Publications by authors named "Rosline Hassan"

37 Publications

Prevalence and characteristics of fever in adult and paediatric patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis of 17515 patients.

PLoS One 2021 6;16(4):e0249788. Epub 2021 Apr 6.

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

Background: Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 started to spread globally since December 2019 from Wuhan, China. Fever has been observed as one of the most common clinical manifestations, although the prevalence and characteristics of fever in adult and paediatric COVID-19 patients is inconclusive. We aimed to conduct a systematic review and meta-analysis to estimate the overall pooled prevalence of fever and chills in addition to fever characteristics (low, medium, and high temperature) in both adult and paediatric COVID-19 patients.

Methods: The protocol of this systematic review and meta-analysis was registered with PROSPERO (CRD42020176327). PubMed, Scopus, ScienceDirect and Google Scholar databases were searched between 1st December 2019 and 3rd April 2020 without language restrictions. Both adult (≥18 years) and paediatric (<18 years) COVID-19 patients were considered eligible. We used random-effects model for the meta-analysis to obtain the pooled prevalence and risk ratio (RR) with 95% confidence intervals (CIs). Quality assessment of included studies was performed using the Joanna Briggs Institute critical appraisal tools. Heterogeneity was assessed using the I² statistic and Cochran's Q test. Robustness of the pooled estimates was checked by different subgroups and sensitivity analyses.

Results: We identified 2055 studies, of which 197 studies (n = 24266) were included in the systematic review and 167 studies with 17142 adults and 373 paediatrics were included in the meta-analysis. Overall, the pooled prevalence of fever in adult and paediatric COVID-19 patients were 79.43% [95% CI: 77.05-81.80, I2 = 95%] and 45.86% [95% CI: 35.24-56.48, I2 = 78%], respectively. Besides, 14.45% [95% CI: 10.59-18.32, I2 = 88%] of the adult COVID-19 patients were accompanied with chills. In adult COVID-19 patients, the prevalence of medium-grade fever (44.33%) was higher compared to low- (38.16%) and high-grade fever (14.71%). In addition, the risk of both low (RR: 2.34, 95% CI: 1.69-3.22, p<0.00001, I2 = 84%) and medium grade fever (RR: 2.79, 95% CI: 2.21-3.51, p<0.00001, I2 = 75%) were significantly higher compared to high-grade fever, however, there was no significant difference between low- and medium-grade fever (RR: 1.17, 95% CI: 0.94-1.44, p = 0.16, I2 = 87%). 88.8% of the included studies were of high-quality. The sensitivity analyses indicated that our findings of fever prevalence for both adult and paediatric patients are reliable and robust.

Conclusions: The prevalence of fever in adult COVID-19 patients was high, however, 54.14% of paediatric COVID-19 patients did not exhibit fever as an initial clinical feature. Prevalence and risk of low and medium-grade fevers were higher compared to high-grade fever.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023501PMC
April 2021

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Front Oncol 2021 25;11:624742. Epub 2021 Feb 25.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4 and CD8 T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.
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http://dx.doi.org/10.3389/fonc.2021.624742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947882PMC
February 2021

Prevalence and distribution of major β-thalassemia mutations and HbE/β-thalassemia variant in Nepalese ethnic groups.

Hematol Oncol Stem Cell Ther 2021 Feb 11. Epub 2021 Feb 11.

Malaysian Node of Human Variome Project, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia; Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia. Electronic address:

Background: Beta-thalassemia is a genetic disorder that is inherited in an autosomal recessive pattern. This genetic disease leads to a defective beta-globin hemoglobin chain causing partial or complete beta-globin chain synthesis loss. Beta-thalassemia major patients need a continuous blood transfusion and iron chelation to maintain the normal homeostasis of red blood cells (RBCs) and other systems in the body. Patients also require treatment procedures that are costly and tedious, resulting in a serious health burden for developing nations such as Nepal.

Methods: A total of 61 individuals clinically diagnosed to have thalassemia were genotyped with multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Twenty-one major mutations were investigated using allele-specific primers grouped into six different panels.

Results: The most common mutations found (23%) were IVS 1-5 (G-C) and Cd 26 (G-A) (HbE), followed by 619 deletion, Cd 8/9 (+G), Cd 16 (-C), Cd 41/42 (-TTCT), IVS 1-1 (G-T), Cd 19 (A-G), and Cd 17 (A-T) at 20%, 12%, 8%, 6%, 4%, 3%, and 1%, respectively.

Conclusion: The results of this study revealed that Nepal's mutational profile is comparable to that of its neighboring countries, such as India and Myanmar. This study also showed that thalassemia could be detected across 17 Nepal's ethnic groups, especially those whose ancestors originated from India and Central Asia.
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http://dx.doi.org/10.1016/j.hemonc.2021.01.004DOI Listing
February 2021

Aberrant Methylation of Tumour Suppressor Gene ADAM12 in Chronic Lympocytic Leukemia Patients: Application of Methylation Specific-PCR Technique.

Asian Pac J Cancer Prev 2021 Jan 1;22(1):85-91. Epub 2021 Jan 1.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Objective: Chronic Lymphocytic Leukemia (CLL) is a common leukemia among Caucasians but rare in Asians population. We postulated that aberrant methylation either hypermethylation or partial methylation might be one of the silencing mechanisms that inactivates the tumour suppressor genes in CLL. This study aimed to compare the methylation status of tumour suppressor gene, ADAM12, among CLL patients and normal individuals. We also evaluated the association between methylation of ADAM12 and clinical and demographic characteristics of the participants.

