ORCID Profile
0000-0001-7127-9107
Current Organisations
Agency for Science, Technology and Research
,
Nanyang Technological University
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: Cold Spring Harbor Laboratory
Date: 18-11-2020
DOI: 10.1101/2020.11.16.20232835
Abstract: The rapid rise of coronavirus disease 2019 patients who suffer from vascular events after their initial recovery is expected to lead to a worldwide shift in disease burden. We aim to investigate the impact of COVID-19 on the pathophysiological state of blood vessels in convalescent patients. Here, convalescent COVID-19 patients with or without preexisting conditions (i.e. hypertension, diabetes, hyperlipidemia) were compared to non-COVID-19 patients with matched cardiovascular risk factors or healthy participants. Convalescent patients had elevated circulating endothelial cells (CECs), and those with underlying cardiovascular risk had more pronounced endothelial activation hallmarks (ICAM1, P-selectin or CX3CL1) expressed by CECs. Multiplex microbead-based immunoassays revealed some levels of cytokine production sustained from acute infection to recovery phase. Several proinflammatory and activated T lymphocyte-associated cytokines correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Finally, the activation markers detected on CECs mapped to the counter receptors (i.e. ITGAL, SELPLG , and CX3CR1 ) found primarily on CD8+ T cells and natural killer cells, suggesting that activated endothelial cells could be targeted by cytotoxic effector cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.
Publisher: Wiley
Date: 28-04-2022
DOI: 10.1002/AJH.26575
Abstract: Sustained hypercoagulability and endotheliopathy are present in convalescent COVID‐19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID‐19 patients were evaluated up to 16 months after recovery from COVID‐19. These values were compared with a control group of healthy volunteers ( n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID‐19 acute ischaemic limb. Elevated D‐dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D‐dimer 0.34 FEU μg/mL (IQR 0.28, 0.46) ( p .001) and Factor VIII 150% (IQR 171, 203) ( p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) ( p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) ( p = 0.01) and delayed lag time 2.4 min (1.42–2.97) ( p = 0.0002) versus controls. Raised vWF:Ag and ICAM‐1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) ( p = 0.02) and ICAM‐1 54.1 ng/mL (IQR 43.8, 64.1) ( p = .004) than controls. IL‐6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL‐6 of 1.5 pg/mL (IQR 0.6, 3.0) ( p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID‐19 severity and COVID‐19 vaccination preceding SARS‐CoV‐2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID‐19.
Publisher: S. Karger AG
Date: 22-03-2022
DOI: 10.1159/000522632
Abstract: b i Introduction: /i /b Concomitant risk factors challenge the mechanistic understanding of cardiac aging. We determined the degree to which the left atrial function could be distinguished by advanced cardiac magnetic resonance (CMR) imaging in older adults and assessed associations between the left atrial function and the plasma biomarkers related to biological aging and cardiovascular disease [serum monocyte chemoattractant protein-1 (MCP1), matrix metallopeptidase 9 (MMP-9), B-type natriuretic peptides (BNPs), galectin-3 (Gal-3), high-sensitivity cardiac troponin I (hsTn1), high-sensitivity C-reactive protein (hs-CRP), and soluble urokinase plasminogen activator receptor (sUPAR)]. b i Methods: /i /b Among a cross-sectional population-based cohort of older adults, longitudinal LA strain including reservoir strain (ε sub s /sub ), conduit strain (ε sub e /sub ), and booster strain (ε sub a /sub ) as well as peak strain rates (SRs, SRe, SRa) were determined using CMR and studied in association with blood biomarkers. b i Results: /i /b We studied 243 community adults (42.8% female, mean age 70.3 ± 9.5 years). In bivariate analysis, ε sub e /sub and SRe were reduced in gradation with increasing risk factors (all i /i values & #x3c .0001). Corresponding levels of sUPAR (ng/mL) were quantitatively higher in older adults with & #x3c risk factors (2.5 ± 1.6 vs. 1.7 ± 1.3, i /i = 0.0005), in those with ≥2 risk factors (3.3 ± 2.4 vs. 1.7 ± 1.3, i /i & #x3c 0.0001), compared to young adults including between older adults with ≥2 risk factors and older adults with & #x3c risk factors (3.3 ± 2.4 vs. 2.5 ± 1.6, i /i = 0.017). Based on multivariate analysis, sUPAR was significantly associated with both ε sub e /sub (OR 1.52, i /i = 0.006) and SRe decline (OR 1.5, i /i = 0.019). The associations between Gal-3 and ε sub e /sub reduction (OR 1.2, i /i = 0.022) and between BNP and SRe decline were generally weaker (OR 1.03, i /i = 0.027). The addition of sUPAR to a model consisting of age, risk factors, Gal-3, and BNPs increased the area under the curve of ε sub e /sub from 0.72 to 0.77 ( i /i = 0.015). b i Conclusion: /i /b By advanced CMR imaging, a panel of circulating biomarkers comprising galectin, MMP-9 and sUPAR were associated with left atrial dysfunction in older adults. Higher levels of Gal-3 and MMP-9 may be suggestive of fibrotic mechanisms in left atrial aging while impairments in left atrial strain seen in association with circulating sUPAR may be related to immune activation in the left atrium in response to left atrial remodeling and fibrotic processes.
