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  1. Fulltext Observation of dendritic cell morphology under light, phase-contrast or confocal laser scanning microscopy
    Tan YF, Leong CF, Cheong SK
    Malays J Pathol, 2010 Dec;32(2):97-102.
    PMID: 21329180 MyJurnal
    Dendritic cells (DCs) are professional antigen presenting cells of the immune system. They can be generated in vitro from peripheral blood monocytes supplemented with GM-CSF, IL-4 and TNF alpha. During induction, DCs will increase in size and acquire multiple cytoplasmic projections when compared to their precursor cells such as monocytes or haematopoietic stem cells which are usually round or spherical. Morphology of DCs can be visualized by conventional light microscopy after staining or phase-contrast inverted microscopy or confocal laser scanning microscopy. In this report, we described the morphological appearances of DCs captured using the above-mentioned techniques. We found that confocal laser scanning microscopy yielded DCs images with greater details but the operating cost for such a technique is high. On the other hand, the images obtained through light microscopy after appropriate staining or phase contrast microscopy were acceptable for identification purpose. Besides, these equipments are readily available in most laboratories and the cost of operation is affordable. Nevertheless, morphological identification is just one of the methods to characterise DCs. Other methods such as phenotypic expression markers and mixed leukocyte reactions are additional tools used in the characterisation of DCs.
  2. Toxicity of single-walled carbon nanotubes
    Ong LC, Chung FF, Tan YF, Leong CO
    Arch Toxicol, 2016 Jan;90(1):103-18.
    PMID: 25273022 DOI: 10.1007/s00204-014-1376-6
    Carbon nanotubes (CNTs) are an important class of nanomaterials, which have numerous novel properties that make them useful in technology and industry. Generally, there are two types of CNTs: single-walled nanotubes (SWNTs) and multi-walled nanotubes. SWNTs, in particular, possess unique electrical, mechanical, and thermal properties, allowing for a wide range of applications in various fields, including the electronic, computer, aerospace, and biomedical industries. However, the use of SWNTs has come under scrutiny, not only due to their peculiar nanotoxicological profile, but also due to the forecasted increase in SWNT production in the near future. As such, the risk of human exposure is likely to be increased substantially. Yet, our understanding of the toxicological risk of SWNTs in human biology remains limited. This review seeks to examine representative data on the nanotoxicity of SWNTs by first considering how SWNTs are absorbed, distributed, accumulated and excreted in a biological system, and how SWNTs induce organ-specific toxicity in the body. The contradictory findings of numerous studies with regards to the potential hazards of SWNT exposure are discussed in this review. The possible mechanisms and molecular pathways associated with SWNT nanotoxicity in target organs and specific cell types are presented. We hope that this review will stimulate further research into the fundamental aspects of CNTs, especially the biological interactions which arise due to the unique intrinsic characteristics of CNTs.
  3. Fulltext Crystal structure of benzyl (E)-2-(3,4-di-meth-oxy-benzyl-idene)hydrazine-1-carbodi-thio-ate
    Tan YF, Break MK, Tahir MI, Khoo TJ
    Acta Crystallogr E Crystallogr Commun, 2015 Feb 1;71(Pt 2):238-40.
    PMID: 25878829 DOI: 10.1107/S205698901500095X
    The title compound, C17H18N2O2S2, synthesized via a condensation reaction between S-benzyl di-thio-carbazate and 3,4-di-meth-oxy-benzaldehyde, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. Both mol-ecules have an L-shape but differ in the orientation of the benzyl ring with respect to the 3,4-di-meth-oxy-benzyl-idine ring, this dihedral angle is 65.59 (8)° in mol-ecule A and 73.10 (8)° in mol-ecule B. In the crystal, the A and B mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming dimers with an R 2 (2)(8) ring motif. The dimers are linked via pairs of C-H⋯O hydrogen bonds, giving inversion dimers of dimers. These units are linked by C-H⋯π inter-actions, forming ribbons propagating in the [100] direction.
