Han Kiat Ho - Academia.edu (original) (raw)

Papers by Han Kiat Ho

Supplemental material, sj-xlsx-1-bmi-10.1177_11772719211018204 for Extracellular Vesicle Proteome... more Supplemental material, sj-xlsx-1-bmi-10.1177_11772719211018204 for Extracellular Vesicle Proteome of Breast Cancer Patients with and Without Cognitive Impairment Following Anthracycline-based Chemotherapy: An Exploratory Study by Yong Qin Koh, Ding Quan Ng, Chiu Chin Ng, Adrian Boey, Meng Wei, Siu Kwan Sze, Han Kiat Ho, Munjal Acharya, Charles L Limoli and Alexandre Chan in Biomarker Insights

Journal of Tissue Engineering and Regenerative Medicine, 2018

Polyethylene glycol‐linked multiwalled carbon nanotube‐coated poly‐acrylamide hydrogel (CNT‐PA) w... more Polyethylene glycol‐linked multiwalled carbon nanotube‐coated poly‐acrylamide hydrogel (CNT‐PA) was customized to mimic human liver stiffness and nanostructured surface in liver cells for modulating differentiation of human amniotic epithelial cells (hAECs) into functional hepatocyte‐like cells (HLCs) in vitro. This composite of CNT‐PA matrix enhanced the hepatic differentiation of hAECs into HLCs with suppression of pluripotent markers and up‐regulation of hepatic markers at both transcript and protein levels. Furthermore, the HLCs on CNT‐PA demonstrated hepatocytic functions in terms of albumin secretion, higher uptake of indocyanine green, and comparable CYP3A4 enzymatic function and inducibility when matched against HepG2 cells. Taken together, CNT‐PA provides an efficient and scalable platform for the expansion of HLCs from hAECs and could be explored further for downstream development.

Currents in Pharmacy Teaching and Learning, 2021

BACKGROUND AND PURPOSE Deep thinking is a desirable trait for higher education especially at a ti... more BACKGROUND AND PURPOSE Deep thinking is a desirable trait for higher education especially at a time where knowledge application, rather than knowledge acquisition, is premium. As assessment plays a critical role in shaping learning behaviors, this study attempted to evaluate the benefits of administering a 'student-designed assessment problems' (SDAP) assignment as a tool to instill deeper learning among students. The supposition was that when tasked to design assessment problems, students are challenged to higher cognitive levels of thinking on the Bloom's revised taxonomy scale. EDUCATIONAL SETTING AND ACTIVITY This study was conducted on a group of third year pharmacy students taking an elective module on pharmacokinetics and toxicokinetics. Students were shown an example of a finished product and were given three weeks to complete the take-home assignment. The questions that students designed were characterized according to the revised Bloom's taxonomy category by two independent reviewers. Feedback on students' experience was also evaluated. FINDINGS All 18 students reading the module submitted their SDAP with questions that demonstrated all levels of thinking, with application-based questions being most significant, followed by analytical questions. Feedback from the students was positive, with clear indications of self-directed and peer learning. SUMMARY This exercise offered a surprising insight into students' way of thinking, by externalizing their inquiring minds and translating their thoughts into written questions. This positive outcome informed that it has stirred deep thinking and learning among the students who participated. Evidently, SDAP is impactful as an assessment for and of learning.

The Asia Pacific Scholar, 2021

International Journal of Molecular Sciences, 2021

Exposure to metallic nanoparticles (NPs) can result in inadvertent NP accumulation in body tissue... more Exposure to metallic nanoparticles (NPs) can result in inadvertent NP accumulation in body tissues. While their subsequent cellular interactions can lead to unintended consequences and are generally regarded as detrimental for health, they can on occasion mediate biologically beneficial effects. Among NPs, cerium oxide nanoparticles (CeO2 NP) possess strong antioxidant properties and have shown to alleviate certain pathological conditions. Herein, we show that the presence of cubic 25 nm CeO2 NP was able to reduce TGF-β-mediated activation in the cultured hepatic stellate cell line LX2 by reducing oxidative stress levels and TGF-β-mediated signalling. These cells displayed reduced classical liver fibrosis phenotypes, such as diminished fibrogenesis, altered matrix degradation, decreased cell motility, modified contractability and potentially lowered autophagy. These findings demonstrate that CeO2 NP may be able to ameliorate hepatic fibrosis and suggest a possible therapeutic pathwa...

