Chee Meng Katherine Chew
Email Address
phschcmk@nus.edu.sg
Organizational Units
PHYSIOLOGY
dept
YONG LOO LIN SCH OF MEDICINE
faculty
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Now showing 1 - 9 of 9
Publication Clinical Outcomes of Dose-escalated Radiotherapy for Localised Prostate Cancer: A Single-institution Experience(INT INST ANTICANCER RESEARCH, 2020-03-01) Meng, Katherine; Lim, Keith; Lee, Chia Ching; Chia, David; Ooi, Kiat Huat; Soon, Yu Yang; Tey, Jeremy; Dr Wei Tsau Chia; MEDICINE; PHYSIOLOGY© 2020 International Institute of Anticancer Research. All rights reserved. Background/Aim: To report the outcomes of patients with prostate cancer treated with dose-escalated radiotherapy over a 15-year period at our Institution. Patients and Methods: Patients with biopsy-proven cT1-4N0M0 disease who received radical external beam radiotherapy (EBRT) were reviewed. The endpoints were 5-year overall survival (OS), freedom from biochemical failure (FFBF) and late treatment toxicities. Results: A total of 236 patients were eligible. Median follow-up was 70 months. Low-, intermediate- and high-risk disease was found in 9%; 29% and 62% of patients, respectively. The median radiation dose was 73.8 Gy. Overall 42% of patients had dose escalation to >74 Gy. Five-year OS and FFBF were 95.2%/81.6%/75.4% and 95.0%/98.0%/82.0% for low- /intermediate-/high-risk patients, respectively. Dose escalation to >74 Gy did not improve FFBF (hazard ratio=0.97, 95% confidence intervaI=0.43-2.19, p=0.93) and was associated with a 4.3-fold increase in the odds of grade 3 or more rectal bleeding (p<0.01). Conclusion: Dose escalation to >74 Gy did not improve OS or FFBF but was associated with a higher rate of grade 3 or more rectal haemorrhage.Publication Different Excitation-Inhibition Correlations Between Spontaneous and Tone-evoked Activity in Primary Auditory Cortex Neurons(PERGAMON-ELSEVIER SCIENCE LTD, 2022-07-09) Chew, Katherine CM; Kumar, Vineet; Tan, Andrew YY; Dr Yong-Yi, Andrew Tan; PHYSIOLOGYTone-evoked synaptic excitation and inhibition are highly correlated in many neurons with V-shaped tuning curves in the primary auditory cortex of pentobarbital-anesthetized rats. In contrast, there is less correlation between spontaneous excitation and inhibition in visual cortex neurons under the same anesthetic conditions. However, it was not known whether the primary auditory cortex resembles visual cortex in having spontaneous excitation and inhibition that is less correlated than tone-evoked excitation and inhibition. Here we report whole-cell voltage-clamp measurements of spontaneous excitation and inhibition in primary auditory cortex neurons of pentobarbital-anesthetized rats. Spontaneous excitatory and inhibitory currents appeared to mainly consist of distinct events, with the inhibitory event rate typically lower than the excitatory event rate. We use the ratio of the excitatory event rate to the inhibitory event rate, and the assumption that the excitatory and inhibitory synaptic currents can each be reasonably described as a filtered Poisson process, to estimate the maximum spontaneous excitatory-inhibitory correlation for each neuron. In a subset of neurons, we also measured tone-evoked excitation and inhibition. In neurons with V-shaped tuning curves, although tone-evoked excitation and inhibition were highly correlated, the spontaneous inhibitory event rate was typically sufficiently lower than the spontaneous excitatory event rate to indicate a lower excitatory-inhibitory correlation for spontaneous activity than for tone-evoked responses.Publication S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit(SOC NEUROSCIENCE, 2018-09-26) Liu, Chao; Zhang, Cheng-Wu; Lo, Shun Qiang; Ang, Seok Ting; Chew, Katherine Chee Meng; Yu, Dejie; Chai, Bing Han; Tan, Bobby; Tsang, Fai; Tai, Yee Kit; Tan, Bryce Wei Quan; Liang, Mui Cheng; Tan, Hwee Tong; Tang, Jia