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Fulltext Immunogenic Burkholderia pseudomallei outer membrane proteins as potential candidate vaccine targets

Hara Y, Mohamed R, Nathan S

PLoS One, 2009 Aug 05;4(8):e6496.
PMID: 19654871 DOI: 10.1371/journal.pone.0006496

BACKGROUND: Burkholderia pseudomallei is the causative agent of melioidosis, a disease of significant morbidity and mortality in both human and animals in endemic areas. There is no vaccine towards the bacterium available in the market, and the efficacy of many of the bacterium's surface and secreted proteins are currently being evaluated as vaccine candidates.
METHODOLOGY/PRINCIPAL FINDINGS: With the availability of the B. pseudomallei whole genome sequence, we undertook to identify genes encoding the known immunogenic outer membrane protein A (OmpA). Twelve OmpA domains were identified and ORFs containing these domains were fully annotated. Of the 12 ORFs, two of these OmpAs, Omp3 and Omp7, were successfully cloned, expressed as soluble protein and purified. Both proteins were recognised by antibodies in melioidosis patients' sera by Western blot analysis. Purified soluble fractions of Omp3 and Omp7 were assessed for their ability to protect BALB/c mice against B. pseudomallei infection. Mice were immunised with either Omp3 or Omp7, subsequently challenged with 1x10(6) colony forming units (cfu) of B. pseudomallei via the intraperitoneal route, and examined daily for 21 days post-challenge. This pilot study has demonstrated that whilst all control unimmunised mice died by day 9 post-challenge, two mice (out of 4) from both immunised groups survived beyond 21 days post-infection.
CONCLUSIONS/SIGNIFICANCE: We have demonstrated that B. pseudomallei OmpA proteins are immunogenic in mice as well as melioidosis patients and should be further assessed as potential vaccine candidates against B. pseudomallei infection.
A genome level survey of Burkholderia pseudomallei immunome expressed during human infection

Su YC, Wan KL, Mohamed R, Nathan S

Microbes Infect., 2008 Oct;10(12-13):1335-45.
PMID: 18761419 DOI: 10.1016/j.micinf.2008.07.034

Burkholderia pseudomallei is the etiological agent of melioidosis, a severe infectious disease of humans and animals. The role of the bacterium's proteins expressed in vivo during human melioidosis continues to remain an enigma. This study's aim was to identify B. pseudomallei target proteins that elicit the humoral immune response in infected humans. A small insert genomic expression library was constructed and immunoscreened to identify peptides that reacted exclusively with melioidosis patients' sera. Sero-positive clones expressing immunogenic peptides were sequenced and annotated, and shown to represent 109 proteins involved in bacterial cell envelope biogenesis, cell motility and secretion, transcription, amino acid, ion and protein metabolism, energy production, DNA repair and unknown hypothetical proteins. Western blot analysis of three randomly selected full-length immunogenic polypeptides with patients' sera verified the findings of the immunome screening. The patients' humoral immune response to the 109 proteins suggests the induction or significant upregulation of these proteins in vivo during human infection and thus may play a role in the pathogenesis of B. pseudomallei. Identification of B. pseudomallei immunogens has shed new light on the elucidation of the bacterium's pathogenesis mechanism and disease severity. These immunogens can be further evaluated as prophylactic and serodiagnostic candidates as well as drug targets.
Burkholderia pseudomallei animal and human isolates from Malaysia exhibit different phenotypic characteristics

Lee SH, Chong CE, Lim BS, Chai SJ, Sam KK, Mohamed R, et al.

