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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 Evaluation of CERS2 Gene as a Potential Biomarker for Bladder Cancer

Aldoghachi AF, Baharudin A, Ahmad U, Chan SC, Ong TA, Yunus R, et al.

Dis Markers, 2019;2019:3875147.
PMID: 31636736 DOI: 10.1155/2019/3875147

The ceramide synthase 2 (CERS2) gene has been linked to tumour recurrence and invasion in many different types of cancers including bladder cancer. In this study, the expression levels of CERS2 in bladder cancer cell lines were analysed using qRT-PCR and the protein expression in clinical bladder cancer histopathological specimens were examined via immunohistochemistry. The potential utility of CERS2 as a predictive biomarker of response to oncolytic virotherapy was assessed by correlating the CERS2 mRNA expression to IC50 values of cells treated with the Newcastle disease virus (NDV), AF2240 strain. This study demonstrates that CERS2 is differentially expressed in different types of bladder cancer cell lines and that the siRNA-mediated downregulation of the expression of CERS2 reduces the migratory potential of UMUC1 bladder cancer cells. However, there were no significant correlations between the expression levels of the CERS2 protein with bladder cancer grade/stage or between the IC50 values of cells treated with NDV and CERS2 expression. Although the utility of CERS2 expression may be limited, its potential as an antimigration cancer therapeutic should be further examined.
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 Synthesis, characterisation and biological activities of Ru(III), Mo(V), Cd(II), Zn(II) and Cu(II) complexes containing a novel Nitrogen-Sulphur Macrocyclic Schiff base derived from Glyoxal

Chah, C.K., Ravoof, T.B.S.A., Veerakumarasivam, A.

Pertanika Journal of Science & Technology, 2018;26(2):653-670.
MyJurnal

A novel nitrogen-sulphur macrocyclic Schiff base, 4,11,20,27-tetrathioxo3,12,19,28-tetrathia-5,6,9,10,21,22,25,26-octaazatricyclo[28.2.2.214,17]hexatriaconta 1(33),6,8,14(36),15,17(35),22,24,30(34),31-decaene-2,13,18,29-tetraone (TGSB) derived from terephthaloyl-bis-dithiocarbazate (TDTC) and glyoxal (ethane-1,2-dione) is synthesised via condensation. Metal complexes are formed by reacting the Schiff base with various metal salts such as Ru(III), Mo(V), Cd(II), Zn(II) and Cu(II). The complexes are expected to have a general formula of M2L or M3L with a square planar or square pyramidal geometry. These compounds were characterised by various physicochemical and spectroscopic techniques. From the data, it is concluded that the azomethine nitrogen atom and the thiolate sulphur atom from the ligand are bonded to the metal ion. In the IR spectra of the complexes, the presence of the C=N band in the region of 1600 cm-1 indicates the successful formation of the Schiff base. The structures of the Schiff base and metal complexes are confirmed via FT-IR, GC-MS and NMR spectroscopic analysis. The magnetic susceptibility measurements, electronic spectral data and molar conductivity analysis support the desired geometry of the complexes. The Schiff base and its metal complexes are evaluated for their biological activities against the invasive human bladder carcinoma cell line (EJ-28) and the minimuminvasive human bladder carcinoma cell line (RT-112). The RuTGSB and CdTGSB complexes showed selective activity against RT-112.
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 Mainstreaming responsible conduct of research education in Malaysia

Chau DM, Chai LC, Cheema MS, Veerakumarasivam A

Forensic Sci Res, 2021;6(4):338-340.
PMID: 35111352 DOI: 10.1080/20961790.2021.1987619
Differential Protein Expression Patterns of HOXA13 and HOXB13 Are Associated with Bladder Cancer Progression

Chin FW, Hussin H, Chau DM, Ong TA, Yunus R, Abdul Razack AH, et al.

Diagnostics (Basel), 2023 Aug 09;13(16).
PMID: 37627895 DOI: 10.3390/diagnostics13162636

Bladder cancer is a common urological cancer and has the highest recurrence rate of any cancer. The aim of our study was to profile and characterize the protein expression of homeobox A13 (HOXA13) and homeobox B13 (HOXB13) genes in Malaysian bladder cancer patients. The protein expression of HOXA13 and HOXB13 in formalin-fixed paraffin-embedded (FFPE) bladder cancer tissues was determined by immunohistochemistry (IHC) analysis. The association between HOXA13/HOXB13 protein expression and demographic/clinicopathological characteristics of the bladder cancer patients was determined by chi-square analysis. Approximately 63.6% of the bladder cancer tissues harbored high HOXA13 expression. High HOXA13 expression was significantly associated with non-muscle invasive bladder cancer, lower tumor grade, higher number of lymph node metastases, and recurrence risk. In contrast, low HOXB13 expression (including those with negative expression) was observed in 71.6% of the bladder cancer tissues analyzed. Low HOXB13 expression was significantly associated with muscle-invasive bladder cancer, higher tumor stage, tumor grade, and metastatic risk. Both HOXA13 and HOXB13 protein expression were found to be associated with bladder tumorigenesis. The putative oncogenic and tumor suppressive roles of HOXA13 and HOXB13, respectively, suggest their potential utility as biomarkers in bladder cancer.
Homeobox Gene Expression Dysregulation as Potential Diagnostic and Prognostic Biomarkers in Bladder Cancer

