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Immunohistochemical expression of NANOG in urothelial carcinoma of the bladder

Md Akhir MKA, Hussin H, Veerakumarasivam A, Choy CS, Abdullah MA, Abd Ghani F

Malays J Pathol, 2017 Dec;39(3):227-234.
PMID: 29279584 MyJurnal

Urothelial carcinoma is a common malignant neoplasm that has a poor prognosis and a high frequency of recurrence and metastasis. Constant disease surveillance with periodic and long term cystoscopy examination is necessary for management of the disease. However, the monitoring and therapy regimen is expensive, incurring a massive burden to patients and the government. Therefore, the development of specific biomarkers for urothelial carcinoma at an early stage and recurrence detection becomes a priority. Homeobox genes are a family of genes that are involved in tumourigenesis. They might be potential prognostic markers for urothelial carcinoma. The study investigated the expression pattern of NANOG which is one of a homeobox gene in different stages and grades of urothelial carcinoma. NANOG expressions were also correlated with patient demographic factors and clinicopathological parameters. The expression of NANOG in 100 formalin-fixed paraffin-embedded urothelial carcinoma tissues was determined by immunohistochemistry. Immunohistochemistry showed positive expression of NANOG in all specimens with detection in the cytoplasm, nuclei and the nuclear membrane of the cancer cells. The immunohistochemical expression of NANOG increased across stages and grades of the tumour. The expression of NANOG was not significantly associated with demographic factors; gender (p = 0.376), race (p = 0.718) and age (p = 0.058) as well as with most of the clinicopathological parameters; pathological stage (p = 0.144), grade (p = 0.625), lymph node involvement (p = 0.174) and distant metastasis (p = 0.228). However, NANOG expression showed significant correlation with tumour invasion (p = 0.019). We concluded that NANOG might be a potential biomarker for early diagnosis of urothelial carcinoma of the bladder.
Hedgehog signalling molecule, SMO is a poor prognostic marker in bladder cancer

Mohd Ariffin K, Abd Ghani F, Hussin H, Md Said S, Yunus R, Veerakumarasivam A, et al.

Malays J Pathol, 2021 Apr;43(1):49-54.
PMID: 33903305

INTRODUCTION: Hedgehog (HH) pathway is an important signalling cascade for growth and patterning during embryonic development. Constitutive activation of Hedgehog pathway can be found in various types of malignancies including medulloblastoma, basal cell carcinoma, gastrointestinal, breast, pancreatic, prostate cancer and leukaemia. Little is known about the expression and role of Hedgehog signalling in bladder cancer.
MATERIALS AND METHODS: The purpose of this study was to investigate the immunohistochemical expression of SMO in 112 bladder cancer cases and determine their association with demographic and clinicopathological parameters. Bladder cancer tissues were obtained from the Hospital Kuala Lumpur.
RESULTS: SMO was expressed in the cytoplasm of all cases of bladder cancer. 6 cases (5.4%) showed low expression, while 106 cases (94.6%) showed high expression. Positive expression of SMO protein was correlated with a few variables which include grade and stage of tumour, lymph node metastasis and distant metastasis. SMO expression showed statistically significant association with higher grade (p=0.001) and higher stage (p=0.042) of bladder cancer. SMO expression also showed borderline association with lymph node metastasis (p=0.056).
CONCLUSION: These findings indicate that SMO expression may be a poor prognostic marker in bladder cancer.
Lentivirus vector driven by polybiquitin C promoter without woodchuck posttranscriptional regulatory element and central polypurine tract generates low level and short-lived reporter gene expression

