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Fulltext EGFR mutation detection by polymerase chain reaction-direct sequencing and allele-specific real-time PCR

Liam CK, Wong CK, Tan JL

J Thorac Oncol, 2014 Sep;9(9):e71-2.
PMID: 25122442 DOI: 10.1097/JTO.0000000000000261
Fulltext Support from Phylogenomic Networks and Subspecies Signatures for Separation of Mycobacterium massiliense from Mycobacterium bolletii

Tan JL, Ngeow YF, Choo SW

J Clin Microbiol, 2015 Sep;53(9):3042-6.
PMID: 26157149 DOI: 10.1128/JCM.00541-15

Mycobacterium abscessus subspecies classification has important clinical implications. We used phylogenomic network and amino acid analyses to provide evidence for the separation of Mycobacterium bolletii and Mycobacterium massiliense into two distinct subspecies which can potentially be differentiated rapidly by their protein signatures.
Fulltext Rare Clinical Presentation of Tuberculous Meningitis: A Case Report

Tan JL, Nordin S, Besari AM

Malays J Med Sci, 2017 Oct;24(5):119-123.
PMID: 29386980 MyJurnal DOI: 10.21315/mjms2017.24.5.14

Introduction: Tuberculosis is the second leading cause of death under the category of infectious diseases, after the human immunodeficiency virus (HIV). Tuberculous meningitis (TBM) constitutes about 5% of all extrapulmonary disease worldwide. This report describes a case of Tuberculous meningitis with rare presentation in a 28-year-old woman, who was treated based on a collection of her social background, clinical findings and Multiplex PCR of tuberculosis.
Case presentation: A 28-year-old Malay woman with no significant medical history presented to HUSM with one month history of on and off fever, two weeks history of generalised limbs weakness and one week history of dysphagia. She was reported to have experienced visual hallucination and significant weight loss. Her laboratory result is significant for leukocytosis, elevated ESR and hypernatremia. Non-enhanced and contrast CT scan of the brain showed severe bilateral frontal cerebral atrophy. Cerebral spinal fluid (CSF) for multiplex PCR for Mycobacterium tuberculosis complex was positive. She was promptly started on anti-TB regime combined with dexamethasone. Subsequent follow-up showed significant improvement.
Conclusion: This is a rare clinical manifestation of Tuberculous meningitis that demonstrates the importance of recognising and initiating the treatment early to reduce disabilities and improve clinical outcome.
Fulltext A phylogenomic approach to bacterial subspecies classification: proof of concept in Mycobacterium abscessus

Tan JL, Khang TF, Ngeow YF, Choo SW

BMC Genomics, 2013;14:879.
PMID: 24330254 DOI: 10.1186/1471-2164-14-879

Mycobacterium abscessus is a rapidly growing mycobacterium that is often associated with human infections. The taxonomy of this species has undergone several revisions and is still being debated. In this study, we sequenced the genomes of 12 M. abscessus strains and used phylogenomic analysis to perform subspecies classification.
Fulltext Genome sequence analysis of multidrug-resistant Mycobacterium tuberculosis from Malaysia

Tan JL, Simbun A, Chan KG, Ngeow YF

Sci Data, 2020 05 05;7(1):135.
PMID: 32371951 DOI: 10.1038/s41597-020-0475-x

Mycobacterium tuberculosis (MTB) is commonly used as a model to study pathogenicity and multiple drug resistance in bacteria. These MTB characteristics are highly dependent on the evolution and phylogeography of the bacterium. In this paper, we describe 15 new genomes of multidrug-resistant MTB (MDRTB) from Malaysia. The assessments and annotations on the genome assemblies suggest that strain differences are due to lineages and horizontal gene transfer during the course of evolution. The genomes show mutations listed in current drug resistance databases and global MTB collections. This genome data will augment existing information available for comparative genomic studies to understand MTB drug resistance mechanisms and evolution.
Fulltext Genomic Comparisons Reveal Microevolutionary Differences in Mycobacterium abscessus Subspecies

