ORCID Profile
0000-0003-4391-1130
Current Organisations
Duke-NUS Medical School
,
University of Tasmania
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 09-2015
DOI: 10.1038/NBT.3299
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-02-2017
DOI: 10.1126/SCITRANSLMED.AAI8312
Abstract: Bladder cancer with loss of KDM6A expression is vulnerable to inhibition of EZH2.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2015
DOI: 10.1038/NG.3409
Abstract: Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.
Publisher: Research Square Platform LLC
Date: 03-10-2023
Publisher: Informa UK Limited
Date: 29-01-2018
DOI: 10.1080/10903127.2017.1423139
Abstract: Endotracheal intubation (ETI) is a critical procedure performed by both air medical and ground based emergency medical services (EMS). Previous work has suggested that ETI success rates are greater for air medical providers. However, air medical providers may have greater airway experience, enhanced airway education, and access to alternative ETI options such as rapid sequence intubation (RSI). We sought to analyze the impact of the type of EMS on RSI success. A systematic literature search of Medline, Embase, and the Cochrane Library was conducted and eligibility, data extraction, and assessment of risk of bias were assessed independently by two reviewers. A bias-adjusted meta-analysis using a quality-effects model was conducted for the primary outcomes of overall intubation success and first-pass intubation success. Forty-nine studies were included in the meta-analysis. There was no difference in the overall success between flight and ground based EMS 97% (95% CI 96-98) vs. 98% (95% CI 91-100), and no difference in first-pass success for flight compared to ground based RSI 82% (95% CI 73-89) vs. 82% (95% CI 70-93). Compared to flight non-physicians, flight physicians have higher overall success 99% (95% CI 98-100) vs. 96% (95% CI 94-97) and first-pass success 89% (95% CI 77-98) vs. 71% (95% CI 57-84). Ground-based physicians and non-physicians have a similar overall success 98% (95% CI 88-100) vs. 98% (95% CI 95-100), but no analysis for physician ground first pass was possible. Both overall and first-pass success of RSI did not differ between flight and road based EMS. Flight physicians have a higher overall and first-pass success compared to flight non-physicians and all ground based EMS, but no such differences are seen for ground EMS. Our results suggest that ground EMS can use RSI with similar outcomes compared to their flight counterparts.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.ANNEMERGMED.2017.03.026
Abstract: Rapid sequence intubation performed by nonphysicians such as paramedics or nurses has become increasingly common in many countries however, concerns have been stated in regard to the safe use and appropriateness of rapid sequence intubation when performed by these health care providers. The aim of our study is to compare rapid sequence intubation success and adverse events between nonphysician and physician in the out-of-hospital setting. A systematic literature search of key databases including MEDLINE, EMBASE, and the Cochrane Library was conducted. Eligibility, data extraction, and assessment of risk of bias were assessed independently by 2 reviewers. A bias-adjusted meta-analysis using a quality-effects model was conducted for the primary outcomes of overall intubation success and first-pass intubation success and for adverse events when possible. Eighty-three studies were included in the meta-analysis. There was a 2% difference in successful intubation proportion for physicians versus nonphysicians, 99% (95% confidence interval [CI] 98% to 99%) versus 97% (95% CI 95% to 99%). A 10% difference in first-pass rapid sequence intubation success was noted between physicians versus nonphysicians, 88% (95% CI 83% to 93%) versus 78% (95% CI 65% to 89%). For airway trauma, bradycardia, cardiac arrest, endobronchial intubation, hypertension, and hypotension, lower prevalences of adverse events were noted for physicians. However, nonphysicians had a lower prevalence of hypoxia and esophageal intubations. Similar proportions were noted for pulmonary aspiration and emesis. Nine adverse events estimates lacked precision, except for endobronchial intubation, and 4 adverse event analyses showed evidence of possible publication bias. Consequently, no reliable evidence exists for differences between physicians and nonphysicians for adverse events. This analysis shows that physicians have a higher rapid sequence intubation first-pass and overall success, as well as mostly lower rates of adverse events for rapid sequence intubation in the out-of-hospital setting. Nevertheless, for all success and adverse events no firm conclusion for a difference could be drawn because of lack of precision of meta-analytic estimates or selective reporting. First-pass success could be an area in which to focus quality improvement strategies for nonphysicians.