Ngai SC, Rosli R, Nordin N, Veerakumarasivam A, Abdullah S

Gene, 2012 May 1;498(2):231-6.
PMID: 22366305 DOI: 10.1016/j.gene.2012.01.071

Lentivirus (LV) encoding woodchuck posttranscriptional regulatory element (WPRE) and central polypurine tract (cPPT) driven by CMV promoter have been proven to act synergistically to increase both transduction efficiency and gene expression. However, the inclusion of WPRE and cPPT in a lentiviral construct may pose safety risks when administered to human. A simple lentiviral construct driven by an alternative promoter with proven extended duration of gene expression without the two regulatory elements would be free from the risks. In a non-viral gene delivery context, gene expression driven by human polybiquitin C (UbC) promoter resulted in higher and more persistent expression in mouse as compared to cytomegalovirus (CMV) promoter. In this study, we measured the efficiency and persistency of green fluorescent protein (GFP) reporter gene expression in cells transduced with LV driven by UbC (LV/UbC/GFP) devoid of the WPRE and cPPT in comparison to the established LV construct encoding WPRE and cPPT, driven by CMV promoter (LV/CMV/GFP). However, we found that LV/UbC/GFP was inferior to LV/CMV/GFP in many aspects: (i) the titer of virus produced; (ii) the levels of reporter gene expression when MOI value was standardized; and (iii) the transduction efficiency in different cell types. The duration of reporter gene expression in selected cell lines was also determined. While the GFP expression in cells transduced with LV/CMV/GFP persisted throughout the experimental period of 14 days, expression in cells transduced with LV/UbC/GFP declined by day 2 post-transduction. In summary, the LV driven by the UbC promoter without the WPRE and cPPT does not exhibit enhanced or durable transgene expression.
Fulltext Advancements in reprogramming strategies for the generation of induced pluripotent stem cells

Lai MI, Wendy-Yeo WY, Ramasamy R, Nordin N, Rosli R, Veerakumarasivam A, et al.

J Assist Reprod Genet, 2011 Apr;28(4):291-301.
PMID: 21384252 DOI: 10.1007/s10815-011-9552-6

Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells has emerged as an invaluable method for generating patient-specific stem cells of any lineage without the use of embryonic materials. Following the first reported generation of iPS cells from murine fibroblasts using retroviral transduction of a defined set of transcription factors, various new strategies have been developed to improve and refine the reprogramming technology. Recent developments provide optimism that the generation of safe iPS cells without any genomic modification could be derived in the near future for the use in clinical settings. This review summarizes current and evolving strategies in the generation of iPS cells, including types of somatic cells for reprogramming, variations of reprogramming genes, reprogramming methods, and how the advancement iPS cells technology can lead to the future success of reproductive medicine.
Fulltext Synthesis, characterization and biological evaluation of transition metal complexes derived from N, S bidentate ligands

Md Yusof EN, S A Ravoof TB, Tiekink ER, Veerakumarasivam A, Crouse KA, Mohamed Tahir MI, et al.

Int J Mol Sci, 2015 May 15;16(5):11034-54.
PMID: 25988384 DOI: 10.3390/ijms160511034

Two bidentate NS ligands were synthesized by the condensation reaction of S-2-methylbenzyldithiocarbazate (S2MBDTC) with 2-methoxybenzaldehyde (2MB) and 3-methoxybenzaldehyde (3MB). The ligands were reacted separately with acetates of Cu(II), Ni(II) and Zn(II) yielding 1:2 (metal:ligand) complexes. The metal complexes formed were expected to have a general formula of [M(NS)2] where M = Cu2+, Ni2+, and Zn2+. These compounds were characterized by elemental analysis, molar conductivity, magnetic susceptibility and various spectroscopic techniques. The magnetic susceptibility measurements and spectral results supported the predicted coordination geometry in which the Schiff bases behaved as bidentate NS donor ligands coordinating via the azomethine nitrogen and thiolate sulfur. The molecular structures of the isomeric S2M2MBH (1) and S2M3MBH (2) were established by X-ray crystallography to have very similar l-shaped structures. The Schiff bases and their metal complexes were evaluated for their biological activities against estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) breast cancer cell lines. Only the Cu(II) complexes showed marked cytotoxicity against the cancer cell lines. Both Schiff bases and other metal complexes were found to be inactive. In concordance with the cytotoxicity studies, the DNA binding studies indicated that Cu(II) complexes have a strong DNA binding affinity.
Fulltext Cytotoxicity study of the interleukin-12-expressing recombinant Newcastle disease virus strain, rAF-IL12, towards CT26 colon cancer cells in vitro and in vivo

Najmuddin SUFS, Amin ZM, Tan SW, Yeap SK, Kalyanasundram J, Ani MAC, et al.