Tan JL, Ng KP, Ong CS, Ngeow YF

Front Microbiol, 2017;8:2042.
PMID: 29109707 DOI: 10.3389/fmicb.2017.02042

Mycobacterium abscessus, a rapid-growing non-tuberculous mycobacterium, has been the cause of sporadic and outbreak infections world-wide. The subspecies in M. abscessus complex (M. abscessus, M. massiliense, and M. bolletii) are associated with different biologic and pathogenic characteristics and are known to be among the most frequently isolated opportunistic pathogens from clinical material. To date, the evolutionary forces that could have contributed to these biological and clinical differences are still unclear. We compared genome data from 243 M. abscessus strains downloaded from the NCBI ftp Refseq database to understand how the microevolutionary processes of homologous recombination and positive selection influenced the diversification of the M. abscessus complex at the subspecies level. The three subspecies are clearly separated in the Minimum Spanning Tree. Their MUMi-based genomic distances support the separation of M. massiliense and M. bolletii into two subspecies. Maximum Likelihood analysis through dN/dS (the ratio of number of non-synonymous substitutions per non-synonymous site, to the number of synonymous substitutions per synonymous site) identified distinct genes in each subspecies that could have been affected by positive selection during evolution. The results of genome-wide alignment based on concatenated locally-collinear blocks suggest that (a) recombination has affected the M. abscessus complex more than mutation and positive selection; (b) recombination occurred more frequently in M. massiliense than in the other two subspecies; and (c) the recombined segments in the three subspecies have come from different intra-species and inter-species origins. The results lead to the identification of possible gene sets that could have been responsible for the subspecies-specific features and suggest independent evolution among the three subspecies, with recombination playing a more significant role than positive selection in the diversification among members in this complex.
Anaplastic lymphoma kinase (ALK) mutations in patients with adenocarcinoma of the lung

Mohamad N, Jayalakshmi P, Rhodes A, Liam CK, Tan JL, Yousoof S, et al.

Br J Biomed Sci, 2017 Oct;74(4):176-180.
PMID: 28705139 DOI: 10.1080/09674845.2017.1331520

BACKGROUND: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death. Approximately 2-16% of NSCLC patients with wild-type epidermal growth factor receptor (EGFR) harbour anaplastic lymphoma kinase (ALK) mutations. Both EGFR and ALK mutations occur most commonly in Asian patients with NSCLC. As targeted therapy is available for NSCLC patients with these mutations, it is important to establish reliable assays and testing strategies to identify those most likely to benefit from this therapy.
MATERIALS AND METHODS: Patients diagnosed with adenocarcinoma of the lung between 2010 and 2014 were tested for EGFR mutations. Of these, 92 cases were identified as EGFR wild type and suitable candidates for ALK testing utilising immunohistochemistry and the rabbit monoclonal antibody D5F3. The reliability of the IHC was confirmed by validating the results against those achieved by fluorescence in situ hybridisation (FISH) to detect ALK gene rearrangements.
RESULTS: Twelve (13%) cases were positive for ALK expression using immunohistochemistry. Of the 18 evaluable cases tested by FISH, there was 100% agreement with respect to ALK rearrangement/ALK expression between the assays, with 11 cases ALK negative and 7 cases ALK positive by both assays. ALK tumour expression was significantly more common in female compared to male patients (29.6% vs. 6.2%, P
Food order and glucose excursion in Indian adults with normal and overweight/obese Body Mass Index: A randomised crossover pilot trial

Lee CL, Shyam S, Lee ZY, Tan JL

Nutr Health, 2021 Jun;27(2):161-169.
PMID: 33349136 DOI: 10.1177/0260106020975573