Diagn Microbiol Infect Dis, 2007 Jul;58(3):263-70.
PMID: 17350202

Burkholderia pseudomallei is a Gram-negative saprophytic soil bacterium, which is the etiologic agent of melioidosis, a severe and fatal infectious disease occurring in human and animals. Distinct clinical and animal isolates have been shown to exhibit differences in phenotypic trait such as growth rate, colony morphology, antimicrobial resistance, and virulence. This study was carried out to gain insight into the intrinsic differences between 4 clinical and 6 animal B. pseudomallei isolates from Malaysia. The 16S rRNA-encoding genes from these 10 isolates of B. pseudomallei were sequenced to confirm the identity of these isolates along with the avirulent Burkholderia thailandensis. The nucleotide sequences indicated that the 16S rRNA-encoding genes among the 10 B. pseudomallei isolates were identical to each other. However, the nucleotide sequence differences in the 16S rRNA-encoding genes appeared to be B. pseudomallei and B. thailandensis specific. The growth rate of all B. pseudomallei isolates was determined by generating growth curves at 37 degrees C for 72 h. The isolates were found to differ in growth rates with doubling time varying from 1.5 to 2.3 h. In addition, the B. pseudomallei isolates exhibited considerable variation in colony morphology when grown on Ashdown media, brain-heart infusion agar, and Luria-Bertani agar over 9 days of observation. Antimicrobial susceptibility tests indicated that 80% of the isolates examined were Amp(R) Cb(R) Kn(R) Gm(R) Chl(S) Te(S). Virulence of the B. pseudomallei clinical and animal isolates was evaluated in B. pseudomallei-susceptible BALB/c mice. Most of the clinical isolates were highly virulent. However, virulence did not correlate with isolate origin since 2 of the animal isolates were also highly virulent.
Fulltext Development of repeatable arrays of proteins using immobilized DNA microplate (RAPID-M) technology

Ashaari NS, Ramarad S, Khairuddin D, Akhir NA, Hara Y, Mahadi NM, et al.

BMC Res Notes, 2015;8:669.
PMID: 26563904 DOI: 10.1186/s13104-015-1637-3

Protein microarrays have enormous potential as in vitro diagnostic tools stemming from the ability to miniaturize whilst generating maximum evaluation of diagnostically relevant information from minute amounts of sample. In this report, we present a method known as repeatable arrays of proteins using immobilized DNA microplates (RAPID-M) for high-throughput in situ protein microarray fabrication. The RAPID-M technology comprises of cell-free expression using immobilized DNA templates and in situ protein purification onto standard microarray slides.
Fulltext Nano-Antenna Coupled Infrared Detector Design

Mubarak MH, Sidek O, Abdel-Rahman MR, Mustaffa MT, Mustapa Kamal AS, Mukras SM

Sensors (Basel), 2018 Oct 31;18(11).
PMID: 30384508 DOI: 10.3390/s18113714

Since the 1940s, infrared (IR) detection and imaging at wavelengths in the two atmospheric windows of 3 to 5 and 8 to 14 μm has been extensively researched. Through several generations, these detectors have undergone considerable developments and have found use in various applications in different fields including military, space science, medicine and engineering. For the most recently proposed generation, these detectors are required to achieve high-speed detection with spectral and polarization selectivity while operating at room temperature. Antenna coupled IR detectors appear to be the most promising candidate to achieve these requirements and has received substantial attention from research in recent years. This paper sets out to present a review of the antenna coupled IR detector family, to explore the main concepts behind the detectors as well as outline their critical and challenging design considerations. In this context, the design of both elements, the antenna and the sensor, will be presented individually followed by the challenging techniques in the impedance matching between both elements. Some hands-on fabrication techniques will then be explored. Finally, a discussion on the coupled IR detector is presented with the aim of providing some useful insights into promising future work.
Development, validation and determination of multiclass pesticide residues in cocoa beans using gas chromatography and liquid chromatography tandem mass spectrometry

Zainudin BH, Salleh S, Mohamed R, Yap KC, Muhamad H

Food Chem, 2015 Apr 1;172:585-95.
PMID: 25442595 DOI: 10.1016/j.foodchem.2014.09.123

An efficient and rapid method for the analysis of pesticide residues in cocoa beans using gas and liquid chromatography-tandem mass spectrometry was developed, validated and applied to imported and domestic cocoa beans samples collected over 2 years from smallholders and Malaysian ports. The method was based on solvent extraction method and covers 26 pesticides (insecticides, fungicides, and herbicides) of different chemical classes. The recoveries for all pesticides at 10 and 50 μg/kg were in the range of 70-120% with relative standard deviations of less than 20%. Good selectivity and sensitivity were obtained with method limit of quantification of 10 μg/kg. The expanded uncertainty measurements were in the range of 4-25%. Finally, the proposed method was successfully applied for the routine analysis of pesticide residues in cocoa beans via a monitoring study where 10% of them was found positive for chlorpyrifos, ametryn and metalaxyl.
The re-emerging of orf virus infection: A call for surveillance, vaccination and effective control measures

Bala JA, Balakrishnan KN, Abdullah AA, Mohamed R, Haron AW, Jesse FFA, et al.