Cancer Cell Int, 2020;20:278.
PMID: 32612457 DOI: 10.1186/s12935-020-01372-y

Background: Oncolytic viruses have emerged as an alternative therapeutic modality for cancer as they can replicate specifically in tumour cells and induce toxic effects leading to apoptosis. Despite the great potentials and promising results shown in multiple studies, it appears that their efficacy is still moderate and deemed as not sufficient in clinical studies. In addressing this issue, genetic/molecular engineering approach has paved its way to improve the therapeutic efficacy as observed in the case of herpes simplex virus (HSV) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). This study aimed to explore the cytotoxicity effects of recombinant NDV strain AF2240-i expressing interleukin-12 (rAF-IL12) against CT26 colon cancer cells.
Methods: The cytotoxicity effect of rAF-IL12 against CT26 colon cancer cell line was determined by MTT assay. Based on the IC50 value from the anti-proliferative assay, further downward assays such as Annexin V FITC and cell cycle progression were carried out and measured by flow cytometry. Then, the in vivo study was conducted where the rAF-IL12 viral injections were given at the intra-tumoral site of the CT26 tumour-burden mice. At the end of the experiment, serum biochemical, T cell immunophenotyping, serum cytokine, histopathology of tumour and organ section, TUNEL assay, and Nanostring gene expression analysis were performed.
Results: The rAF-IL12 induced apoptosis of CT26 colon cancer cells in vitro as revealed in the Annexin V FITC analysis and also arrested the cancer cells progression at G1 phase of the cell cycle analysis. On the other hand, the rAF-IL12 significantly (p
Clinical clues for head injuries amongst Malaysian infants: accidental or non-accidental?

Thalayasingam M, Veerakumarasivam A, Kulanthayan S, Khairuddin F, Cheah IG

Injury, 2012 Dec;43(12):2083-7.
PMID: 22424957 DOI: 10.1016/j.injury.2012.02.010

Identifying the differences between infants with non-accidental head injuries (NAHI) and accidental head injuries (AHI) may help alert clinicians to recognize markers of abuse. A retrospective review of infants <1 year of age admitted to a tertiary referral centre in Malaysia over a two year period with a diagnosis of head injury or abnormal computed tomography head scans was conducted to identify the clinical features pointing towards a diagnosis of NAHI by comparing the socio-demographics, presenting complaints, clinical features and the extent of hospital investigations carried out. NAHI infants were more likely to be symptomatic, under a non-related caregiver's supervision, and presented with inconsistent or no known mechanism of injury. Subdural haemorrhages were more common in NAHI infants. The history, mechanism of injury, presenting signs and symptoms as well as the nature of the injuries sustained are all valuable clues as to whether a head injury sustained during infancy is likely to be accidental or not.
Neuroprotective Effects of Lactoferrin in Alzheimer's and Parkinson's Diseases: A Narrative Review

