Wei Min Catherine Ong
Email Address
mdccowm@nus.edu.sg
Organizational Units
MEDICINE
dept
YONG LOO LIN SCH OF MEDICINE
faculty
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Publication Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis(2015) Ong C.W.M.; Elkington P.T.; Brilha S.; Ugarte-Gil C.; Tome-Esteban M.T.; Tezera L.B.; Pabisiak P.J.; Moores R.C.; Sathyamoorthy T.; Patel V.; Gilman R.H.; Porter J.C.; Friedland J.S.; MEDICINEPulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease. ? 2015 Ong et al.Publication Interim Treatment Guidelines for COVID-19 (Version 3.0, dated 6th July 2020)(2020-07-06) Vasoo, Shawn; Tan, Thuan Tong; Archuleta, Sophia; Lye, David; Thong, Bernard; Howe, Hwee Siew; Cross, Gail; Kwa, Andrea; Law, Hwa Lin; Hoo, Grace; Lin, Raymond; Tan, Lisa; Foo, Yang Tong; Ong, Kiat Hoe; Kurup, Asok; Lee, Tau Hong; Ong, Wei Min Catherine; Ang, Brenda; Dr Wei Min Catherine Ong; MEDICINE; DUKE-NUS MEDICAL SCHOOLPublication TB and COVID-19 co-infection: rationale and aims of a global study(International Union Against Tuberculosis and Lung Disease, 2021-01-01) Wei Min Catherine Ong; The TB/COVID-19 Global Study Group; Dr Wei Min Catherine Ong; MEDICINEPublication Position Statement from the National Centre for Infectious Diseases and the Chapter of Infectious Disease Physicians, Academy of Medicine, Singapore: Period of Infectivity to Inform Strategies for De-isolation for COVID-19 Patients.(2020-05-23) CATHERINE ONG WEI MIN; Dr Catherine Ong Wei Min; MEDICINEPublication Lack of latent tuberculosis (TB) screening and delay in anti-retroviral therapy initiation in HIV-TB co-infection: an 11-year study in an intermediate TB-burden country(ELSEVIER SCI LTD, 2021-11-05) Teng, Vannesa Yue May; Chua, Yan Ting; Lai, Eunice En Ni; Mukherjee, Shilpa; Michaels, Jessica; Wong, Chen Seong; Shen, Liang; Leo, Yee Sin; Young, Barnaby; Archuleta, Sophia; Ong, Catherine WM; Assoc Prof Sophia Archuleta; DEAN'S OFFICE (MEDICINE); MEDICINE; SAW SWEE HOCK SCHOOL OF PUBLIC HEALTHObjectives: To examine the prevalence and characteristics of HIV-tuberculosis (TB) co-infected patients in Singapore, an intermediate TB-burden country. Methods: Retrospective data across 11 years was obtained from the National University Hospital (NUH), a quaternary hospital and the National Centre for Infectious Diseases (NCID), the national HIV center. Results: From December 2005 to December 2016, 4015 HIV-infected patients were managed at NUH and NCID, of whom, respectively, 48 and 272 were diagnosed with active TB disease. Only 2 patients (0.6%) were screened for latent TB infection on HIV diagnosis. Mean CD4 count at TB diagnosis was 125.0 ± 153.9 cells/mm3. More patients with HIV diagnosed ≥6 weeks before TB (41%) were associated with CD4 counts >200 cells/mm3 than patients with TB diagnosed ≥6 weeks before HIV (2%). Of 124 (38.6%) HIV-TB patients with CD4 count ≤50 cells/mm3, only 18 (14.2%) started anti-retroviral therapy (ART) in <2 weeks. Of patients with pulmonary TB, 33.5% had normal chest x-ray. Conclusions: Latent TB infection screening in HIV-infected patients is low, and ART initiation is delayed in HIV-TB patients with CD4 ≤50 cells/mm3. Pulmonary TB patients with HIV can be infectious despite normal chest x-ray. Clinical practices can be further improved to benefit HIV-TB patients.Publication Perspectives of Singaporean biomedical researchers and research support staff on actual and ideal IRB review functions and characteristics: A quantitative analysis(Public Library of Science, 2020) Labude, M.K.; Shen, L.; Zhu, Y.; Schaefer, G. O.; Ong, C.; Xafis, V.; DEAN'S OFFICE (MEDICINE); MEDICINEBackground Biomedical research is overseen by numerous Institutional Review Boards (IRBs) in Singapore but there has been no research that examines how the research review process is perceived by the local research community nor is there any systematic data on perceptions regarding the review process or other research ethics processes and IRB characteristics. The aim of this study was to ascertain general views regarding the overall perceived value of ethics review processes; to measure perceptions about local IRB functions and characteristics; to identify IRB functions and characteristics viewed as important; and to compare these views with those of other international studies. Methods An online survey was used with the main component being the IRB-Researcher Assessment Tool (IRB-RAT), a validated tool, to evaluate perceptions of ideal and actual IRB functions and characteristics held by Singaporean researchers and research support staff. Data were analysed descriptively first, with mean and SD of each item of IRB-RAT questionnaire reported, excluding the respondents whose answers were unknown or not applicable. The Wilcoxon Sign Rank test was used to compare the ideal and actual ratings of each IRB-RAT item, while the Mann-Whitney U test was used to compare the ratings of each IRB-RAT item between respondents with different characteristics. The Z-test was used to compare the mean ratings of our cohort with the mean ratings reported in the literature. The correlation between our mean ideal scores and those of two international studies also employing the IRB-RAT was examined. Results Seventy-one respondents completed the survey. This cohort generally held positive views of the impact of the ethics review process on: the quality of research; establishing and maintaining public trust in research; the protection of research participants; and on the scientific validity of research. The most important ideal IRB characteristics were timeliness, upholding participants’ rights while also facilitating research, working with investigators to find solutions when there are disagreements, and not allowing biases to affect reviews. For almost all 