Publications by authors named "Narazah Mohd Yusoff"

46 Publications

Blood transfusion services amidst the COVID-19 pandemic.

J Glob Health 2021 Apr 17;11:03053. Epub 2021 Apr 17.

Cluster of Regenerative Medicine, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Malaysia.

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http://dx.doi.org/10.7189/jogh.11.03053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053396PMC
April 2021

Homozygous Southeast Asian Ovalocytosis in five live-born neonates.

Haematologica 2021 06 1;106(6):1758-1761. Epub 2021 Jun 1.

Cluster of Regenerative Medicine, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Penang.

Not available.
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http://dx.doi.org/10.3324/haematol.2020.268581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168517PMC
June 2021

Conditioned Medium of Human Menstrual Blood-Derived Endometrial Stem Cells Protects Against MPP-Induced Cytotoxicity .

Front Mol Neurosci 2019 5;12:80. Epub 2019 Apr 5.

Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life, Science and Technology, Xinxiang Medical University, Xinxiang, China.

Mesenchymal stem cells (MSCs) showed the potential to treat Parkinson's disease (PD). However, it is unknown whether the conditioned medium of human menstrual blood-derived endometrial stem cells (MenSCs-CM) has the function to alleviate syndromes of PD. In this study, human neuroblastoma SH-SY5Y cells were exposed to neurotoxicant 1-methyl-4-phenylpyridinium (MPP) for inducing a range of response characteristics of PD. After culturing this cell model with 24 h/48 h collected MenSCs-CM for different days, cell viability, pro-inflammation cytokines, mitochondrial membrane potential (ΔΨm), oxidative stress, and cell apoptosis were detected. Finally, protein assay was performed to detect 12 kinds of neurotrophic factors inside MenSCs-CM. Our results showed that MPP caused SH-SY5Y cell viability reduction as an increasing dose and time dependent manner. MPP treatment resulted in inflammation, mitochondrial dysfunction, reactive oxygen species (ROS) production accumulation, and apoptosis of SH-SY5Y at its IC50 concentration. Forty-eight hours-collected MenSCs-CM and culturing with the MPP-treated SH-SY5Y for 2 days are the optimized condition to increase cell viability. Besides, MenSCs-CM was efficacious against MPP induced inflammation, ΔΨm loss, ROS generation, and it could significantly decrease cells numbers in late apoptosis stage. What's more, protein assay showed that MenSCs-CM contained various neuroprotective factors. Our study provided the first evidence that MenSCs-CM has a protective effect on MPP-induced cytotoxicity in various aspects, and firstly showed that MenSCs can release at least 12 kinds of neurotrophic factors to medium, which may contribute to the protective function of MenSCs-CM to treat PD. This research enlightening that MenSCs-CM is beneficial in the therapy for PD and probably also for other neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnmol.2019.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460823PMC
April 2019

Disruption of MAPK1 expression in the ERK signalling pathway and the RUNX1‑RUNX1T1 fusion gene attenuate the differentiation and proliferation and induces the growth arrest in t(8;21) leukaemia cells.

Oncol Rep 2019 Mar 12;41(3):2027-2040. Epub 2018 Dec 12.

Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas, Pulau Pinang 13200, Malaysia.

The t(8;21) translocation is one of the most frequent chromosome abnormalities associated with acute myeloid leukaemia (AML). This abberation deregulates numerous molecular pathways including the ERK signalling pathway among others. Therefore, the aim of the present study was to investigate the gene expression patterns following siRNA‑mediated suppression of RUNX1‑RUNX1T1 and MAPK1 in Kasumi‑1 and SKNO‑1 cells and to determine the differentially expressed genes in enriched biological pathways. BeadChip microarray and gene ontology analysis revealed that RUNX1‑RUNX1T1 and MAPK1 suppression reduced the proliferation rate of the t(8;21) cells with deregulated expression of several classical positive regulator genes that are otherwise known to enhance cell proliferation. RUNX1‑RUNX1T1 suppression exerted an anti‑apoptotic effect through the overexpression of BCL2, BIRC3 and CFLAR genes, while MAPK1 suppression induced apopotosis in t(8;21) cells by the apoptotic mitochondrial changes stimulated by the activity of upregulated TP53 and TNFSF10, and downregulated JUN gene. RUNX1‑RUNX1T1 suppression supported myeloid differentiation by the differential expression of CEBPA, CEBPE, ID2, JMJD6, IKZF1, CBFB, KIT and CDK6, while MAPK1 depletion inhibited the differentiation of t(8;21) cells by elevated expression of ADA and downregulation of JUN. RUNX1‑RUNX1T1 and MAPK1 depletion induced cell cycle arrest at the G0/G1 phase. Accumulation of cells in the G1 phase was largely the result of downregulated expression of TBRG4, CCNE2, FOXO4, CDK6, ING4, IL8, MAD2L1 and CCNG2 in the case of RUNX1‑RUNX1T1 depletion and increased expression of RASSF1, FBXO6, DADD45A and P53 in the case of MAPK1 depletion. Taken together, the current results demonstrate that MAPK1 promotes myeloid cell proliferation and differentiation simultaneously by cell cycle progression while suppresing apoptosis.
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http://dx.doi.org/10.3892/or.2018.6926DOI Listing
March 2019

Inhibition of NF-κB Signaling Reduces the Stemness Characteristics of Lung Cancer Stem Cells.