Ying; Lai, Mitchell Kim Peng; Chua, John Jia En; Chung, Maxey Ching Ming; Khanna, Sanjay; Lim, Kah-Leong; Soong, Tuck Wah; Dr Tai Yee Kit; PHARMACOLOGY; CENTRE FOR QUANTUM TECHNOLOGIES; PHYSIOLOGY; SURGERY; CHEMISTRY; BIOCHEMISTRY© 2018 the authors. Elevated iron deposition has been reported in Parkinson’s disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe 2+ uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn 2+ or Fe 2+ uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry, and DMT1 C23A or C540A substitutions abolished nitric oxide (NO)-mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe 2+ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitor L -NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.Publication Iron mitigates DMT1-mediated manganese cytotoxicity via the ASK1-JNK signaling axis: Implications of iron supplementation for manganese toxicity(Nature Publishing Group, 2016) Tai Y.K.; Chew K.C.M.; Tan B.W.Q.; Lim K.-L.; Soong T.W.; PHYSIOLOGY; SURGERYPublication Stress-induced alterations in parkin solubility promote parkin aggregation and compromise parkin's protective function(2005) Wang, C.; Chew, K.C.M.; Tay, S.-P.; Ho, M.W.L.; Lim, K.-L.; Lim, T.-M.; Tsang, F.; Soong, T.-W.; Ko, H.S.; Thomas, B.; Dawson, V.L.; Dawson, T.M.; Troncoso, J.; Pletnikova, O.; PHYSIOLOGY; BIOLOGICAL SCIENCESPublication APPARATUS AND METHOD FOR MEASURING IN VIVO BIOMECHANICAL PROPERTIES OF SKIN(2011-12-29) LIM KENG HUI; POSTON TIMOTHY; HO HOAN NGHIA; CHEW CHEE MENG; CHEN CHAO YU PETER; JEYAPALINA SUJEEVINI; LIM BENG HAI; PHYSIOLOGY; MATHEMATICS; ORTHOPAEDIC SURGERY; MECHANICAL ENGINEERINGAn assembly for measuring in vivo biomechanical properties of skin, comprising a testing device, said testing device comprising; a first pad attachable to the skin a second pad attachable to the skin, at a known distance from the first pad; said attachability of the pads to the skin to prevent relative movement between the respective pad and the skin to which it is attached; a forcing means for applying a force to the first pad, whilst said pads are attached to the skin, along a first axis connecting the first and second pad, to induce a corresponding relative movement between the pads due to deformation of the skin between said pads; a force measurement device for measuring the applied force, and; a displacement measurement device for measuring the corresponding induced movement.Publication Proteasome inhibition promotes Parkin-Ubc13 interaction and lysine 63-linked ubiquitination.(2013) Lim G.G.; Neurodegeneration Research Laboratory National Neuroscience Institute; Chew K.C.; Ng X.H.; Henry-Basil A.; Sim R.W.; Tan J.M.; Chai C.; PHYSIOLOGY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); INSTITUTE OF MOLECULAR & CELL BIOLOGY; DUKE-NUS MEDICAL SCHOOLDisruption of the ubiquitin-proteasome system, which normally identifies and degrades unwanted intracellular proteins, is thought to underlie neurodegeneration. Supporting this, mutations of Parkin, a ubiquitin ligase, are associated with autosomal recessive parkinsonism. Remarkably, Parkin can protect neurons against a wide spectrum of stress, including those that promote proteasome dysfunction. Although the mechanism underlying the preservation of proteasome function by Parkin is hitherto unclear, we have previously proposed that Parkin-mediated K63-linked ubiquitination (which is usually uncoupled from the proteasome) may serve to mitigate proteasomal stress by diverting the substrate load away from the machinery. By means of linkage-specific antibodies, we demonstrated here that proteasome inhibition indeed promotes K63-linked ubiquitination of proteins especially in Parkin-expressing cells. Importantly, we further demonstrated that the recruitment of Ubc13 (an E2 that mediates K63-linked polyubiquitin chain formation exclusively) by Parkin is selectively enhanced under conditions of proteasomal stress, thus