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4. Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency

Author

Simoni, Yannick, Fehlings, Michael, Kløverpris, Henrik N., McGovern, Naomi, Koo, Si-Lin, Loh, Chiew Yee, Lim, Shawn, Kurioka, Ayako, Fergusson, Joannah R., Tang, Choong-Leong, Kam, Ming Hian, Dennis, Koh, Lim, Tony Kiat Hon, Fui, Alexander Chung Yaw, Hoong, Chan Weng, Chan, Jerry Kok Yen, Curotto de Lafaille, Maria, Narayanan, Sriram, Baig, Sonia, Shabeer, Muhammad, Toh, Sue-Anne Ee Shiow, Tan, Henry Kun Kiaang, Anicete, Rosslyn, Tan, Eng-Huat, Takano, Angela, Klenerman, Paul, Leslie, Alasdair, Tan, Daniel S.W., Tan, Iain Beehuat, Ginhoux, Florent, and Newell, Evan W.

Published
2017
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5. Abstract 4119: Anti-KRAS antibody aggregates KRAS in the cytoplasm of live ex vivo cultured human colorectal adenocarcinoma cells and prevents its trafficking to the plasma membrane

Author

Cheah, Peh Yean, primary, Lam, Kuen Kuen, additional, Low, Yee Syuen, additional, Lo, Michelle, additional, Wong, Michelle, additional, Tang, Choong Leong, additional, Tan, Emile, additional, Chok, Aik Yong, additional, En, Issac Seow, additional, and Wong, Siew Heng, additional

Published
2023
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8. The chromatin structuring protein HMGA2 influences human subtelomere stability and cancer chemosensitivity.

Author

Syed Moiz Ahmed, Priya Dharshana Ramani, Stephen Qi Rong Wong, Xiaodan Zhao, Roland Ivanyi-Nagy, Tang Choong Leong, Clarinda Chua, Zhizhong Li, Hannes Hentze, Iain BeeHuat Tan, Jie Yan, Ramanuj DasGupta, and Peter Dröge

Subjects
Medicine, Science
Abstract

The transient build-up of DNA supercoiling during the translocation of replication forks threatens genome stability and is controlled by DNA topoisomerases (TOPs). This crucial process has been exploited with TOP poisons for cancer chemotherapy. However, pinpointing cellular determinants of the best clinical response to TOP poisons still remains enigmatic. Here, we present an integrated approach and demonstrate that endogenous and exogenous expression of the oncofetal high-mobility group AT-hook 2 (HMGA2) protein exhibited broad protection against the formation of hydroxyurea-induced DNA breaks in various cancer cells, thus corroborating our previously proposed model in which HMGA2 functions as a replication fork chaperone that forms a protective DNA scaffold at or close to stalled replication forks. We now further demonstrate that high levels of HMGA2 also protected cancer cells against DNA breaks triggered by the clinically important TOP1 poison irinotecan. This protection is most likely due to the recently identified DNA supercoil constraining function of HMGA2 in combination with exclusion of TOP1 from binding to supercoiled substrate DNA. In contrast, low to moderate HMGA2 protein levels surprisingly potentiated the formation of irinotecan-induced genotoxic covalent TOP1-DNA cleavage complexes. Our data from cell-based and several in vitro assays indicate that, mechanistically, this potentiating role involves enhanced drug-target interactions mediated by HMGA2 in ternary complexes with supercoiled DNA. Subtelomeric regions were found to be extraordinarily vulnerable to these genotoxic challenges induced by TOP1 poisoning, pointing at strong DNA topological barriers located at human telomeres. These findings were corroborated by an increased irinotecan sensitivity of patient-derived xenografts of colorectal cancers exhibiting low to moderate HMGA2 levels. Collectively, we uncovered a therapeutically important control mechanism of transient changes in chromosomal DNA topology that ultimately leads to enhanced human subtelomere stability.

Published
2019
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9. Functional annotation with expression validation identifies novel metastasis-relevant genes from post-GWAS risk loci in sporadic colorectal carcinomas

Author

Thean, Lai Fun, Wong, Michelle, Lo, Michelle, Tan, Iain, Wong, Evelyn, Gao, Fei, Tan, Emile, Tang, Choong Leong, and Cheah, Peh Yean

Abstract

BackgroundColorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients.MethodsA case-case genome-wide association study comprising 2677 sporadic Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human SNP6 microarray platform and analysed with the correlation/trend test based on the additive model. SNP variants with association testing −log10 p value ≥5 were imported into Functional Mapping and Annotation (FUMA) for functional annotation.ResultsGlycolysis was uncovered as the top hallmark gene set. Transcripts from two of the five genes profiled, hematopoietic substrate 1 associated protein X 1 (HAX1) and hyaluronan-mediatedmotility receptor (HMMR), were significantly upregulated in the metastasis-positive tumours. In contrast to disease-risk variants, HAX1appeared to act synergistically with HMMRin significantly impacting metastasis-free survival. Examining the subtype datasets with FUMA and Ingenuity Pathway Analysis (IPA) identified distinct pathways demonstrating sexual dimorphism in CRC metastasis.ConclusionsCombining genome-wide association testing with in silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as features to develop subtype-specific metastasis-risk signatures for tailored management of patients with stage I-III CRC.