Front Oncol 2018 17;8:166. Epub 2018 May 17.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia.

Cancer stem cells (CSCs) are a subpopulation of cancer cells that play a pivotal role in tumor development, invasion, metastasis, and recurrence. We and others have reported significant involvement of the NF-κB pathway in regulating CSCs of non-small cell lung cancer (NSCLC). In this study, we evaluated the effects of NF-κB inhibition on self-renewal, stemness, migration, and expression of genes involved in the epithelial to mesenchymal transition (EMT) and apoptosis resistance in lung CSCs. Different concentrations of the NF-κB inhibitor BMS-345541 (0.4, 4.0, and 10.0 µM), an inhibitor the NF-κB upstream kinase IKKβ, were used to treat both lung CSCs (CD166CD44, CD166EpCAM) and non-CSC NSCLC cells (CD166CD44, CD166EpCAM) in A549 and H2170 cell lines. We assessed the impact of BMS-345541 on the ability to form tumorspheres (self-renewal assay), expression of stemness genes (, and ), migration, and expression of EMT and apoptosis-related genes. Inhibition of NF-κB by BMS-345541 effectively reduced the stemness, self-renewal, and migration capacity of lung CSCs. Moreover, expression of genes involved in the EMT ( and ) and apoptosis resistance (, and ) was significantly reduced following the treatments, suggesting that NF-κB inhibition is sufficient to prevent the EMT and induce apoptosis in lung CSCs. Our findings suggest that NF-κB inhibition could reduce the capability of CSCs to maintain their population within the tumor mass, potentially decelerating cancer progression, relapse, and chemotherapy resistance.
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http://dx.doi.org/10.3389/fonc.2018.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966538PMC
May 2018

The BRCA1 and BRCA2 Genes in Early-Onset Breast Cancer Patients.

Adv Exp Med Biol 2020 ;1292:1-12

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia.

Approximately 5-10% of breast cancers are attributable to genetic susceptibility. Mutations in the BRCA1 and BRCA2 genes are the best known genetic factors to date. The goal of this study was to determine the structure and distribution of haplotypes of the BRCA1 and BRCA2 genes in early-onset breast cancer patients. We enrolled 70 patients diagnosed with early-onset breast cancer. A total of 21 SNPs (11 on BRCA1 and 10 on BRCA2) and 1 dinucleotide deletion on BRCA1 were genotyped using nested allele-specific PCR methods. Linkage disequilibrium (LD) analysis was conducted, and haplotypes were deduced from the genotype data. Two tightly linked LD blocks were observed on each of the BRCA1 and BRCA2 genes. Variant-free haplotypes (TAT-AG for BRCA1 and ATA-AAT for BRCA2) were observed at a frequency of more than 50% on each gene along with variable frequencies of derived haplotypes. The variant 3'-subhaplotype CGC displayed strong LD with 5'-subhaplotypes GA, AA, and GG on BRCA1 gene. Haplotypes ATA-AGT, ATC-AAT, and ATA-AAC were the variant haplotypes frequent on BRCA2 gene. Although the clinical significance of these derived haplotypes has not yet been established, it is expected that some of these haplotypes, especially the less frequent subhaplotypes, eventually will be shown to be indicative of a predisposition to early-onset breast cancer.
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http://dx.doi.org/10.1007/5584_2018_147DOI Listing
January 2021

Direction of commissural axon projections in different regions of the spinal cord during chicken embryonic development.

Neuroscience 2017 09 4;358:269-276. Epub 2017 Jul 4.

College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang 453003, China; Institute of Anatomy I, University of Jena School of Medicine, Jena University Hospital, Jena 07743, Germany; College of Biomedical Engineering, Xinxiang Medical University, Xinxiang 453003, China. Electronic address:

Few researchers have investigated the direction of commissural axon projections on the contralateral side of the vertebrate embryonic spinal cord, especially for comparison between its different regions. In this study, pCAGGS-GFP plasmid expression was limited to different regions of the chicken embryonic spinal cord (cervical, anterior limb, anterior thorax, posterior thorax and posterior limb) at E3 using in ovo electroporation with modified electrodes and optimal electroporation conditions. Then open-book technique was performed at E6 to analyze the direction of axon projections in different spinal cord regions. The results show that in the five investigated regions, most axons projected rostrally after crossing the floor plate while a minority projected caudally. And there was a significant difference between the rostral and caudal projection quantities (P<0.01). The ratio of rostral and caudal projections was significantly different between the five investigated regions (P<0.05), except between the cervical region and the anterior limb (P>0.05). The projections were most likely to be rostral for the posterior limb followed by the posterior thorax, cervical region, anterior limb and anterior thorax. Our data for the direction of the commissural axon projections will be helpful in the future analyses of axon projection mechanisms and spinal cord-brain circuit formation.
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http://dx.doi.org/10.1016/j.neuroscience.2017.06.053DOI Listing
September 2017

Targeting Lung Cancer Stem Cells: Research and Clinical Impacts.

Front Oncol 2017 5;7:80. Epub 2017 May 5.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia.

Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. Non-small cell lung cancer (NSCLC), which is one of two types of lung cancer, accounts for 85-90% of all lung cancers. Despite advances in therapy, lung cancer still remains a leading cause of death. Cancer relapse and dissemination after treatment indicates the existence of a niche of cancer cells that are not fully eradicated by current therapies. These chemoresistant populations of cancer cells are called cancer stem cells (CSCs) because they possess the self-renewal and differentiation capabilities similar to those of normal stem cells. Targeting the niche of CSCs in combination with chemotherapy might provide a promising strategy to eradicate these cells. Thus, understanding the characteristics of CSCs has become a focus of studies of NSCLC therapies.
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http://dx.doi.org/10.3389/fonc.2017.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418222PMC
May 2017

Human mesenchymal stem cells promote CD34 hematopoietic stem cell proliferation with preserved red blood cell differentiation capacity.

Cell Biol Int 2017 Jun 3;41(6):697-704. Epub 2017 May 3.

Advanced Medical and Dental Institute, UniversitiSains Malaysia, Bertam 13200 Kepala Batas, Penang, Malaysia.

Studies showed that co-transplantation of mesenchymal stem cells (MSCs) and cord blood-derived CD34 hematopoietic stem cells (HSCs) offered greater therapeutic effects but little is known regarding the effects of human Wharton's jelly derived MSCs on HSC expansion and red blood cell (RBC) generation in vitro. This study aimed to investigate the effects of MSCs on HSC expansion and differentiation. HSCs were co-cultured with MSCs or with 10% MSCs-derived conditioned medium, with HSCs cultured under standard medium served as a control. Cell expansion rates, number of mononuclear cell post-expansion and number of enucleated cells post-differentiation were evaluated. HSCs showed superior proliferation in the presence of MSC with mean expansion rate of 3.5 × 10  ± 1.8 × 10 after day 7 compared to the conditioned medium and the control group (8.9 × 10  ± 1.1 × 10 and 7.0 × 10  ± 3.3 × 10 respectively, P < 0.001). Although no significant differences in RBC differentiation were observed between groups at passage IV, the number of enucleated cell was greater compared to earlier passages, indicating successful RBC differentiation. Cord blood-derived CD34 HSCs can be greatly expanded by co-culturing with MSCs without affecting the RBC differentiation capability, suggesting the importance of direct MSC-HSCs contact in HSC expansion and RBC differentiation.
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http://dx.doi.org/10.1002/cbin.10774DOI Listing
June 2017

Genetic analysis of the M2/ANXA5 haplotype as recurrent pregnancy loss predisposition in the Malay population.

J Assist Reprod Genet 2017 Apr 20;34(4):517-524. Epub 2017 Jan 20.

Advanced Medical and Dental Institute, University Sains Malaysia, Bertam, Penang, Malaysia.

Purpose: The aim of this study was to evaluate a new predisposition factor, M2/ANXA5 (RPRGL3), in recurrent pregnancy loss (RPL) patients of Malay origin, since it was previously known that the prevalence of this condition is relatively high among the Malay population of Malaysia, where conventional hereditary thrombophilia factors have been generally ruled out.

Methods: A total of 232 women who had experienced ≥2 unexplained RPL and 141 available male partners were recruited, with 360 healthy Malay and 166 parous female controls. Prevalence of M2 carriage and RPL odds ratios were calculated in (a) control and patient groups; (b) clinically defined subgroups in categories of pregnancy loss, primary, secondary, and tertiary; and (c) timing of pregnancy loss in early, ≤15th gestation week and "late" fetal losses, and >15th gestation week subgroups.

Results: Both male and female subjects had similar M2/ANXA5 allele frequencies. The carrier rate of M2/ANXA5 for the general Malay population was 42.2 and 34.9% for parous controls. These carrier rates compared to Malay RPL subjects (52% M2 carriers) resulted in elevated odds ratios (95% confidence interval) of 1.53 (1.1 to 2.1) and 1.97 (1.3 to 3.1) accordingly for early fetal losses. Moreover, exceeding copy numbers of M2/ANXA5 alleles seemed to afflict a greater chance of RPL in couples, especially when both partners were M2 carriers.

Conclusion: This study confirmed the proposed role of M2/ANXA5 as embryonic, genetically associated thrombophilia predisposition factor for early RPL among ethnic Malay of Malaysia.
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http://dx.doi.org/10.1007/s10815-017-0871-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401693PMC
April 2017

Combination of Multiple Ligation-Dependent Probe Amplification and Illumina MiSeq Amplicon Sequencing for TSC1/TSC2 Gene Analyses in Patients with Tuberous Sclerosis Complex.

J Mol Diagn 2017 03 11;19(2):265-276. Epub 2017 Jan 11.

Center for Neuroscience Services and Research, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia; Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation-dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate. Thirty-four Malaysian patients diagnosed with TSC were referred to Human Genome Center, Universiti Sains Malaysia. We used a combination of MLPA to detect large copy number changes and AS to detect smaller mutations. TSC1 pathogenic or likely pathogenic mutations were found in 6 patients (18%) and TSC2 in 21 patients (62%), whereas 6 patients (18%) show no mutations and 1 patient (2%) showed only TSC2 missense variant with uncertain significance. Six of the mutations are novel. Our detection strategy costs 81% less and require 1 working week less than the conventional strategy. Confirmatory sequencing using Sanger method on a few representative mutations showed agreement with results of the AS. Combination of MLPA and Illumina MiSeq AS provides a simplified strategy and reasonably high detection rate for TSC1/TSC2 mutation, which suggested application of the strategies into clinical molecular diagnostics.
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http://dx.doi.org/10.1016/j.jmoldx.2016.10.009DOI Listing
March 2017

Fusion genes in malignant neoplastic disorders of haematopoietic system.