  4. Fulltext Pteropine orthoreovirus: An important emerging virus causing infectious disease in the tropics?
    Tan YF, Teng CL, Chua KB, Voon K
    J Infect Dev Ctries, 2017 Mar 31;11(3):215-219.
    PMID: 28368854 DOI: 10.3855/jidc.9112
    INTRODUCTION: Pteropine orthoreovirus (PRV) is an emerging zoonotic respiratory virus that has spilled over from bats to humans. Though initially found only in bats, further case studies have found viable virus in ill patients.

    METHODOLOGY: PubMed was queried with the keywords of Nelson Bay orthoreovirus OR Pteropine orthoreovirus OR Melaka orthoreovirus OR Kampar orthoreovirus, and returned 17 hits.

    RESULTS: Based on prevalence studies, the presence of PRV has been reported in Malaysia and Vietnam, both developing countries. Other case reports also provide further evidence of the presence of PRV in the Southeast Asian region. Despite the absence of PRV in their home countries, travellers from Hong Kong and Japan to Indonesia have returned to their countries ill with this virus, indicating that local communities in Indonesia might be affected by this virus.

    CONCLUSIONS: This work aims to bring to light this emerging zoonotic respiratory virus circulating among developing countries in Southeast Asia. To improve the understanding of PRV of the medical and scientific community in the Southeast Asian region, this work introduces the general features of PRV, reports of imported PRV, prevalence, and clinical features of PRV. Gaps in knowledge about PRV have also been identified in this work, and we hope that future studies can be undertaken to improve our understanding of this virus.

  5. Fulltext Experimental production of clinical-grade dendritic cell vaccine for acute myeloid leukemia
    Tan YF, Sim GC, Habsah A, Leong CF, Cheong SK
    Malays J Pathol, 2008 Dec;30(2):73-9.
    PMID: 19291915 MyJurnal
    Dendritic cells (DC) are professional antigen presenting cells of the immune system. Through the use of DC vaccines (DC after exposure to tumour antigens), cryopreserved in single-use aliquots, an attractive and novel immunotherapeutic strategy is available as an option for treatment. In this paper we describe an in vitro attempt to scale-up production of clinical-grade DC vaccines from leukemic cells. Blast cells of two relapsed AML patients were harvested for DC generation in serum-free culture medium containing clinical-grade cytokines GM-CSF, IL-4 and TNF-alpha. Cells from patient 1 were cultured in a bag and those from patient 2 were cultured in a flask. The numbers of seeding cells were 2.24 x 10(8) and 0.8 x 10(8), respectively. DC yields were 10 x 10(6) and 29.8 x 10(6) cells, giving a conversion rate of 4.7% and 37%, respectively. These DC vaccines were then cryopreserved in approximately one million cells per vial with 20% fresh frozen group AB plasma and 10% DMSO. At 12 months and 21 months post cryopreservation, these DC vaccines were thawed, and their sterility, viability, phenotype and functionality were studied. DC vaccines remained sterile up to 21 months of storage. Viability of the cryopreserved DC in the culture bag and flask was found to be 50% and 70% at 12 months post cryopreservation respectively; and 48% and 67% at 21 months post cryopreservation respectively. These DC vaccines exhibited mature DC surface phenotypic markers of CD83, CD86 and HLA-DR, and negative for haemopoietic markers. Mixed lymphocyte reaction (MLR) study showed functional DC vaccines. These experiments demonstrated that it is possible to produce clinical-grade DC vaccines in vitro from blast cells of leukemic patients, which could be cryopreserved up to 21 months for use if repeated vaccinations are required in the course of therapy.
  6. Single-walled carbon nanotubes (SWCNTs) inhibit heat shock protein 90 (HSP90) signaling in human lung fibroblasts and keratinocytes
    Ong LC, Tan YF, Tan BS, Chung FF, Cheong SK, Leong CO
    Toxicol Appl Pharmacol, 2017 08 15;329:347-357.
