Publications by authors named "Ahmad Farizan"

10 Publications

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Lentivirus vector‑mediated genetic manipulation of oncogenic pathways induces tumor formation in rabbit brain.

Mol Med Rep 2021 Jun 13;23(6). Epub 2021 Apr 13.

A.I Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI‑70211 Kuopio, Finland.

Translation of promising experimental therapies from rodent models to clinical success has been complicated as the novel therapies often fail in clinical trials. Existing rodent glioma models generally do not allow for preclinical evaluation of the efficiency of novel therapies in combination with surgical resection. Therefore, the aim of the present study was to develop a larger animal model utilizing lentivirus vector‑mediated oncogenic transformation in the rabbit brain. Lentiviruses carrying constitutively active AKT and H‑Ras oncogenes, and p53 small interfering (si)RNA were introduced into newborn rabbit neural stem cells (NSCs) and intracranially implanted into rabbits' brains to initiate tumor formation. In one of the ten rabbits a tumor was detected 48 days after the implantation of transduced NSCs. Histological features of the tumor mimic was similar to a benign Grade II ganglioglioma. Immunostaining demonstrated that the tissues were positive for AKT and H‑Ras. Strong expression of GFAP and Ki‑67 was also detected. Additionally, p53 expression was notably lower in the tumor area. The implantation of AKT, H‑Ras and p53 siRNA transduced NSCs for tumor induction resulted in ganglioglioma formation. Despite the low frequency of tumor formation, this preliminary data provided a proof of principle that lentivirus vectors carrying oncogenes can be used for the generation of brain tumors in rabbits. Moreover, these results offer noteworthy insights into the pathogenesis of a rare brain tumor, ganglioglioma.
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http://dx.doi.org/10.3892/mmr.2021.12061DOI Listing
June 2021

Accumulation of Mitochondrial DNA Microsatellite Instability in Malaysian Patients with Primary Central Nervous System Tumors.

Turk Neurosurg 2021 ;31(1):99-106

Sains Malaysia University, School of Medical Sciences, Health Campus, Department of Neurosciences, 16150 Kubang Kerian, Kelantan, Malaysia.

Aim: To determine the mitochondrial microsatellite instability (mtMSI) status in a series of Malaysian patients with brain tumors. Furthermore, we analyzed whether the mtMSI status is associated with the clinicopathological features of the patients.

Material And Methods: Forty fresh frozen tumor tissues along with blood samples of brain tumor patients were analyzed for mtMSI by PCR amplification of genomic DNAs, and the amplicons were directly sequenced in both directions using Sanger sequencing.

Results: Microsatellite analysis revealed that 20% (8 out of 40) of the tumors were mtMSI positive with a total of 8 mtMSI changes. All mtMSI markers were detected in D310 and D16184 of the D-loop region. Additionally, no significant association was observed between mtMSI status and clinicopathological features.

Conclusion: The variations, specifically the mtMSI, suggest that the mitochondrial DNA (mtDNA) can be targeted for genomic alteration in brain tumors. Therefore, the specific role of mtDNA alteration in brain tumor development and prognosis requires further investigation.
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http://dx.doi.org/10.5137/1019-5149.JTN.27893-20.4DOI Listing
March 2021

Anti-Cancer Properties of sp. Honey Via Induction of Apoptosis in Malignant Glioma Cells.

Malays J Med Sci 2019 Mar 30;26(2):30-39. Epub 2019 Apr 30.

Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Background: There has been increasing evidence showing that stingless bee honey exhibits anti-oxidant, anti-inflammatory and anti-cancer properties. Pharmacologically-active components in honey such as flavonoids and phenolic constituents are known to contribute to its medicinal benefits. To the best of our knowledge, this is the first study on evaluating anti-cancer effects of locally-produced Malaysian stingless bee honey from sp. on malignant glioma cells.

Methods: Proliferation and apoptosis studies of U-87 MG cells following stingless bee honey treatment were carried out using MTS assay and acridine orange/propidium iodide dual staining, respectively.

Results: Results demonstrated time and dose-dependent cytotoxicity using 0.625%, 1.25% and 10% stingless bee honey ( < 0.05). IC values were calculated using cells treated with 10% stingless bee honey. It was also observed that 10% stingless bee honey induced nuclear shrinkage, chromatin condensation and nucleus fragmentation, indicating that cellular changes were consistent with the apoptotic characteristics of the cells.