Scientific Reports, 2021

Moderate hypothermia (32 °C) has been previously shown to ameliorate drug-induced liver injuries ... more Moderate hypothermia (32 °C) has been previously shown to ameliorate drug-induced liver injuries in vitro. However, there are concerns regarding its clinical relevance as it remains a challenge to perform selective liver cooling in a non-invasive manner. To reconcile this dilemma, we propose the use of pulsed cooling for regional hypothermic conditioning in liver. This involves intermittent cooling applied in pulses of 15 min each, with a one-hour recovery interval between pulses. Cooling is achieved by applying ice packs to the cutaneous region overlying the liver. Through an in vivo C57BL/6NTac mouse study, we demonstrated the feasibility of attaining localized hypothermia close to the liver while maintaining core body temperature. This has successfully ameliorated acetaminophen-induced liver injury based on the liver function tests, liver histology and total weight change. Collectively, we provide a proof of concept for pulsed external localized cooling as being clinically action...

Heliyon, 2020

Background: The selective occurrence of hepatotoxicity observed with use of pazopanib may be attr... more Background: The selective occurrence of hepatotoxicity observed with use of pazopanib may be attributed to its high level of plasma protein binding and low hepatic extraction ratio. The primary objective was to investigate changes in free drug concentration amongst patients with varying albumin concentrations. Methods: A HPLC-MS/MS method using C18 column (4.6 Â 150 mm, 5 μm) with ESI source in positive mode had been developed and validated for the quantitative determination of free pazaopanib concentration in human plasma. Prior to sample preparation, patient samples were subjected to 6-hour equilibrium dialysis with molecular weight cutoff set at 8000 Da. Results: The calibration curves were linear over the range of 5-1000 ng/mL, with a lower limit of quantification of 5 ng/mL. The intra-day and inter-day precisions and accuracies were all within AE 15 %, at 3 different quality controls. Higher median fraction unbound of pazopanib were observed in patients (n ¼ 17) with lower than normal albumin concentrations. Conclusion: With the developed assay, monitoring of plasma free concentrations may be evaluated as an indicator of pazopanib exposure in patients.

Journal of Clinical Oncology, 2013

9506 Background: Although existing evidence suggests that cytokines play an intermediary role in ... more 9506 Background: Although existing evidence suggests that cytokines play an intermediary role in the development of post-chemotherapy cognitive changes, specific cytokines associated with this neurotoxic sequela of chemotherapy are still unknown. This study was designed to identify pro-inflammatory biomarkers that are associated with memory and attention impairment in Asian patients receiving chemotherapy. Methods: This is a prospective, cohort study conducted at the National Cancer Centre Singapore. Early-stage Asian breast cancer patients (Stage I to III), who received anthracycline and/or taxane-based chemotherapy were recruited. Computerized neuropsychological assessments (Headminder) were administered to evaluate patients’ memory and attention performances and a panel of pro-inflammatory plasma cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ and TNF-α) was evaluated using multiplex immunoassay at three time points: prior to chemotherapy (T1), at midpoint (T2), an...

Journal of Clinical Oncology, 2012

e13023 Background: Concomitant usage of lapatinib (L) and dexamethasone (D), which are cytochrome... more e13023 Background: Concomitant usage of lapatinib (L) and dexamethasone (D), which are cytochrome P450 (CYP) 3A4 substrate and inducer respectively, may increase the formation of potentially hepatotoxic reactive L metabolites. This study aims to evaluate the effect of D on the occurrence of liver enzyme elevation and to ascertain its role using a parallel in vitro experiment. Methods: Clinical effects of D on L-induced liver enzyme elevation were evaluated in a nested case-control study. Liver enzyme elevation is defined as the first clinically significant change (from baseline) of either total bilirubin (TB), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) by at least 1 grade, based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.02. In the in vitro study, metabolically-competent transforming growth factor α mouse hepatocytes (TAMH) cells were treated with L and viabilities were compared in the presence or absence of D. Results: Among 97 p...