identifying a mechanism by which Parkin could promote K63-linked ubiquitin modification in cells undergoing proteolytic stress. This mode of ubiquitination appears to facilitate the subsequent clearance of Parkin substrates via autophagy. Consistent with the proposed protective role of K63-linked ubiquitination in times of proteolytic stress, we found that Ubc13-deficient cells are significantly more susceptible to cell death induced by proteasome inhibitors compared to their wild type counterparts. Taken together, our study suggests a role for Parkin-mediated K63 ubiquitination in maintaining cellular protein homeostasis, especially during periods when the proteasome is burdened or impaired.Publication Proteasome inhibition promotes Parkin-Ubc13 interaction and lysine 63-linked ubiquitination.(2013) Lim, G.G.; Chew, K.C.; Ng, X.H.; Henry-Basil, A.; Sim, R.W.; Tan, J.M.; Chai, C.; Lim, K.L.; PHYSIOLOGY; DUKE-NUS GRADUATE MEDICAL SCHOOL S'POREDisruption of the ubiquitin-proteasome system, which normally identifies and degrades unwanted intracellular proteins, is thought to underlie neurodegeneration. Supporting this, mutations of Parkin, a ubiquitin ligase, are associated with autosomal recessive parkinsonism. Remarkably, Parkin can protect neurons against a wide spectrum of stress, including those that promote proteasome dysfunction. Although the mechanism underlying the preservation of proteasome function by Parkin is hitherto unclear, we have previously proposed that Parkin-mediated K63-linked ubiquitination (which is usually uncoupled from the proteasome) may serve to mitigate proteasomal stress by diverting the substrate load away from the machinery. By means of linkage-specific antibodies, we demonstrated here that proteasome inhibition indeed promotes K63-linked ubiquitination of proteins especially in Parkin-expressing cells. Importantly, we further demonstrated that the recruitment of Ubc13 (an E2 that mediates K63-linked polyubiquitin chain formation exclusively) by Parkin is selectively enhanced under conditions of proteasomal stress, thus identifying a mechanism by which Parkin could promote K63-linked ubiquitin modification in cells undergoing proteolytic stress. This mode of ubiquitination appears to facilitate the subsequent clearance of Parkin substrates via autophagy. Consistent with the proposed protective role of K63-linked ubiquitination in times of proteolytic stress, we found that Ubc13-deficient cells are significantly more susceptible to cell death induced by proteasome inhibitors compared to their wild type counterparts. Taken together, our study suggests a role for Parkin-mediated K63 ubiquitination in maintaining cellular protein homeostasis, especially during periods when the proteasome is burdened or impaired.Publication Bidirectional modulation of hippocampal synaptic plasticity by Dopaminergic D4-receptors in the CA1 area of hippocampus(2017) Navakkode S.; Chew K.C.M.; Tay S.J.N.; Lin Q.; Behnisch T.; Soong T.W.; PHYSIOLOGYLong-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP. This effect was dependent on protein synthesis, activation of NMDA-receptors and CaMKII. We also show that GABAA-receptor mediated mechanisms are involved in the enhancement of late-LTP. We could show that short-term plasticity and baseline synaptic transmission were unaffected by D4R inhibition. On the other hand, antagonizing D4R prevented both early and late forms of LTD, showing that activation of D4Rs triggered a dual function. Synaptic tagging experiments on LTD showed that D4Rs act as plasticity related proteins rather than the setting of synaptic tags. D4R activation by PD 168077 induced a slow-onset depression that was protein synthesis, NMDAR and CaMKII dependent. The D4 receptors, thus exert a bidirectional modulation of CA1 pyramidal neurons by restricting synaptic strengthening and facilitating synaptic weakening. © 2017 The Author(s).