BACKGROUND: Postprandial glycaemia has an impact on health but there is limited data about the effect of food order on postprandial glycaemia by body weight status.
AIM: To investigate the effects of food order on postprandial glucose (PPG) excursion, in Indian adults with normal (NL) and overweight/obese (OW) Body Mass Index.
METHODS: This randomised crossover study was conducted at a Malaysian university among Indian adults without diabetes. The participants consumed isocaloric test meals at three study visits based on randomised food orders: carbohydrate first/protein last (CF); protein first/carbohydrate last (CL); and a composite meal containing carbohydrate and protein (CM). Capillary blood glucose was measured at baseline, 30, 60, 90 and 120 minutes after starting the meal.
RESULTS: The CL food order had a blunting effect on PPG excursion at 30 and 60 minutes (p < 0.01). The CL food order resulted in lower glucose peak when compared with the CF and CM food order (p < 0.001). The CL food order resulted in lower incremental glucose peak (mmol/L) (NL: CF 3.9 ± 0.3, CM 3.0 ± 0.3, CL 2.0 ± 0.2; OW: CF 2.9 ± 0.3, CM 2.5 ± 0.3, CL 1.8 ± 0.2) and iAUC 0-120 min (mmol/Lxmin) (NL: CF 272.4 ± 26.7, CM 206.2 ± 30.3, CL 122.0 ± 14.8; OW: CF 193.2 ± 23.1, CM 160.1 ± 21.7, CL 113.6 ± 15.3) when compared with the CF food order (p < 0.001). The effect of food order on postprandial excursion did not differ between the NL (n = 14) and the OW (n = 17) groups.
CONCLUSION: In participants with normal and overweight/obese BMI, consuming food in the protein first/carbohydrate last order had the biggest effect in reducing PPG excursion.
Fulltext Comparative genomic analysis of Mycobacterium iranicum UM_TJL against representative mycobacterial species suggests its environmental origin

Tan JL, Ngeow YF, Wee WY, Wong GJ, Ng HF, Choo SW

Sci Rep, 2014;4:7169.
PMID: 25417557 DOI: 10.1038/srep07169

Mycobacterium iranicum is a newly reported mycobacterial species. We present the first comparative study of M. iranicum UM_TJL and other mycobacteria. We found M. iranicum to have a close genetic association with environmental mycobacteria infrequently associated with human infections. Nonetheless, UM_TJL is also equipped with many virulence genes (some of which appear to be the consequence of transduction-related gene transfer) that have been identified in established human pathogens. Taken all together, our data suggest that M. iranicum is an environmental bacterium adapted for pathogenicity in the human host. This comparative study provides important clues and forms the basis for future functional studies on this mycobacterium.
Fulltext First Whole-Genome Sequence of Mycobacterium iranicum, a Newly Reported Mycobacterial Species

Tan JL, Ng HF, Wee WY, Ang MY, Wong GJ, Ngeow YF, et al.

Genome Announc, 2013;1(5).
PMID: 24072861 DOI: 10.1128/genomeA.00732-13

Mycobacterium iranicum is a new species of nontuberculous mycobacterium reported in 2013. Here, we describe the first whole-genome sequence of this species, that of M. iranicum strain UM_TJL, isolated from a patient in Malaysia.
Fulltext Identification of new genomospecies in the Mycobacterium terrae complex

Ngeow YF, Wong YL, Tan JL, Hong KW, Ng HF, Ong BL, et al.