Publisher: Wiley
Date: 23-01-2019
DOI: 10.1002/BIT.26910
Abstract: Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) present an attractive alternative to primary EC sources for vascular grafting. However, there is a need to mature them towards either an arterial or venous subtype. A vital environmental factor involved in the arteriovenous specification of ECs during early embryonic development is fluid shear stress therefore, there have been attempts to employ adult arterial shear stress conditions to mature hPSC-ECs. However, hPSC-ECs are naïve to fluid shear stress, and their shear responses are still not well understood. Here, we used a multiplex microfluidic platform to systematically investigate the dose-time shear responses on hPSC-EC morphology and arterial-venous phenotypes over a range of magnitudes coincidental with physiological levels of embryonic and adult vasculatures. The device comprised of six parallel cell culture chambers that were in idually linked to flow-setting resistance channels, allowing us to simultaneously apply shear stress ranging from 0.4 to 15 dyne/cm
Publisher: eLife Sciences Publications, Ltd
Date: 23-03-2021
DOI: 10.7554/ELIFE.64909
Abstract: Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8 + T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.NEUINT.2017.01.005
Abstract: Biomarkers provide critical mechanistic insights to key biologic processes that occur during cerebral ischemia which, when carefully applied, can improve clinical decision-making in acute stroke management. The translation of a blood-based biomarker in ischemic stroke to clinical practice is challenging, in part, due to the complexity of ischemic stroke pathogenesis and the presence of a blood-brain barrier that restricts the release of brain-specific markers into the circulation. The pathologic and clinical aspects of ischemic stroke are described in this review, where a non-exhaustive list of biomarkers that interrogate different aspects of ischemic stroke such as oxidative damage, inflammation, thrombus formation, cardiac function and brain injury are described. The potential roles of these biomarkers are further examined under different clinical scenarios aimed at (1) averting the risk of hemorrhagic transformation, (2) identifying in iduals at risk of early neurologic deterioration and malignant infarction, (3) aiding in the diagnosis of ischemic stroke and its differentiation from other stroke mimics, (4) guiding the search for stroke etiology, and (5) assessing stroke risk within the community. Researchers should explore the roles of stroke biomarkers to enhance clinical decision-making that is presently largely based on intuition and subjective reasoning.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.BIOMATERIALS.2019.119747
Abstract: The effective deployment of arterial (AECs), venous (VECs) and stem cell-derived endothelial cells (PSC-ECs) in clinical applications requires understanding of their distinctive phenotypic and functional characteristics, including their responses to microenvironmental cues. Efforts to mimic the in-vivo vascular basement membrane milieu have led to the design and fabrication of nano- and micro-topographical substrates. Although the basement membrane architectures of arteries and veins are different, investigations into the effects of substrate topographies have so far focused on generic EC characteristics. Thus, topographical modulation of arterial- or venous-specific EC phenotype and function remains unknown. Here, we comprehensively evaluated the effects of 16 unique topographies on primary AECs, VECs and human PSC-ECs using a Multi Architectural (MARC) Chip. Gratings and micro-lenses augmented venous-specific phenotypes and depressed arterial functions in VECs while AECs did not respond consistently to topography. PSC-ECs exhibited phenotypic and functional maturation towards an arterial subtype with increased angiogenic potential, NOTCH1 and Ac-LDL expression on gratings. Specific topographies could elicit different phenotypic and functional changes, despite similar morphological response in different ECs, demonstrating no direct correlation between the two responses.