Published
2024
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12. Gracilis pull-through flap for the repair of a recalcitrant recto-vaginal fistula

Author

James Mok, Wan Loong, Goh, Ming Hui, Tang, Choong Leong, and Tan, Bien Keem

Subjects
medicine.medical_specialty, medicine.medical_treatment, Fistula, lcsh:Surgery, Case Report, 030230 surgery, Rectovaginal fistula, 03 medical and health sciences, 0302 clinical medicine, Colorectal surgery, Reconstructive surgical procedures, medicine, Gracilis muscle, business.industry, Colostomy, lcsh:RD1-811, Anus, medicine.disease, Surgery, Tendon, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Vagina, business
Abstract

Recto-vaginal fistulas are difficult to treat due to their high recurrence rate. Currently, no single surgical intervention is universally regarded as the best treatment option for rectovaginal fistulas. We present a case of recurrent recto-vaginal fistula surgically treated with a gracilis pull-through flap. The surgical goals in this patient were complete excision of the recto-vaginal fistula and introduction of fresh, vascularized muscle to seal the fistula. A defunctioning colostomy was performed 1 month prior to the present procedure. The gracilis muscle and tendon were mobilized, pulled through the freshened recto-vaginal fistula, passed through the anus, and anchored externally. Excess muscle and tendon were trimmed 1 week after the procedure. Follow-up at 4 weeks demonstrated complete mucosal coverage over an intact gracilis muscle, and no leakage. At 8 weeks post-procedure, the patient resumed sexual intercourse with no dyspareunia. At 6 months post-procedure, her stoma was closed. The patient reported transient fecal staining of her vagina after stoma reversal, which resolved with conservative treatment. The fistula had not recurred at 20 months post-procedure. The gracilis pull-through flap is a reliable technique for a scarred vagina with an attenuated rectovaginal septum. It can function as a well-vascularized tissue plug to promote healing.

Published
2019

23. Abstract 5725: Systematic identification of tumour-specific neoantigens(by whole-genome sequencing) and correlation between tumour neoantigen burden, PD-L1 expression and immune infiltrates in 158Asian colorectal cancers

Author

Koo, Si-Lin, primary, Yeong, Joe Poh Sheng, additional, Nguyen, Andy, additional, Chua, Clarinda Wei Ling, additional, Sanborn, J Zachary, additional, Benz, Steve, additional, Tan, Wah Siew, additional, Tang, Choong Leong, additional, Yan, Su, additional, Chew, Min Hoe, additional, Goh, Brian, additional, Chan, Chung Yip, additional, Koh, Xiao Qing, additional, Lezhava, Alexander, additional, Lim, Tony Kiat Hon, additional, Rabizadeh, Shahrooz, additional, Skanderup, Anders, additional, and Tan, Iain Beehuat, additional

Published
2018
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25. Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency

Author

Simoni, Yannick, primary, Fehlings, Michael, additional, Kløverpris, Henrik N., additional, McGovern, Naomi, additional, Koo, Si-Lin, additional, Loh, Chiew Yee, additional, Lim, Shawn, additional, Kurioka, Ayako, additional, Fergusson, Joannah R., additional, Tang, Choong-Leong, additional, Kam, Ming Hian, additional, Dennis, Koh, additional, Lim, Tony Kiat Hon, additional, Fui, Alexander Chung Yaw, additional, Hoong, Chan Weng, additional, Chan, Jerry Kok Yen, additional, Curotto de Lafaille, Maria, additional, Narayanan, Sriram, additional, Baig, Sonia, additional, Shabeer, Muhammad, additional, Toh, Sue-Anne Ee Shiow, additional, Tan, Henry Kun Kiaang, additional, Anicete, Rosslyn, additional, Tan, Eng-Huat, additional, Takano, Angela, additional, Klenerman, Paul, additional, Leslie, Alasdair, additional, Tan, Daniel S.W., additional, Tan, Iain Beehuat, additional, Ginhoux, Florent, additional, and Newell, Evan W., additional

Published
2018
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29. Critical evaluation of contemporary management in a new Pelvic Exenteration Unit: The first 25 consecutive cases