Hematology 2016 Oct 24;21(9):501-12. Epub 2016 Feb 24.

a Advanced Medical and Dental Institute , Universiti Sains Malaysia , Kepala Batas , Penang , Malaysia.

Objectives: The new World Health Organization's (WHO) classification of haematopoietic and lymphoid tissue neoplasms incorporating the recurrent fusion genes as the defining criteria for different haematopoietic malignant phenotypes is reviewed. The recurrent fusion genes incorporated in the new WHO's classification and other chromosomal rearrangements of haematopoietic and lymphoid tissue neoplasms are reviewed.

Methodology: Cytokines and transcription factors in haematopoiesis and leukaemic mechanisms are described. Genetic features and clinical implications due to the encoded chimeric neoproteins causing malignant haematopoietic disorders are reviewed.

Results And Discussion: Multiple translocation partner genes are well known for leukaemia such as MYC, MLL, RARA, ALK, and RUNX1. With the advent of more sophisticated diagnostic tools and bioinformatics algorithms, an exponential growth in fusion genes discoveries is likely to increase.

Conclusion: Demonstration of fusion genes and their specific translocation breakpoints in malignant haematological disorders are crucial for understanding the molecular pathogenesis and clinical phenotype of cancer, determining prognostic indexes and therapeutic responses, and monitoring residual disease and relapse status.
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http://dx.doi.org/10.1080/10245332.2015.1106816DOI Listing
October 2016

A Cell Internalizing Antibody Targeting Capsid Protein (p24) Inhibits the Replication of HIV-1 in T Cells Lines and PBMCs: A Proof of Concept Study.

PLoS One 2016 7;11(1):e0145986. Epub 2016 Jan 7.

Regenerative Medicine, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Kepala Batas, Pulau Pinang, Malaysia.

There remains a need for newer therapeutic approaches to combat HIV/AIDS. Viral capsid protein p24 plays important roles in HIV pathogenesis. Peptides and small molecule inhibitors targeting p24 have shown to inhibit virus replication in treated cell. High specificity and biological stability of monoclonal antibodies (mAbs) make them an attractive contender for in vivo treatments. However, mAbs do not enter into cells, thus are restricted to target surface molecules. This also makes targeting intracellular HIV-1 p24 a challenge. A mAb specific to p24 that can internalize into the HIV-infected cells is hypothesized to inhibit the virus replication. We selected a mAb that has previously shown to inhibit p24 polymerization in an in vitro assay and chemically conjugated it with cell penetrating peptides (CPP) to generate cell internalizing anti-p24 mAbs. Out of 8 CPPs tested, κFGF-MTS -conjugated mAbs internalized T cells most efficiently. At nontoxic concentration, the κFGF-MTS-anti-p24-mAbs reduced the HIV-1 replication up to 73 and 49% in T-lymphocyte and PBMCs respectively. Marked inhibition of HIV-1 replication in relevant cells by κFGF-MTS-anti-p24-mAbs represents a viable strategy to target HIV proteins present inside the cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145986PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711802PMC
June 2016

Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines.

Oncol Rep 2016 Jan 2;35(1):13-25. Epub 2015 Nov 2.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia.

Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10-40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC.
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http://dx.doi.org/10.3892/or.2015.4371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699625PMC
January 2016

High allele frequency of CYP2C9*3 (rs1057910) in a Negrito's subtribe population in Malaysia; Aboriginal people of Jahai.

Ann Hum Biol 2016 Sep 24;43(5):445-50. Epub 2015 Sep 24.

a Department of Paediatrics , School of Medical Sciences, Universiti Sains Malaysia , Health Campus, Kubang Kerian , Kelantan , Malaysia .

Background: CYP2C9 gene polymorphisms modulate inter-individual variations in the human body's responses to various endogenous and exogenous drug substrates. To date, little is known about the CYP2C9 gene polymorphisms among the aboriginal populations of the world, including those in Malaysia.

Aim: To characterise and compare the CYP2C9 polymorphisms (CYP2C9*2, CYP2C9*3, CYP2C9*4 and CYP2C9*5) between one of Malaysia's aboriginal populations, Jahai, with the national major ethnic, Malay. To also compare the allele frequencies from these two populations with available data of other aboriginal populations around the world.

Subjects And Methods: The extracted DNA of 155 Jahais and 183 Malays was genotyped for CYP2C9 polymorphisms using a nested multiplex allele-specific polymerase chain reaction technique. The results were confirmed by DNA direct sequencing.

Results: Genotyping results revealed that CYP2C9*2, CYP2C9*4 and CYP2C9*5 were absent in Jahais, while only the latter two were absent in Malays. The CYP2C9*3 allelic frequency in Jahais was 36.2%, making them the most frequent carriers of the allele thus far reported in any ethnic group from Southeast Asia.

Conclusions: The high frequency of CYP2C9*3 and the absence of CYP2C9*2 in Jahais suggest that genetic drift may be occurring in this ethnic group. This is the first study to determine the CYP2C9 polymorphisms in an aboriginal population in Malaysia.
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http://dx.doi.org/10.3109/03014460.2015.1068372DOI Listing
September 2016

High resolution melting analysis of the NR1I3 genetic variants: Is there an association with neonatal hyperbilirubinemia?

Gene 2015 Dec 16;573(2):198-204. Epub 2015 Jul 16.

Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia, Kelantan 16150, Malaysia; Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kelantan 16150, Malaysia. Electronic address:

Constitutive androstane receptor (CAR) encoded by the nuclear receptor subfamily 1, group I, member 3 (NR1I3) gene regulates the elimination of bilirubin through activating the components of the bilirubin clearance pathway. Hence, NR1I3 genetic variants may affect bilirubin metabolism and result in neonatal hyperbilirubinemia. Thus far, research which investigates the association between NR1I3 variants and neonatal hyperbilirubinemia has not been undertaken in any population. The present study aimed to evaluate the influence of MPJ6_1I3008 (rs10157822), IVS8+116T>G (rs4073054) and 540A>G (rs2307424) on neonatal hyperbilirubinemia development in the Malay population. Buccal swabs were collected from 232 hyperbilirubinemia and 277 control term newborns with gestational age ≥37weeks and birth weight ≥2500g. The NR1I3 variants were genotyped by using high resolution melting (HRM) assays and verified by DNA sequencing. Gender, mode of delivery and birth weight did not differ between hyperbilirubinemia and control groups. The genotypic and allelic frequencies of MPJ6_1I3008, IVS8+116T>G and 540A>G were not significantly different between the groups. However, stratification by gender revealed a significant inverse association between homozygous variant genotype of MPJ6_1I3008 and risk of neonatal hyperbilirubinemia in the females (OR, 0.44; 95% CI, 0.20-0.95; p=0.034). This study demonstrates that the homozygous variant genotype of MPJ6_1I3008 was associated with a significant reduced risk of neonatal hyperbilirubinemia in the females.
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http://dx.doi.org/10.1016/j.gene.2015.07.045DOI Listing
December 2015

Engineering and Validation of a Vector for Concomitant Expression of Rare Transfer RNA (tRNA) and HIV-1 nef Genes in Escherichia coli.

PLoS One 2015 6;10(7):e0130446. Epub 2015 Jul 6.

Oncological and Radiological Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang, Malaysia.

Relative ease in handling and manipulation of Escherichia coli strains make them primary candidate to express proteins heterologously. Overexpression of heterologous genes that contain codons infrequently used by E. coli is related with difficulties such as mRNA instability, early termination of transcription and/or translation, deletions and/or misincorporation, and cell growth inhibition. These codon bias -associated problems are addressed by co-expressing ColE1-compatible, rare tRNA expressing helper plasmids. However, this approach has inadequacies, which we have addressed by engineering an expression vector that concomitantly expresses the heterologous protein of interest, and rare tRNA genes in E. coli. The expression vector contains three (argU, ileY, leuW) rare tRNA genes and a useful multiple cloning site for easy in-frame cloning. To maintain the overall size of the parental plasmid vector, the rare tRNA genes replaced the non-essential DNA segments in the vector. The cloned gene is expressed under the control of T7 promoter and resulting recombinant protein has a C-terminal 6His tag for IMAC-mediated purification. We have evaluated the usefulness of this expression vector by expressing three HIV-1 genes namely HIV-1 p27 (nef), HIV-1 p24 (ca), and HIV-1 vif in NiCo21(DE3) E.coli and demonstrated the advantages of using expression vector that concomitantly expresses rare tRNA and heterologous genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492947PMC
March 2016

WITHDRAWN: Rh genotypes among Malaysian blood donors.

Transfus Apher Sci 2014 Dec 12. Epub 2014 Dec 12.

Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM), Bertam, Penang, Malaysia.

This article has been withdrawn at the request of the author and editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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http://dx.doi.org/10.1016/j.transci.2014.12.001DOI Listing
December 2014

Gene Silencing by RNAi in Mammalian Cells.

Curr Protoc Mol Biol 2015 Jul 1;111:26.2.1-26.2.17. Epub 2015 Jul 1.

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.

This unit provides information how to use short interfering RNA (siRNA) for sequence-specific gene silencing in mammalian cells. Several methods for siRNA generation and optimization, as well as recommendations for cell transfection and transduction, are presented.
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http://dx.doi.org/10.1002/0471142727.mb2602s111DOI Listing
July 2015

Human non-small cell lung cancer expresses putative cancer stem cell markers and exhibits the transcriptomic profile of multipotent cells.

BMC Cancer 2015 Feb 25;15:84. Epub 2015 Feb 25.

Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bertam, 13200, Kepala Batas, Pulau Pinang, Malaysia.

Background: Despite significant advances in staging and therapies, lung cancer remains a major cause of cancer-related lethality due to its high incidence and recurrence. Clearly, a novel approach is required to develop new therapies to treat this devastating disease. Recent evidence indicates that tumours contain a small population of cells known as cancer stem cells (CSCs) that are responsible for tumour maintenance, spreading and resistant to chemotherapy. The genetic composition of CSCs so far is not fully understood, but manipulation of the specific genes that maintain their integrity would be beneficial for developing strategies to combat cancer. Therefore, the goal of this study isto identify the transcriptomic composition and biological functions of CSCs from non-small cell lung cancer (NSCLC).

Methods: We isolated putative lung CSCs from lung adenocarcinoma cells (A549 and H2170) and normal stem cells from normal bronchial epithelial cells (PHBEC) on the basis of positive expression of stem cell surface markers (CD166, CD44, and EpCAM) using fluorescence-activated cell sorting. The isolated cells were then characterised for their self-renewal characteristics, differentiation capabilities, expression of stem cell transcription factor and in vivo tumouregenicity. The transcriptomic profiles of putative lung CSCs then were obtained using microarray analysis. Significantly regulated genes (p < 0.05, fold change (FC) > 2.0) in putative CSCs were identified and further analysed for their biological functions using the Database for Annotation, Visualization, and Integrated Discovery (DAVID).