Yong SJ, Veerakumarasivam A, Lim WL, Chew J

ACS Chem Neurosci, 2023 Mar 30.
PMID: 36995304 DOI: 10.1021/acschemneuro.2c00679

Recent advancements in lactoferrin research have uncovered that lactoferrin does function not only as an antimicrobial protein but also as an immunomodulatory, anticancer, and neuroprotective agent. Focusing on neuroprotection, this literature review delineates how lactoferrin interacts in the brain, specifically its neuroprotective effects and mechanisms against Alzheimer's and Parkinson's diseases (AD and PD), the two most common neurodegenerative diseases. The neuroprotective pathways involving surface receptors (heparan sulfate proteoglycan (HSPG) and lactoferrin receptor (LfR)), signaling pathways (extracellular regulated protein kinase-cAMP response element-binding protein (ERK-CREB) and phosphoinositide 3-kinase/Akt (PI3K/Akt)), and effector proteins (A disintegrin and metalloprotease10 (ADAM10) and hypoxia-inducible factor 1α (HIF-1α)) in cortical/hippocampal and dopaminergic neurons are described. These cellular effects of lactoferrin are likely responsible for attenuating cognitive and motor deficits, amyloid-β and α-synuclein accumulation, and neurodegeneration in animal and cellular models of AD and PD. This review also discusses the inconsistent findings related to the neuroprotective effects of lactoferrin against AD. Overall, this review contributes to the existing literature by clarifying the potential neuroprotective effects and mechanisms of lactoferrin in the context of AD and PD neuropathology.
Fulltext Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes

Chan LC, Kalyanasundram J, Leong SW, Masarudin MJ, Veerakumarasivam A, Yusoff K, et al.

BMC Cancer, 2021 May 27;21(1):625.
PMID: 34044804 DOI: 10.1186/s12885-021-08345-y

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood.
METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR.
RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/β-catenin and KRAS signalling pathways were upregulated while the TGF-β signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV.
CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.
Fulltext The Role of ISL1 and LHX5 LIM Homeobox Genes in Bladder Tumourigenesis

Akhir MKAM, Choy CS, Abdullah MA, Ghani FA, Veerakumarasivam A, Hussin H

Malays J Med Sci, 2020 Feb;27(1):37-45.
PMID: 32158343 MyJurnal DOI: 10.21315/mjms2020.27.1.4

Introduction: Lin-11, Isl-1 and Mec-3 domains (LIM) homeobox genes are among the most important sub-families of homeobox genes. These genes are thought to play an important role in cancer. In this study, the protein expression of these genes was examined in urothelial carcinoma of the bladder. The expression pattern of Islet-1 (ISL1) and LIM homeobox 5 (LHX5) across different cancer stages and grades, as well as the association between the protein expression of these genes and patient demographics and clinicopathological features, were examined.
Methods: A total of 100 formalin-fixed paraffin-embedded urothelial carcinoma tissues were selected from the Department of Pathology, Hospital Kuala Lumpur and the protein expression of ISL1 and LHX5 was determined using immunohistochemistry.
Results: Positive expression of ISL1 and LHX5 was detected in 94% and 98% of the samples, respectively. There were no distinct LHX5 expression patterns associated with different cancer stages, but the proportion of high-expressing tumours was higher in high-grade tumours. In addition, there was a significant association between the expression of LHX5 and tumour grade. The proportion of tumours expressing high levels of ISL1 was found to be highest in later stage tumours.
Conclusion: The high percentage of tumours expressing both these genes suggests that ISL1 and LHX5 play an important role in bladder tumourigenesis across multiple stages.
Fulltext Screening of brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms and plasma BDNF levels among Malaysian major depressive disorder patients

Aldoghachi AF, Tor YS, Redzun SZ, Lokman KAB, Razaq NAA, Shahbudin AF, et al.