International Journal of Molecular Sciences, 2018

Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the ... more Liver sinusoidal endothelial cells (LSECs) represent the permeable interface that segregates the blood compartment from the hepatic cells, regulating hepatic vascular tone and portal pressure amidst changes in the blood flow. In the presence of pathological conditions, phenotypic changes in LSECs contribute to the progression of chronic liver diseases, including the loss of endothelial permeability. Therefore, modulating LSECs offers a possible way to restore sinusoidal permeability and thereby improve hepatic recovery. Herein, we showed that titanium dioxide nanoparticles (TiO2 NPs) could induce transient leakiness in primary human hepatic sinusoidal endothelial cells (HHSECs). Interestingly, HHSECs exposed to these NPs exhibited reduced protein kinase B (Akt) phosphorylation, an important protein kinase which regulates cell attachment. Using a 3D co-culture system, we demonstrated that TiO2 NPs diminished the attachment of HHSECs onto normal human hepatic cell LO2. To further illu...

Nature Nanotechnology, 2019

ancer metastasis is a phenomenon in which cancer cells disseminate from a primary tumour to event... more ancer metastasis is a phenomenon in which cancer cells disseminate from a primary tumour to eventually grow at distant sites 1-3. The metastatic stage of many solid tumour cancers usually presents a poor prognosis and likewise accounts for the vast majority of cancer-related mortality (~90%) 4. Central to the pathophysiology of metastasis is the intravasation and extravasation of cancer cells through disrupted blood vessels 5,6. This highlights the importance of intact vasculature against isolated but migratory cancer cells 7,8. Cancer nanotechnology offers numerous possibilities in diagnosing and treating cancers due to their many possible and interesting interactions 9-13. Since some nanoparticles (NPs) could induce endothelial leakiness (NanoEL) 14-18 , cancer nanomedicines, designed to kill the tumour 19-21 , may also unintentionally induce leakiness of the tumour vasculature, thereby lowering the barrier for intravasational entry of surviving cancer cells into the circulation. NanoEL came to light when certain nanomaterials disrupted endothelial cell-cell interactions by binding to critical adherens junction proteins such as vascular endothelial-cadherin (VE-cadherin) 14. After binding, the high-density particles exerted a disruptive force to break the VE-cadherin homophilic interactions 16. These disruptions of the endothelial cell junctions were found to depend on the particles' size 15 , intrinsic mass density 16 and surface charge 17. Relief of the endothelial cell tension together with intracellular cell signalling subsequently resulted in the micrometre-sized gaps between neighbouring endothelial cells 14. With the growing evidence that nanomaterials can cause endothelial gaps that could be tens to hundreds of micrometres in width and large enough for whole cells to traverse 14,15,22 , it is imperative then to establish whether cancer metastasis may be appreciably enhanced by nanomaterials. Investigating such effects on metastasis, if any, would increase the awareness of side effects of nanomedicines

Journal of Clinical Oncology, 2017

10018 Background: Cancer-related fatigue (CRF) is reported to be associated with mitochondrial dy... more 10018 Background: Cancer-related fatigue (CRF) is reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF. This study aimed to evaluate the association between peripheral blood mtDNA content and CRF in patients receiving chemotherapy. Methods: This was a prospective cohort study. Early-stage breast cancer patients (Stages I to III) receiving anthracycline or taxane-based chemotherapy were recruited. CRF was assessed using the validated Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) at two time points: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). Worsening of CRF was defined as ≥10% increase in the overall MFSI-SF score at T2. Peripheral blood mtDNA content was measured at both time points using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluat...

Clinical cardiology, Jan 18, 2017

Real-world effectiveness and safety of antithrombotics in nonvalvular atrial fibrillation (NVAF) ... more Real-world effectiveness and safety of antithrombotics in nonvalvular atrial fibrillation (NVAF) patients in Singapore has not been thoroughly studied. Users of various antithrombotics experience a significantly different risk of stroke and major bleed compared with warfarin users. This multicenter retrospective cohort study included patients age ≥ 21 years newly diagnosed with NVAF between July 2012 and September 2015. Using electronic medical records, data on patients' demographics, antithrombotics prescribed, and CHA2 DS2 -VASc and HAS-BLED risk factors were collected. Patients were followed for 1 year from diagnosis for the primary effectiveness and safety endpoints of incident stroke or systemic embolism and major bleed, respectively. The secondary safety endpoint was overall bleed. Hazard ratios (HR) were determined from Cox regression. Of 743 patients included, 224 were on warfarin, 156 on direct oral anticoagulants (DOACs), 277 on single antiplatelet therapy (SAPT), 28 o...

Journal of Clinical Oncology, 2014

439 Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-week... more 439 Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients initiating AD sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and plasma steady-state levels (Cmax) were quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Results: 36 patients with a mean age of 59.1 ± 10.1 years were recruited. Majority were males (81%) and Chinese (86%). Among the 24 and 16 analyzable cases fo...