Chin FW, Chan SC, Veerakumarasivam A

Diagnostics (Basel), 2023 Aug 10;13(16).
PMID: 37627900 DOI: 10.3390/diagnostics13162641

Homeobox genes serve as master regulatory transcription factors that regulate gene expression during embryogenesis. A homeobox gene may have either tumor-promoting or tumor-suppressive properties depending on the specific organ or cell lineage where it is expressed. The dysregulation of homeobox genes has been reported in various human cancers, including bladder cancer. The dysregulated expression of homeobox genes has been associated with bladder cancer clinical outcomes. Although bladder cancer has high risk of tumor recurrence and progression, it is highly challenging for clinicians to accurately predict the risk of tumor recurrence and progression at the initial point of diagnosis. Cystoscopy is the routine surveillance method used to detect tumor recurrence. However, the procedure causes significant discomfort and pain that results in poor surveillance follow-up amongst patients. Therefore, the development of reliable non-invasive biomarkers for the early detection and monitoring of bladder cancer is crucial. This review provides a comprehensive overview of the diagnostic and prognostic potential of homeobox gene expression dysregulation in bladder cancer.
Fulltext The location of the inferior alveolar nerve in the malaysian population: Implications for dental implant planning

Kumar SR, Patil PG, Choy CS, Veerakumarasivam A

Indian J Dent Res, 2020 5 22;31(2):197-202.
PMID: 32436897 DOI: 10.4103/ijdr.IJDR_553_17

Background: The location of the inferior alveolar nerve (IAN) is generally constant in fully grown mandibles. If we know its average distance from the lower border of the mandible, available bone length from the crest of the edentulous ridge can be estimated by physical measurement of the whole length of mandible in that area. This study aimed to measure the superio-inferior distance of the inferior alveolar nerve (SIDIAN) from the base of the mandible in posterior regions on the right and left side based on cone-beam-computed tomography (CBCT) scans and to evaluate gender and ethnicity-related variations in the Malaysian population.
Materials and Methods: A total of 100 CBCT-Digital Imaging and Communications in Medicine files of the patients of 3 ethnic populations (Malay, Chinese and Indian) between the ages of 18 and 80 years were selected for the study. The files were imported onto the iCAT software. The measurements of the SIDIAN to the lower border of the mandible in molar regions were done on both sides. The data was analysed using t-test, one-way analysis of variance test, and correlation coefficient test via the SPSS software.
Results: Statistically significant positive correlations were identified between the SIDIAN from the lower border of the mandible in the first and second molar regions within the same side as well as between both sides of the mandible (r ≈ 0.8). There were no statistically significant differences between genders. However, there were statistically significant differences on both molar regions and on both sides in all three ethnic groups (P < 0.05). In general, the SIDIAN from the lower border of the mandible was greatest amongst Chinese and smallest amongst Indians.
Conclusions: The strong positive correlations on both sides of the mandible indicate the presence of symmetry. Ethnicity-related variations exist in terms of the location of the IAN in the mandible.
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.
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.
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 Evaluation of a Recombinant Newcastle Disease Virus Expressing Human IL12 against Human Breast Cancer

Mohamed Amin Z, Che Ani MA, Tan SW, Yeap SK, Alitheen NB, Syed Najmuddin SUF, et al.

Sci Rep, 2019 Sep 30;9(1):13999.
PMID: 31570732 DOI: 10.1038/s41598-019-50222-z

The Newcastle disease virus (NDV) strain AF2240 is an avian avulavirus that has been demonstrated to possess oncolytic activity against cancer cells. However, to illicit a greater anti-cancer immune response, it is believed that the incorporation of immunostimulatory genes such as IL12 into a recombinant NDV backbone will enhance its oncolytic effect. In this study, a newly developed recombinant NDV that expresses IL12 (rAF-IL12) was tested for its safety, stability and cytotoxicity. The stability of rAF-IL12 was maintained when passaged in specific pathogen free (SPF) chicken eggs from passage 1 to passage 10; with an HA titer of 29. Based on the results obtained from the MTT cytotoxic assay, rAF-IL12 was determined to be safe as it only induced cytotoxic effects against normal chicken cell lines and human breast cancer cells while sparing normal cells. Significant tumor growth inhibition (52%) was observed in the rAF-IL12-treated mice. The in vivo safety profile of rAF-IL12 was confirmed through histological observation and viral load titer assay. The concentration and presence of the expressed IL12 was quantified and verified via ELISA assay. In summary, rAF-IL12 was proven to be safe, selectively replicating in chicken and cancer cells and was able to maintain its stability throughout several passages; thus enhancing its potential as an anti-breast cancer vaccine.
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.
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
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 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.
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.

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