Conclusion: These data provide a good basis for further evaluation of the medicinal properties of stingless bee honey from sp. This source of honey may serve as a potential therapy for malignant glioma.
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http://dx.doi.org/10.21315/mjms2019.26.2.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687214PMC
March 2019

Roles of EphA2 Receptor in Angiogenesis Signaling Pathway of Glioblastoma Multiforme.

Malays J Med Sci 2018 Nov 28;25(6):22-27. Epub 2018 Dec 28.

Universiti Teknologi MARA, Shah Alam, 40450 Shah Alam, Selangor, Malaysia.

Glioblastoma multiforme (GBM) is one of the most common primary brain tumours in adults, accounting for almost 65% of all cases. Among solid tumours, GBM is characterised by strong angiogenesis, including the highest degree of vascular proliferation and endothelial cell hyperplasia. Despite numerous improvements in existing treatment approaches, the prognosis of GBM patients remains poor, with a mean survival of only 14.6 months. Growing evidence has shown significant overexpression of the ephrin type-A receptor 2 (EphA2) receptor in various malignancies, including GBM, as well as a correlation to poor prognoses. It is believed that EphA2 receptors play important roles in mediating GBM tumourigenesis, including invasion, metastasis, and angiogenesis. Despite the clinical and pathological importance of tumour-associated vasculature, the underlying mechanism involving EphA2 is poorly known. Here, we have summarised the current knowledge in the field regarding EphA2 receptors' roles in the angiogenesis of GBM.
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http://dx.doi.org/10.21315/mjms2018.25.6.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422564PMC
November 2018

Mouse model of intracerebellar haemorrhage.

Behav Brain Res 2016 10 17;312:374-84. Epub 2016 Jun 17.

Center for Neuroscience Services and Research(P3Neuro), Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, 16150, Kubang Kerian, Kota Bharu, Kelantan,Malaysia; Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Jalan Hospital Universiti Sains Malaysia, 16150, Kubang Kerian, Kota Bharu, Kelantan, Malaysia. Electronic address:

The present study aimed to investigate the behavior and neuronal morphological changes in the perihaemorrhagic tissue of the mouse intracerebellar haemorrhage experimental model. Adult male Swiss albino mice were stereotactically infused with collagenase type VII (0.4U/μl of saline) unilaterally in to the cerebellum, following anaesthesia. Motor deficits were assessed using open field and composite score for evaluating the mouse model of cerebellar ataxia at 1, 3, 7, 14 and 21 days after collagenase infusion. The animals were sacrificed at the same time interval for evaluation of perihaematomal neuronal degeneration using haematoxylin and eosin staining and Annexin V-FITC/Propidium iodide assay. At the end of the study, it was found that infusion of 0.4U collagenase produces significant locomotor and ataxic deficit in the mice especially within the first week post surgery, and that this gradually improved within three weeks. Neuronal degeneration evident by cytoplasmic shrinkage and nuclear pyknosis was observed at the perihaematomal area after one day; especially at 3 and 7 days post haemorrhage. By 21 days, both the haematoma and degenerating neurons in the perihaematomal area were phagocytosed and the remaining neuronal cells around the scar tissue appeared normal. Moreover, Annexin-V/propidium iodide-positive cells were observed at the perihaematomal area at 3 and 7 days implying that the neurons likely die via apoptosis. It was concluded that a population of potentially salvageable neurons exist in the perihaematomal area after cerebellar haemorrhage throughout a wide time window that could be amenable to treatment.
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http://dx.doi.org/10.1016/j.bbr.2016.06.034DOI Listing
October 2016

15-Lipoxygenase-1 induces lipid peroxidation and apoptosis, and improves survival in rat malignant glioma.

In Vivo 2012 Jan-Feb;26(1):1-8

Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.

Background: Previous studies suggest either an anti- or pro-apoptotic role for 15-lipoxygenase-1 in carcinogenesis.

Materials And Methods: We used adenovirus gene transfer of human 15-lipoxygenase-1 to characterize its effects in vitro and in vivo.