PLoS One, 2019;14(1):e0211241.
PMID: 30677092 DOI: 10.1371/journal.pone.0211241

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin found in abundance in brain regions such as the hippocampus, cortex, cerebellum and basal forebrain. It has been associated with the risk of susceptibility to major depressive disorder (MDD). This study aimed to determine the association of three BDNF variants (rs6265, rs1048218 and rs1048220) with Malaysian MDD patients.
METHODS: The correlation of these variants to the plasma BDNF level among Malaysian MDD patients was assessed. A total of 300 cases and 300 matched controls recruited from four public hospitals within the Klang Valley of Selangor State, Malaysia and matched for age, sex and ethnicity were screened for BDNF rs6265, rs1048218 and rs1048220 using high resolution melting (HRM).
FINDINGS: BDNF rs1048218 and BDNF rs1048220 were monomorphic and were excluded from further analysis. The distribution of the alleles and genotypes for BDNF rs6265 was in Hardy-Weinberg equilibrium for the controls (p = 0.13) but was in Hardy Weinberg disequilibrium for the cases (p = 0.011). Findings from this study indicated that having BDNF rs6265 in the Malaysian population increase the odds of developing MDD by 2.05 folds (95% CI = 1.48-3.65). Plasma from 206 cases and 206 controls were randomly selected to measure the BDNF level using enzyme-linked immunosorbent assay (ELISA). A significant decrease in the plasma BDNF level of the cases as compared to controls (p<0.0001) was observed. However, there was no evidence of the effect of the rs6265 genotypes on the BDNF level indicating a possible role of other factors in modulating the BDNF level that warrants further investigation.
CONCLUSION: The study indicated that having the BDNF rs6265 allele (A) increase the risk of developing MDD in the Malaysian population suggesting a possible role of BDNF in the etiology of the disorder.
Fulltext Two Secreted Proteoglycans, Activators of Urothelial Cell-Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression

Papadaki V, Asada K, Watson JK, Tamura T, Leung A, Hopkins J, et al.

Cancers (Basel), 2020 Nov 13;12(11).
PMID: 33202923 DOI: 10.3390/cancers12113362

Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial-mesenchymal transition (EMT), activated cell-cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.
Fulltext The role of the university in recovering from COVID-19 and preparing for future crises-perspectives and experiences from Sunway University, Malaysia

Renganathan E, Guinto R, Mahmood J, Lacey-Hall O, Veerakumarasivam A, Poppema S

Front Public Health, 2023;11:1072823.
PMID: 37168072 DOI: 10.3389/fpubh.2023.1072823

This article is part of the Research Topic 'Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'. Universities, as engines of knowledge creation and dissemination and as incubators of disciplined yet original thinking, have a key role to play in tackling the most complex challenges that societies and our planet face, from infectious diseases to the climate emergency. This commentary presents the perspectives from Sunway University, a young private university in Malaysia that made a strong commitment to the sustainable development goals (SDGs) prior to the pandemic, and its experiences in promoting research, innovation, and learning as part of COVID-19 recovery and in preparation for future crises such as the climate emergency. Some of the university's initiatives include embracing the planetary health approach, reviving essential public health functions, exploring pandemic resilience, addressing 'infodemics' and promoting science diplomacy. The example of Sunway University provides some insights on the opportunities and challenges that academic institutions face as they seek to reorient the paradigm of education, research, and service away from disciplinary siloes and towards a more integrated, preventive, accessible and translational approach.
Human mesenchymal stromal cells modulate T-cell immune response via transcriptomic regulation

Vellasamy S, Tong CK, Azhar NA, Kodiappan R, Chan SC, Veerakumarasivam A, et al.

Cytotherapy, 2016 10;18(10):1270-83.
PMID: 27543068 DOI: 10.1016/j.jcyt.2016.06.017

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have been identified as pan-immunosuppressant in various in vitro and in vivo inflammatory models. Although the immunosuppressive activity of MSCs has been explored in various contexts, the precise molecular signaling pathways that govern inhibitory functions remain poorly elucidated.
METHODS: By using a microarray-based global gene expression profiling system, this study aimed to decipher the underlying molecular pathways that may mediate the immunosuppressive activity of umbilical cord-derived MSCs (UC-MSCs) on activated T cells.
RESULTS: In the presence of UC-MSCs, the proliferation of activated T cells was suppressed in a dose-depended manner by cell-to-cell contact mode via an active cell-cycle arrest at the G0/G1 phase of the cell cycle. The microarray analysis revealed that particularly, IFNG, CXCL9, IL2, IL2RA and CCND3 genes were down-regulated, whereas IL11, VSIG4, GFA1, TIMP3 and BBC3 genes were up-regulated by UC-MSCs. The dysregulated gene clusters associated with immune-response-related ontologies, namely, lymphocyte proliferation or activation, apoptosis and cell cycle, were further analyzed.
CONCLUSIONS: Among the nine canonical pathways identified, three pathways (namely T-helper cell differentiation, cyclins and cell cycle regulation, and gap/tight junction signalling pathways) were highly enriched with these dysregulated genes. The pathways represent putative molecular pathways through which UC-MSCs elicit immunosuppressive activity toward activated T cells. This study provides a global snapshot of gene networks and pathways that contribute to the ability of UC-MSCs to suppress activated T cells.
Fulltext o-Vanillin Derived Schiff Bases and Their Organotin(IV) Compounds: Synthesis, Structural Characterisation, In-Silico Studies and Cytotoxicity

