-50 criteria.

Results: Liver cirrhosis and fatty liver were histologically confirmed in 35.6% and 53% of patients. 4.7% (n = 22) of patients had PHLF. A 90-day mortality was 5.1% (n = 24). Pre-operative albumin-bilirubin score (p = 0.0385), prothrombin time (p < 0.0001) and the natural logarithm of the ratio of post-operative day 1 to pre-operative serum bilirubin (SB) (ln(Bil/Bil); p < 0.0001) were significantly independent predictors of PHLF. The PHLF prognostic nomogram was developed using these factors with receiver operating curve showing area under curve of 0.88. Excellent sensitivity (94.7%) and specificity (95.7%) for the prediction of PHLF (50-50 criteria) were achieved at cut-offs of 9 and 11 points on this model. This score was also predictive of PHLF according to Bil > 7 and International Study Group for Liver Surgery criteria, intensive care unit admissions, length of stay, all complications, major complications, re-admissions and mortality (p < 0.05).

Conclusions: The PHLF nomogram ( https://tinyurl.com/SGH-PHLF-Risk-Calculator ) can serve as a useful tool for early identification of patients at high risk of PHLF before the 'point of no return'. This allows enforcement of closer monitoring, timely intervention and mitigation of adverse outcomes.
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http://dx.doi.org/10.1007/s00268-020-05713-wDOI Listing
December 2020

Randomized control trial comparing an Alvarado Score-based management algorithm and current best practice in the evaluation of suspected appendicitis.

World J Emerg Surg 2020 05 1;15(1):30. Epub 2020 May 1.

Department of General Surgery, Singapore General Hospital, Singapore, Singapore.

Background: An objective algorithm for the management of suspected appendicitis guided by the Alvarado Score had previously been proposed. This algorithm was expected to reduce computed tomography (CT) utilization without compromising the negative appendectomy rate. This study attempts to validate the proposed algorithm in a randomized control trial.

Methods: A randomized control trial comparing the management of suspected acute appendicitis using the proposed algorithm compared to current best practice, with the rate of CT utilization as the primary outcome of interest. Secondary outcomes included the percentage of missed diagnosis, negative appendectomies, length of stay in days, and overall cost of stay in dollars.

Results: One hundred sixty patients were randomized. Characteristics such as age, ethnic group, American Society of Anesthesiologist score, white cell count, and symptom duration were similar between the two groups. The overall CT utilization rate of the intervention arm and the usual care arm were similar (93.7% vs 92.5%, p = 0.999). There were no differences in terms of negative appendectomy rate, length of stay, and cost of stay between the intervention arm as compared to the usual care arm (p = 0.926, p = 0.705, and p = 0.886, respectively). Among patients evaluated with CT, 75% (112 out of 149) revealed diagnoses for the presenting symptoms.

Conclusion: The proposed AS-based management algorithm did not reduce the CT utilization rate. Outcomes such as missed diagnoses, negative appendectomy rates, length of stay, and cost of stay were also largely similar. CT utilization was prevalent as 93% of the study cohort was evaluated by CT scan.

Trial Registration: The study has been registered at ClinicalTrials.gov (NCT03324165, Registered October 27 2017).
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http://dx.doi.org/10.1186/s13017-020-00309-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193351PMC
May 2020

Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma.

Cancer Res 2019 Oct 23;79(20):5131-5139. Epub 2019 Jul 23.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0255DOI Listing
October 2019

Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Sci Rep 2019 07 18;9(1):10464. Epub 2019 Jul 18.

Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore.

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3 cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.
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http://dx.doi.org/10.1038/s41598-019-46872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639394PMC
July 2019

Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.

FASEB J 2019 08 25;33(8):8759-8770. Epub 2019 Apr 25.

Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore.

