Displaying publications 41 - 49 of 49 in total

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  1. Abdul Aziz NA, Mokhtar NM, Harun R, Mollah MM, Mohamed Rose I, Sagap I, et al.
    BMC Med Genomics, 2016;9(1):58.
    PMID: 27609023 DOI: 10.1186/s12920-016-0218-1
    Histopathological assessment has a low potential to predict clinical outcome in patients with the same stage of colorectal cancer. More specific and sensitive biomarkers to determine patients' survival are needed. We aimed to determine gene expression signatures as reliable prognostic marker that could predict survival of colorectal cancer patients with Dukes' B and C.
  2. Abdullah N, Abd Jalal N, Ismail N, Kamaruddin MA, Abd Mutalib NS, Alias MR, et al.
    Cancer Epidemiol, 2020 04;65:101656.
    PMID: 31923638 DOI: 10.1016/j.canep.2019.101656
    BACKGROUND: There has been a rapid increase in colorectal cancer (CRC) cases in Asian countries, including Malaysia. CRC is usually diagnosed at a late stage, and early detection of CRC is vital in improving survival. This study was conducted to determine the uptake rate of the immunochemical faecal occult blood test (iFOBT), the response rate to colonoscopy, and the CRC detection rate. We also wanted to identify the association between colorectal neoplasia and the Asia Pacific Colorectal Cancer Screening (APCS) scoring system.

    METHODS: We recruited 2264 individuals from The Malaysian Cohort participants aged 35-65 years who consented to colorectal screening using the iFOBT kit from July 2017 until January 2019.

    RESULTS: The response rate and positive iFOBT test rate of this study were 79.6% and 13.1% respectively. Among those with positive results, 125 individuals (52.7%) underwent colonoscopy; CRC was detected in six of them while 45 others (36.0%) had polyps. The overall CRC detection rate was 0.3% while the colorectal neoplasia detection rate (both colorectal cancer and colorectal polyps) was 2.3%. The APCS scoring indicated a significant association with colorectal neoplasia risk, with increasing trend by severity from moderate to high risk (3.46-11.14) compared to low risk. Most of the participants who were positive for iFOBT were those at high risk.

    CONCLUSIONS: The awareness of CRC risk and iFOBT screening are important strategies for early detection of CRC. We showed a CRC detection rate of 0.3 % among those who volunteered to have the iFOBT screening.

  3. Salem SA, Hwie AN, Saim A, Chee Kong CH, Sagap I, Singh R, et al.
    Malays J Med Sci, 2013 Jul;20(4):80-7.
    PMID: 24044001 MyJurnal
    Adipose tissue provides an abundant source of multipotent cells, which represent a source of cell-based regeneration strategies for urinary bladder smooth muscle repair. Our objective was to confirm that adipose-derived stem cells (ADSCs) can be differentiated into smooth muscle cells.
  4. Soh JE, Abu N, Sagap I, Mazlan L, Yahaya A, Mustangin M, et al.
    Immunotherapy, 2019 10;11(14):1205-1219.
    PMID: 31478431 DOI: 10.2217/imt-2019-0073
    Colorectal cancer is the third commonest malignancy in Asia including Malaysia. The immunogenic cancer-testis antigens, which are expressed in a variety of cancers but with limited expression in normal tissues except the testis, represent an attractive approach to improve treatment options for colorectal cancer. We aimed to validate four PASD1 peptides as the immunotherapeutic targets in colorectal cancer. First, PASD1 mRNA and protein expression were determined via real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. The PASD1 peptides specific to HLA-A*24:02 were investigated using IFN-y-ELISpot assay, followed by the cytolytic and granzyme-B-ELISpot assays to analyze the cytolytic effects of CD8+ T cells. Gene and protein expressions of PASD1 were detected in 20% and 17.3% of colorectal cancer samples, respectively. PASD1(4) peptide was shown to be immunogenic in colorectal cancer samples. CD8+ T cells raised against PASD1(4) peptide were able to lyze HLA-A*24:02+ PASD1+ cells. Our results reveal that PASD1(4) peptide represents a potential target for colorectal cancer.
  5. Salem SA, Rashidbenam Z, Jasman MH, Ho CCK, Sagap I, Singh R, et al.
    Tissue Eng Regen Med, 2020 08;17(4):553-563.
    PMID: 32583275 DOI: 10.1007/s13770-020-00271-7
    BACKGROUND: The urinary tract can be affected by both congenital abnormalities as well as acquired disorders, such as cancer, trauma, infection, inflammation, and iatrogenic injuries, all of which may lead to organ damage requiring eventual reconstruction. As a gold standard, gastrointestinal segment is used for urinary bladder reconstruction. However, one major problem is that while bladder tissue prevents reabsorption of specific solutes, gastrointestinal tissue actually absorbs them. Therefore, tissue engineering approach had been attempted to provide an alternative tissue graft for urinary bladder reconstruction.