Microb Pathog, 2018 Jul;120:55-63.
PMID: 29709684 DOI: 10.1016/j.micpath.2018.04.057

Orf disease is known to be enzootic among small ruminants in Asia, Africa, and some other parts of the world. The disease caused by orf virus is highly contagious among small ruminant species. Unfortunately, it has been neglected for decades because of the general belief that it only causes a self-limiting disease. On the other hand, in the past it has been reported to cause huge cumulative financial losses in livestock farming. Orf disease is characterized by localized proliferative and persistent skin nodule lesions that can be classified into three forms: generalized, labial and mammary or genitals. It can manifest as benign or malignant types. The later type of orf can remain persistent, often fatal and usually causes a serious outbreak among small ruminant population. Morbidity and mortality rates of orf are higher especially in newly infected kids and lambs. Application of antibiotics together with antipyretic and/or analgesic is highly recommended as a supportive disease management strategy for prevention of subsequent secondary microbial invasion. The presence of various exotic orf virus strains of different origin has been reported in many countries mostly due to poorly controlled cross-border virus transmission. There have been several efforts to develop orf virus vaccines and it was with variable success. The use of conventional vaccines to control orf is a debatable topic due to the concern of short term immunity development. Following re-infection in previously vaccinated animals, it is uncommon to observe the farms involved to experience rapid virus spread and disease outbreak. Meanwhile, cases of zoonosis from infected animals to animal handler are not uncommon. Despite failures to contain the spread of orf virus by the use of conventional vaccines, vaccination of animals with live orf virus is still considered as one of the best choice. The review herein described pertinent issues with regard to the development and use of potential effective vaccines as a control measure against orf virus infection.
Homology modeling of human BAP1 and analysis of its binding properties through molecular docking and molecular dynamics simulation

Husain S, Mohamed R, Abd Halim KB, Mohd Mutalip SS

J Biomol Struct Dyn, 2023;41(15):7158-7173.
PMID: 36039769 DOI: 10.1080/07391102.2022.2117244

BRCA1-associated protein 1 (BAP1) is a nuclear-localized Ubiquitin C-terminal hydrolase (UCH) that functions as a tumour suppressor, and although BAP1 has been linked to cancer, the molecular mechanism by which BAP1 regulates cancer and its crystal structure have not been elucidated. In this study, computational approaches were used to identify the protein model of BAP1 and its potential inhibitors. The structure of the BAP1 model was constructed through homology modeling and the generated BAP1 model was observed to exhibit good quality protein model as the distribution of its amino acids in the Ramachandran's plot corresponded to 87.7% in the most favoured regions. Docking and simulating of the ubiquitin on the BAP1 model structure revealed the rearrangement of F228, F50, and H169 residues of the BAP1 and switching of BAP1's conformation into a productive state. Our screening results of potential BAP1 inhibitors against the FDA approved drugs shortlisted two potential inhibitors, which are FDA1065 and FDA755. We then performed molecular dynamics simulations and Molecular mechanics Poisson-Boltzmann surface area (MMPBSA) analysis on both inhibitors and found that only the BAP1-FDA755 formed a stable complex and the FDA755 ligand remained its position inside the active site of the BAP1 with a total binding energy of (-51.77 ± 3.49 kcal/mol). We speculate that the presence of methyl group in FDA755 play an important role in stabilizing the BAP1-FDA755 complex.Communicated by Ramaswamy H. Sarma.
Fulltext Dermatopathology of Orf Virus (Malaysian Isolates) in Mice Experimentally Inoculated at Different Sites with and without Dexamethasone Administration

Bala JA, Balakrishnan KN, Abdullah AA, Kimmy T, Abba Y, Bin Mohamed R, et al.