Hepatocellular carcinoma (HCC) is a common and deadly cancer with limited treatment options. Through genome-wide growth depletion screens using clustered regularly interspaced short palindromic repeats and expression profiling of primary HCC tumors, we identified 13 clinically relevant target genes with therapeutic potential. Subsequent functional annotation analysis revealed significant enrichment of these 13 genes in the cell cycle, cell death, and survival pathways. Non-structural maintenance of chromosomes condensin I complex subunit G (NCAPG) was ranked the highest among the depletion screens and multiple HCC expression datasets. Transient inhibition of NCAPG using specific small interfering RNAs resulted in a significant reduction in cell growth, migration, and the down-regulation of mitochondrial gene expression . Small homologous RNA-mediated knockdown of NCAPG significantly impaired cell viability, caused aberrant mitotic division, fragmented the mitochondrial network, and increased cell death . HCC cells with a reduced expression of NCAPG formed significantly smaller xenograft tumors . Importantly, high NCAPG expression was significantly associated with poorer overall and disease-free survival in HCC patients. High NCAPG expression is a novel prognostic biomarker to predict HCC early recurrence after surgical resection. In conclusion, NCAPG is an essential gene for HCC tumor cell survival. It represents a promising novel target for treating HCC and a prognostic biomarker for clinical management of HCC.-Wang, Y., Gao, B., Tan, P. Y., Handoko, Y. A., Sekar, K., Deivasigamani, A., Seshachalam, V. P., OuYang, H.-Y., Shi, M., Xie, C., Goh, B. K. P., Ooi, L. L., Hui, K. M. Genome-wide CRISPR knockout screens identify NCAPG as an essential oncogene for hepatocellular carcinoma tumor growth.
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http://dx.doi.org/10.1096/fj.201802213RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662966PMC
August 2019

NUF2 is a valuable prognostic biomarker to predict early recurrence of hepatocellular carcinoma after surgical resection.

Int J Cancer 2019 08 4;145(3):662-670. Epub 2019 Feb 4.

Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore.

Early tumor recurrence after curative surgical resection poses a great challenge to the clinical management of hepatocellular carcinoma (HCC). We conducted whole genome expression microarrays on 64 primary HCC tumors with clinically defined recurrence status and cross-referenced with RNA-seq data from 18 HCC tumors in the Cancer Genome Atlas project. We identified a 77-gene signature, which is significantly associated with early recurrent (ER) HCC tumors. This ER-associated signature shows significant enrichment in genes involved in cell cycle pathway. We performed receiver operating characteristic (ROC) analysis to evaluate the prognostic biomarker potential of these 77 genes and Pearson correlation analysis to identify 11 close clusters. The one gene with the best area under the ROC curve in each of the 11 clusters was selected for validation using reverse-transcription quantitative PCR in an independent cohort of 24 HCC tumors. NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. In conclusion, NUF2 in combination with liver cirrhosis is a promising prognostic biomarker for early HCC recurrence.
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http://dx.doi.org/10.1002/ijc.32134DOI Listing
August 2019

CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling.

EMBO J 2018 10 14;37(20). Epub 2018 Sep 14.

Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, School of Medicine, Holistic Integrative Pharmacy Institutes (HIPI), Hangzhou Normal University, Hangzhou, China

Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt destruction complex; this function was further controlled by CDK1-driven phosphorylation of BCL9 N-terminal, especially T172. Interestingly, T172 phosphorylation was correlated with cancer patient prognosis and enriched in tumours. Thus, our results revealed a novel role of BCL9 in controlling mitotic Wnt signalling to promote cell division and growth.
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http://dx.doi.org/10.15252/embj.201899395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187222PMC
October 2018

A retrospective review of correlative radiological assessment and surgical exploration for hilar cholangiocarcinoma.

Ann Hepatobiliary Pancreat Surg 2018 Aug 31;22(3):216-222. Epub 2018 Aug 31.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.

Backgrounds/aims: Hilar cholangiocarcinomas (HCCAs) are tumors that involve the biliary confluence; at present, radical surgery offers the only chance of long-term survival, but this can be challenging given the complexity of the hilar anatomy. Blumgart and Jarnagin described a preoperative staging system that incorporates the effect of local tumor extent and its impact on adjacent structures and that has been demonstrated to correlate better with actual surgical resectability. The primary aim of this study is to describe the correlation between preoperative Blumgart-Jarnagin staging and its correlation with surgical resectability.

Methods: Patients who underwent surgical resection for hilar cholangiocarcinoma at Singapore General Hospital between January 1, 2002, and January 1, 2013, were identified from a prospectively maintained institutional database. All patients were staged based on the criteria described by Blumgart and Jarnagin. Correlation with surgical resectability was then determined.

Results: A total of 19 patients were identified. Overall resectability was 57.8% (n=11). Patients with Blumgart-Jarnagin stage T1 had the highest rates of resectability at 80%; patients with stage T2 and T3 disease had resectability rates of 25% and 40% respectively. Median overall survival was 13.6 months.