Methods: A total of 25 CLL patients and 25 normal individuals were recruited in this study. The methylation status of ADAM12 was determined using Methylation-Specific PCR (MSP); whereas, DNA sequencing method was applied for validation of the MSP results.

Results: Among CLL patients, 12 (48%) were partially methylated and 13 (52%) were unmethylated. Meanwhile, 5 (20%) and 20 (80.6%) of healthy individuals were partially methylated and unmethylated, respectively. There was a statistically significant association between the status of methylation at ADAM12 and the presence of CLL (p=0.037).

Conclusion: The aberrant methylation of ADAM12 found in this study using MSP assay may provide new exposure to CLL that may improve the gaps involved in genetic epigenetic study in CLL.
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http://dx.doi.org/10.31557/APJCP.2021.22.1.85DOI Listing
January 2021

Immunomodulatory Effects of Diet and Nutrients in Systemic Lupus Erythematosus (SLE): A Systematic Review.

Front Immunol 2020 22;11:1477. Epub 2020 Jul 22.

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

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, including the skin, joints, kidneys, lungs, central nervous system and the haematopoietic system, with a large number of complications. Despite years of study, the etiology of SLE remains unclear; thus, safe and specifically targeted therapies are lacking. In the last 20 years, researchers have explored the potential of nutritional factors on SLE and have suggested complementary treatment options through diet. This study systematically reviews and evaluates the clinical and preclinical scientific evidence of diet and dietary supplementation that either alleviate or exacerbate the symptoms of SLE. For this review, a systematic literature search was conducted using PubMed, Scopus and Google Scholar databases only for articles written in the English language. Based on the currently published literature, it was observed that a low-calorie and low-protein diet with high contents of fiber, polyunsaturated fatty acids, vitamins, minerals and polyphenols contain sufficient potential macronutrients and micronutrients to regulate the activity of the overall disease by modulating the inflammation and immune functions of SLE.
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http://dx.doi.org/10.3389/fimmu.2020.01477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387408PMC
May 2021

Gene Therapy Approaches in an Autoimmune Demyelinating Disease: Multiple Sclerosis.

Curr Gene Ther 2020 ;19(6):376-385

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Multiple Sclerosis (MS) is the most common autoimmune demyelinating disease of the Central Nervous System (CNS). It is a multifactorial disease which develops in an immune-mediated way under the influences of both genetic and environmental factors. Demyelination is observed in the brain and spinal cord leading to neuro-axonal damage in patients with MS. Due to the infiltration of different immune cells such as T-cells, B-cells, monocytes and macrophages, focal lesions are observed in MS. Currently available medications treating MS are mainly based on two strategies; i) to ease specific symptoms or ii) to reduce disease progression. However, these medications tend to induce different adverse effects with limited therapeutic efficacy due to the protective function of the blood-brain barrier. Therefore, researchers have been working for the last four decades to discover better solutions by introducing gene therapy approaches in treating MS generally by following three strategies, i) prevention of specific symptoms, ii) halt or reverse disease progression and iii) heal CNS damage by promoting remyelination and axonal repair. In last two decades, there have been some remarkable successes of gene therapy approaches on the experimental mice model of MS - experimental autoimmune encephalomyelitis (EAE) which suggests that it is not far that the gene therapy approaches would start in human subjects ensuring the highest levels of safety and efficacy. In this review, we summarised the gene therapy approaches attempted in different animal models towards treating MS.
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http://dx.doi.org/10.2174/1566523220666200306092556DOI Listing
January 2020

Genetic polymorphisms of HbE/beta thalassemia related to clinical presentation: implications for clinical diversity.

Ann Hematol 2020 Apr 20;99(4):729-735. Epub 2020 Feb 20.

Department Hematology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

HbE/Beta thalassemia (HbE/β-thalassemia) is one of the common genetic disorders in South East Asia. It is heterogeneous in its clinical presentation and molecular defects. There are genetic modifiers which have been reported to influence the disease severity of this disorder. The aim of this study was to determine the genetic polymorphisms which were responsible for the disease clinical diversity. A case-control study was conducted among Malay transfusion-dependent HbE/β-thalassemia patients. Patients who were confirmed HbE/β-thalassemia were recruited and genotyping study was performed on these subjects. Ninety-eight patients were selected and divided into moderate and severe groups based on clinical parameters using Sripichai scoring system (based on hemoglobin level, spleen size, growth development, the age of first transfusion and age of disease presentation). Forty-three (44.9%) and 55 (56.1%) patients were found to have moderate and severe clinical presentation, respectively. Genotyping analysis was performed using Affymetrix 6.0 microarray platform. The SNPs were filtered using PLINK and Manhattan plot by R software. From the GWAS results, 20 most significant SNPs were selected based on disease severity when compared between moderate and severe groups. The significant SNPs found in this study were mostly related to thalassemia complications such as rs7372408, associated with KCNMB2-AS1 and SNPs associated with disease severity. These findings could be used as genetic predictors in managing patients with HbE/β-thalassemia and served as platform for future study.
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http://dx.doi.org/10.1007/s00277-020-03927-5DOI Listing
April 2020

Prevalence of antiphospholipid antibodies in Behçet's disease: A systematic review and meta-analysis.

PLoS One 2020 13;15(1):e0227836. Epub 2020 Jan 13.

Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka , Bangladesh.