J Pathog, 2018;2018:9207576.
PMID: 30155311 DOI: 10.1155/2018/9207576

Orf is a clinical manifestation of parapoxvirus infection often fatal in goats and sheep especially when they are under stress or influenced by unfavorable environment. This study investigated the pathogenicity of two Orf virus isolates (ORFV UPM1/14 and UPM2/14) and host response in mouse model by using different inoculation sites with/without prior exposure to dexamethasone. Treatments with dexamethasone served as an immunosuppressant that may mimic stress situation in affected animals. Groups of five mice were given intradermal injection of 0.2 mL of tissue culture infective dose 50 (TCID50) of UPM1/14 (Group 1) and UPM2/14 (Group 2) at the dorsum (Group 1A; Group 2A), ear pinna (Group 1B; Group 2B), and labial commissure (Group 1C; Group 2C). An inoculum 0.2 mL of UPM1/14 was administered to animals treated with dexamethasone (n=5; 5 mg/kg/day intraperitoneally) and nondexamethasone (n=5) groups at the dorsum, ear pinna, and labial commissure. No significant difference (p>0.05) was observed in the mean lesion scores among the groups of different inoculation sites or between dexamethasone-treated and nontreated groups. However, there was a significant difference (p<0.05) in the mean stratum thickness of affected skin following inoculation with UPM2/14 isolate at the ear pinna and labial commissure. Histopathology examination revealed keratosis, acanthosis, and ballooning degeneration in the skin of affected mice. Orf virus DNA was detected in the skin samples by targeting F1L and B2L virus-specific genes in polymerase chain reaction (PCR) assay. Intradermal inoculation with UPM1/14 or UPM2/14 isolate produced a mild skin lesion in mice, and there was no significant difference in orf disease manifestation despite variation of inoculation sites. Similarly, short-term dexamethasone administration gave no adverse effects on pathogenicity of orf virus isolates.
Fulltext Genome-wide analysis of copy number variation identifies candidate gene loci associated with the progression of non-alcoholic fatty liver disease

Zain SM, Mohamed R, Cooper DN, Razali R, Rampal S, Mahadeva S, et al.

PLoS One, 2014;9(4):e95604.
PMID: 24743702 DOI: 10.1371/journal.pone.0095604

Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in 'second hit' hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH.
Conflicting reports on the role of the glycemic effect of Catha edulis (Khat): A systematic review and meta-analysis

Alsalahi A, Alshawsh MA, Mohamed R, Alyousefi NA, Alshagga MA, Shwter AN, et al.

J Ethnopharmacol, 2016 Jun 20;186:30-43.
PMID: 27025406 DOI: 10.1016/j.jep.2016.03.045

ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, the leaves of Catha edulis Forsskal (Khat) are consumed by the people of Yemen primarily for its recreational effect, and secondarily, for achieving certain tasks. Additionally, Yemeni diabetics chew such leaves in the belief that this can control their elevated blood glucose level.
AIMS: This review focuses on outlining the findings of studies that have been conducted to display the glycemic effect of Catha edulis, while trying to balance it with findings of the association of its chewing with the development of type 2 diabetes mellitus (DM).
MATERIALS AND METHODS: The search strategy adopted was based on a comprehensive research in Medline, PubMed, Web of Science, JSTOR, Scopus and Cochrane for articles, proceeding abstracts and theses to identify complete reports written in the English language about the glycemic effect of Catha edulis in humans and animals from 1976 to 2016. In addition, bibliographies were also reviewed to find additional reports not otherwise published. Thirty seven records were identified of which, 25 eligible studies were included in the meta-analysis using blood glucose as an outcome measurement. Studies were divided into four subgroups according to the experimental model, namely; non-diabetic animals, diabetic animals, non-diabetic humans and diabetic humans. The pooled mean difference (MD) of blood glucose between experimental and control were calculated using random effects model of the weighted mean difference of blood glucose with 95% confidence interval (CI). Heterogeneity between studies was tested using I(2) statistic and a value of P<0.05 was considered to indicate statistical significance.
RESULTS: The scientific reports in the literature prevailed that the glycemic effect of Catha edulis were greatly conflicting with the majority of studies indicating that Catha edulis has a mild hypoglycemic effect. However, the meta-analysis indicted that the overall result showed an insignificant reduction in blood glucose (MD=-9.70, 95% CI: -22.17 to 2.76, P=0.13, with high heterogeneity between subgroups, I(2)=88.2%, P<0.0001). In addition, pooled mean difference of blood glucose of non-diabetic animals, diabetic animals and non-diabetic humans showed an insignificant reduction in blood glucose (MD=-18.55, 95% CI: -39.55 to 2.50, P<0.08, MD=-52.13%, 95% CI: -108.24 to 3.99, P=0.07 and MD=-2.71%, 95% CI: -19.19 to -13.77, P=0.75) respectively. Conversely, a significant elevation in the pooled mean difference of blood glucose in diabetic humans was indicated (MD=67.18, 95% CI: 36.93-97.43, P<0.0001). The conflict shown in the glycemic effect of Catha edulis is thought to be cultivar-related, while demographic and epidemiological reports suggested that chewing Catha edulis might be a predisposing factor contributing to the development of type 2 DM.
CONCLUSION: It was difficult to draw a meaningful conclusion from both the systematic and the meta-analysis with respect to the glycemic effect of Catha edulis since the meta-analysis results were insignificant with high heterogeneity among subgroups and are greatly conflicting. The variation is most likely due to unadjusted experimental factors or is related to Catha edulis itself, such as the differences in the phytochemical composition. Therefore, it is highly recommended that further studies of the glycemic effect of the cultivar of Catha edulis being studied should come with the identification and quantification of phytochemical content so that a meaningful assessment can be made with regard to its hypoglycemic properties. In addition, well-controlled clinical studies should be conducted to confirm whether or not chewing Catha edulis is associated with the development of type 2 DM, since this would be a source of concern seeing that the plant is widely consumed in certain populations.
Fulltext A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease

Zain SM, Mohamed R, Mahadeva S, Cheah PL, Rampal S, Basu RC, et al.

Hum Genet, 2012 Jul;131(7):1145-52.
PMID: 22258181 DOI: 10.1007/s00439-012-1141-y

The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69-3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12-3.37, p = 0.018; OR 3.51, 95% CI 1.69-7.26, p = 0.001 and OR 2.05, 95% CI 1.25-3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85-3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05-3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17-3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurrence of fibrosis in patients with NAFLD.
Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene

Tan HL, Zain SM, Mohamed R, Rampal S, Chin KF, Basu RC, et al.

J Gastroenterol, 2014 Jun;49(6):1056-64.
PMID: 23800943 DOI: 10.1007/s00535-013-0850-x

BACKGROUND: Recent genome-wide association studies demonstrated an association between single nucleotide polymorphisms (SNPs) on the glucokinase regulatory gene (GCKR) with hepatic steatosis. This study attempted to investigate the association of GCKR rs780094 and rs1260326 with susceptibility to non-alcoholic fatty liver disease (NAFLD) and its severity.
METHODS: The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform.
RESULTS: The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09-2.05, p = 0.012; and OR 1.51, 95 % CI 1.09-2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10-2.17, p = 0.013; and OR 1.56, 95 % CI 1.10-2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01-2.21, p = 0.044; and OR 1.52, 95 % CI 1.03-2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28-5.43, p = 0.009; and OR 4.35, 95 % CI 1.93-9.81, p < 0.0001, respectively). The joint effect of GCKR with adiponutrin rs738409 indicated greatly increased the risk of NAFLD (OR 4.14, 95 % CI 1.41-12.18, p = 0.010). Histological data showed significant association of GCKR rs1260326 with high steatosis grade (OR 1.76, 95 % CI 1.08-2.85, p = 0.04).
CONCLUSION: This study suggests that risk allele T of the GCKR rs780094 and rs1260326 is associated with predisposition to NAFLD and NASH with significant fibrosis. The GCKR and PNPLA3 genes interact to result in increased susceptibility to NAFLD.
Fulltext Circulating microRNA as a marker for predicting liver disease progression in patients with chronic hepatitis B

Riazalhosseini B, Mohamed R, Apalasamy YD, Langmia IM, Mohamed Z

Rev Soc Bras Med Trop, 2017 Mar-Apr;50(2):161-166.
PMID: 28562750 DOI: 10.1590/0037-8682-0416-2016

INTRODUCTION: Hepatitis B virus (HBV) constitutes an important risk factor for cirrhosis and hepatocellular carcinoma (HCC). The link between circulating microRNAs and HBV has been previously reported, although not as a marker of liver disease progression in chronic hepatitis B (CHB). The aim of this study was to characterize miRNA expression profiles between CHB with and without cirrhosis or HCC.