Conclusions: The Blumgart-Jarnagin staging system is useful for predicting tumor resectability in HCCA.
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http://dx.doi.org/10.14701/ahbps.2018.22.3.216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125271PMC
August 2018

Predictors of post-hepatectomy liver failure in patients undergoing extensive liver resections for hepatocellular carcinoma.

Ann Hepatobiliary Pancreat Surg 2018 Aug 31;22(3):185-196. Epub 2018 Aug 31.

Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore.

Backgrounds/aims: To determine the prevalence of post-hepatectomy liver failure/insufficiency (PHLF/I) in patients undergoing extensive hepatic resections for hepatocellular carcinoma (HCC) and to assess the predictive value of preoperative factors for post-hepatectomy liver failure or insufficiency (PHLF/I).

Methods: A retrospective review of patients who underwent liver resections for HCC between 2001 and 2013 was conducted. Preoperative parameters were assessed and analyzed for their predictive value of PHLF/I. Definitions used included the 50-50, International Study Group of Liver Surgery (ISGLS) and Memorial Sloan Kettering Cancer Centre (MSKCC) criteria.

Results: Among the 848 patients who underwent liver resections for HCC between 2001 and 2013, 157 underwent right hepatectomy (RH) and extended right hepatectomy (ERH). The prevalence of PHLF/I was 7%, 41% and 28% based on the 50-50, ISGLS and MSKCC criteria, respectively. There were no significant differences in PHLF/I between RH and ERH. Model for End-Stage Liver Disease (MELD) score and bilirubin were the strongest independent predictors of PHLF/I based on the 50-50 and ISGLS/MSKCC criteria, respectively. Predictive models were developed for each of the criteria with multiple logistic regression.

Conclusions: MELD score, bilirubin, alpha-fetoprotein and platelet count showed significant predictive value for PHLF/I (all <0.05). A composite score based on these factors serves as guideline for physicians to better select patients undergoing extensive resections to minimize PHLF.
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http://dx.doi.org/10.14701/ahbps.2018.22.3.185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125273PMC
August 2018

Simultaneous silencing of ACSL4 and induction of GADD45B in hepatocellular carcinoma cells amplifies the synergistic therapeutic effect of aspirin and sorafenib.

Cell Death Discov 2017 11;3:17058. Epub 2017 Sep 11.

Laboratory of Cancer Genomics, National Cancer Centre, Singapore, Singapore.

Sorafenib is currently the only US Food and Drug Administration (FDA)-approved molecular inhibitor for the systemic therapy of advanced hepatocellular carcinoma (HCC). Aspirin has been studied extensively as an anti-inflammation, cancer preventive and therapeutic agent. However, the potential synergistic therapeutic effects of sorafenib and aspirin on advanced HCC treatment have not been well studied. Drug combination studies and their synergy quantification were performed using the combination index method of Chou-Talalay. The synergistic therapeutic effects of sorafenib and aspirin were evaluated using an orthotopic mouse model of HCC and comprehensive gene profiling analyses were conducted to identify key factors mediating the synergistic therapeutic effects of sorafenib and aspirin. Sorafenib was determined to act synergistically on HCC cells with aspirin . Using Hep3B and HuH7 HCC cells, it was demonstrated that sorafenib and aspirin acted synergistically to induce apoptosis. Mechanistic studies demonstrated that combining sorafenib and aspirin yielded significant synergistically anti-tumor effects by simultaneously silencing ACSL4 and the induction of GADD45B expression in HCC cells both and in the orthotopic HCC xenograft mouse model. Importantly, clinical evidence has independently corroborated that survival of HCC patients expressing ACSL4GADD45B was significantly poorer compared to patients with ACSL4GADD45B, thus demonstrating the potential clinical value of combining aspirin and sorafenib for HCC patients expressing ACSL4GADD45B. In conclusion, sorafenib and aspirin provide synergistic therapeutic effects on HCC cells that are achieved through simultaneous silencing of ACSL4 and induction of GADD45B expression. Targeting HCC with ACSL4GADD45B expression with aspirin and sorafenib could provide potential synergistic therapeutic benefits.
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http://dx.doi.org/10.1038/cddiscovery.2017.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592242PMC
September 2017

GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition.

J Clin Invest 2017 Sep 31;127(9):3527-3542. Epub 2017 Jul 31.

Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.