Publisher: BMJ
Date: 04-12-2014
Publisher: Elsevier BV
Date: 09-2014
Publisher: Wiley
Date: 30-04-2019
Abstract: Endotracheal intubation is an advanced airway procedure performed in the ED and the out-of-hospital setting for acquired brain injuries that include non-traumatic brain pathologies such as stroke, encephalopathies, seizures and toxidromes. Controlled trial evidence supports intubation in traumatic brain injuries, but it is not clear that this evidence can be applied to non-traumatic brain pathologies. We sought to analyse the impact of emergency intubation on survival in non-traumatic brain pathologies and also to quantify the prevalence of intubation in these pathologies. We conducted a systematic literature search of Medline, Embase and the Cochrane Library. Eligibility, data extraction and assessment of risk of bias were assessed independently by two reviewers. A bias-adjusted meta-analysis using a quality-effects model pooled prevalence of intubation in non-traumatic brain pathologies. Forty-six studies were included in this systematic review. No studies were suitable for meta-analysis the primary outcome of survival. Thirty-nine studies reported the prevalence of intubation in non-traumatic brain pathologies and a meta-analysis showed that emergency intubation was used in 12% (95% CI 0-33) of pathologies. Endotracheal intubation was used commonly in haemorrhagic stroke 79% (95% CI 47-100) and to a lesser extent for seizures 18% (95% CI 10-27) and toxidromes 25% (95% CI 6-48). This systematic review shows that there is no high-quality clinical evidence to support or refute emergency intubation in non-traumatic brain pathologies. Our analysis shows that intubation is commonly used in non-traumatic brain pathologies, and the need for rigorous evidence is apparent.
Publisher: Oxford University Press (OUP)
Date: 10-2018
Abstract: Growing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer. We recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells. In general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation. A substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2015
Publisher: Springer Science and Business Media LLC
Date: 03-05-2021
DOI: 10.1038/S42003-021-02056-7
Abstract: The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese s les. Three East Asian specific variants in/near POT1 , TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10 −14 –6.94×10 −10 ). Rs79314063, a missense variant (p.Asp410His) at POT1 , shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR 95%CI = 1.544 (1.173, 2.032), P Adj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR 95%CI = 1.123 (1.051, 1.201), P adj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.
Publisher: Cold Spring Harbor Laboratory
Date: 30-01-2020
DOI: 10.1101/2020.01.29.926139
Abstract: Family history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs, with less emphasis on family history assessment. We evaluated the utility of family history for genomic sequencing selection. We analysed whole genome sequences of 1750 healthy research participants, with and without preselection based on standardised family history collection, screening 95 cancer genes. The frequency of likely pathogenic/ pathogenic (LP/P) variants in 884 participants with no family history available (FH not available group) (2%) versus 866 participants with family history available (FH available group) (3.1%) was not significant ( p =0.158). However, within the FH available group, amongst 73 participants with an increased family history cancer risk (increased FH risk), 1 in 7 participants carried a LP/P variant inferring a six-fold increase compared with 1 in 47 participants assessed at average family history cancer risk (average FH risk) and a seven-fold increase compared to the FH not available group. The enrichment was further pronounced (up to 18-fold) when assessing the 25 cancer genes in the ACMG 59-gene panel. Furthermore, 63 participants had an increased family history cancer risk in absence of an apparent LP/P variant. Our findings show that systematic family history collection remains critical for health risk assessment, providing important actionable data and augmenting the yield from genomic data. Family history also highlights the potential impact of additional hereditary, environmental and behavioural influences not reflected by genomic sequencing.