Behçet's disease (BD) is a multifactorial systemic inflammatory disease of unknown aetiology characterised by several clinical manifestations including vascular involvements (i.e., both arterial and venous thrombosis). Antiphospholipid antibodies (aPLs)-including anticardiolipin (aCL), anti-β2-glycoprotein I (β2-GPI) antibodies and lupus anticoagulant (LA) are detected in systemic autoimmune diseases which contribute to thrombosis. The aim of this systematic review and meta-analysis was to evaluate the prevalence of aPLs in patients with BD as compared to controls. A protocol was registered in PROSPERO (Registration No. CRD42018088125) and a systematic literature search was conducted through PubMed, Web of Science, Embase, Scopus and ScienceDirect databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). Publication bias was evaluated via visualisation of contour- enhanced and trim and fill funnel plots along with Begg's and Egger's tests. We included ten case-control studies (a total of 999 participants from 380 BD patients and 619 controls) based on the inclusion criteria. The prevalence of aCL (OR: 12.10, 95% CI: 5.15-28.41, p<0.00001) and anti-β2-GPI antibodies (OR: 23.57, 95% CI: 1.31-423.63, p = 0.03) were statistically significant, however, the prevalence of LA was not significant (OR: 13.77, 95% CI: 0.65-293.59, p = 0.09). The results remained statistically significant from different sensitivity analyses which represented the robustness of this meta-analysis. According to the NOS, 50.0% of the studies were considered as of high methodological quality (low risk of bias). No significant publication bias was detected from contour-enhanced and trim and fill funnel plots or Begg's and Egger's tests. This meta-analysis established that there is a significantly high prevalence of aPLs (i.e., aCL and anti-β2-GPI antibodies) in patients with BD when compared to controls.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227836PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957187PMC
April 2020

Alpha-hemoglobin-stabilizing protein (AHSP): a modulatory factor in β-thalassemia.

Int J Hematol 2020 Mar 1;111(3):352-359. Epub 2020 Jan 1.

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

Hemoglobin (Hb) is an iron-containing metalloprotein that transports oxygen molecules from the lungs to the rest of the human body. Among the different variants of Hb, HbA1 is the most common and is composed of two alpha (αHb) and two beta globin chains (βHb) constructing a heterotetrameric protein complex (αβ). Due to the higher number of AHSP genes, there is a tendency to produce approximately twice as much of α subunit as β subunit. Therefore, there is a chance of presenting excess α subunit leftover in human blood plasma; excess subunits subsequently bind with each other and aggregates β-thalassemia occurs due to lack of or reduced numbers of βHb subunit. Alpha-hemoglobin-stabilizing protein (AHSP) is a scavenger protein which acts as a molecular chaperon by reversibly binding with free αHb forming a complex (AHSP-αHb) that prevents aggregation and precipitation preventing deleterious effects towards developing serious human diseases including β-thalassemia. Clinical severity worsens if mutations in AHSP gene co-occur in patients with β-thalassemia. Considering the mechanism of action of AHSP and its contribution to ameliorating β-thalassemia severity, it could potentially be used as a modulatory agent in the treatment of β-thalassemia.
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http://dx.doi.org/10.1007/s12185-019-02806-8DOI Listing
March 2020

Vitamin D status in patients with systemic lupus erythematosus (SLE): A systematic review and meta-analysis.

Autoimmun Rev 2019 Nov 11;18(11):102392. Epub 2019 Sep 11.

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease where chronic inflammation and tissue or organ damage is observed. Due to various suspected causes, inadequate levels of vitamin D (a steroid hormone with immunomodulatory effects) has been reported in patients with SLE, however, contradictory.

Aims: The aim of this systematic review and meta-analysis was to evaluate the serum levels of vitamin D in patients with SLE in compared to healthy controls.

Methods: PubMed, SCOPUS, ScienceDirect and Google Scholar electronic databases were searched systematically without restricting the languages and year (up to March 2, 2019) and studies were selected based on the inclusion criteria. Mean difference (MD) along with 95% confidence intervals (CI) were used and the analyses were carried out by using a random-effects model. Different subgroup and sensitivity analyses were conducted. Study quality was assessed by the modified Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by a contour-enhanced funnel plot, Begg's and Egger's tests.

Results: We included 34 case-control studies (2265 SLE patients and 1846 healthy controls) based on the inclusion criteria. Serum levels of vitamin D was detected significantly lower in the SLE patients than that in the healthy controls (MD: -10.44, 95% CI: -13.85 to -7.03; p < .00001). SLE patients from Asia (MD: -13.75, 95% CI: -21.45 to -6.05; p = .0005), South America (MD: -3.16, 95% CI: -4.62 to -1.70; p < .0001) and Africa (MD: -16.15, 95% CI: -23.73 to -8.56; p < .0001); patients residing below 37° latitude (MD: -11.75, 95% CI: -15.79 to -7.70; p < .00001); serum vitamin D during summer season (MD: -7.89, 95% CI: -11.70 to -4.09; p < .0001), patients without vitamin D supplementation (MD: -15.57, 95% CI: -19.99 to -11.14; p < .00001) or on medications like hydroxychloroquine, corticosteroids or immunosuppressants without vitamin D supplementation (MD: -16.46, 95% CI: -23.86 to -9.05; p < .0001) are in higher risk in presenting inadequate serum levels of vitamin D. The results remained statistically significant from different sensitivity analyses which represented the robustness of this meta-analysis. According to the NOS, 91.2% of the studies were considered as of high methodological quality (low risk of bias). No significant publication bias was detected from contour-enhanced and trim and fill funnel plots or Begg's test.

Conclusion: Inadequate levels of serum vitamin D is significantly high in patients with SLE compared to healthy subjects, therefore, vitamin D supplementation with regular monitoring should be considered as part of their health management plans.
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http://dx.doi.org/10.1016/j.autrev.2019.102392DOI Listing
November 2019

Commemorating the 40-Year Journey of the School of Medical Sciences, Universiti Sains Malaysia.