Results: 15-Lipoxygenase-1 expression in mouse macrophages resulted in a significant, 25-fold, induction in the production of the specific 15-lipoxygenase-1 product 13-hydroxyoctadecadienoic acid. Tail vein gene transfers in mice led to highest expression of the transduced 15-lipoxygenase-1 in liver and spleen. In the liver, 15-lipoxygenase-1 significantly increased lipid peroxidation by 3.5-fold and 2-fold, three and seven days after transduction, respectively. A significant 32-fold induction in caspase-3 activity was detected in 15-lipoxygenase-1 expressing livers seven days after transduction. In a syngeneic rat model of malignant glioma, 15-lipoxygenase-1 extended survival significantly (p=0.001).

Conclusion: Our results support the pro-apoptotic role of 15-lipoxygenase-1 and suggest that 15-lipoxygenase-1 could be a potential new target gene for the therapy of malignant glioma.
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June 2012

Molecular genetic analysis of a suprasellar immature teratoma : mutation of exon 4 p53 gene.

Malays J Med Sci 2008 Apr;15(2):43-6

Department of Neurosciences.

We described an intracranial immature teratoma in a 13 year old Malay boy who presented with history of chronic headache and blurring of vision. Physical findings revealed bilateral papilloedema but no other localizing sign. A Magnetic Resonance Imaging of the brain revealed a suprasellar well defined lobulated midline heterogenous mass which was intraoperatively described as mainly solid tumour with multiple small cystic component filled with yellowish jelly like material. Histopathological finding confirmed the case as immature teratoma. Molecular genetic analysis of p53 and p27 genes revealed substitution of nucleotide G to C at location nucleotide 12139, exon 4 of gene p53. No alteration was detected at exon 5-6 and 8 of p53 gene and exon 1 and 2 of p27 gene. This is the first case report of an intracranial immature teratoma with genetic mutation occuring in a Malay boy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341889PMC
April 2008

Molecular genetic analysis of BAX and cyclin D1 genes in patients with malignant glioma.

Neurol Res 2007 Apr;29(3):239-42

Department of Neurosciences, Department of Pathology, and Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Introduction And Objectives: Brain tumorigenesis is a complex process involving multiple genetic alterations. Cyclin D1 and BAX genes are two of the most important regulators in controlling the normal proliferation and apoptosis of cells, respectively. In this study, we analysed the possibilities of involvement of cyclin D1 and BAX genes in the gliomagenesis.

Methods And Results: In determining gene alterations of exon 4 of cyclin D1 gene and exon 6 of BAX gene, all samples were amplified by polymerase chain reaction (PCR) and subsequently by direct sequencing. Our results showed a frameshift mutation (G base deletion) at nucleotide 82 of codon 28 in exon 4 of the cyclin D1 gene and another frameshift mutation with a deletion of C base at nucleotide 153 of exon 6 of the BAX gene in two separate cases of a glioblastoma multiform (WHO Grade IV) sample.

Conclusion: These findings suggest that both cyclin D1 and BAX genes alteration are rarely found in brain tumors. However, the alteration might cause a significant effect of the normal protein production and this might contribute to the development of brain tumorigenesis in Malaysian patients.
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http://dx.doi.org/10.1179/016164107X158965DOI Listing
April 2007

Association of loss of heterozygosity and PTEN gene abnormalities with paraclinical, clinical modalities and survival time of glioma patients in Malaysia.

Asian J Surg 2006 Oct;29(4):274-82

Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Background: The pattern of allelic loss of heterozygosity (LOH) and PTEN mutations appear to be associated with the progression of gliomas leading to a decrement in the survival rate of patients. This present study was carried out to determine the LOH and PTEN mutational status in glioma patients and its association with patients' survival.

Methods: Thirty-seven Malaysian glioma patients of the Malay race were subject to PTEN mutational analysis and the presence of LOH using the cold single-strand conformation polymorphism method, and their clinical and paraclinical response were correlated.

Results: Among analysed glioma patients, seven (21.6%) cases with PTEN mutations were detected and 12 (32.4%) of 37 patients showed presence of LOH. Univariate analysis showed that tumour grade, vascularization, PTEN mutation, LOH and combination of both PTEN mutation and LOH were significantly associated with glioma patients' survival. Multivariate analysis revealed that no factors contributed to survival time.

Conclusion: The results show that PTEN mutation and LOH are quite frequent in Malaysian glioma patients. However, they have no impact on the survival outcome of patients.
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http://dx.doi.org/10.1016/S1015-9584(09)60102-0DOI Listing
October 2006