Yusof ENM, Latif MAM, Tahir MIM, Sakoff JA, Simone MI, Page AJ, et al.

Int J Mol Sci, 2019 Feb 15;20(4).
PMID: 30781445 DOI: 10.3390/ijms20040854

Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate [R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with 2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by elemental analysis, various spectroscopic techniques including infrared, UV-vis, multinuclear (¹H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray diffraction. The organotin(IV) compounds were synthesised from the reaction of Ph₂SnCl₂ or Me₂SnCl₂ with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a total of six new organotin(IV) compounds that had a general formula of [R₂Sn(L)] (where L = Schiff base; R = Ph or Me). The molecular geometries of Me₂Sn(S2MoVa), Me₂Sn(S4MoVa) and Me₂Sn(SBoVa) were established by X-ray crystallography and verified using density functional theory calculations. Interestingly, each experimental structure contained two independent but chemically similar molecules in the crystallographic asymmetric unit. The coordination geometry for each molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen atoms derived from a dinegative, tridentate dithiocarbazate ligand with the remaining positions occupied by the methyl-carbon atoms of the organo groups. In each case, the resulting five-coordinate C₂NOS geometry was almost exactly intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries. The cytotoxic activities of the Schiff bases and organotin(IV) compounds were investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater potency than either the Schiff bases or the respective dimethyltin(IV) compounds. Mechanistic studies on the action of these compounds against bladder cancer cells revealed that they induced the production of reactive oxygen species (ROS). The bladder cancer cells were apoptotic after 24 h post-treatment with the diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption spectroscopy. This study revealed that the organotin(IV) compounds have strong DNA binding affinity, verified via molecular docking simulations, which suggests that these organotin(IV) compounds interact with DNA via groove-binding interactions.
Fulltext Soluble Flt-1 gene delivery in acute myeloid leukemic cells mediating a nonviral gene carrier

Amini R, Azizi Jalilian F, Veerakumarasivam A, Abdullah S, Abdulamir AS, Nadali F, et al.

Biomed Res Int, 2013;2013:752603.
PMID: 23509773 DOI: 10.1155/2013/752603

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in angiogenesis-mediated progression of acute myeloid leukemia (AML). Studies have reported the role of soluble form of fms-like tyrosine kinase (sFlT-1) delivery as an antitumor agent by inhibiting VEGF. This study investigates the outcome of delivery of a VEGF165 antagonist, soluble vascular endothelial growth factor receptor, namely sFLT-1, mediating lipofectamine 2000 in acute myeloid leukemic cells. A recombinant plasmid expressing sFLT-1 was constructed and transfected into the K562 and HL60 cells using lipofectamine 2000 transfection reagent. sFLT-1 expression/secretion in pVAX-sFLT-1 transfected cells was verified by RT-PCR and western blot. MTS assay was carried out to evaluate the effect of sFLT-1 on human umbilical vein endothelial cells and K562 and HL60 cells in vitro. Treatment with pVAX-sFLT-1 showed no association between sFLT-1 and proliferation of infected K562 and HL60 cells, while it demonstrated a significant inhibitory impact on the proliferation of HUVECs. The results of the current study imply that the combination of nonviral gene carrier and sFLT-1 possesses the potential to provide efficient tool for the antiangiogenic gene therapy of AML.
Dynamics of PEGylated-dextran-spermine nanoparticles for gene delivery to leukemic cells

Amini R, Jalilian FA, Abdullah S, Veerakumarasivam A, Hosseinkhani H, Abdulamir AS, et al.