Malays J Med Sci 2019 Mar 30;26(2):1-7. Epub 2019 Apr 30.

School of Medical Sciences, Universiti Sains Malaysia, USM Health Campus, Kubang Kerian, Kelantan, Malaysia.

The School of Medical Sciences of Universiti Sains Malaysia (USM) is the launching pad for this journal. From the school's humble beginning at the USM Main Campus in Pulau Pinang, Malaysia, it has grown in stature at its current location in the USM Health Campus, Kubang Kerian, Kelantan, Malaysia. Commemorating its 40th anniversary, this editorial aims to recollect, although not exhaustively, the wealth of returns for the USM, as well as for the nation, which the school has managed to deliver in that period. Resolute to its vision and mission, this article highlights the outstanding accomplishments in various core aspects of the school's academic, research and professional growth as we continually strive to train globally competitive and compassionate medical graduates, medical specialists and scientists, skilled to serve nation's needs and broader markets worldwide. Currently guided by the Malaysian Higher Education Blueprint (2015-2025), the school shall remain ingenious in its duties in the many more years to come, as we head for a world-class trajectory.
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http://dx.doi.org/10.21315/mjms2019.26.2.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687216PMC
March 2019

Interleukin-10 (1082G/A) Polymorphism is Associated with Susceptibility of Acute Myeloid Leukemia Patients in Sudanese Population.

Asian Pac J Cancer Prev 2019 07 1;20(7):1939-1943. Epub 2019 Jul 1.

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

Background: Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and antiangiogenicfunctions and may have both tumor-promoting and -inhibiting properties. We examined the association between a single nucleotide polymorphism (SNP) in IL-10 -1082G/A (rs1800896) in Sudanese acute myeloid leukemia (AML) patients and to assess the association between polymorphisms in IL-10 -1082G/A (rs1800896) and the hematological profile in Sudanese patients with AML. Methods: A total of 30 patients with acute myeloid leukemia and 30 control subjects were enrolled in this study. Blood samples were collected from all patients in EDTA containing tubes. Genomic DNA was extracted from all blood samples using salting out method. The genotypic variants of IL-10 (-1082G/A) polymorphism were detected by allele specific-PCR. Results: We found that (36.7%) of patients have homogenous GG genotype, (43.3%) have heterogeneous GA genotype and (20.0%) have AA genotype. GA genotype was significantly associated with higher risk of AML compared with the homozygous Genotypes (GG and AA), there is no association between IL-10 (-1082G/A) polymorphism and AML sub-type, gender, age group, mean of hematological parameters. Conclusion: Our study concluded that GA genotype of IL-10 -1082G/A (rs1800896) polymorphism is a risk factor for AML and G allele is insignificantly higher than A allele in AML patient. No association between IL-10 (-1082G/A) polymorphism and AML sub-type, gender, age group, mean of hematological parameters.
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http://dx.doi.org/10.31557/APJCP.2019.20.7.1939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745212PMC
July 2019

Molecular Detection of Glycophorins A and B Variant Phenotypes and their Clinical Relevance.

Transfus Med Rev 2019 04 23;33(2):118-124. Epub 2019 Feb 23.

School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia. Electronic address:

Crossover or conversion between the homologous regions of glycophorin A (GYPA) and glycophorin B (GYPB) gives rise to several different hybrid glycophorin genes encoding a number of different glycophorin variant phenotypes which bear low prevalence antigens in the MNS blood group system. GP.Mur is the main glycophorin variant phenotype which causes hemolytic transfusion reaction (HTR) and hemolytic disease of the fetus and newborn (HDFN) in East and Southeast Asians. The detection of glycophorin variant phenotypes using serological methods is limited to phenotyping reagents that are not commercially available. Moreover, the red blood cells used for antibody identification are usually of the GP.Mur phenotype. The current Polymerase Chain Reaction (PCR)-based methods and loop-mediated isothermal amplification (LAMP) are available alternatives to phenotyping that allow for the specific detection of glycophorin variant phenotypes. This review highlights the molecular detection method for glycophorins A and B variant phenotypes and their clinical relevance.
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http://dx.doi.org/10.1016/j.tmrv.2019.02.003DOI Listing
April 2019

Polycythaemia Vera among Sudanese Patients with Special Emphasis on JAK2 Mutations

Asian Pac J Cancer Prev 2019 Jan 25;20(1):41-44. Epub 2019 Jan 25.

Department of Haematology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan.

Background: In recent years, a somatic point mutation in the Janus Kinase 2 (JAK2) gene (1849 G→T, V617F) has been reported to occur in over 90% of patients with polycythemia vera (PV). Another JAK2 mutation in exon 12 had been described and shown capable of activating erythropoietin signaling pathways. Objective: In this study, we aimed to determine the frequency of Jak2 mutations (JAK2V617F and JAK2 exon 12) as well as their relationships with hematological parameters in Sudanese patients with myeloproliferative disorders (MPD). A comparison with findings of published studies from other geographic regions was included. Materials and Methods: From each of a total of 83 polycythaemia patients, six milliliters (ml) of venous blood were collected and processed for molecular analysis and measurement of serum erythropoietin level by enzyme-linked immunoassay (ELISA). The JAK2 V617F mutation was determined using an allele-specific competitive blocker (ACB) -PCR assay and High Resolution Melting (HRM) analysis was applied for the JAK2 exon 12 mutation. Results: According to patients’ history and the results for EPO levels, nine (10.7 %) out of 83 patients were found to have secondary polycythaemia and 74 (89.3%) PV. The overall frequency of the 2 JAK2 mutations was 94.6% in our Sudanese PV patients, JAK2V617F being found in 91% and JAK2 exon 12 mutations in 8.1%.Conclusion: In summary JAK2 V617F and JAK2 exon 12 mutations are very common in Sudanese PC cases.
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http://dx.doi.org/10.31557/APJCP.2019.20.1.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485582PMC
January 2019

Autologous Peripheral Blood Stem Cell Transplantation Among Lymphoproliferative Disease Patients: Factors Influencing Engraftment.

