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  1. Ponnampalam SN, Kamaluddin NR, Zakaria Z, Matheneswaran V, Ganesan D, Haspani MS, et al.
    Oncol Rep, 2017 Jan;37(1):10-22.
    PMID: 28004117 DOI: 10.3892/or.2016.5285
    The aims of the present study were to undertake gene expression profiling of the blood of glioma patients to determine key genetic components of signaling pathways and to develop a panel of genes that could be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples. In this study, blood samples were obtained from glioma patients, non-glioma and control subjects. Ten samples each were obtained from patients with high and low grade tumours, respectively, ten samples from non-glioma patients and twenty samples from control subjects. Total RNA was isolated from each sample after which first and second strand synthesis was performed. The resulting cRNA was then hybridized with the Agilent Whole Human Genome (4x44K) microarray chip according to the manufacturer's instructions. Universal Human Reference RNA and samples were labeled with Cy3 CTP and Cy5 CTP, respectively. Microarray data were analyzed by the Agilent Gene Spring 12.1V software using stringent criteria which included at least a 2-fold difference in gene expression between samples. Statistical analysis was performed using the unpaired Student's t-test with a p<0.01. Pathway enrichment was also performed, with key genes selected for validation using droplet digital polymerase chain reaction (ddPCR). The gene expression profiling indicated that were a substantial number of genes that were differentially expressed with more than a 2-fold change (p<0.01) between each of the four different conditions. We selected key genes within significant pathways that were analyzed through pathway enrichment. These key genes included regulators of cell proliferation, transcription factors, cytokines and tumour suppressor genes. In the present study, we showed that key genes involved in significant and well established pathways, could possibly be used as a potential blood-based biomarker to differentiate between high and low grade gliomas, non-gliomas and control samples.
  2. Mat Yusoff Y, Ahid F, Abu Seman Z, Abdullah J, Kamaluddin NR, Esa E, et al.
    Mol Cytogenet, 2021 Sep 24;14(1):45.
    PMID: 34560908 DOI: 10.1186/s13039-021-00561-2
    BACKGROUND: Relapsed acute myeloid leukemia (AML) is associated with the acquisition of additional somatic mutations which are thought to drive phenotypic adaptability, clonal selection and evolution of leukemic clones during treatment. We performed high throughput exome sequencing of matched presentation and relapsed samples from 6 cytogenetically normal AML (CN-AML) patients treated with standard remission induction chemotherapy in order to contribute with the investigation of the mutational landscape of CN-AML and clonal evolution during AML treatment.

    RESULT: A total of 24 and 32 somatic variants were identified in presentation and relapse samples respectively with an average of 4.0 variants per patient at presentation and 5.3 variants per patient at relapse, with SNVs being more frequent than indels at both disease stages. All patients have somatic variants in at least one gene that is frequently mutated in AML at both disease presentation and relapse, with most of these variants are classic AML and recurrent hotspot mutations including NPM1 p.W288fs, FLT3-ITD, NRAS p.G12D and IDH2 p.R140Q. In addition, we found two distinct clonal evolution patterns of relapse: (1) a leukemic clone at disease presentation acquires additional mutations and evolves into the relapse clone after the chemotherapy; (2) a leukemic clone at disease presentation persists at relapse without the addition of novel somatic mutations.

    CONCLUSIONS: The findings of this study suggest that the relapse-initiating clones may pre-exist prior to therapy, which harbor or acquire mutations that confer selective advantage during chemotherapy, resulting in clonal expansion and eventually leading to relapse.

  3. Taufiq H, Shaik Fakiruddin K, Muzaffar U, Lim MN, Rusli S, Kamaluddin NR, et al.
    Ther Adv Respir Dis, 2023;17:17534666231158276.
    PMID: 37128999 DOI: 10.1177/17534666231158276
    BACKGROUND: In coronavirus disease 2019 (COVID-19) patients, elevated levels of inflammatory cytokines from over stimulation of immune cells have become a concern due to the potential outburst of cytokine storm that damages the tissues and organs, especially the lungs. This leads to the manifestation of COVID-19 symptoms, such as pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure, and eventually death. Mesenchymal stromal/stem cells (MSCs) are currently one of hopeful approaches in treating COVID-19 considering its anti-inflammatory and immunomodulatory functions. On that account, the number of clinical trials concerning the use of MSCs for COVID-19 has been increasing. However, the number of systematic reviews and meta-analysis that specifically discuss its potential as treatment for the disease is still lacking. Therefore, this review will assess the safety and efficacy of MSC administration in COVID-19 patients.

    OBJECTIVES: To pool evidence on the safety and efficacy of MSCs in treating COVID-19 by observing MSC-related adverse effects as well as evaluating its effects in reducing inflammatory response and improving pulmonary function.