Publisher: Wiley
Date: 18-06-2022
Abstract: Video laryngoscopy (VL) is increasingly used as an alternative to direct laryngoscopy (DL) to improve airway visualisation and endotracheal intubation (ETI) success. Intensive Care Paramedics in New South Wales Ambulance, Australia started using VL in 2020, and recorded success in a new advanced airway registry. We used this registry to compare VL to DL. The present study was a retrospective analysis of out-of-hospital data for ETI by specialist paramedics using an airway registry. We calculated overall and first-pass success for VL versus DL, and compared success using a Χ The DL overall success was 61 out of 78 (78.2%) and VL was 233 out of 246 (94.7%) difference of 16.5% (P < 0.001). First-pass for DL was successful for 49 out of 78 (62.8%) and for VL in 195 out of 246 (79.3%) difference of 16.5% (P = 0.003). There were five (1.6%) patients where both VL and DL were used and in all instances, DL was used first. This analysis of a new airway registry used by specialist paramedics in New South Wales shows a substantial increase in overall and first-pass intubation success with the use of VL when compared to DL.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
Publisher: Springer Science and Business Media LLC
Date: 04-08-2017
DOI: 10.1038/S41598-017-07191-Y
Abstract: Clear cell renal cell carcinoma (ccRCC) has been previously classified into putative discrete prognostic subtypes by gene expression profiling. To investigate the robustness of these proposed subtype classifications, we evaluated 12 public datasets, together with a new dataset of 265 ccRCC gene expression profiles. Consensus clustering showed unstable subtype and principal component analysis (PCA) showed a continuous spectrum both within and between datasets. Considering the lack of discrete delineation and continuous spectrum observed, we developed a continuous quantitative prognosis score (Continuous Linear Enhanced Assessment of RCC, or CLEAR score). Prognostic performance was evaluated in independent cohorts from The Cancer Genome Atlas (TCGA) (n = 414) and EMBL-EBI (n = 53), CLEAR score demonstrated both superior prognostic estimates and inverse correlation with anti-angiogenic tyrosine-kinase inhibition in comparison to previously proposed discrete subtyping classifications. Inverse correlation with high-dose interleukin-2 outcomes was also observed for the CLEAR score. Multiple somatic mutations (VHL, PBRM1, SETD2, KDM5C, TP53, BAP1, PTEN, MTOR) were associated with the CLEAR score. Application of the CLEAR score to independent expression profiling of intratumoral ccRCC regions demonstrated that average intertumoral heterogeneity exceeded intratumoral expression heterogeneity. Wider investigation of cancer biology using continuous approaches may yield insights into tumor heterogeneity single cell analysis may provide a key foundation for this approach.
Publisher: BMJ
Date: 16-07-2021
DOI: 10.1136/EMERMED-2020-210887
Abstract: Rapid Sequence intubation (RSI) is an airway procedure that uses sedative and paralytic drugs to facilitate endotracheal intubation. It is known that RSI could impact blood pressure in the peri-intubation period. However, little is known about blood pressure changes in longer time frames. Therefore, this analysis aims to describe the changes in systolic blood pressure in a large cohort of paramedic-led RSI cases over the whole prehospital timespan. Intensive Care Paramedics in Victoria, Australia, are authorised to use RSI in medical or trauma patients with a Glasgow Coma Scale . This retrospective cohort study analysed data from patientcare records for patients aged 12 years and above that had received RSI, from 1 January 2008 to 31 December 2019. This study quantifies the systolic blood pressure changes using regression with fractional polynomial terms. The analysis is further stratified by high versus Low Shock Index (LSI). The shock index is calculated by iding pulse rate by systolic blood pressure. During the study period RSI was used in 8613 patients. The median number of blood pressure measurements was 5 (IQR 3–8). Systolic blood pressure rose significantly by 3.4 mm Hg (p .001) and then returned to baseline in the first 5 min after intubation for LSI cases. No initial rise in blood pressure is apparent in High Shock Index (HSI) cases. Across the whole cohort, systolic blood pressure decreased by 7.1 mm Hg (95% CI 7.9 to 6.3 mm Hg p .001) from the first to the last blood pressure measured. Our study shows that in RSI patients a small transient elevation in systolic blood pressure in the immediate postintubation period is found in LSI, but this elevation is not apparent in HSI. Blood pressure decreased over the prehospital phase in RSI patients with LSI, but increased for HSI cases.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2017
DOI: 10.1038/S41598-017-10333-X