The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.
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http://dx.doi.org/10.1172/JCI93488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669578PMC
September 2017

Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma.

Cancer Discov 2017 10 30;7(10):1116-1135. Epub 2017 Jun 30.

Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in amplifications and mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and / expression, or epigenetic mutations () and /-related gene rearrangements. Whole-genome analysis highlighted 3' untranslated region deletion as a mechanism of upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer. Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628134PMC
October 2017

Genomic and proteomic characterization of ARID1A chromatin remodeller in ampullary tumors.

Am J Cancer Res 2017 1;7(3):484-502. Epub 2017 Mar 1.

Department of Pathology, Singapore General Hospital Singapore, Singapore.

is one of the most commonly mutated genes in a broad variety of tumors. The mechanisms that involve in ampullary cancer progression remains elusive. Here, we evaluated the frequency of and mutations in ampullary adenomas and adenocarcinomas and in duodenal adenocarcinomas from two cohorts of patients from Singapore and Romania, correlated with clinical and pathological tumor features, and assessed the functional role of . In the ampullary adenocarcinomas, the frequency of and mutations was 34.7% and 8.2% respectively, with a loss or reduction of ARID1A protein in 17.2% of the cases. mutational status was significantly correlated with ARID1A protein expression level (P=0.023). There was a significant difference in frequency of mutation between Romania and Singapore (2.7% versus 25%, P=0.04), suggestive of different etiologies. One somatic mutation was detected in the ampullary adenoma group. studies indicated the tumor suppressive role of . Our results warrant further investigation of this chromatin remodeller as a potential early biomarker of the disease, as well as identification of therapeutic targets in mutated ampullary cancers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385638PMC
March 2017

MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence.

Cancer Lett 2016 12 28;383(1):85-93. Epub 2016 Sep 28.

Bek Chai Heah Laboratory of Cancer Genomics, Humphrey Oei Institute of Cancer Research, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore. Electronic address:

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Many kinases have been found to be intimately involved in oncogenesis and the deregulation of kinase function has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. Previously, we have performed gene expression profile analysis on HCC samples and have identified a host of kinases that are remarkably overexpressed in HCC. Among these, the Maternal Embryonic Leucine Zipper Kinase (MELK) is highly overexpressed in HCC and its overexpression strongly correlates with early recurrence and poor patients' survival. Silencing MELK inhibited cell growth, invasion, stemness and tumorigenicity of HCC cells by inducing apoptosis and mitosis. We further showed that the overexpression of MELK in HCC samples strongly correlated with the cell cycle- and mitosis-related genes which are directly regulated as part of the forkhead transcription factor FoxM1-related cell division program. Together, our data establish MELK as an oncogenic kinase involved in the pathogenesis and recurrence of HCC and could provide a promising molecular target to develop therapeutic strategies for patients with advanced HCC.
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http://dx.doi.org/10.1016/j.canlet.2016.09.017DOI Listing
December 2016

The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway.

Gut 2016 09 3;65(9):1522-34. Epub 2016 Mar 3.

Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore, Singapore Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Objectives: Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms underlying these alterations remain poorly understood. Our aim was to study the roles of the MAP protein regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis and early HCC recurrence.

Design: PRC1 expression in HCC samples was evaluated by microarray, immunoblotting and immunohistochemistry analysis. Molecular and cellular techniques including siRNA-mediated and lentiviral vector-mediated knockdown were used to elucidate the functions and mechanisms of PRC1.

Results: PRC1 expression was associated with early HCC recurrence and poor patient outcome. In HCC, PRC1 exerted an oncogenic effect by promoting cancer proliferation, stemness, metastasis and tumourigenesis. We further demonstrated that the expression and distribution of PRC1 is dynamically regulated by Wnt3a signalling. PRC1 knockdown impaired transcription factor (TCF) transcriptional activity, decreased Wnt target expression and reduced nuclear β-catenin levels. Mechanistically, PRC1 interacts with the β-catenin destruction complex, regulates Wnt3a-induced membrane sequestration of this destruction complex, inhibits adenomatous polyposis coli (APC) stability and promotes β-catenin release from the APC complex. In vivo, high PRC1 expression correlated with nuclear β-catenin and Wnt target expression. PRC1 acted as a master regulator of a set of 48 previously identified Wnt-regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via Wnt signalling.