    DATA SOURCES AND METHODS: Following literature search across six databases and one trial register, full-text retrieval, and screening against eligibility criteria, only eight studies were included for data extraction. All eight studies evaluated the use of umbilical cord-derived mesenchymal stromal/stem cell (UC-MSC), infused intravenously. Of these eight studies, six studies were included in meta-analysis on the incidence of mortality, adverse events (AEs), and serious adverse events (SAEs), and the levels of C-reactive protein (CRP) and interleukin (IL)-6. Meta-analysis on pulmonary function was not performed due to insufficient data.

    RESULTS: MSC-treated group showed significantly lower risk of mortality than the control group (p = 0.03). No statistical significance was observed on the incidence of AEs (p = 0.78) and SAEs (p = 0.44), and the levels of CRP (p = 0.06) and IL-6 (p = 0.09).

    CONCLUSION: MSCs were safe for use, with lower risk of mortality and no association with AEs. Regarding efficacy, descriptive analysis showed indications of improvement on the inflammatory reaction, lung clearance, and oxygenation status despite the lack of statistical significance in meta-analysis of CRP and IL-6. Nevertheless, more studies are needed for affirmation.

    REGISTRATION: This systematic review and meta-analysis was registered on the PROSPERO database (no. CRD42022307730).

  4. Mat Yusoff Y, Abu Seman Z, Othman N, Kamaluddin NR, Esa E, Zulkiply NA, et al.
    Asian Pac J Cancer Prev, 2018 Dec 25;19(12):3317-3320.
    PMID: 30583336
    Objective: Chronic Myeloid Leukemia (CML) is caused by a reciprocal translocation between chromosomes 9
    and 22, t(9;22) (q34;q11) which encodes for the BCR-ABL fusion protein. Discovery of Imatinib Mesylate (IM) as
    first line therapy has brought tremendous improvement in the management of CML. However, emergence of point
    mutations within the BCR-ABL gene particularly T315I mutation, affects a common BCR-ABL kinase contact residue
    which impairs drug binding thus contribute to treatment resistance. This study aims to investigate the BCR-ABL T315I
    mutation in Malaysian patients with CML. Methods: A total of 285 patients diagnosed with CML were included in this
    study. Mutation detection was performed using qualitative real-time PCR (qPCR). Results: Fifteen out of 285 samples
    (5.26%) were positive for T315I mutations after amplification with real-time PCR assay. From the total number of
    positive samples, six patients were in accelerated phase (AP), four in chronic phase (CP) and five in blast crisis (BC).
    Conclusion: Mutation testing is recommended for choosing various tyrosine kinase inhibitors (TKIs) to optimize
    outcomes for both cases of treatment failure or suboptimal response to imatinib. Therefore, detection of T315I mutation
    in CML patients are clinically useful in the selection of appropriate treatment strategies to prevent disease progression.
  5. Mat Yusoff Y, Abu Seman Z, Othman N, Kamaluddin NR, Esa E, Zulkiply NA, et al.
    Asian Pac J Cancer Prev, 2019 06 01;20(6):1749-1755.
    PMID: 31244296 DOI: 10.31557/APJCP.2019.20.6.1749
    Objective: The most frequent acquired molecular abnormalities and important prognostic indicators in patients
    with Acute Myeloid Leukaemia (AML) are fms-like tyrosine kinase-3 gene (FLT3) and nucleophosmin-1 (NPM1)
    mutations. Our study aims to develop a cost effective and comprehensive in-house conventional PCR method for
    detection of FLT3-ITD, FLT3-D835 and NPM1 mutations and to evaluate the frequency of these mutations in patients
    with cytogenetically normal (CN) AML in our population. Methods: A total of 199 samples from AML patients (95
    women, 104 men) were included in the study. Mutation analyses were performed using polymerase chain reaction
    (PCR) and gene sequencing. Result: Sixty-eight patients were positive for the mutations. FLT3-ITD mutations were
    detected in 32 patients (16.1%), followed by FLT3-D835 in 5 (2.5%) and NPM1 in 54 (27.1%). Double mutations of
    NPM1 and FLT3-ITD were detected in 23 cases (11.6%). Assays validation were performed using Sanger sequencing
    and showed 100% concordance with in house method. Conclusion: The optimized in-house PCR assays for the
    detection of FLT3-ITD, FLT3-D835 and NPM1 mutations in AML patients were robust, less labour intensive and cost
    effective. These assays can be used as diagnostic tools for mutation detection in AML patients since identification of
    these mutations are important for prognostication and optimization of patient care.
  6. Zakaria Z, Othman N, Ismail A, Kamaluddin NR, Esa E, Abdul Rahman EJ, et al.
    Asian Pac J Cancer Prev, 2017 04 01;18(4):1169-1175.
    PMID: 28548470
    Background: ETV6/RUNX1 gene fusion is the most frequently seen chromosomal abnormality in childhood acute
    lymphobastic leukamia (ALL). However, additional genetic changes are known to be required for the development of
    this type of leukaemia. Therefore, we here aimed to assess the somatic mutational profile of four ALL cases carrying the
    ETV6/RUNX1 fusion gene using whole-exome sequencing. Methods: DNA was isolated from bone marrow samples
    using a QIAmp DNA Blood Mini kit and subsequently sequenced using the Illumina MiSeq system. Results: We
    identified 12,960 to17,601 mutations in each sample, with a total of 16,466 somatic mutations in total. Some 15,533
    variants were single nucleotide polymorphisms (SNPs), 129 were substitutions, 415 were insertions and 389 were
    deletions. When taking into account the coding region and protein impact, 1,875 variants were synonymous and 1,956
    were non-synonymous SNPs. Among non-synonymous SNPs, 1,862 were missense, 13 nonsense, 35 frameshifts, 11
    nonstop, 3 misstart, 15 splices disrupt and 17 in-frame indels. A total of 86 variants were located in leukaemia-related
    genes of which 32 variants were located in the coding regions of GLI2, SP140, GATA2, SMAD5, KMT2C, CDH17,
    CDX2, FLT3, PML and MOV10L1. Conclusions: Detection and identification of secondary genetic alterations are
    important in identifying new therapeutic targets and developing rationally designed treatment regimens with less
    toxicity in ALL patients.
  7. Islam M, Mohamed EH, Esa E, Kamaluddin NR, Zain SM, Yusoff YM, et al.
    Br. J. Cancer, 2017 Nov 07;117(10):1551-1556.
    PMID: 28898234 DOI: 10.1038/bjc.2017.316
    BACKGROUND: Although aberrant expression of cytokines and small molecules (analytes) is well documented in acute myeloid leukaemia (AML), their co-expression patterns are not yet identified. In addition, plasma baselines for some analytes that are biomarkers for other cancers have not been previously reported in AML.