Abstract: Associations of sarcoma with inherited cancer syndromes implicate genetic predisposition in sarcoma development. However, due to the apparently sporadic nature of sarcomas, little attention has been paid to the role genetic susceptibility in sporadic sarcoma. To address this, we performed targeted-genomic sequencing to investigate the prevalence of germline mutations in known cancer-associated genes within an Asian cohort of sporadic sarcoma patients younger than 50 years old. We observed 13.6% (n = 9) amongst 66 patients harbour at least one predicted pathogenic germline mutation in 10 cancer-associated genes including ATM , BRCA2, ERCC4, FANCC, FANCE, FANCI, MSH6, POLE, SDHA and TP53 . The most frequently affected genes are involved in the DNA damage repair pathway, with a germline mutation prevalence of 10.6%. Our findings suggests that genetic predisposition plays a larger role than expected in our Asian cohort of sporadic sarcoma, therefore clinicians should be aware of the possibility that young sarcoma patients may be carriers of inherited mutations in cancer genes and should be considered for genetic testing, regardless of family history. The prevalence of germline mutations in DNA damage repair genes imply that therapeutic strategies exploiting the vulnerabilities resulting from impaired DNA repair may be promising areas for translational research.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2019
DOI: 10.1038/S42003-019-0605-1
Abstract: Sleep is associated with various health outcomes. Despite their growing adoption, the potential for consumer wearables to contribute sleep metrics to sleep-related biomedical research remains largely uncharacterized. Here we analyzed sleep tracking data, along with questionnaire responses and multi-modal phenotypic data generated from 482 normal volunteers. First, we compared wearable-derived and self-reported sleep metrics, particularly total sleep time (TST) and sleep efficiency (SE). We then identified demographic, socioeconomic and lifestyle factors associated with wearable-derived TST they included age, gender, occupation and alcohol consumption. Multi-modal phenotypic data analysis showed that wearable-derived TST and SE were associated with cardiovascular disease risk markers such as body mass index and waist circumference, whereas self-reported measures were not. Using wearable-derived TST, we showed that insufficient sleep was associated with premature telomere attrition. Our study highlights the potential for sleep metrics from consumer wearables to provide novel insights into data generated from population cohort studies.
Publisher: BMJ
Date: 07-04-2016
DOI: 10.1136/JCLINPATH-2015-203590
Abstract: Recent reports have identified recurrent MED12 somatic mutations in fibroadenomas and phyllodes tumours. The frequency and type of somatic mutations were noted to be similar to those of uterine leiomyomas. We aimed to investigate protein expression of MED12, correlating it to MED12 mutational status and expression of oestrogen receptors (ER). Immunohistochemistry was performed on a total of 232 fibroepithelial lesions (100 fibroadenomas, 132 phyllodes tumours) diagnosed at the Department of Pathology, Singapore General Hospital using MED12, ERα and ERβ antibodies. Expressions were evaluated in both stroma and epithelium, and correlated with MED12 mutational status. MED12 mutation was significantly associated with high MED12 protein expression (H-score >150) in the stroma (p=0.029), but not in the epithelium. It was not associated with ERα and ERβ protein expression in both stroma and epithelium. MED12 protein expression was significantly correlated with ERα in epithelial (p=0.007) and ERβ in stromal (p=0.049) components. MED12 was not significantly different between fibroadenomas and phyllodes tumours. Epithelial expression of ERα was significantly higher in fibroadenomas (p<0.001) than in phyllodes tumours. Conversely, both epithelial and stromal expression of ERβ was significantly higher in phyllodes tumours (p<0.001). Positive associations observed between MED12 and ERα, ERβ immunohistochemical expression suggest a biological interplay between the proteins. The lack of significant association of MED12 mutation with ER protein expression indicates a need to further explore the functional impact of MED12 mutations on the ER signalling pathway in breast fibroepithelial lesions.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2014
DOI: 10.1038/NG.3037
Abstract: Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood s les revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2017
DOI: 10.1038/NG.3972
Abstract: Durian (Durio zibethinus) is a Southeast Asian tropical plant known for its hefty, spine-covered fruit and sulfury and onion-like odor. Here we present a draft genome assembly of D. zibethinus, representing the third plant genus in the Malvales order and first in the Helicteroideae subfamily to be sequenced. Single-molecule sequencing and chromosome contact maps enabled assembly of the highly heterozygous durian genome at chromosome-scale resolution. Transcriptomic analysis showed upregulation of sulfur-, ethylene-, and lipid-related pathways in durian fruits. We observed paleopolyploidization events shared by durian and cotton and durian-specific gene expansions in MGL (methionine γ-lyase), associated with production of volatile sulfur compounds (VSCs). MGL and the ethylene-related gene ACS (aminocyclopropane-1-carboxylic acid synthase) were upregulated in fruits concomitantly with their downstream metabolites (VSCs and ethylene), suggesting a potential association between ethylene biosynthesis and methionine regeneration via the Yang cycle. The durian genome provides a resource for tropical fruit biology and agronomy.