Oman Med J 2019 Jan;34(1):34-43

Department of Hematology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia.

Objectives: Autologous peripheral blood stem cells transplantation (APBSCT) is a therapeutic option which can be used in various hematological, neoplastic disorders including lymphoproliferative disease (LPD). Differences in patient populations and treatment modalities in different transplant centers mean it is important to improve the knowledge of the different factors affecting engraftment after APBSCT for the success of this procedure. We sought to determine the factors influencing neutrophil and platelet engraftment after APBSCT in patients with LPD.

Methods: We conducted a retrospective review of 70 patients with LPD (35 with lymphoma and 35 with multiple myeloma) who had undergone APBSCT between January 2008 and December 2016. Data obtained included disease type, treatment, and stem cell characteristics. Kaplan-Meier analysis was performed for probabilities of neutrophil and platelet engraftment occurred and was compared by the log-rank test. The multivariate Cox proportional hazards regression model was used for the analysis of potential independent factors influencing engraftment. A -value < 0.050 was considered statistically significant.

Results: Most patients were ethnic Malay, the median age at transplantation was 49.5 years. Neutrophil and platelet engraftment occurred in a median time of 18 (range 4-65) and 17 (range 6-66) days, respectively. The majority of patients showed engraftment with 65 (92.9%) and 63 (90.0%) showing neutrophil and platelet engraftment, respectively. We observed significant differences between neutrophil engraftment and patient's weight (< 60/≥ 60 kg), stage of disease at diagnosis, number of previous chemotherapy cycles (< 8/≥ 8), and pre-transplant radiotherapy. While for platelet engraftment, we found significant differences with gender, patient's weight (< 60/≥ 60 kg), pre-transplant radiotherapy, and CD34+ dosage (< 5.0/≥ 5.0 × 10/kg and < 7.0/≥ 7.0 × 10/kg). The stage of disease at diagnosis ( 0.012) and pre-transplant radiotherapy ( 0.025) were found to be independent factors for neutrophil engraftment whereas patient's weight (< 60/≥ 60 kg, 0.017), age at transplantation (< 50/≥ 50 years, 0.038), and CD34+ dosage (< 7.0/≥ 7.0 × 10/kg, 0.002) were found to be independent factors for platelet engraftment.

Conclusions: Patients with LPD who presented at an early stage and with no history of radiotherapy had faster neutrophil engraftment after APBSCT, while a younger age at transplantation with a higher dose of CD34+ cells may predict faster platelet engraftment. However, additional studies are necessary for better understanding of engraftment kinetics to improve the success of APBSCT.
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http://dx.doi.org/10.5001/omj.2019.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330180PMC
January 2019

Antileukemic Effect of Tualang Honey on Acute and Chronic Leukemia Cell Lines.

Biomed Res Int 2015 3;2015:307094. Epub 2015 Nov 3.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Complementary medicine using natural product as antitumor is on the rise. Much research has been performed on Tualang Honey and it was shown to have therapeutic potential in wound healing, and antimicrobial activity and be antiproliferative against several cancer models such as human osteosarcoma (HOS), human breast (MCF-7 and MDA-MB-231), and cervical (HeLa) cancer cell lines. To date, there was limited study on antileukemic properties of Tualang (Koompassia excelsa) Honey. The aim of this study was to evaluate the antileukemic effect of Tualang Honey on acute and chronic leukemia cell lines. Leukemia cell lines (K562 and MV4-11) and human mononuclear cell isolated from peripheral blood were grown in RPM1 1640 culture medium. The cells were incubated with increasing concentrations of Tualang Honey. After incubation, the evaluation of viability and apoptosis was performed. The morphological changes of leukemia cells were the presence of cytoplasmic blebs followed by apoptotic bodies and round shape of cells. IC50 against K562 and MV4-11 was determined. Tualang Honey gave 53.9% and 50.6% apoptosis activity on K562 and MV4-11, respectively, while on human mononuclear cell it was 37.4%. Tualang Honey has the apoptosis-inducing ability for acute and chronic myeloid leukemia (K562 and MV4-11) cell lines.
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http://dx.doi.org/10.1155/2015/307094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647029PMC
September 2016

Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia.

BMC Cancer 2015 Nov 7;15:869. Epub 2015 Nov 7.

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

Background: Tumor-suppressor genes are inactivated by methylation in several cancers including acute myeloid leukemia (AML). Src homology-2 (SH2)-containing protein-tyrosine phosphatase 1 (SHP-1) is a negative regulator of the JAK/STAT pathway. Transcriptional silencing of SHP-1 plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced SHP-1. Lestaurtinib (CEP-701) is a multi-targeted tyrosine kinase inhibitor that potently inhibits FLT3 tyrosine kinase and induces hematological remission in AML patients harboring the internal tandem duplication of the FLT3 gene (FLT3-ITD). However, the majority of patients in clinical trials developed resistance to CEP-701. Therefore, the aim of this study, was to assess the effect of re-expression of SHP-1 on sensitivity to CEP-701 in resistant AML cells.