    PMID: 28673683 DOI: 10.1016/j.taap.2017.06.024
    Single-walled carbon nanotubes (SWCNTs) are carbon-based nanomaterials that possess immense industrial potential. Despite accumulating evidence that exposure to SWCNTs might be toxic to humans, our understanding of the mechanisms for cellular toxicity of SWCNTs remain limited. Here, we demonstrated that acute exposure of short (1-3μm) and regular-length (5-30μm) pristine, carboxylated or hydroxylated SWCNTs inhibited cell proliferation in human somatic and human stem cells in a cell type-dependent manner. The toxicity of regular-length pristine SWCNT was most evidenced in NP69>CYT00086>MCF-10A>MRC-5>HaCaT > HEK-293T>HepG2. In contrast, the short pristine SWCNTs were relatively less toxic in most of the cells being tested, except for NP69 which is more sensitive to short pristine SWCNTs as compared to regular-length pristine SWCNTs. Interestingly, carboxylation and hydroxylation of regular-length SWCNTs, but not the short SWCNTs, significantly reduced the cytotoxicity. Exposure of SWCNTs also induced caspase 3 and 9 activities, mitochondrial membrane depolarization, and significant apoptosis and necrosis in MRC-5 embryonic lung fibroblasts. In contrast, SWCNTs inhibited the proliferation of HaCaT human keratinocytes without inducing cell death. Further analyses by gene expression profiling and Connectivity Map analysis showed that SWCNTs induced a gene expression signature characteristic of heat shock protein 90 (HSP90) inhibition in MRC-5 cells, suggesting that SWCNTs may inhibit the HSP90 signaling pathway. Indeed, exposure of MRC-5 cells to SWCNTs results in a dose-dependent decrease in HSP90 client proteins (AKT, CDK4 and BCL2) and a concomitant increase in HSP70 expression. In addition, SWCNTs also significantly inhibited HSP90-dependent protein refolding. Finally, we showed that ectopic expression of HSP90, but not HSP40 or HSP70, completely abrogated the cytotoxic effects of SWCNTs, suggesting that SWCNT-induced cellular toxicity is HSP90 dependent. In summary, our findings suggest that the toxic effects of SWCNTs are mediated through inhibition of HSP90 in human lung fibroblasts and keratinocytes.
  7. Green synthesis of graphene-silver nanocomposites and its application as a potent marine antifouling agent
    Yee MS, Khiew PS, Chiu WS, Tan YF, Kok YY, Leong CO
    Colloids Surf B Biointerfaces, 2016 Dec 01;148:392-401.
    PMID: 27639489 DOI: 10.1016/j.colsurfb.2016.09.011
    Fouling of marine surfaces has been a perpetual problem ever since the days of the early sailors. The tenacious attachment of seaweed and invertebrates to man-made surfaces, notably on ship hulls, has incurred undesirable economic losses. Graphene receives great attention in the materials world for its unique combination of physical and chemical properties. Herein, we present a novel 2-step synthesis method of graphene-silver nanocomposites which bypasses the formation of graphene oxide (GO), and produces silver nanoparticles supported on graphene sheets through a mild hydrothermal reduction process. The graphene-Ag (GAg) nanocomposite combines the antimicrobial property of silver nanoparticles and the unique structure of graphene as a support material, with potent marine antifouling properties. The GAg nanocomposite was composed of micron-scaled graphene flakes with clusters of silver nanoparticles. The silver nanoparticles were estimated to be between 72 and 86nm (SEM observations) while the crystallite size of the silver nanoparticles (AgNPs) was estimated between 1 and 5nm. The nanocomposite also exhibited the SERS effect. GAg was able to inhibit Halomonas pacifica, a model biofilm-causing microbe, from forming biofilms with as little as 1.3wt.% loading of Ag. All GAg samples displayed significant biofilm inhibition property, with the sample recording the highest Ag loading (4.9wt.% Ag) associated with a biofilm inhibition of 99.6%. Moreover, GAg displayed antiproliferative effects on marine microalgae, Dunaliella tertiolecta and Isochrysis sp. and inhibited the growth of the organisms by more than 80% after 96h. The marine antifouling properties of GAg were a synergy of the biocidal AgNPs anchored on the stable yet flexible graphene sheets, providing maximum active contact surface areas to the target organisms.