Publisher: BMJ
Date: 30-05-2019
DOI: 10.1136/EMERMED-2019-208613
Abstract: Ambulance transport of patients with stroke is common, with rapid sequence intubation (RSI) to secure the airway used regularly. Randomised controlled trial evidence exists to support the use of RSI in traumatic brain injuries (TBIs), but it is not clear whether the RSI evidence from TBI can be applied to the patient with stroke. To this end, we analysed a retrospective stroke dataset to compare survival of patients with RSI compared with patients that did not receive RSI. This study was a retrospective analysis of 10 years of in-hospital and out-of-hospital data for all patients with stroke attended by Ambulance Victoria, in Victoria Australia. Generalised boosted logistic regression was used to predict propensity scores, with initial vital signs, age and demographic variables as well as measures of illness severity and comorbidity included in the prediction model. This analysis employed a 1:1 nearest-neighbour matching which was applied to generate a dataset from which we calculated the OR of survival to hospital discharge of patients receiving RSI versus no-RSI. The sensitivity of these results to unmeasured confounding was assessed with deterministic sensitivity analysis. The propensity score-matched cohort showed a decreased survival for RSI in strokes with an OR 0.61 (95% CI 0.45 to 0.82 p=0.001) when compared with no-RSI. A subgroup analysis showed no significant survival difference for ischaemic strokes: OR 0.66 (95% CI 40 to 1.07 p=0.09). The survival for haemorrhagic stroke was OR 0.60 (95% CI 0.41 to 0.90 p=0.01) lesser for RSI. Results were likely robust to unmeasured confounding and missing data. Our retrospective analysis shows a decrease in survival when RSI is utilised by paramedics for stroke. Since RSI is commonly used for strokes, controlled trial evidence to support this practice is urgently needed.
Publisher: Springer Science and Business Media LLC
Date: 03-11-2013
DOI: 10.1038/NG.2806
Abstract: The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non-O. viverrini-related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini-related and non-O. viverrini-related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non-O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CELL.2019.09.019
Abstract: Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic ersity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in erse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions.
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/CC11924
Publisher: American Society of Hematology
Date: 21-03-2013
DOI: 10.1182/BLOOD-2012-07-446120
Abstract: The ERG stem cell enhancer is active in acute myeloid leukemia and is regulated by a heptad of transcription factors. Expression signatures derived from ERG promoter–enhancer activity and heptad expression are associated with clinical outcome.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-08-2013
DOI: 10.1126/SCITRANSLMED.3006086
Abstract: Genome-wide mutational signatures of the group 1 carcinogen aristolochic acid are observed in urothelial cancers and liver cancers from Asia.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
DOI: 10.1038/S41598-019-55146-2
Abstract: Generation of large amounts of genomic data is now feasible and cost-effective with improvements in next generation sequencing (NGS) technology. Ribonucleic acid sequencing (RNA-Seq) is becoming the preferred method for comprehensively characterising global transcriptome activity. Unique to cytoreductive surgery (CRS), multiple spatially discrete tumour specimens could be systematically harvested for genomic analysis. To facilitate such downstream analyses, laser capture microdissection (LCM) could be utilized to obtain pure cell populations. The aim of this protocol study was to develop a methodology to obtain high-quality expression data from matched primary tumours and metastases by utilizing LCM to isolate pure cellular populations. We demonstrate an optimized LCM protocol which reproducibly delivered intact RNA used for RNA sequencing and quantitative polymerase chain reaction (qPCR). After pathologic annotation of normal epithelial, tumour and stromal components, LCM coupled with cDNA library generation provided for successful RNA sequencing. To illustrate our framework’s potential to identify targets that would otherwise be missed with conventional bulk tumour sequencing, we performed qPCR and immunohistochemical technical validation to show that the genes identified were truly expressed only in certain sub-components. This study suggests that the combination of matched tissue specimens with tissue microdissection and NGS provides a viable platform to unmask hidden biomarkers and provides insight into tumour biology at a higher resolution.