METHODS:: A total of 12 subjects were recruited in this study. We employed an Affymetrix Gene Chip miRNA 3.0 Array to provide universal miRNA coverage. We compared microRNA expression profiles between CHB with and without cirrhosis/HCC to discover possible prognostic markers associated with the progression of CHB.

RESULTS:: Our results indicated 8 differently expressed microRNAs, of which miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, and miRNA-3200 were up-regulated, whereas miRNA-182 and miRNA-4485 were down-regulated in patients with CHB who progressed to cirrhosis/HCC as compared to those without progression.

CONCLUSIONS:: We demonstrated the differential expression of miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, miRNA-3200, miRNA-182, and miRNA-4485 between patients with HBV without cirrhosis/HCC and those who had progressed to these more severe conditions. These miRNAs may serve as novel and non-invasive prognostic markers for early detection of CHB-infected patients who are at risk of progression to cirrhosis and/or HCC.
Association of deleted in liver cancer-1 gene polymorphism with increased risk of chronicity of disease among Malaysian patients with hepatitis B infection

Riazalhosseini B, Mohamed R, Devi Apalasamy Y, Mohamed Z

Pharmacogenet Genomics, 2021 Dec 01;31(9):185-190.
PMID: 34320605 DOI: 10.1097/FPC.0000000000000439

OBJECTIVE: The aim of this study is to examine the association between genetic variations in deleted in liver cancer 1 (DLC1) gene with progression of the hepatitis B virus (HBV) infection.
METHODS: A total of 623 subjects were included in this study, of whom, 423 were chronic hepatitis B (CHB) patients without liver cirrhosis or hepatocellular carcinoma (HCC), 103 CHB with either liver cirrhosis ± HCC and 97 individuals who had resolved HBV. Two single-nucleotide polymorphisms rs3739298 and rs532841 of DLC1 gene were genotyped using the Sequenom MassARRAY platform.
RESULTS: Our results indicated significant differences between the chronic HBV and resolved HBV groups in genotype and allele frequencies of DLC1-rs3739298 [odds ratio (OR) = 2.23; 95% confidence interval (CI): 1.24-3.99; P = 0.007] and (OR = 1.54; 95% CI: 1.07-2.22; P = 0.021), respectively. Moreover, haplotype analysis revealed significant associations between chronicity of HBV with TG and GA haplotypes (P = 0.041 and P = 0.042), respectively.
CONCLUSION: A significant association exists between the rs3739298 variant and susceptibility to CHB infection.
Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer

Haron NH, Mohamad Hanif EA, Abdul Manaf MR, Yaakub JA, Harun R, Mohamed R, et al.

Asian Pac J Cancer Prev, 2019 Feb 26;20(2):509-517.
PMID: 30803214

Introduction: Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes
especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric
cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted
to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its
association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method:
A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while
MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite
analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite
markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes.
Results: Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed
absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI
positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were
located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All
these results however were not statistically significant. Our sequencing data displayed novel mutations. However these
data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to
small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was
comparable with published results. Determination of affected MMR genes by more than two antibodies may increase
the sensitivity of IHC to that of MSI analysis.
Fulltext Hepatitis C and kidney disease: An overview and approach to management

Azmi AN, Tan SS, Mohamed R

World J Hepatol, 2015 Jan 27;7(1):78-92.
PMID: 25624999 DOI: 10.4254/wjh.v7.i1.78

Hepatitis C infection and chronic kidney disease are major health burden worldwide. Hepatitis C infection is associated with a wide range of extra-hepatic manifestations in various organs including the kidneys. A strong association between hepatitis C and chronic kidney disease has come to light. Hemodialysis in supporting the end stage renal disease patients unfortunately carries a risk for hepatitis C infection. Despite much improvement in the care of this group of patients, the prevalence of hepatitis C infection in hemodialysis patients is still higher than the general population. Hepatitis C infection has a negative effect on the survival of hemodialysis and renal transplant patients. Treatment of hepatitis C in end stage renal disease patients using conventional or pegylated interferon with or without ribavirin remains a clinical challenge with low response rate, high dropout rate due to poor tolerability and many unmet needs. The approval of new direct acting antiviral agents for hepatitis C may dramatically change the treatment approach in hepatitis C infected patients with mild to moderate renal impairment. However it remains to be confirmed if the newer Hepatitis C therapies are safe in individuals with severe renal impairment. This review article discusses the relationship between hepatitis C and chronic kidney disease, describe the various types of renal diseases associated with hepatitis C and the newer as well as the existing treatments for hepatitis C in the context of this subpopulation of hepatitis C patients.
Common variant in the glucokinase regulatory gene rs780094 and risk of nonalcoholic fatty liver disease: a meta-analysis