45 IRB-RAT statements, the rating of the importance of the characteristic was higher than the rating of how much that characteristic was descriptive of IRBs the respondents were familiar with. There was a significant strong correlation between our study’s scores on the ideal IRB characteristics and those of the first and largest published study that employed the IRB-RAT, the US National Validation (USNV) sample in Keith-Spiegel et al. [19]. Conclusions An understanding of the perceptions held by Singaporean researchers and research support staff on the value that the ethics review process adds, their perceptions of actual IRB functions and characteristics as well as what they view as central to high functioning IRBs is the first step to considering the aspects of the review process that might benefit from improvements. This study provides insight into how our cohort compares to others internationally and highlights strengths and areas for improvement of Singapore IRBs as perceived by a small sample of the local research community. Such insights provide a springboard for additional research and may assist in further enhancing good relations so that both are working towards the same end. Copyright: © 2020 Labude et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Publication Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNF?, NF?B, p38 and caspase 8 dependent pathways(BMC, 2011) Green, J.A; Dholakia, S; Janczar, K; Ong, C.W.M; Moores, R; Fry, J; Elkington, P.T; Roncaroli, F; Friedland, J.S; MEDICINETuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-?. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NF?B pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NF?B pathways; p38 phosphorylation was increased and p50/p65 NF?B nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-?, p38 MAP kinase and NF?B in addition to a novel caspase 8-dependent pathway. © 2011 Green et al; licensee BioMed Central Ltd.Publication Erratum to: Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis (Scientific Reports, (2017), 7, 1, (16031), 10.1038/s41598-017-16250-3)(Nature Publishing Group, 2018) Brilha S.; Ong C.W.M.; Weksler B.; Romero N.; Couraud P.-O.; Friedland J.S.; MEDICINEA correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. © 2018, The Author(s).Publication Clinical standards for the assessment, management and rehabilitation of post-TB lung disease(International Union Against Tuberculosis and Lung Disease, 2021-10-01) Migliori, G. B.; Marx, F. M.; Ambrosino, N.; Zampogna, E.; Schaaf, H. S.; van der Zalm, M. M.; Allwood, B.; Byrne, A. L.; Mortimer, K.; Wallis, R. S.; Fox, G. J.; Leung, C. C.; Chakaya, J. M.; Seaworth, B.; Rachow, A.; Marais, B. J.; Furin, J.; Akkerman, O. W.; Al Yaquobi, F.; Amaral, A. F. S.; Borisov, S.; Caminero, J. A.; Carvalho, A. C. C.; Chesov, D.; Codecasa, L. R.; Teixeira, R. C.; Dalcolmo, M. P.; Datta, S.; Dinh-Xuan, A-T.; Duarte, R.; Evans, C. A.; García-García, J.-M.; Günther, G.; Hoddinott, G.; Huddart, S.; Ivanova, O.; Laniado-Laborín, R.; Manga, S.; Manika, K.; Mariandyshev, A.; Mello, F. C. Q.; Mpagama, S. G.; Muñoz-Torrico, M.; Nahid, P.; Ong, C. W. M.; Palmero, D. J.; Piubello, A.; Pontali, E.; Silva, D. R.; Singla, R.; Spanevello, A.; Tiberi, S.; Udwadia, Z. F.; Vitacca, M.; Centis, R.; D'Ambrosio, L.; Sotgiu, G.; Lange, C.; Visca, D.; MEDICINEBACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR). METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement). RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR. CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD. © 2021 The UnionPublication Integrin à2?1 expression regulates matrix metalloproteinase-1-dependent bronchial epithelial repair in pulmonary tuberculosis(Frontiers Media S.A., 2018) Brilha S.; Chong D.L.W.; Khawaja A.A.; Ong C.W.M.; Guppy N.J.; Porter J.C.; Friedland J.S.; MEDICINEPulmonary tuberculosis (TB) is caused by inhalation of Mycobacterium tuberculosis, which damages the bronchial epithelial barrier to establish local infection. Matrix metalloproteinase-1 plays a crucial role in the immunopathology of TB, causing breakdown of type I collagen and cavitation, but this collagenase is also potentially involved in bronchial epithelial repair. We hypothesized that the extracellular matrix (ECM) modulates M. tuberculosis-driven matrix metalloproteinase-1 expression by human bronchial epithelial cells (HBECs), regulating respiratory epithelial cell migration and repair. Medium from monocytes stimulated with M. tuberculosis induced collagenase activity in bronchial epithelial cells, which was reduced by ~87% when cells were cultured on a type I collagen matrix. Matrix metalloproteinase-1 had a focal localization, which is consistent with cell migration, and overall secretion decreased by 32% on type I collagen. There were no associated changes in the specific tissue inhibitors of metalloproteinases. Decreased matrix metalloproteinase-1 secretion was due to ligand-binding to the à2?1 integrin and was dependent on the actin cytoskeleton. In lung biopsies, samples from patients with pulmonary TB, integrin à2?1 is highly expressed on the bronchial epithelium. Areas of lung with disrupted collagen matrix showed an increase in matrix metalloproteinases-1 expression compared with areas where collagen was comparable to control lung. Type I collagen matrix increased respiratory epithelial cell migration in a wound-healing assay, and this too was matrix metalloproteinase-dependent, since it was blocked by the matrix metalloproteinase inhibitor GM6001. In summary, we report a novel mechanism by which à2?1-mediated signals from the ECM modulate matrix metalloproteinase-1 secretion by HBECs, regulating their migration and epithelial repair in TB. ? 2018 Brilha, Chong, Khawaja, Ong, Guppy, Porter and Friedland.