Conclusions: We identified PRC1 as a novel Wnt target that functions in a positive feedback loop that reinforces Wnt signalling to promote early HCC recurrence.
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http://dx.doi.org/10.1136/gutjnl-2015-310625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036256PMC
September 2016

Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma.

Gut 2017 02 15;66(2):342-351. Epub 2015 Dec 15.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.

Objective: The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis.

Design: Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study.

Results: Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells.

Conclusions: The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.
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http://dx.doi.org/10.1136/gutjnl-2015-310814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5284473PMC
February 2017

SETD2 histone modifier loss in aggressive GI stromal tumours.

Gut 2016 12 3;65(12):1960-1972. Epub 2015 Sep 3.

Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore.

Background: GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients.

Objectives: We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers.

Designs: Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined.

Results: High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10).

Conclusions: Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.
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http://dx.doi.org/10.1136/gutjnl-2015-309482DOI Listing
December 2016

Technical Note: Automatic real-time ultrasound tracking of respiratory signal using selective filtering and dynamic template matching.

Med Phys 2015 Aug;42(8):4536-41

Department of Biomedical Engineering, National University of Singapore, Singapore 117575.

Purpose: In respiratory motion modeling for liver interventions, the respiratory signal is usually obtained by using special tracking devices to monitor external skin. However, due to intrinsic limits and cost consideration of these tracking devices, a purely ultrasound image-based approach to tracking the signal is a more feasible option.

Methods: In this study, a novel image-based method is proposed to obtain the respiratory signal directly from 2D ultrasound images by automatically identifying and tracking the liver boundary. The boundary identification is a multistage process, which is the key to utilize a Hessian matrix-based 2D filter to enhance the line-like liver boundary and weaken other liver tissues. For tracking the identified boundary, a new dynamic template matching technique is first applied to estimate 2D displacements, and a boundary-specific selection mechanism is then introduced to extract the respiratory signal from the 2D displacements.

Results: The experiments demonstrate that their method can obtain accurate breathing signals, which are in key phases comparable to the manually annotation and highly consistent to the electromagnetic-tracked ground-truth signals (average correlation coefficients 0.9209 and statistically significant p < 0.01). Meanwhile, the experiments also prove their method can achieve high real-time performance of about 80-160 Hz.

Conclusions: This method provides a good alternative to traditional external-landmark-based tracking methods and may be widely applied for respiratory compensation in ultrasound-guided liver interventions.
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http://dx.doi.org/10.1118/1.4924803DOI Listing
August 2015

Abundant copy-number loss of CYCLOPS and STOP genes in gastric adenocarcinoma.

Gastric Cancer 2016 Apr 24;19(2):453-465. Epub 2015 Jul 24.

Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.

Background: Gastric cancer, a leading cause of cancer death worldwide, has been little studied compared with other cancers that impose similar health burdens. Our goal is to assess genomic copy-number loss and the possible functional consequences and therapeutic implications thereof across a large series of gastric adenocarcinomas.

Methods: We used high-density single-nucleotide polymorphism microarrays to determine patterns of copy-number loss and allelic imbalance in 74 gastric adenocarcinomas. We investigated whether suppressor of tumorigenesis and/or proliferation (STOP) genes are associated with genomic copy-number loss. We also analyzed the extent to which copy-number loss affects Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS (CYCLOPS) genes-genes that may be attractive targets for therapeutic inhibition when partially deleted.

Results: The proportion of the genome subject to copy-number loss varies considerably from tumor to tumor, with a median of 5.5 %, and a mean of 12 % (range 0-58.5 %). On average, 91 STOP genes were subject to copy-number loss per tumor (median 35, range 0-452), and STOP genes tended to have lower copy-number compared with the rest of the genes. Furthermore, on average, 1.6 CYCLOPS genes per tumor were both subject to copy-number loss and downregulated, and 51.4 % of the tumors had at least one such gene.

Conclusions: The enrichment of STOP genes in regions of copy-number loss indicates that their deletion may contribute to gastric carcinogenesis. Furthermore, the presence of several deleted and downregulated CYCLOPS genes in some tumors suggests potential therapeutic targets in these tumors.
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http://dx.doi.org/10.1007/s10120-015-0514-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824836PMC
April 2016

EDIL3 is a novel regulator of epithelial-mesenchymal transition controlling early recurrence of hepatocellular carcinoma.

J Hepatol 2015 Oct 14;63(4):863-73. Epub 2015 May 14.

Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis Drive Proteos, Singapore. Electronic address:

Background & Aims: Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Early recurrence, metastases and angiogenesis are the major obstacles to improve the outcome of HCC. Epithelial-mesenchymal transition (EMT) is a key contributor to cancer metastasis and recurrence, which are the major obstacles to improve prognosis of HCC.

Methods: Combining gene expression profiles of HCC samples with or without early recurrence and established cell lines with epithelial or mesenchymal phenotype, EDIL3 was identified as a novel regulator of EMT. The expression of EDIL3 was evaluated by quantitative PCR, Western blotting or immunohistochemistry. The effects of EDIL3 on the angiogenesis and metastasis of HCC cells were examined by wound healing, Matrigel invasion and tube formation assay in vitro and orthotopic xenograft mouse model of HCC in vivo. The signaling pathways of EDIL3 mediated were investigated through microarray and Western blotting analysis.

Results: EDIL3 was identified as a novel regulator of EMT, which contributes to angiogenesis, metastasis and recurrence of HCC. EDIL3 induces EMT and promotes HCC migration, invasion and angiogenesis in vitro. Mechanistically, overexpression of EDIL3, which was regulated by the downregulation of miR-137 in HCC, triggered the activation of ERK and TGF-β signaling through interactions with αvβ3 integrin. Blocking ERK and TGF-β signaling overcomes EDIL3 induced angiogenesis and invasion. Using the orthotopic xenograft mouse model of HCC, we demonstrated that EDIL3 enhanced the tumorigenic, metastatic and angiogenesis potential of HCC in vivo.

Conclusions: EDIL3-mediated activation of TGF-β and ERK signaling could provide therapeutic implications for HCC.
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http://dx.doi.org/10.1016/j.jhep.2015.05.005DOI Listing
October 2015

Metastasectomy for metachronous pulmonary and hepatic metastases from nasopharyngeal carcinoma: Report of 6 cases and review of the literature.

Head Neck 2016 Feb 15;38(2):E37-40. Epub 2015 Jul 15.

Division of Surgical Oncology, National Cancer Centre Singapore.

Background: Metastatic nasopharyngeal carcinoma (NPC) is commonly treated with palliative chemotherapy. The purpose of this study was to review the feasibility of metastasectomy for metachronous pulmonary and hepatic metastases from NPC.

Methods: We present 6 patients who developed metachronous metastases from NPC (4 patients with pulmonary metastases and 2 patients with hepatic metastases) and underwent curative resection.

Results: Four patients are still alive with no recurrence of NPC after metastasectomy. Two patients died with postoperative survival periods of 57 and 70 months and recurrence-free intervals of 14 and 39 months, respectively.

Conclusion: Metastasectomy is a feasible option for the treatment of metachronous and resectable oligometastatic NPC to the lung and liver. Application of appropriate selection criteria would be required.
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http://dx.doi.org/10.1002/hed.24099DOI Listing
February 2016

The Singapore Liver Cancer Recurrence (SLICER) Score for relapse prediction in patients with surgically resected hepatocellular carcinoma.

PLoS One 2015 1;10(4):e0118658. Epub 2015 Apr 1.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Republic of Singapore.

Background And Aims: Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection.

Methods: Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992-2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis.

Results: A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities.

Conclusion: The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118658PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382157PMC
December 2015

The over-expression of survivin enhances the chemotherapeutic efficacy of YM155 in human hepatocellular carcinoma.

Oncotarget 2015 Mar;6(8):5990-6000

Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p-survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell-cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467416PMC
http://dx.doi.org/10.18632/oncotarget.3337DOI Listing
March 2015

ECT2 regulates the Rho/ERK signalling axis to promote early recurrence in human hepatocellular carcinoma.

J Hepatol 2015 Jun 21;62(6):1287-95. Epub 2015 Jan 21.

Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis Drive Proteos, Singapore, Singapore; Cancer & Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background & Aims: Early recurrence is the major obstacle for improving the outcome of patients with hepatocellular carcinoma (HCC). Therefore, identifying key molecules contributing to early HCC recurrence can enable the development of novel therapeutic strategies for the clinical management of HCC. Epithelial cell transforming sequence 2 (ECT2) has been implicated in human cancers, but its function in HCC is largely unknown.