PLoS One, 2015;10(4):e0120789.
PMID: 25830768 DOI: 10.1371/journal.pone.0120789

Members of the Mycobacterium terrae complex are slow-growing, non-chromogenic acid-fast bacilli found in the natural environment and occasionally in clinical material. These genetically closely-related members are difficult to differentiate by conventional phenotypic and molecular tests. In this paper we describe the use of whole genome data for the identification of four strains genetically similar to Mycobacterium sp. JDM601, a newly identified member of the M. terrae complex. Phylogenetic information from the alignment of genome-wide orthologous genes and single nucleotide polymorphisms show consistent clustering of the four strains together with M. sp. JDM601 into a distinct clade separate from other rapid and slow growing mycobacterial species. More detailed inter-strain comparisons using average nucleotide identity, tetra-nucleotide frequencies and analysis of synteny indicate that our strains are closely related to but not of the same species as M. sp. JDM601. Besides the 16S rRNA signature described previously for the M. terrae complex, five more hypothetical proteins were found that are potentially useful for the rapid identification of mycobacterial species belonging to the M. terrae complex. This paper illustrates the versatile utilization of whole genome data for the delineation of new bacterial species and introduces four new genomospecies to add to current members in the M. terrae complex.
A mutation in anti-sigma factor MAB_3542c may be responsible for tigecycline resistance in Mycobacterium abscessus

Ng HF, Tan JL, Zin T, Yap SF, Ngeow YF

J Med Microbiol, 2018 Dec;67(12):1676-1681.
PMID: 30351265 DOI: 10.1099/jmm.0.000857

In this study, we characterized 7C, a spontaneous mutant selected from tigecycline-susceptible Mycobacterium abscessus ATCC 19977. Whole-genome sequencing (WGS) was used to identify possible resistance determinants in this mutant. Compared to the wild-type, 7C demonstrated resistance to tigecycline as well as cross-resistance to imipenem, and had a slightly retarded growth rate. WGS and subsequent biological verifications showed that these phenotypes were caused by a point mutation in MAB_3542c, which encodes an RshA-like protein. In Mycobacterium tuberculosis, RshA is an anti-sigma factor that negatively regulates the heat/oxidative stress response mechanisms. The MAB_3542c mutation may represent a novel determinant of tigecycline resistance. We hypothesize that this mutation may dysregulate the stress-response pathways which have been shown to be linked to antibiotic resistance in previous studies.
Fulltext Chromosomal rearrangements and protein globularity changes in Mycobacterium tuberculosis isolates from cerebrospinal fluid

Saw SH, Tan JL, Chan XY, Chan KG, Ngeow YF

PeerJ, 2016;4:e2484.
PMID: 27688977 DOI: 10.7717/peerj.2484

BACKGROUND: Meningitis is a major cause of mortality in tuberculosis (TB). It is not clear what factors promote central nervous system invasion and pathology but it has been reported that certain strains of Mycobacterium tuberculosis (Mtb) might have genetic traits associated with neurotropism.
METHODS: In this study, we generated whole genome sequences of eight clinical strains of Mtb that were isolated from the cerebrospinal fluid (CSF) of patients presenting with tuberculous meningitis (TBM) in Malaysia, and compared them to the genomes of H37Rv and other respiratory Mtb genomes either downloaded from public databases or extracted from local sputum isolates. We aimed to find genomic features that might be distinctly different between CSF-derived and respiratory Mtb.
RESULTS: Genome-wide comparisons revealed rearrangements (translocations, inversions, insertions and deletions) and non-synonymous SNPs in our CSF-derived strains that were not observed in the respiratory Mtb genomes used for comparison. These rearranged segments were rich in genes for PE (proline-glutamate)/PPE (proline-proline-glutamate), transcriptional and membrane proteins. Similarly, most of the ns SNPs common in CSF strains were noted in genes encoding PE/PPE proteins. Protein globularity differences were observed among mycobacteria from CSF and respiratory sources and in proteins previously reported to be associated with TB meningitis. Transcription factors and other transcription regulators featured prominently in these proteins. Homologs of proteins associated with Streptococcus pneumoniae meningitis and Neisseria meningitidis virulence were identified in neuropathogenic as well as respiratory mycobacterial spp. examined in this study.
DISCUSSION: The occurrence of in silico genetic differences in CSF-derived but not respiratory Mtb suggests their possible involvement in the pathogenesis of TBM. However, overall findings in this comparative analysis support the postulation that TB meningeal infection is more likely to be related to the expression of multiple virulence factors on interaction with host defences than to CNS tropism associated with specific genetic traits.
Tigecycline resistance may be associated with dysregulated response to stress in Mycobacterium abscessus