Zain SM, Mohamed Z, Mohamed R

J Gastroenterol Hepatol, 2015 Jan;30(1):21-7.
PMID: 25167786 DOI: 10.1111/jgh.12714

BACKGROUND AND AIM: Although studies have suggested that rs780094, a common variant in the glucokinase regulatory (GCKR) gene to be associated with type 2 diabetes, obesity, and their related traits, the genetic basis of the association between GCKR rs780094 and nonalcoholic fatty liver disease (NAFLD) is still being examined. This meta-analysis was performed to evaluate the effect strength caused by GCKR rs780094 on NAFLD.
METHODS: We searched Medline, PubMed, Scopus, and Embase for relevant articles published up to April 2014. Data were extracted, and summary estimates of the association between GCKR rs780094 and NAFLD were examined. Heterogeneity and publication bias were also examined.
RESULTS: This meta-analysis incorporated a total of 2091 NAFLD cases and 3003 controls from five studies. Overall, the pooled result indicated that the GCKR rs780094 was significantly associated with increased risk of NAFLD (additive: odds ratio (OR) 1.25, 95% confidence interval (CI) 1.14-1.36, P
Fulltext Genetic polymorphisms in LDLR, APOB, PCSK9 and other lipid related genes associated with familial hypercholesterolemia in Malaysia

Lye SH, Chahil JK, Bagali P, Alex L, Vadivelu J, Ahmad WA, et al.

PLoS One, 2013;8(4):e60729.
PMID: 23593297 DOI: 10.1371/journal.pone.0060729

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevations in total cholesterol (TC) and low density lipoprotein cholesterol (LDLc). Development of FH can result in the increase of risk for premature cardiovascular diseases (CVD). FH is primarily caused by genetic variations in Low Density Lipoprotein Receptor (LDLR), Apolipoprotein B (APOB) or Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) genes. Although FH has been extensively studied in the Caucasian population, there are limited reports of FH mutations in the Asian population. We investigated the association of previously reported genetic variants that are involved in lipid regulation in our study cohort. A total of 1536 polymorphisms previously implicated in FH were evaluated in 141 consecutive patients with clinical FH (defined by the Dutch Lipid Clinic Network criteria) and 111 unrelated control subjects without FH using high throughput microarray genotyping platform. Fourteen Single Nucleotide Polymorphisms (SNPs) were found to be significantly associated with FH, eleven with increased FH risk and three with decreased FH risk. Of the eleven SNPs associated with an increased risk of FH, only one SNP was found in the LDLR gene, seven in the APOB gene and three in the PCSK9 gene. SNP rs12720762 in APOB gene is associated with the highest risk of FH (odds ratio 14.78, p<0.001). Amongst the FH cases, 108 out of 141 (76.60%) have had at least one significant risk-associated SNP. Our study adds new information and knowledge on the genetic polymorphisms amongst Asians with FH, which may serve as potential markers in risk prediction and disease management.
Fulltext Hemorrhagic cardiac tamponade: rare complication of radiofrequency ablation of hepatocellular carcinoma

Loh KB, Bux SI, Abdullah BJ, Raja Mokhtar RA, Mohamed R

Korean J Radiol, 2012 Sep-Oct;13(5):643-7.
PMID: 22977334 DOI: 10.3348/kjr.2012.13.5.643

Local treatment for hepatocellular carcinoma (HCC) has been widely used in clinical practice due to its minimal invasiveness and high rate of cure. Percutaneous radiofrequency ablation (RFA) is widely used because its treatment effectiveness. However, some serious complications can arise from percutaneous RFA. We present here a rare case of hemorrhagic cardiac tamponade secondary to an anterior cardiac vein (right marginal vein) injury during RFA for treatment of HCC.

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