Methods: Resistant cells harboring the FLT3-ITD were developed by overexposure of MV4-11 to CEP-701, and the effects of 5-Aza treatment were investigated. Apoptosis and cytotoxicity of CEP-701 were determined using Annexin V and MTS assays, respectively. Gene expression was performed by quantitative real-time PCR. STATs activity was examined by western blotting and the methylation profile of SHP-1 was studied using MS-PCR and pyrosequencing analysis. Repeated-measures ANOVA and Kruskal-Wallis tests were used for statistical analysis.

Results: The cytotoxic dose of CEP-701 on resistant cells was significantly higher in comparison with parental and MV4-11R-cep + 5-Aza cells (p = 0.004). The resistant cells showed a significant higher viability and lower apoptosis compared with other cells (p < 0.001). Expression of SHP-1 was 7-fold higher in MV4-11R-cep + 5-Aza cells compared to parental and resistant cells (p = 0.011). STAT3 was activated in resistant cells. Methylation of SHP-1 was significantly decreased in MV4-11R-cep + 5-Aza cells (p = 0.002).

Conclusions: The restoration of SHP-1 expression induces sensitivity towards CEP-701 and could serve as a target in the treatment of AML. Our findings support the hypothesis that, the tumor-suppressor effect of SHP-1 is lost due to epigenetic silencing and its re-expression might play an important role in re-inducing sensitivity to TKIs. Thus, SHP-1 is a plausible candidate for a role in the development of CEP-701 resistance in FLT3-ITD+ AML patients.
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http://dx.doi.org/10.1186/s12885-015-1695-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637135PMC
November 2015

Guidelines for nucleic acid detection and analysis in hematological disorders.

Malays J Pathol 2015 Aug;37(2):165-73

Universiti Sains Malaysia, School of Medical Sciences, Department of Haematology, 16150, Kubang Kerian, Kelantan, Malaysia.

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August 2015

Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia.

Asian Pac J Cancer Prev 2015 ;16(12):4869-72

Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia E-mail :

Background: Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis.

Materials And Methods: We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia.

Results: FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value=0.008) and white blood cell count (p-value=0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value=0.374).

Conclusions: The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.
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http://dx.doi.org/10.7314/apjcp.2015.16.12.4869DOI Listing
April 2016

The first Malay database toward the ethnic-specific target molecular variation.

BMC Res Notes 2015 Apr 30;8:176. Epub 2015 Apr 30.

Department of Pediatric, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia.

Background: The Malaysian Node of the Human Variome Project (MyHVP) is one of the eighteen official Human Variome Project (HVP) country-specific nodes. Since its inception in 9(th) October 2010, MyHVP has attracted the significant number of Malaysian clinicians and researchers to participate and contribute their data to this project. MyHVP also act as the center of coordination for genotypic and phenotypic variation studies of the Malaysian population. A specialized database was developed to store and manage the data based on genetic variations which also associated with health and disease of Malaysian ethnic groups. This ethnic-specific database is called the Malaysian Node of the Human Variome Project database (MyHVPDb).

Findings: Currently, MyHVPDb provides only information about the genetic variations and mutations found in the Malays. In the near future, it will expand for the other Malaysian ethnics as well. The data sets are specified based on diseases or genetic mutation types which have three main subcategories: Single Nucleotide Polymorphism (SNP), Copy Number Variation (CNV) followed by the mutations which code for the common diseases among Malaysians. MyHVPDb has been open to the local researchers, academicians and students through the registration at the portal of MyHVP ( http://hvpmalaysia.kk.usm.my/mhgvc/index.php?id=register ).

Conclusions: This database would be useful for clinicians and researchers who are interested in doing a study on genomics population and genetic diseases in order to obtain up-to-date and accurate information regarding the population-specific variations and also useful for those in countries with similar ethnic background.
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http://dx.doi.org/10.1186/s13104-015-1123-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440489PMC
April 2015

Fibrinolytic activity and dose-dependent effect of incubating human blood clots in caffeic acid phenethyl ester: in vitro assays.

Biomed Res Int 2015 15;2015:627471. Epub 2015 Jan 15.

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Background. Caffeic acid phenethyl ester (CAPE) has been reported to possess time-dependent fibrinolytic activity by in vitro assay. This study is aimed at investigating fibrinolytic dose-dependent activity of CAPE using in vitro assays. Methods. Standardized human whole blood (WB) clots were incubated in either blank controls or different concentrations of CAPE (3.75, 7.50, 15.00, 22.50, and 30.00 mM). After 3 hours, D-dimer (DD) levels and WB clot weights were measured for each concentration. Thromboelastography (TEG) parameters were recorded following CAPE incubation, and fibrin morphology was examined under a confocal microscope. Results. Overall, mean DD (μg/mL) levels were significantly different across samples incubated with different CAPE concentrations, and the median pre- and postincubation WB clot weights (grams) were significantly decreased for each CAPE concentration. Fibrin removal was observed microscopically and indicated dose-dependent effects. Based on the TEG test, the Ly30 fibrinolytic parameter was significantly different between samples incubated with two different CAPE concentrations (15.0 and 22.50 mM). The 50% effective dose (ED50) of CAPE (based on DD) was 1.99 mg/mL. Conclusions. This study suggests that CAPE possesses fibrinolytic activity following in vitro incubation and that it has dose-dependent activities. Therefore, further investigation into CAPE as a potential alternative thrombolytic agent should be conducted.
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http://dx.doi.org/10.1155/2015/627471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312562PMC
October 2015

Multiplex amplification refractory mutation system (MARMS) for the detection of β-globin gene mutations among the transfusion-dependent β-thalassemia Malay patients in Kelantan, Northeast of Peninsular Malaysia.

Am J Blood Res 2014 5;4(1):33-40. Epub 2014 Sep 5.

Department of Pediatrics, School of Medical Sciences, Universiti Sains Malaysia Malaysia.