Ng HF, Ngeow YF, Yap SF, Zin T, Tan JL

Int J Med Microbiol, 2019 Nov 18.
PMID: 31784213 DOI: 10.1016/j.ijmm.2019.151380

Previously, we characterized 7C, a laboratory-derived tigecycline-resistant mutant of Mycobacterium abscessus ATCC 19977, and found that the resistance was conferred by a mutation in MAB_3542c, which encodes an RshA-like protein. In M. tuberculosis, RshA is an anti-sigma factor that negatively regulates the SigH-dependent heat/oxidative stress response. We hypothesized that this mutation in 7C might dysregulate the stress response which has been generally linked to antibiotic resistance. In this study, we tested this hypothesis by subjecting 7C to transcriptomic dissection using RNA sequencing. We found an over-expression of genes encoding the SigH ortholog, chaperones and oxidoreductases. In line with these findings, 7C demonstrated better survival against heat shock when compared to the wild-type ATCC 19977. Another interesting observation from the RNA-Seq analysis was the down-regulation of ribosomal protein-encoding genes. This highlights the possibility of ribosomal conformation changes which could negatively affect the binding of tigecycline to its target, leading to phenotypic resistance. We also demonstrated that transient resistance to tigecycline could be induced in the ATCC 19977 by elevated temperature. Taken together, these findings suggest that dysregulated stress response may be associated with tigecycline resistance in M. abscessus.
Fulltext Critical Inhaler Administration Errors of Patients on Pressurized Meter Dose Inhaler (pMDI): A Hospital-Based Cross-Sectional Study in Malaysia

Rajah R, Tang YW, Ho SC, Tan JL, Mat Said MS, Ooi LH

Hosp Pharm, 2022 Apr;57(2):217-222.
PMID: 35601709 DOI: 10.1177/00185787211010164

Background: Inhaler technique errors can affect the disease outcome through reduced deposition of medication in the lungs with certain errors were more likely to deter the optimum drug from reaching the lung. The objective of this study was to evaluate the pressurized metered-dose inhaler (pMDI) critical technique errors among asthma and COPD patients, and to investigate the predictors of those errors. Methods: A cross-sectional, observational, and multi-centered study conducted in 3 major hospitals in the state of Penang, Malaysia. Asthma and COPD patients aged 18 years or older consented to the study were consecutively recruited if they were at least on 1 pMDI without mouthpiece spacer or facemask space. Direct observation of the patient's technique was recorded using a standard checklist and certain steps in the checklist were pre-determined as critical steps. The number of patients missed or incorrectly performed the steps including the critical steps were documented. Using logistic regression, the factors associated with the critical errors were determined, and the correlation was evaluated between age and pMDI knowledge score with critical inhalation steps score. Results: Of 209 patients observed, only less than half (40.7%) could perform all the critical pMDI steps correctly. Low education level was the only factor associated with critical inhaler errors. The increased knowledge of their inhaled medication was found to positively correlate with the correct critical inhalation steps. The critical errors also increase with the increased age of patients. Conclusion: The majority of the study population make inhalation error particularly in critical steps. Training and education intervention programs may help patients with lower education level, as well as those of advanced age and lack of knowledge of their inhaled medication because those populations are at a greater risk of committing critical errors in their use of pMDI.
The effect of medical education and counselling on treatment adherence and disease severity in patients with acne vulgaris: a non-randomised interventional study