Results: The putative lung CSCs phenotypes of CD166(+)/CD44(+) and CD166(+)/EpCAM(+) showed multipotent characteristics of stem cells, including the ability to differentiate into adipogenic and osteogenic cells, self-renewal, and expression of stem cell transcription factors such as Sox2 and Oct3/4. Moreover, the cells also shows the in vivo tumouregenicity characteristic when transplanted into nude mice. Microarray and bioinformatics data analyses revealed that the putative lung CSCs have molecular signatures of both normal and cancer stem cells and that the most prominent biological functions are associated with angiogenesis, migration, pro-apoptosis and anti-apoptosis, osteoblast differentiation, mesenchymal cell differentiation, and mesenchyme development. Additionally, self-renewal pathways such as the Wnt and hedgehog signalling pathways, cancer pathways, and extracellular matrix (ECM)-receptor interaction pathways are significantly associated with the putative lung CSCs.

Conclusion: This study revealed that isolated lung CSCs exhibit the characteristics of multipotent stem cells and that their genetic composition might be valuable for future gene and stem cells therapy for lung cancer.
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http://dx.doi.org/10.1186/s12885-015-1086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349658PMC
February 2015

Molecular basis of Rh blood group system in the Malaysian population.

Asian J Transfus Sci 2015 Jan-Jun;9(1):48-54

Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Pulau Penang, Malaysia.

Background: Rh molecular studies have been previously mainly conducted in Caucasians and African population. There is a limited data on the molecular basis for Rh genotypes among Asians.

Aims: This study aims to characterize the Rh genes and frequency of the various RH genotypes among blood donors in National Blood Centre (NBC), Kuala Lumpur.

Materials And Methods: A total of 1014 blood samples were obtained from blood donors from four different ethnic groups (360 Malays, 434 Chinese, 164 Indians and 56 others). Serological and molecular analysis of all 1014 blood samples were performed. An automated deoxyribonucleic acid sequencing analysis was performed.

Results: Rh phenotypes and RH genotypes showed heterogeneity and significant association with ethnicities. Discrepancies in allele D, C/c and E/e between phenotypes and genotypes results were observed. Discrepancy results in allele D showed significant association with the ethnic groups of the blood donors in NBC. There were multiple novel mutations (23) and published mutations (5) found in this study. Significant associations between discrepancy results and mutations were found in allele D and C/c.

Conclusion: Performing RH molecular analysis in Malaysian population provided the basic database for the distribution of Rh genotypes of donors from major ethnic groups in Malaysia.
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http://dx.doi.org/10.4103/0973-6247.150951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339932PMC
February 2015

M2/ANXA5 haplotype as a predisposition factor in Malay women and couples experiencing recurrent spontaneous abortion: a pilot study.

Reprod Biomed Online 2015 Apr 13;30(4):434-9. Epub 2015 Jan 13.

Institute of Human Genetics, University of Muenster, Muenster, Germany. Electronic address:

Recurrent spontaneous abortion (RSA) is a prevalent condition among the Malay population of Malaysia, where carriage risk of conventional hereditary thrombophilia factors has been generally ruled out. The contribution of M2/ANXA5, a common haplotype in the annexin A5 gene promoter, was evalauted for RSA in Malay. Seventy-seven women who had experienced two or more unexplained RSA and 41 available male partners were selected for study, with 360 population controls recruited from healthy Malay individuals. Incidence of M2 carriage and odds ratios were calculated between control and patient groups, and clinically defined subgroups and RSA risk was evaluated. M2/ANXA5, found in 42.2% of the general Malay population, was associated with greater risks for women with primary and secondary RSA with early (gestational week 5-15) losses. The risk was somewhat higher in Malay couples when both partners were carriers and a trend of higher prevalence was seen for the male partners patients who had experienced RSA. M2 carriage seems to be a risk factor with unusually high incidence in Malay women and couples with primary and secondary RSA with 'early' spontaneous abortions. The associated male partner risk confirms the proposed role of M2/ANXA5 as a genetic trait impeding embryonic anticoagulation.
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http://dx.doi.org/10.1016/j.rbmo.2014.12.014DOI Listing
April 2015

The effects of virgin coconut oil (VCO) as supplementation on quality of life (QOL) among breast cancer patients.

Lipids Health Dis 2014 Aug 27;13:139. Epub 2014 Aug 27.

Institut Perubatan dan Pergigian Termaju, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia.

Background: Breast cancer is the most common cancer amongst Malaysian women. Both the disease and its treatment can disrupt the lives of the woman and adversely affect all aspects of life and thus can alter a woman's quality of life. The aim of this study was to examine the effect of virgin coconut oil (VCO) on the quality of life (QOL) of patients diagnosed with breast cancer.

Methods: This was a prospective study of breast cancer patients admitted into the Oncology Unit of Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. The sample consisted of 60 patients with stage III and IV breast cancer allocated to either an intervention group (n = 30) or a control group (n = 30) using a simple random table. QOL was evaluated from the first cycle of chemotherapy to the sixth cycle, and data were collected using a validated Bahasa Malaysia version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer Module (EORTC QLQ-C30) and its breast-specific module (QLQ-BR 23).