The aim of this study was to adapt MARMS with some modifications to detect beta mutation in our cohort of thalassemia patients. We focused only on transfusion-dependent thalassemia Malay patients, the predominant ethnic group (95%) in the Kelantanese population. Eight mutations were identified in 46 out of 48 (95.83%) beta thalassemia alleles. Most of the patients (54.2%) were compound heterozygous with co-inheritance Cd 26 (G>A). The frequencies of spectrum beta chain mutation among these patients are presented in Table 2. Among the transfusion dependent beta thalassemia Malay patients studied, 26 patients were found to be compound heterozygous and the main alleles were Cd 26 (G>A). Compound heterozygous mutation of Cd 26 (G>A) and IVS 1-5 (G>C) were 12 (46.2%), Cd 26 (G>A) and Cd 41/42 (TTCT) were 9 (34.6%), Cd 26 (G>A) and IVS 1-1 (G>C) were 2 (7.7%) respectively. Meanwhile the minority were made of a single compound heterozygous of Cd 26 (G>A) and Cd 71/72, Cd 26 (>A) and Cd 17 (A>T), Cd 26 (G>A) and -28 (G>A) respectively. Twenty out of forty six patients were shown to have homozygous of IVS 1-5 (G>C) were 2 (10.0%), Cd 26 (G>A) were 15 (75.0%), Cd 19 (A>G) were 1 (5.0%), and IVS 1-1 (G>T) were 2 (10.0%). The beta chain mutations among the Kelantanese Malays followed closely the distribution of beta chain mutations among the Thais and the Malays of the Southern Thailand. The G-C transition at position 5 of the IVS 1-5 mutation was predominant among the Malay patients. In conclusion, this method has successfully identified the mutation spectrum in our cohort of transfusion-dependent beta thalassemia patients, and this method is equally effective in screening for mutation among thalassemia patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165115PMC
September 2014

Silencing of suppressor of cytokine signaling-3 due to methylation results in phosphorylation of STAT3 in imatinib resistant BCR-ABL positive chronic myeloid leukemia cells.

Asian Pac J Cancer Prev 2014 ;15(11):4555-61

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia E-mail :

Background: Silencing due to methylation of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator gene for the JAK/STAT signaling pathway has been reported to play important roles in leukemogenesis. Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets the BCR-ABL protein and induces hematological remission in patients with chronic myeloid leukemia (CML). Unfortunately, the majority of CML patients treated with imatinib develop resistance under prolonged therapy. We here investigated the methylation profile of SOCS-3 gene and its downstream effects in a BCR-ABL positive CML cells resistant to imatinib.

Materials And Methods: BCR-ABL positive CML cells resistant to imatinib (K562-R) were developed by overexposure of K562 cell lines to the drug. Cytotoxicity was determined by MTS assays and IC50 values calculated. Apoptosis assays were performed using annexin V-FITC binding assays and analyzed by flow cytometry. Methylation profiles were investigated using methylation specific PCR and sequencing analysis of SOCS-1 and SOCS-3 genes. Gene expression was assessed by quantitative real-time PCR, and protein expression and phosphorylation of STAT1, 2 and 3 were examined by Western blotting.

Results: The IC50 for imatinib on K562 was 362 nM compared to 3,952 nM for K562-R (p=0.001). Percentage of apoptotic cells in K562 increased upto 50% by increasing the concentration of imatinib, in contrast to only 20% in K562-R (p<0.001). A change from non-methylation of the SOCS-3 gene in K562 to complete methylation in K562-R was observed. Gene expression revealed down- regulation of both SOCS-1 and SOCS-3 genes in resistant cells. STAT3 was phosphorylated in K562-R but not K562.

Conclusions: Development of cells resistant to imatinib is feasible by overexposure of the drug to the cells. Activation of STAT3 protein leads to uncontrolled cell proliferation in imatinib resistant BCR-ABL due to DNA methylation of the SOCS-3 gene. Thus SOCS-3 provides a suitable candidate for mechanisms underlying the development of imatinib resistant in CML patients.
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http://dx.doi.org/10.7314/apjcp.2014.15.11.4555DOI Listing
March 2015

In vitro whole blood clot lysis for fibrinolytic activity study using d-dimer and confocal microscopy.

Adv Hematol 2014 11;2014:814684. Epub 2014 Feb 11.

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

This study aimed to evaluate in vitro whole blood (WB) clot lysis method for the assessment of fibrinolytic activity. Standardized unresected (uncut) retracted WB clot was incubated in pool platelet poor plasma (PPP) for varying incubation times and in streptokinase (SK) at different concentrations. The fibrinolytic activity was assessed by D-dimer (DD), confocal microscopy, and clot weight. DD was measured photometrically by immunoturbidimetric method. There was a significant difference in mean DD levels according to SK concentrations (P = 0.007). The mean DD ± SD according to the SK concentrations of 5, 30, 50, and 100 IU/mL was: 0.69 ± 0.12, 0.78 ± 0.14, 1.04 ± 0.14 and 2.40 ± 1.09  μ g/mL. There were no significant changes of clot weight at different SK concentrations. Gradual loss and increased branching of fibrin in both PPP and SK were observed. Quantitation of DD and morphology of fibrin loss as observed by the imaging features are in keeping with fibrinolytic activity. Combination of DD levels and confocal microscopic features was successfully applied to evaluate the in vitro WB clot lysis method described here.
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http://dx.doi.org/10.1155/2014/814684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934584PMC
March 2014

Low level of TERC gene amplification between chronic myeloid leukaemia patients resistant and respond to imatinib mesylate treatment.