Publisher: AIP Publishing
Date: 05-2020
DOI: 10.1063/5.0004286
Abstract: Human pluripotent stem cell (hPSC) is a great resource for generating cell derivatives for drug efficiency testing. Metabolites of nutraceuticals can exert anti-inflammatory effects on blood vessels. However, the concentration of nutraceutical metabolites produced in hPSC-derived hepatocytes (hPSC-HEPs) is usually low. To enable the detection of these metabolites under the in vitro environment, we have developed a co-culture model consisting of parallel co-culture chambers and a recirculating microfluidic system with minimum fluid volume, optimal cell culture environment. The model allows cells to be exposed continuously to nutraceutical metabolites. In this perfused culturing model, hPSC-derived endothelial cells and hPSC-HEPs are co-cultured without physical contact. When an anti-inflammatory nutraceutical, quercetin, was administrated to the co-culture, higher levels of quercetin metabolites were detected on-chip compared with static control. We further induced inflammation with Interleukin-1β in the co-culture model and measured interleukin 8 (IL-8) generation. The IL-8 level was suppressed more significantly by quercetin metabolites in the perfusion co-culture, as compared to static culture. This is due to enhanced metabolites production on-chip. This microfluidic co-culture model enables in vitro screening of nutraceuticals using hPSC-derived cells.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.HRTHM.2021.01.032
Abstract: Accumulating data suggest blood biomarkers could inform stroke etiology. The purpose of this study was to investigate the performance of multiple blood biomarkers in elucidating stroke etiology with a focus on new-onset atrial fibrillation (AF) and cardioembolism. Between January and December 2017, information on clinical and laboratory parameters and stroke characteristics was prospectively collected from ischemic stroke patients recruited from the National University Hospital, Singapore. Multiple blood biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], d-dimer, S100β, neuron-specific enolase, vitamin D, cortisol, interleukin-6, insulin, uric acid, and albumin) were measured in plasma. These variables were compared with stroke etiology and the risk of new-onset AF and cardioembolism using multivariable regression methods. Of the 515 ischemic stroke patients (mean age 61 years 71% men), 44 (8.5%) were diagnosed with new-onset AF, and 75 (14.5%) had cardioembolism. The combination of 2 laboratory parameters (total cholesterol ≤169 mg/dL triglycerides ≤44.5 mg/dL) and 3 biomarkers (NT-proBNP ≥294 pg/mL S100β ≥64 pg/mL cortisol ≥471 nmol/l) identified patients with new-onset AF (negative predictive value [NPV] 90% positive predictive value [PPV] 73% area under curve [AUC] 85%). The combination of 2 laboratory parameters (total cholesterol ≤169 mg/dL triglycerides ≤44.5 mg/dL) and 2 biomarkers (NT-proBNP ≥507 pg/mL S100β ≥65 pg/mL) identified those with cardioembolism (NPV 86% PPV 78% AUC 87%). Adding clinical predictors did not improve the performance of these models. Blood biomarkers could identify patients with increased likelihood of cardioembolism and direct the search for occult AF.
Publisher: Mary Ann Liebert Inc
Date: 15-10-2019
Abstract: The ability of human stem cells to generate somatic cell lineages makes them ideal candidates for use in toxicological testing and eventually, preclinical drug development. Such resources would support an evolution away from human primary cells or research animal models, which suffer from variability and poor predictability, toward off-the-shelf assays of chemical toxicity and drug efficacy using human cells and tissues. To this end, we generated vascular cell populations (smooth muscle cells and endothelial cells) from human pluripotent stem cells (hPSCs), arranged them into 3D co-cultures within supportive gel matrices, and directed their propensity for self-organization resembling microvasculature. The resulting vascular cell populations and co-cultured constructs were then arrayed in high throughput and used for screening a library of environmental and clinical chemical agents for immunological and toxicological responses. The screen effectively stratified the chemicals into various levels of toxicity, with both cell type-specific and co-culture-dependent responses observed. Thus, hPSC-derived vascular cells and constructs could be progressed further toward use in toxicant and drug screening.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.CELREP.2014.08.065
Abstract: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christine Cheung.