Results: The mean age of breast cancer patients was 50.2 (SD = 13.5) years. There were significant mean score differences for functioning and global QOL between groups (α < 0.01). The intervention group also had better scores for symptoms including fatigue, dyspnea, sleep difficulties, and loss of appetite compared to the control group. Although there are deteriorations for sexual enjoyment, the intervention group exhibited improvement in breast functioning and symptom scores for body image, sexual function, future perspective, breast symptoms, and systemic therapy side effects.

Conclusion: VCO consumption during chemotherapy helped improve the functional status and global QOL of breast cancer patients. In addition, it reduced the symptoms related to side effects of chemotherapy.
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http://dx.doi.org/10.1186/1476-511X-13-139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176590PMC
August 2014

Dengue virus type 2 (DENV2)-induced oxidative responses in monocytes from glucose-6-phosphate dehydrogenase (G6PD)-deficient and G6PD normal subjects.

PLoS Negl Trop Dis 2014 Mar 13;8(3):e2711. Epub 2014 Mar 13.

Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia.

Background: Dengue virus is endemic in peninsular Malaysia. The clinical manifestations vary depending on the incubation period of the virus as well as the immunity of the patients. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is prevalent in Malaysia where the incidence is 3.2%. It has been noted that some G6PD-deficient individuals suffer from more severe clinical presentation of dengue infection. In this study, we aim to investigate the oxidative responses of DENV2-infected monocytes from G6PD-deficient individuals.

Methodology: Monocytes from G6PD-deficient individuals were infected with DENV2 and infection rate, levels of oxidative species, nitric oxide (NO), superoxide anions (O2-), and oxidative stress were determined and compared with normal controls.

Principal Findings: Monocytes from G6PD-deficient individuals exhibited significantly higher infection rates compared to normal controls. In an effort to explain the reason for this enhanced susceptibility, we investigated the production of NO and O2- in the monocytes of individuals with G6PD deficiency compared with normal controls. We found that levels of NO and O2- were significantly lower in the DENV-infected monocytes from G6PD-deficient individuals compared with normal controls. Furthermore, the overall oxidative stress in DENV-infected monocytes from G6PD-deficient individuals was significantly higher when compared to normal controls. Correlation studies between DENV-infected cells and oxidative state of monocytes further confirmed these findings.

Conclusions/significance: Altered redox state of DENV-infected monocytes from G6PD-deficient individuals appears to augment viral replication in these cells. DENV-infected G6PD-deficient individuals may contain higher viral titers, which may be significant in enhanced virus transmission. Furthermore, granulocyte dysfunction and higher viral loads in G6PD-deificient individuals may result in severe form of dengue infection.
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http://dx.doi.org/10.1371/journal.pntd.0002711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953068PMC
March 2014

Anti-tumor activity of Eurycoma longifolia root extracts against K-562 cell line: in vitro and in vivo study.

PLoS One 2014 7;9(1):e83818. Epub 2014 Jan 7.

Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM), Kepala Batas, Pulau Pinang, Malaysia.

Eurycoma longifolia Jack has been widely used in traditional medicine for its antimalarial, aphrodisiac, anti-diabetic, antimicrobial and anti-pyretic activities. Its anticancer activity has also been recently reported on different solid tumors, however no anti-leukemic activity of this plant has been reported. Thus the present study assesses the in vitro and in vivo anti-proliferative and apoptotic potentials of E. longifolia on K-562 leukemic cell line. The K-562 cells (purchased from ATCC) were isolated from patients with chronic myelocytic leukemia (CML) were treated with the various fractions (TAF273, F3 and F4) of E. longifolia root methanolic extract at various concentrations and time intervals and the anti-proliferative activity assessed by MTS assay. Flow cytometry was used to assess the apoptosis and cell cycle arrest. Nude mice injected subcutaneously with 10(7) K-562 cells were used to study the anti-leukemic activity of TAF273 in vivo. TAF273, F3 and F4 showed various degrees of growth inhibition with IC50 values of 19, 55 and 62 µg/ml, respectively. TAF273 induced apoptosis in a dose and time dependent manner. TAF273 arrested cell cycle at G1 and S phases. Intraperitoneal administration of TAF273 (50 mg/kg) resulted in a significant growth inhibition of subcutaneous tumor in TAF273-treated mice compared with the control mice (P = 0.024). TAF273 shows potent anti-proliferative activity in vitro and in vivo models of CML and therefore, justifies further efforts to define more clearly the potential benefits of using TAF273 as a novel therapeutic strategy for CML management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083818PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883656PMC
September 2014

Production and purification of polymerization-competent HIV-1 capsid protein p24 (CA) in NiCo21(DE3) Escherichia coli.

BMC Biotechnol 2013 Dec 4;13:107. Epub 2013 Dec 4.

Oncological and Radiological Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia.

Background: HIV genome is packaged and organized in a conical capsid, which is made up of ~1,500 copies of the viral capsid protein p24 (CA). Being a primary structural component and due to its critical roles in both late and early stages of the HIV replication cycle, CA has attracted increased interest as a drug discovery target in recent years. Drug discovery studies require large amounts of highly pure and biologically active protein. It is therefore desirable to establish a simple and reproducible process for efficient production of HIV-1 CA.