  8. Isolation and Quantification of Mimivirus-Like and Marseillevirus-Like Viruses from Soil Samples in An Aboriginal (Orang asli) Village in Peninsular Malaysia
    Tan YF, Lim CY, Chong CW, Lim PKC, Yap IKS, Leong PP, et al.
    Intervirology, 2018;61(2):92-95.
    PMID: 30121676 DOI: 10.1159/000491602
    BACKGROUND: The giant amoebal viruses of Mimivirus and Marseillevirus are large DNA viruses and have been documented in water, soil, and sewage samples. The trend of discovering these giant amoebal viruses has been increasing throughout Asia with Japan, India, and Saudi Arabia being the latest countries to document the presence of these viruses. To date, there have been no reports of large amoebal viruses being isolated in South East Asia.

    OBJECTIVE: In this study, we aim to discover these viruses from soil samples in an aboriginal village (Serendah village) in Peninsular -Malaysia.

    METHOD AND RESULTS: We successfully detected and isolated both Mimivirus-like and Marseillevirus-like viruses using Acanthamoeba castellanii. Phylogeny analysis identified them as Mimivirus and Marseillevirus, respectively.

    CONCLUSION: The ubiquitous nature of both Mimivirus and Marseillevirus is further confirmed in our study as they are detected in higher quantity in soil that is near to water vicinities in an aboriginal village in Peninsular Malaysia. However, this study is limited by our inability to investigate the impact of Mimivirus and Marseillevirus on the aboriginal villagers. More studies on the potential impact of these viruses on human health, especially on the aborigines, are warranted.

  9. Fulltext Intestinal stem cells and gut microbiota therapeutics: hype or hope?
    Ahmad Sophien AN, Jusop AS, Tye GJ, Tan YF, Wan Kamarul Zaman WS, Nordin F
    Front Med (Lausanne), 2023;10:1195374.
    PMID: 37547615 DOI: 10.3389/fmed.2023.1195374
    The vital role of the intestines as the main site for the digestion and absorption of nutrients for the body continues subconsciously throughout one's lifetime, but underneath all the complex processes lie the intestinal stem cells and the gut microbiota that work together to maintain the intestinal epithelium. Intestinal stem cells (ISC) are multipotent stem cells from which all intestinal epithelial cells originate, and the gut microbiota refers to the abundant collection of various microorganisms that reside in the gastrointestinal tract. Both reside in the intestines and have many mechanisms and pathways in place with the ultimate goal of co-managing human gastrointestinal tract homeostasis. Based on the abundance of research that is focused on either of these two topics, this suggests that there are many methods by which both players affect one another. Therefore, this review aims to address the relationship between ISC and the gut microbiota in the context of regenerative medicine. Understanding the principles behind both aspects is therefore essential in further studies in the field of regenerative medicine by making use of the underlying designed mechanisms.
  10. Fulltext Pteropine orthoreovirus infection among out-patients with acute upper respiratory tract infection in Malaysia
    Voon K, Tan YF, Leong PP, Teng CL, Gunnasekaran R, Ujang K, et al.
    J Med Virol, 2015 Dec;87(12):2149-53.
    PMID: 26106066 DOI: 10.1002/jmv.24304
    This study aims to assess the incidence rate of Pteropine orthreovirus (PRV) infection in patients with acute upper respiratory tract infection (URTI) in a suburban setting in Malaysia, where bats are known to be present in the neighborhood. Using molecular detection of PRVs directly from oropharyngeal swabs, our study demonstrates that PRV is among one of the common causative agents of acute URTI with cough and sore throat as the commonest presenting clinical features. Phylogenetic analysis on partial major outer and inner capsid proteins shows that these PRV strains are closely related to Melaka and Kampar viruses previously isolated in Malaysia. Further study is required to determine the public health significance of PRV infection in Southeast Asia, especially in cases where co-infection with other pathogens may potentially lead to different clinical outcomes.