Publisher: American Society of Hematology
Date: 05-2014
Publisher: Informa UK Limited
Date: 16-06-2017
DOI: 10.1080/10903127.2017.1325952
Abstract: Rapid sequence intubation (RSI) is not only used in traumatic brain injuries in the out-of-hospital setting, but also for non-traumatic brain pathologies (NTBP) such as brain tumors, meningitis, encephalitis, hypoxic/anoxic brain injury, stroke, arteriovenous malformations, tumors, aneurysms, brain hemorrhage, as well as brain injury due to diabetes, seizures and toxicity, metabolic conditions, and alcohol and drug overdose. Previous research suggests that RSI is common in non-traumatic coma, but with an unknown prevalence of NTBP in those that receive RSI. If NTBP is common and if brain trauma RSI evidence is not valid for NTBP then a sizable proportion of NTBP receive this treatment without evidence of benefit. This study calculated the out-of-hospital NTBP prevalence in patients that had received RSI and explored factors that predicted survival. A retrospective cohort study based on data collected from an ambulance service and seven hospitals based in Melbourne, Australia. Non-traumatic brain pathologies were defined using ICD10-AM codes for the calculation of NTBP prevalence. Logistic regression modelled out-of-hospital predictors of survival to hospital discharge after adjustment for comorbidities. The seven participating hospitals treated 2,277 patients that received paramedic RSI for all illnesses and indications from January 1, 2008 to December 31, 2015, with survival data available for 1,940 (85%). Of the 1,940, 1,125 (58%) patients had at least one hospital-diagnosed NTBP. Sixty-nine percent all of NTBP survived to hospital discharge, compared to 65% for traumatic intracranial injury. Strokes were the most common and had poor survival to discharge (37%) compared to the second most common NTBP toxicity/toxic encephalopathy that had very high survival (98%). No out-of-hospital clinical intervention or prehospital time interval predicted survival. Factors that did predict survival include Glasgow Coma Scale (GCS), duration of mechanical ventilation, age, ICU length of stay, and comorbidities. Non-traumatic brain pathologies are seven times more prevalent than traumatic brain injuries in patients that underwent out-of-hospital RSI in Victoria, Australia. Since the mechanisms through which RSI impacts mortality might differ between traumatic brain injuries and NTBP, and given that NTBP is very prevalent, it follows that the use of RSI in NTBP could be unsupported.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2019
DOI: 10.1038/S41525-019-0085-8
Abstract: Whilst the underlying principles of precision medicine are comparable across the globe, genomic references, health practices, costs and discrimination policies differ in Asian settings compared to the reported initiatives involving European-derived populations. We have addressed these variables by developing an evolving reference base of genomic and phenotypic data and a framework to return medically significant variants to consenting research participants applicable for the Asian context. Targeting 10,000 participants, over 2000 Singaporeans, with no known pre-existing health conditions, have consented to an extensive clinical health screen, family health history collection, genome sequencing and ongoing follow-up. Genomic variants in a subset of genes associated with Mendelian disorders and drug responses are analysed using an in-house bioinformatics pipeline. A multidisciplinary team reviews the classification of variants and a research report is generated. Medically significant variants are returned to consenting participants through a bespoke return-of-result genomics clinic. Variant validation and subsequent clinical referral are advised as appropriate. The design and implementation of this flexible learning framework enables a cohort of detailed phenotyping and genotyping of healthy Singaporeans to be established and the frequency of disease-causing variants in this population to be determined. Our findings will contribute to international precision medicine initiatives, bridging gaps with ethnic-specific data and insights from this understudied population.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2016
DOI: 10.1038/LEU.2016.13
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.BPG.2015.02.002
Abstract: Cholangiocarcinoma (CCA) is a malignant tumour of bile duct epithelial cells with dismal prognosis and rising incidence. Chronic inflammation resulting from liver fluke infection, hepatitis and other inflammatory bowel diseases is a major contributing factor to cholangiocarcinogenesis, likely through accumulation of serial genetic and epigenetic alterations resulting in aberration of oncogenes and tumour suppressors. Recent studies making use of advances in high-throughput genomics have revealed the genetic landscape of CCA, greatly increasing our understanding of its underlying biology. A series of highly recurrent mutations in genes such as TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 and BAP1, which are known to be involved in cell cycle control, cell signalling pathways and chromatin dynamics, have led to investigations of their roles, through molecular to mouse modelling studies, in cholangiocarcinogenesis. This review focuses on the landscape genetic alterations in CCA and its functional relevance to the formation and progression of CCA.