Result: In this work, 6-His-tagged wild type CA from HIV-1 (NL4.3) was expressed in rare tRNA-supplemented NiCo21(DE3) Escherichia coli, and its production was studied in shake flask culture condition of expression. Influences of various key cultivation parameters were examined to identify optimal conditions for HIV-1 CA production. It was found that a culture temperature of 22°C and induction with 0.05 mM IPTG at the early stage of growth were ideal, leading to a maximum biomass yield when grown in Super broth supplemented with 1% glucose. With optimized culture conditions, a final biomass concentration of ~27.7 g L⁻¹ (based on optical density) was obtained in 12 hours post-induction, leading to a yield of about ~170 mg L⁻¹ HIV-1 CA. A two-step purification strategy (chitin beads + IMAC) was employed, which efficiently removed metal affinity resin-binding bacterial proteins that contaminate recombinant His-tagged protein preparation, and resulted in highly pure HIV-1 CA. The purified protein was capable of polymerization when tested in an in vitro polymerization assay.

Conclusions: By using this optimized expression and purification procedure, milligram amounts of highly pure and polymerization-competent recombinant HIV-1 CA can be produced at the lab-scale and thus used for further biochemical studies.
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http://dx.doi.org/10.1186/1472-6750-13-107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235032PMC
December 2013

Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial cell function.

Microvasc Res 2013 Nov 27;90:30-9. Epub 2013 Jul 27.

Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM), 13200 Kepala Batas, Pulau Pinang, Malaysia.

Targeting angiogenesis could be an excellent strategy to combat angiogenesis-dependent pathophysiological conditions such as cancer, rheumatoid arthritis, obesity, systemic lupus erythematosus, psoriasis, proliferative retinopathy and atherosclerosis. Recently a number of clinical investigations are being undertaken to assess the potential therapeutic application of various anti-angiogenic agents. Many of these angiogenesis inhibitors are directed against the functions of endothelial cells, which are considered as the building blocks of blood vessels. Similarly, roots of a traditional medicinal plant, Eurycoma longifolia, can be used as an alternative treatment to prevent and treat the angiogenesis-related diseases. In the present study, antiangiogenic potential of partially purified quassinoid-rich fraction (TAF273) of E. longifolia root extract was evaluated using ex vivo and in vivo angiogenesis models and the anti-angiogenic efficacy of TAF273 was investigated in human umbilical vein endothelial cells (HUVEC). TAF273 caused significant suppression in sprouting of microvessels in rat aorta with IC50 11.5μg/ml. TAF273 (50μg/ml) showed remarkable inhibition (63.13%) of neovascularization in chorioallantoic membrane of chick embryo. Tumor histology also revealed marked reduction in extent of vascularization. In vitro, TAF273 significantly inhibited the major angiogenesis steps such as proliferation, migration and differentiation of HUVECs. Phytochemical analysis revealed high content of quassinoids in TAF273. Specially, HPLC characterization showed that TAF273 is enriched with eurycomanone, 13α(21)-epoxyeurycomanone and eurycomanol. These results demonstrated that the antiangiogenic activity of TAF273 may be due to its inhibitory effect on endothelial cell proliferation, differentiation and migration which could be attributed to the high content of quassinoids in E. longifolia.
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http://dx.doi.org/10.1016/j.mvr.2013.07.007DOI Listing
November 2013

X-linked chronic granulomatous disease in a male child with an X-CGD carrier, Klinefelter brother.

Asian Pac J Allergy Immunol 2013 Jun;31(2):167-72

Institute for Medical Research, Jalan Pahang, Kuala Lumpur, Malaysia.

Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency (PID) caused by a dysfunctional respiratory burst enzyme NADPH-oxidase. The concurrence of Klinefelter's Syndrome (KS) and CGD would be extremely rare.

Objective: We describe the study of a family where the youngest male child had X-linked CGD (X-CGD) while his older brother was both an X-CGD carrier and a Klinefelter.

Methods: Flow cytometry was used to study respiratory burst and gp91-phox expression, while genetic investigation was done by RT-PCR, PCR and X-chromosome short tandem repeat (X-STR) analysis.

Results: The Dihydrorhodamine (DHR) assay showed the patient's neutrophils failed to produce a respiratory burst, while both the mother and an older brother showed a bimodal response. gp91-phox expression was absent in the patient's neutrophils, and bimodal in the mother's and brother's neutrophils. The patient's cDNA showed a C>T change at nucleotide 676 of the CYBB gene. The same change was seen in the patient's gDNA, while the brother and mother were heterozygous, with C and T, in this position. The c.676C>T is a nonsense mutation that leads to premature termination of the gp91-phox protein. The brother karyotyped as 47, XXY and X chromosome analysis showed that he had inherited both his mother's X chromosomes.

Conclusions: This study showed that the patient had gp91-phox deficient CGD while his older brother was a CGD carrier and a Klinefelter, who had inherited both his mother's X chromosomes. This is the first report of such a concurrence in an individual, and argues for family members to be included in PID studies.
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http://dx.doi.org/10.12932/AP0274.31.2.2013DOI Listing
June 2013

Identification of novel mutations in exon 14 of the f8 gene in malaysian patients with severe hemophilia a.

Indian J Clin Biochem 2012 Apr 30;27(2):207-8. Epub 2011 Sep 30.

Advanced Medical & Dental Institute, Universiti Sains Malaysia, No. 1-8, Persiaran Seksyen 4/1, Bandar Putra Bertam, 13200 Kepala Batas, Penang, Malaysia.

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http://dx.doi.org/10.1007/s12291-011-0161-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358369PMC
April 2012