    METHODS: We used multiplex array technology to simultaneously detect and quantify 32 plasma analyte (22 reported analytes and 10 novel analytes) levels in 38 patients.

    RESULTS: In our study, 16 analytes are found to be significantly deregulated (13 higher, 3 lower, Mann-Whitney U-test, P-value <0.005), where 5 of them have never been reported before in AML. We predicted a seven-analyte-containing multiplex panel for diagnosis of AML and, among them, MIF could be a possible therapeutic target. In addition, we observed that circulating analytes show five co-expression signatures.

    CONCLUSIONS: Circulating analyte expression in AML significantly differs from normal, and follow distinct expression patterns.

  8. Esa E, Hashim AK, Mohamed EHM, Zakaria Z, Abu Hassan AN, Mat Yusoff Y, et al.
    Genet Test Mol Biomarkers, 2021 Mar;25(3):199-210.
    PMID: 33734890 DOI: 10.1089/gtmb.2020.0182
    Background: The association between dysregulated microRNAs (miRNAs) and acute myeloid leukemia (AML) is well known. However, our understanding of the regulatory role of miRNAs in the cytogenetically normal AML (CN-AML) subtype pathway is still poor. The current study integrated miRNA and mRNA profiles to explore novel miRNA-mRNA interactions that affect the regulatory patterns of de novo CN-AML. Methods: We utilized a multiplexed nanoString nCounter platform to profile both miRNAs and mRNAs using similar sets of patient samples (n = 24). Correlations were assessed, and an miRNA-mRNA network was constructed. The underlying biological functions of the mRNAs were predicted by gene enrichment. Finally, the interacting pairs were assessed using TargetScan and microT-CDS. We identified 637 significant negative correlations (false discovery rate <0.05). Results: Network analysis revealed a cluster of 12 miRNAs representing the majority of mRNA targets. Within the cluster, five miRNAs (miR-495-3p, miR-185-5p, let-7i-5p, miR-409-3p, and miR-127-3p) were posited to play a pivotal role in the regulation of CN-AML, as they are associated with the negative regulation of myeloid leukocyte differentiation, negative regulation of myeloid cell differentiation, and positive regulation of hematopoiesis. Conclusion: Three novel interactions in CN-AML were predicted as let-7i-5p:HOXA9, miR-495-3p:PIK3R1, and miR-495-3p:CDK6 may be responsible for regulating myeloid cell differentiation in CN-AML.
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