Asian Pac J Cancer Prev 2014 ;15(4):1863-9

Human Genome Center, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia E-mail :

The amplification of telomerase component (TERC) gene could play an important role in generation and treatment of haematological malignancies. This present study was aimed to investigate copy number amplification status of TERC gene in chronic myeloid leukaemia (CML) patients who were being treated with imatinib mesylate (IM). Genomic DNA was extracted from peripheral blood of CML-IM Resistant (n=63), CML-IM Respond (n=63) and healthy individuals (n=30). TERC gene copy number predicted (CNP) and copy number calculated (CNC) were determined based on Taqman® Copy Number Assay. Fluorescence in situ hybridization (FISH) analysis was performed to confirm the normal signal pattern in C4 (calibrator) for TERC gene. Nine of CML patients showed TERC gene amplification (CNP=3), others had 2 CNP. A total of 17 CML patients expressed CNC>2.31 and the rest had 2.31>CNC>1.5. TERC gene CNP value in healthy individuals was 2 and their CNC value showed in range 1.59-2.31. The average CNC TERC gene copy number was 2.07, 1.99 and 1.94 in CML- IM Resistant patients, CML-IM Respond and healthy groups, respectively. No significant difference of TERC gene amplification observed between CML-IM Resistant and CML-IM Respond patients. Low levels of TERC gene amplification might not have a huge impact in haematological disorders especially in terms of resistance towards IM treatment.
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http://dx.doi.org/10.7314/apjcp.2014.15.4.1863DOI Listing
November 2014

Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients.

Biomed Pharmacother 2014 Apr 7;68(3):343-9. Epub 2014 Feb 7.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia. Electronic address:

The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.
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http://dx.doi.org/10.1016/j.biopha.2014.01.009DOI Listing
April 2014

BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome.

Leuk Res 2014 Apr 6;38(4):454-9. Epub 2014 Jan 6.

Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Malaysia. Electronic address:

Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.
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http://dx.doi.org/10.1016/j.leukres.2013.12.025DOI Listing
April 2014

Single-Center Experience of von Willebrand Disease (vWD) Among Patients with Menorrhagia: A Diagnosis which could be Missed.

Indian J Hematol Blood Transfus 2012 Sep 1;28(3):157-61. Epub 2012 Feb 1.

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

Menorrhagia is one of the gynecological complaints, seen in women of reproductive age. In majority of cases no organic pathology is found. To date there is no consensus on application of von Willebrand disease (vWD) testing as part of the routine investigations in menorrhagia. Diagnosis of vWD is challenging. It is complicated by intra-individual variations in von Willebrand antigen, activity, and factor VIII levels due to fluctuation of these factor levels during the menstrual cycle or hormonal therapy. The aim of this study is to detect vWD presenting with menorrhagia among Malays attending gynecology clinic by using a standard panel of haemostatic profiles. Thirty Malay patients attending gynecology clinic with unexplained menorrhagia were included in this study. Haemostatic profile such as platelet count, prothrombin time, activated partial thromboplastin time (APTT), factor VIII assay, von Willebrand factor antigen, and von Willebrand factor activity, and collagen binding assay were measured in all patients. Pre- and post hormonal haemostatic profiles were also performed in the patients diagnosed as vWD. All patients had normal APTT. Based on von Willebrand factor work-up, vWD was diagnosed in four patients (13.3%). Three of them were Type 1 and the other one was Type 2M. Investigation for vWD is essential in patients with menorrhagia and thus the laboratories performing vWD testing should provide a complete panel of diagnostic work-up in order to reduce the interpretation error. Screening for vWD should be performed before hormonal treatment as haemostatic profile post treatment could mask the diagnosis.
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http://dx.doi.org/10.1007/s12288-011-0135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422391PMC
September 2012

HOXA4 gene promoter hypermethylation as an epigenetic mechanism mediating resistance to imatinib mesylate in chronic myeloid leukemia patients.

Biomed Res Int 2013 26;2013:129715. Epub 2012 Dec 26.

Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150 Kubang Kerian, Kelantan, Malaysia.

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673-12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.
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http://dx.doi.org/10.1155/2013/129715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591123PMC
September 2013

Contribution of BCR-ABL kinase domain mutations to imatinib mesylate resistance in Philadelphia chromosome positive Malaysian chronic myeloid leukemia patients.

Hematol Rep 2012 Nov 23;4(4):e23. Epub 2012 Nov 23.

Human Genome Centre;

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is mediated by different mechanisms that can be classified as BCR-ABL dependent or BCR-ABL independent pathways. BCR-ABL dependent mechanisms are most frequently associated with point mutations in tyrosine kinase domain (TKD) of BCR-ABL1 and also with BCR-ABL gene amplification. Many different types and frequencies of mutations have been reported in different studies, probably due to the different composition of study cohorts. Since no reports are available from Malaysia, this study was undertaken to investigate the frequency and pattern of BCR-ABL kinase domain mutations using dHPLC followed by sequencing, and also status of BCR-ABL gene amplification using fluorescence in situ hybridization (FISH) on 40 IM resistant Malaysian CML patients. Mutations were detected in 13 patients (32.5%). Five different types of mutations (T315I, E255K, Y253H, M351T, V289F) were identified in these patients. In the remaining 27 IM resistant CML patients, we investigated the contribution made by BCR-ABL gene amplification, but none of these patients showed amplification. It is presumed that the mechanisms of resistance in these 27 patients might be due to BCR-ABL independent pathways. Different mutations confer different levels of resistance and, therefore, detection and characterization of TKD mutations is highly important in order to guide therapy in CML patients.
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http://dx.doi.org/10.4081/hr.2012.e23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555211PMC
November 2012