  11. Fulltext Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway
    Soo HC, Chung FF, Lim KH, Yap VA, Bradshaw TD, Hii LW, et al.
    PLoS One, 2017;12(1):e0170551.
    PMID: 28107519 DOI: 10.1371/journal.pone.0170551
    Cudraflavone C (Cud C) is a naturally-occurring flavonol with reported anti-proliferative activities. However, the mechanisms by which Cud C induced cytotoxicity have yet to be fully elucidated. Here, we investigated the effects of Cud C on cell proliferation, caspase activation andapoptosis induction in colorectal cancer cells (CRC). We show that Cud C inhibits cell proliferation in KM12, Caco-2, HT29, HCC2998, HCT116 and SW48 CRC but not in the non-transformed colorectal epithelial cells, CCD CoN 841. Cud C induces tumor-selective apoptosis via mitochondrial depolarization and activation of the intrinsic caspase pathway. Gene expression profiling by microarray analyses revealed that tumor suppressor genes EGR1, HUWE1 and SMG1 were significantly up-regulated while oncogenes such as MYB1, CCNB1 and GPX2 were down-regulated following treatment with Cud C. Further analyses using Connectivity Map revealed that Cud C induced a gene signature highly similar to that of protein synthesis inhibitors and phosphoinositide 3-kinase (PI3K)-AKT inhibitors, suggesting that Cud C might inhibit PI3K-AKT signaling. A luminescent cell free PI3K lipid kinase assay revealed that Cud C significantly inhibited p110β/p85α PI3K activity, followed by p120γ, p110δ/p85α, and p110α/p85α PI3K activities. The inhibition by Cud C on p110β/p85α PI3K activity was comparable to LY-294002, a known PI3K inhibitor. Cud C also inhibited phosphorylation of AKT independent of NFκB activity in CRC cells, while ectopic expression of myristoylated AKT completely abrogated the anti-proliferative effects, and apoptosis induced by Cud C in CRC. These findings demonstrate that Cud C induces tumor-selective cytotoxicity by targeting the PI3K-AKT pathway. These findings provide novel insights into the mechanism of action of Cud C, and indicate that Cud C further development of Cud C derivatives as potential therapeutic agents is warranted.
  12. Human cytokeratin 1 plays a role in the interaction of Pteropine orthoreovirus with Hek293 cells but not HeLa cells
    Siew ZY, Tan YF, Iswara RP, Wong SF, Wong ST, Tan BK, et al.
    Microbes Infect, 2024;26(1-2):105243.
    PMID: 38380604 DOI: 10.1016/j.micinf.2023.105243
    Pteropine orthoreovirus (PRV) causes respiratory tract infections in humans. Despite its emergence as a zoonotic and respiratory virus, little is known about its cell tropism, which hampers progress in fully understanding its pathogenesis in humans. Hek293 cells are most susceptible to PRV infection, while HeLa cells are the least. Human cytokeratin 1 (CK1) was identified as the protein that interacts with PRV. The immunofluorescence assay and qPCR results revealed prior treatment with anti-CK1 may provide Hek293 cells protection against PRV. The KRT1-knockout Hek293 cells were less susceptible to PRV infection. Further study into the pathogenesis of PRV in humans is needed.
  13. Fulltext Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival
    Tiong KH, Tan BS, Choo HL, Chung FF, Hii LW, Tan SH, et al.
    Oncotarget, 2016 Sep 06;7(36):57633-57650.
    PMID: 27192118 DOI: 10.18632/oncotarget.9328
    Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.
  14. Fulltext Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)
    Chung FF, Tan PF, Raja VJ, Tan BS, Lim KH, Kam TS, et al.
    Sci Rep, 2017 02 15;7:42504.
    PMID: 28198434 DOI: 10.1038/srep42504
    Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization.
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