Appl Biochem Biotechnol, 2013 Jun;170(4):841-53.
PMID: 23615733 DOI: 10.1007/s12010-013-0224-0

Leukemic cells are hard-to-transfect cell lines. Many transfection reagents which can provide high gene transfer efficiency in common adherent cell lines are not effective to transfect established blood cell lines or primary leukemic cells. This study aims to examine a new class of cationic polymer non-viral vector, PEGylated-dextran-spermine (PEG-D-SPM), to determine its ability to transfect the leukemic cells. Here, the optimal conditions of the complex preparation (PEG-D-SPM/plasmid DNA (pDNA)) were examined. Different weight-mixing (w/w) ratios of PEG-D-SPM/pDNA complex were prepared to obtain an ideal mixing ratio to protect encapsulated pDNA from DNase degradation and to determine the optimal transfection efficiency of the complex. Strong complexation between polymer and pDNA in agarose gel electrophoresis and protection of pDNA from DNase were detected at ratios from 25 to 15. Highest gene expression was detected at w/w ratio of 18 in HL60 and K562 cells. However, gene expression from both leukemic cell lines was lower than the control MCF-7 cells. The cytotoxicity of PEG-D-SPM/pDNA complex at the most optimal mixing ratios was tested in HL60 and K562 cells using MTS assay and the results showed that the PEG-D-SPM/pDNA complex had no cytotoxic effect on these cell lines. Spherical shape and nano-nature of PEG-D-SPM/pDNA complex at ratio 18 was observed using transmission electron microscopy. As PEG-D-SPM showed modest transfection efficiency in the leukemic cell lines, we conclude that further work is needed to improve the delivery efficiency of the PEG-D-SPM.
Fulltext Induced pluripotent stem cells: history, properties and potential applications

Nordin N, Lai MI, Veerakumarasivam A, Ramasamy R, Abdullah S, Wendy-Yeo WY, et al.

Med J Malaysia, 2011 Mar;66(1):4-9.
PMID: 23765134 MyJurnal

The development of induced pluripotent stem cells (iPSCs) has been met with much enthusiasm and hailed as a breakthrough discovery by the scientific and research communities amidst the divisive and ongoing debates surrounding human embryonic stem cells (hESC) research. The discovery reveals the fact that embryonic pluripotency can be generated from adult somatic cells by the induction of appropriate transcriptional factor genes essential for maintaining the pluripotency. They provide an alternative source for pluripotent stem cells, thus representing a powerful new research tool besides their potential application in the field of regenerative medicine. In this review, the historical background of iPSCs generation will be discussed together with their properties and characteristics as well as their potential therapeutic applications.
Calreticulin and cancer

Zamanian M, Veerakumarasivam A, Abdullah S, Rosli R

Pathol Oncol Res, 2013 Apr;19(2):149-54.
PMID: 23392843 DOI: 10.1007/s12253-012-9600-2

Calreticulin (CRT) as a multi-functional endoplasmic reticulum protein is involved in a spectrum of cellular processes which ranges from calcium homeostasis and chaperoning to cell adhesion and finally malignant formation and progression. Previous studies have shown a contributing role for CRT in a range of different cancers. This present review will focus on the possible roles of CRT in the progression of malignant proliferation and the mechanisms involved in its contribution to cancer invasion.
Fulltext Calreticulin mediates an invasive breast cancer phenotype through the transcriptional dysregulation of p53 and MAPK pathways

Zamanian M, Qader Hamadneh LA, Veerakumarasivam A, Abdul Rahman S, Shohaimi S, Rosli R

Cancer Cell Int, 2016;16:56.
PMID: 27418879 DOI: 10.1186/s12935-016-0329-y

The introduction of effective novel biomarkers of invasion and metastasis is integral for the advancement of breast cancer management. The present study focused on the identification and evaluation of calreticulin (CRT) as a potential biomarker for breast cancer invasion.

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