Ling WY, Loo CH, Nurul Shafaril Niza MA, Tan JL, Norazlima MA, Tan WC

Med J Malaysia, 2023 May;78(3):263-269.
PMID: 37271834

INTRODUCTION: Acne vulgaris (AV) is a common inflammatory skin disease affecting adolescents and young adults. It affects one's self-esteem and social relationship. In addition, poor adherence to treatment can cause poor treatment response and disease recurrence. This study aims to determine the effectiveness of medical education and counselling on treatment adherence and disease severity.
METHODS: This is a non-randomised interventional study with age- and treatment- matched control conducted in a tertiary dermatology clinic from July 2021 to June 2022. Patients in the intervention group received a 10 min video presentation on acne, followed by treatment counselling. The adherence rate was determined objectively (pill counting and tube weighing) and subjectively (ECOB questionnaire). The disease severity was assessed using the Comprehensive Acne Severity Scale (CASS) and Global Acne Grading System (GAGS).
RESULTS: A total of 100 patients completed the 12-week study. With intervention, patients have better adherence to topical medication (5% benzoyl peroxide gel: 71% vs 57.9%, p= 0.031; 0.05% tretinoin cream: 58.7% vs 45.4%, p= 0.044) at week 12. However, the intervention program did not improve adherence to oral medication. Overall, with intervention, a significantly higher percentage of improvement in disease severity was noted (47.3% vs. 39.1%, p=0.044). Nonadherence to treatment was attributed mostly to forgetfulness in 54% of the patients, followed by a busy lifestyle (41%) and little knowledge of acne (26%).
CONCLUSION: Patients have significantly better adherence to topical medication with education and counselling. Better adherence to treatment leads to more remarkable disease improvement.
Fulltext Genome sequence of Mycobacterium abscessus strain M152

Ngeow YF, Wong YL, Tan JL, Ong CS, Ng KP, Choo SW

J Bacteriol, 2012 Dec;194(23):6662.
PMID: 23144407 DOI: 10.1128/JB.01846-12

Mycobacterium abscessus is an environmental bacterium with increasing clinical relevance. Here, we report the annotated whole-genome sequence of M. abscessus strain M152.
Fulltext Genomic analysis of Mycobacterium abscessus strain M139, which has an ambiguous subspecies taxonomic position

Ngeow YF, Wee WY, Wong YL, Tan JL, Ongi CS, Ng KP, et al.

J Bacteriol, 2012 Nov;194(21):6002-3.
PMID: 23045507 DOI: 10.1128/JB.01455-12

Mycobacterium abscessus is a ubiquitous, rapidly growing species of nontuberculous mycobacteria that colonizes organic surfaces and is frequently associated with opportunistic infections in humans. We report here the draft genome sequence of Mycobacterium abscessus strain M139, which shows genomic features reported to be characteristic of both Mycobacterium abscessus subsp. abscessus and Mycobacterium abscessus subsp. massiliense.
Fulltext Draft genome sequence of Mycobacterium bolletii strain M24, a rapidly growing mycobacterium of contentious taxonomic status

Wong YL, Choo SW, Tan JL, Ong CS, Ng KP, Ngeow YF

J Bacteriol, 2012 Aug;194(16):4475.
PMID: 22843600 DOI: 10.1128/JB.00916-12

The whole-genome sequence of Mycobacterium bolletii M24, isolated from the bronchoalveolar lavage fluid of a Malaysian patient, is reported here. The circular chromosome of 5,507,730 bp helped to clarify the taxonomic position of this organism within the M. abscessus complex and revealed the presence of proteins potentially important for pathogenicity in a human host.
Fulltext Annotated genome sequence of Mycobacterium massiliense strain M154, belonging to the recently created taxon Mycobacterium abscessus subsp. bolletii comb. nov

Choo SW, Wong YL, Tan JL, Ong CS, Wong GJ, Ng KP, et al.

J Bacteriol, 2012 Sep;194(17):4778.
PMID: 22887675 DOI: 10.1128/JB.01043-12

Mycobacterium massiliense has recently been proposed as a member of Mycobacterium abscessus subsp. bolletii comb. nov. Strain M154, a clinical isolate from the bronchoalveolar lavage fluid of a Malaysian patient presenting with lower respiratory tract infection, was subjected to shotgun DNA sequencing with the Illumina sequencing technology to obtain whole-genome sequence data for comparison with other genetically related strains within the M. abscessus species complex.

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