Methods: ECT2 expression was studied by microarrays, immunoblotting and immunohistochemistry in human HCC samples. siRNA- and lentiviral vector-mediated knockdown were employed to decipher the molecular functions of ECT2.

Results: The upregulation of ECT2 is significantly associated with early recurrent HCC disease and poor survival. Knockdown of ECT2 markedly suppressed Rho GTPases activities, enhanced apoptosis, attenuated oncogenicity and reduced the metastatic ability of HCC cells. Moreover, knockdown of ECT2 or Rho also suppressed ERK activation, while the silencing of Rho or ERK led to a marked reduction in cell migration. Stable knockdown of ECT2 in vivo resulted in significant retardation of tumour growth and the suppression of ERK activation. High expression of ECT2 correlates with high ERK phosphorylation and poor survival of HCC patients. Furthermore, ECT2 enhances the expression and stability of RACGAP1, accelerating ECT2-mediated Rho activation to promote metastasis.

Conclusions: ECT2 is closely associated with the activation of the Rho/ERK signalling axis to promote early HCC recurrence. In addition, ECT2 can crosstalk with RACGAP1 to catalyse the GTP exchange involved in Rho signalling to further regulate tumour initiation and metastasis.
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http://dx.doi.org/10.1016/j.jhep.2015.01.014DOI Listing
June 2015

A manifold learning method to detect respiratory signal from liver ultrasound images.

Comput Med Imaging Graph 2015 Mar 2;40:194-204. Epub 2014 Dec 2.

Singapore Bioimaging Consortium, Agency for Science, Technology and Research, #08-01, Matrix, 30 Biopolis Street, 138671 Singapore. Electronic address:

Respiratory gating has been widely applied for respiratory correction or compensation in image acquisition and image-guided interventions. A novel image-based method is proposed to extract respiratory signal directly from 2D ultrasound liver images. The proposed method utilizes a typical manifold learning method, based on local tangent space alignment based technique, to detect principal respiratory motion from a sequence of ultrasound images. This technique assumes all the images lying on a low-dimensional manifold embedding into the high-dimensional image space, constructs an approximate tangent space of each point to represent its local geometry on the manifold, and then aligns the local tangent spaces to form the global coordinate system, where the respiratory signal is extracted. The experimental results show that the proposed method can detect relatively accurate respiratory signal with high correlation coefficient (0.9775) with respect to the ground-truth signal by tracking external markers, and achieve satisfactory computing performance (2.3s for an image sequence of 256 frames). The proposed method is also used to create breathing-corrected 3D ultrasound images to demonstrate its potential application values.
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http://dx.doi.org/10.1016/j.compmedimag.2014.11.013DOI Listing
March 2015

Prospective comparison of the Alvarado score and CT scan in the evaluation of suspected appendicitis: a proposed algorithm to guide CT use.

J Am Coll Surg 2015 Feb 25;220(2):218-24. Epub 2014 Oct 25.

Department of General Surgery, Singapore General Hospital, Singapore.

Background: Although computed tomography (CT) has reduced negative appendectomy rates, its radiation risk remains a concern. We compared the performance statistics of the Alvarado Score (AS) with those of CT scan in the evaluation of suspected appendicitis, with the aim of identifying a subset of patients who will benefit from CT evaluation.

Study Design: We performed prospective data collection on 350 consecutive patients with suspected appendicitis who were evaluated with CT scans. The AS for each patient was scored at admission and correlated with eventual histology and CT findings. The sensitivity, specificity, and positive likelihood ratios were determined for various AS and for CT scan. The AS ranges that benefitted most from CT evaluation were determined by comparing the positive likelihood ratios of CT scan with each of the AS cutoff values.

Results: The study included 134 males (38.3%) and 216 females (61.7%). The overall prevalence of appendicitis was 44.3% in the total study population; 37.5% in females and 55.2% in males. There were 168 patients (48%) who underwent surgery, with a negative appendectomy rate of 7.7%. Positive likelihood ratio of disease was significantly greater than 1 only in patients with an AS of 4 and above. An AS of 7 and above in males and 9 and above in females has a positive likelihood ratio comparable to that of CT scan.

Conclusions: Evaluation by CT is beneficial mainly in patients with AS of 6 and below in males and 8 and below in females. We propose an objective management algorithm with the AS guiding subsequent evaluation.
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http://dx.doi.org/10.1016/j.jamcollsurg.2014.10.010DOI Listing
February 2015