Proceedings of Singapore Healthcare, 2014

Background: Despite primary prophylaxis of febrile neutropenia (FN) with pegfilgrastim, studies h... more Background: Despite primary prophylaxis of febrile neutropenia (FN) with pegfilgrastim, studies have demonstrated a significant number of breakthrough FN events among Asian lymphoma patients receiving chemotherapy. This study was designed to investigate the association of pegfilgrastim concentrations during the lowest point of absolute neutrophil count (ANC nadir) after chemotherapy administration and the occurrence of breakthrough FN, to evaluate whether Therapeutic drug monitoring of pegfilgrastim can guide management of FN. Methods: This was a single-centre, prospective cohort study of Asian lymphoma patients who received prophylactic pegfilgrastim after completion of their chemotherapy. Pegfilgrastim serum concentrations were measured from blood samples taken during ANC nadir and at development of breakthrough FN using an enzyme-linked immunosorbent assay. Descriptive statistics, t-tests and correlation curves were used in the statistical analyses. Results: Nineteen patients wer...

Neuro-Oncology, 2015

Background. Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal func... more Background. Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment. Methods. Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8+8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates. Results. Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] ¼ 0.26; 95% CI: 0.08-0.92; P ¼ .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR ¼ 0.34; 95% CI: 0.12-0.90; P ¼ .031) and multitasking ability (OR ¼ 0.37; 95% CI: 0.15-0.91; P ¼ .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism. Conclusions. This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapyassociated cognitive impairment. Further studies are required to validate the findings.

Cancer Treatment Reviews, 2014

A systematic review was performed to describe the findings from 19 genetic association studies th... more A systematic review was performed to describe the findings from 19 genetic association studies that have examined the genetic variants underlying four common treatment-induced chronic and late toxicities in breast cancer patients, and to evaluate the quality of reporting. Three out of 5 studies found an association between HER2 lle655Val polymorphisms and trastuzumab-induced cardiotoxicity. Two studies found a positive association between cognitive impairment and the Val allele of the COMT gene and the ε4 allele of the apolipoprotein E gene. Genetic associations were established between fatigue and the G/G genotype of IL6-174 and TNF-308, and the Met allele of the COMT gene in 4 studies. Among studies (N=8) that evaluated the genetic associations underlying peripheral neuropathy, CYP2C8∗3 variant is commonly reported as the associated gene. Most studies failed to conform to the major criteria listed in the STREGA guidelines, with a lack of transparent reporting of methods and results.

Advanced Drug Delivery Reviews, 2013

In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promis... more In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNTbased drug delivery system (DDS) had been engineered to combat cancers, there are also emerging reports that employ CNTs as either the main carrier or adjunct material for the delivery of various non-anticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNTbased DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs.

ACS Applied Materials & Interfaces, 2018

Chronic liver dysfunction usually begins with hepatic fibrosis. To date, there are still no effec... more Chronic liver dysfunction usually begins with hepatic fibrosis. To date, there are still no effective anti-fibrotic drugs approved for clinical use in humans. In the current work, titanium dioxide (TiO) nanoparticles (NPs) and silicon dioxide (SiO 2) NPs are used as active inhibitors with intrinsic chemico-physico properties to block fibrosis and the associated phenotypes through acting on hepatic stellate cells (HSCs, the liver machinery for depositing scar tissues seen in fibrosis). Using LX-2 cells as the HSC model, internalized nanomaterials are found to suppress classical outcomes of cellular fibrosis, e.g., inhibit the expression of collagen I (Col-I) and alpha smooth muscle actin (α-SMA), initiated by transforming growth factor β (TGF-β)-activated HSCs in both a concentration-dependent and a time-dependent manner. Biochemically, these nanomaterials could also facilitate the proteolytic breakdown of collagen by up-regulation of matrix metalloproteinases (MMPs) and down-regulation of tissue inhibitors of matrix metalloproteinases (TIMPs). Furthermore, through regulating epithelial-mesenchymal transition (EMT) genes (e.g., E-cadherin (E-Cad) and N-cadherin (N-Cad)), the adhesion and migration profiles of TGF-β-activated LX-2 cells treated with nanomaterials were further inhibited, reverting them to a more quiescent state. Thus, the collective evidences pave the new way that nanomaterials can be used as potential therapeutic inhibitors for the treatment of in vivo fibrosis.