Author

Chew, Min Hoe, primary, Yeh, Yu-Ting, additional, Toh, Ee-Lin, additional, Sumarli, Stephen Aditya, additional, Chew, Ghee Kheng, additional, Lee, Lui Shiong, additional, Tan, Mann Hong, additional, Hennedige, Tiffany Priyanthi, additional, Ng, Shin Yi, additional, Lee, Say Kiat, additional, Chong, Tze Tec, additional, Abdullah, Hairil Rizal, additional, Goh, Terence Lin Hon, additional, Rasheed, Mohamed Zulfikar, additional, Tan, Kok Chai, additional, and Tang, Choong Leong, additional

Published
2017
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30. Toxic Haemorrhagic Colitis: A Rare Presentation of Eosinophilic Colitis

Author

Yeo, Shen-Ann Eugene, Lim, Yon Kuei, Lim, Kiat Hon Tony, and Tang, Choong-Leong

Subjects
Article Subject
Abstract

Eosinophilic colitis is a rare condition that usually presents with non specific abdominal symptoms. Very uncommonly it presents with an acute surgical emergency such as peritonitis or haemorrhage. We present a rare presentation of eosinophilic colitis with toxic hemorrhagic colitis and ischaemic bowel requiring laparotomy and bowel resection.

Published
2012
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37. Genome-wide association study identified copy number variants associated with sporadic colorectal cancer risk

Author

Thean, Lai Fun, Low, Yee Syuen, Lo, Michelle, Teo, Yik-Ying, Koh, Woon-Puay, Yuan, Jian-Min, Chew, Min Hoe, Tang, Choong Leong, and Cheah, Peh Yean

Abstract

BackgroundMultiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC.MethodsA genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests.ResultsA rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing CHD8, and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing CD47and RERG/ARHGDIB, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at CHD8was significantly associated with dysregulation of several genes that perturb the Wnt, TP53and inflammatory pathways.ConclusionsA rare CNVR at 14q11 encompassing the chromatin modifier CHD8was significantly associated with sporadic CRC risk. Copy number loss at CHD8altered expressions of genes implicated in colorectal tumourigenesis.

Published
2018
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42. Development of a chronic colonic intubation model in rats for the study of luminal factors in colonic diseases

Author

Tang, Choong-Leong, Wong, Cynthia S. M., Sengupta, Shomik, Tjandra, Joe J., Gibson, Peter R., Tang, Choong-Leong, Wong, Cynthia S. M., Sengupta, Shomik, Tjandra, Joe J., and Gibson, Peter R.

Abstract

INTRODUCTION: A rat model of long-term colonic intubation has been developed to facilitate the in vivo study of colonic biology. This study aims to characterize this model. METHODS: The effects of intubation and sham surgery on animal behavior and weight gain were measured and compared with unoperated controls. The reproducibility of the model was assessed by comparing complication and failure rates for three operators. The distribution and excretion of infused materials were studied using radiology and gas chromatograhy of feces, respectively. The effects of the colonic tube and infusions on the mucosa were assessed histologically. RESULTS: There was about 10 percent weight loss postoperatively, more marked in those rats undergoing more extensive surgery. Subsequent weight gain was similar in all groups, and no behavioral effects of surgery were noted. There were no differences in histologic appearances or proliferative indices among the groups. All three operators had similar complication and tube dislodgement rates. Radiologic examination showed even distribution of infusate regardless of fecal consistency. Infusion through the two tubes allowed the cecum and the distal bowel to be targeted differentially. The infusions did not alter the consistency of the fecal pellets or induce defecation. Gas chromatography at various time points after butyrate infusion showed a small, but statistically insignificant, rise in fecal excretion, representing less than 10 percent of the infused butyrate. CONCLUSIONS: A highly reproducible in vivo rat model, with an experimental life span of five to six weeks, has been achieved. Biological agents can be accurately delivered via the colonic tubes and are retained in the colonic segment of interest. This intubation model should provide a valuable tool in the future for in vivo studies of colonic biology.

Published
2002

43. Colonic epithelial atrophy induced by a fibre-free diet in rats is reversed by minimal amounts of luminal butyrate, but only in the short term

Author

Sengupta, Shomik, Tang, Choong-Leong, Wong, Cynthia S., Tjandra, Joe J., Gibson, Peter R., Sengupta, Shomik, Tang, Choong-Leong, Wong, Cynthia S., Tjandra, Joe J., and Gibson, Peter R.