Publisher: Informa UK Limited
Date: 10-10-2013
DOI: 10.3109/10903127.2013.831509
Abstract: To determine the differences in survival for out-of-hospital advanced airway intervention (AAI) compared with basic airway intervention (BAI) in cardiac arrest. AAI is commonly utilized in cardiac arrest in the out-of-hospital setting as a means to secure the airway. Observational studies and clinical trials of AAI suggest that AAI is associated with worse outcomes in terms of survival. No controlled trials exist that compares AAI to BAI. We conducted a bias-adjusted meta-analysis on 17 observational studies. The outcomes were survival, short-term (return of spontaneous circulation and to hospital admission), and longer-term (to discharge, to one month survival). We undertook sensitivity analyses by analyzing patients separately: those who were 16 years and older, nontrauma only, and attempted versus successful AAI. This meta-analysis included 388,878 patients. The short-term survival for AAI compared to BAI were overall OR 0.84(95% CI 0.62 to 1.13), for endotracheal intubation (ETI) OR 0.79 (95% CI 0.54 to 1.16), and for supraglottic airways (SGA) OR 0.59 (95% CI 0.39 to 0.89). Long-term survival for AAI were overall OR 0.49 (95% CI 0.37 to 0.65), for ETI OR 0.48 (95% CI 0.36 to 0.64), and for SGA OR 0.35 (95% CI 0.28 to 0.44). Sensitivity analyses shows that limiting analyses to adults, non-trauma victims, and instances where AAI was both attempted and successful did not alter results meaningfully. A third of all studies did not adjust for any other confounding factors that could impact on survival. This meta-analysis shows decreased survival for AAIs used out-of-hospital in cardiac arrest, but are likely biased due to confounding, especially confounding by indication. A properly conducted prospective study or a controlled trial is urgently needed and are possible to do.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2019
DOI: 10.1038/S41467-019-09799-2
Abstract: The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for % of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2013
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.ORALONCOLOGY.2014.12.012
Abstract: Extracapsular spread (ECS) is an important prognostic factor for oral squamous cell carcinoma (OSCC) and is used to guide management. In this study, we aimed to identify an expression profile signature for ECS in node-positive OSCC using data derived from two different sources: a cohort of OSCC patients from our institution (National Cancer Centre Singapore) and The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) cohort. We also sought to determine if this signature could serve as a prognostic factor in node negative cancers. Patients with a histological diagnosis of OSCC were identified from an institutional database and fresh tumor s les were retrieved. RNA was extracted and gene expression profiling was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray platform. RNA sequence data and corresponding clinical data for the TCGA HNSCC cohort were downloaded from the TCGA Data Portal. All data analyses were conducted using R package and SPSS. We identified an 11 gene signature (GGH, MTFR1, CDKN3, PSRC1, SMIM3, CA9, IRX4, CPA3, ZSCAN16, CBX7 and ZFP3) which was robust in segregating tumors by ECS status. In node negative patients, patients harboring this ECS signature had a significantly worse overall survival (p=0.04). An eleven gene signature for ECS was derived. Our results also suggest that this signature is prognostic in a separate subset of patients with no nodal metastasis Further validation of this signature on other datasets and immunohistochemical studies are required to establish utility of this signature in stratifying early stage OSCC patients.
No related grants have been discovered for Weng Khong Lim.