Abstract

Background: Luminal butyrate may be trophic to the colonic epithelium, but this effect is poorly characterized. The aim of the present study was to define the dose−response, time‐course, site‐specificity and the dependence on background diet of the effects of butyrate on epithelial proliferation in normal distal colon, using an in vivo rat model of colonic substrate delivery. Methods: Male Sprague‐Dawley rats, maintained on a fibre‐free diet, had butyrate infused twice daily into the colonic lumen via polyethylene tubes placed at laparotomy. Varying dose levels (0−80 µmol/d; 4 d), site (caecal vs distal colonic), duration of infusions (1−5 weeks; 80 µmol/d), or dietary fibre intake were investigated. Epithelial proliferative indices were assessed stathmokinetically. Results: Four‐day infusions of butyrate led to a progressive trophic effect (cells/crypt column increased from 37.9 ± 1.6 at 0 µmol/d to 44.7 ± 1.2 at 80 µmol/d) on fibre‐deprived colonic mucosa, related linearly to the daily butyrate dose (P 0.001, linear regression). This effect was mediated by increases in the number and proportion of mitoses, related to the square of the butyrate dose (P 0.001 in each case, polynomial regression). Butyrate (80 µmol/d) was associated with significantly higher cellularity (59.9 ± 1.4) and mitotic activity (4.9 ± 0.6) per crypt column compared to vehicle controls (50.3 ± 1.6 and 0.9 ± 0.2, respectively; P 0.05, t‐tests), at 1 and 3 weeks, but not at 5 weeks. Butyrate had similar effects on distal colonic crypt cellularity (62.0 ± 1.5) when delivered caecally, but in rats fed a fibre‐containing diet, colonic crypt cellularity (55.3 ± 3.2) was similar to baseline (59.6 ± 1.9). Conclusions: Trophic effects of butyrate are concentration‐dependent and occur at low doses in the short term, but are not sustained over longer periods. They are seen only in a fibre‐deprived state and

Published
2002

48. A novel indel in exon 9 of APC upregulates a 'skip exon 9' isoform and causes very severe familial adenomatous polyposis.

Author

Cheah, Peh Yean, Wong, Yu Hui, Koh, Poh Koon, Loi, Carol, Chew, Min Hoe, and Tang, Choong Leong

Subjects
GERM cells, GENETIC mutation, ADENOMATOUS polyposis coli, COLON cancer, EXONS (Genetics), GENE expression, T cells
Abstract

Germline mutation in the adenomatous polyposis coli (APC) gene causes the majority (80%) of familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC). Mutation in 5′end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset and fewer polyps. The presence of exon 9a, an in-frame isoform with exon 8 spliced to 3′end of exon 9, modulates any deleterious effect of the mutation. A third lowly expressed isoform that completely skips exon 9 is present in both healthy individuals and FAP patients. We report here an interesting case of a proband with an APC mutation in 5′end of exon 9 that presented with six synchronous advanced CRCs at age 37. The novel insertion-deletion (indel) at codon 409, c.1226-1229delTTTTinsAAA, caused upregulation of the 'skip exon 9' isoform, r934-1312del, resulting in a premature stop codon at exon 10 and a truncated protein that removed all of the β-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. Exon 9a isoform was concomitantly downregulated. This finding emphasizes the necessity of examining the various isoforms of exon 9 to avoid clinical mismanagement and counseling based on just the mutation site by genomic DNA sequencing alone. [ABSTRACT FROM AUTHOR]

Published
2014
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50. Opportunistic screening for colorectal neoplasia in Singapore using faecal immunochemical occult blood test.

Author

Tan, W S, Tang, C L, Koo, W H, Tan, Wah Siew, Tang, Choong Leong, and Koo, Wen Hsin

Abstract

Introduction: The use of faecal immunochemical occult blood test (FIT) has been reported to decrease mortality from colorectal cancer. The Singapore Cancer Society (SCS) gives out FIT kits to encourage opportunistic screening of colorectal cancer. Any Singapore citizen or permanent resident aged ≥ 50 years is eligible to receive two FIT kits. Participants with at least one positive FIT are referred for further evaluation. We aimed to analyse the results of SCS data from the year 2008.Methods: The factors evaluated included compliance, positive test rate (PR) and positive predictive value (PPV) of FIT.Results: 20,989 participants received 41,978 kits in 2008. Compliance was 38.9%, with 8,156 participants returning at least one kit. 8% of participants tested positive, and 75% of these test-positive participants agreed to undergo further investigations. 33 participants had colorectal cancers, 45 had advanced polyps (≥ 1 cm) and 90 had polyps < 1 cm. Histologically, 114 polyps were adenomatous, 20 were hyperplastic and 1 was serrated. PPV of colorectal neoplasia for those who underwent further colonoscopy was 34%. Over half of the participants who had only one positive test had colorectal neoplasia.Conclusion: PR and PPV of FIT in our study were comparable to that in the literature. However, compliance was low and a quarter of all participants who tested positive refused further investigations. Extensive population education programmes are required to improve compliance and tackle inhibitions among the masses. It is also important to take steps to enhance the cost effectiveness of future screening programmes. [ABSTRACT FROM AUTHOR]

Published
2013
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