    METHODS: Human adipose-derived stem cells isolated from fat tissues were differentiated into smooth muscle cells and then seeded onto a triple-layered PLGA sheet to form a bladder construct. Adult athymic rats underwent subtotal urinary bladder resection and were divided into three treatment groups (n = 3): Group 1 ("sham") underwent anastomosis of the remaining basal region, Group 2 underwent reconstruction with the cell-free scaffold, and Group 3 underwent reconstruction with the tissue-engineered bladder construct. Animals were monitored on a daily basis and euthanisation was performed whenever a decline in animal health was detected.

    RESULTS: All animals in Groups 1, 2 and 3 survived for at least 7 days and were followed up to a maximum of 12 weeks post-operation. It was found that by Day 14, substantial ingrowth of smooth muscle and urothelial cells had occurred in Group 2 and 3. In the long-term follow up of group 3 (tissue-engineered bladder construct group), it was found that the urinary bladder wall was completely regenerated and bladder function was fully restored. Urodynamic and radiological evaluations of the reconstructed bladder showed a return to normal bladder volume and function.Histological analysis revealed the presence of three muscular layers and a urothelium similar to that of a normal bladder. Immunohistochemical staining using human-specific myocyte markers (myosin heavy chain and smoothelin) confirmed the incorporation of the seeded cells in the newly regenerated muscular layers.

    CONCLUSION: Implantation of PLGA construct seeded with smooth muscle cells derived from human adipose stem cells can lead to regeneration of the muscular layers and urothelial ingrowth, leading to formation of a completely functional urinary bladder.

  6. Abdul SN, Ab Mutalib NS, Sean KS, Syafruddin SE, Ishak M, Sagap I, et al.
    Front Pharmacol, 2017;8:465.
    PMID: 28769798 DOI: 10.3389/fphar.2017.00465
    Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC) remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS), it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes' B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion Ampliseq(TM) Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes' B (n = 10) and Dukes' C (n = 9) CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45%) were predicted to be deleterious, 38 variants (27%) possibly deleterious while the other 39 variants (28%) have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes' B and C. The adenomatous polyposis coli gene (APC) was the most frequently altered gene in both groups (n = 6 in Dukes' B and C). In addition, TP53 was more frequently altered in Dukes' C (n = 7) compared to Dukes' B (n = 4). Ten variants in APC, namely p.R283(∗), p.N778fs, p.R805(∗), p.Y935fs, p.E941fs, p.E1057(∗), p.I1401fs, p.Q1378(∗), p.E1379(∗), and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS, TGF-β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape.
  7. Mokhtar NM, Nawawi KNM, Verasingam J, Zhiqin W, Sagap I, Azman ZAM, et al.
    BMC Public Health, 2019 Jun 13;19(Suppl 4):550.
    PMID: 31196184 DOI: 10.1186/s12889-019-6858-2
    BACKGROUND: Inflammatory bowel disease (IBD) was once considered as a Western disease. However, recent epidemiological data showed an emerging trend of IBD cases in the Eastern Asia countries. Clinico-epidemiological data of IBD in Malaysia is scarce. This study aimed to address this issue.

    METHODS: Retrospective analysis of ulcerative colitis (UC) and Crohn's disease (CD), diagnosed from January 1980 till June 2018 was conducted at our centre.

    RESULTS: A total of 413 IBD patients (281 UC, 132 CD) were identified. Mean crude incidence of IBD has increased steadily over the first three decades: 0.36 (1980-1989), 0.48 (1990-1999) and 0.63 per 100,000 person-years (2000-2009). In the 2010 to 2018 period, the mean crude incidence has doubled to 1.46 per 100,000 person-years. There was a significant rise in the incidence of CD, as depicted by reducing UC:CD ratio: 5:1 (1980-1989), 5:1 (1990-1999), 1.9:1 (2000-2009) and 1.7:1 (2010-2018). The prevalence rate of IBD, UC and CD, respectively were 23.0, 15.67 and 7.36 per 100,000 persons. Of all IBD patients, 61.5% (n = 254) were males. When stratified according to ethnic group, the highest prevalence of IBD was among the Indians: 73.4 per 100,000 persons, followed by Malays: 24.8 per 100,000 persons and Chinese: 14.6 per 100,000 persons. The mean age of diagnosis was 41.2 years for UC and 27.4 years for CD. Majority were non-smokers (UC: 76.9%, CD: 70.5%). The diseases were classified as follows: UC; proctitis (9.2%), left-sided colitis (50.2%) and extensive colitis (40.6%), CD; isolated ileal (22.7%), colonic (28.8%), ileocolonic (47.7%) and upper gastrointestinal (0.8%). 12.9% of CD patients had concurrent perianal disease. Extra intestinal manifestations were observed more in CD (53.8%) as compared to UC (12%). Dysplasia and malignancy, on the other hand, occurred more in UC (4.3%, n = 12) than in CD (0.8%, n = 1). Over one quarter (27.3%) of CD patients and 3.6% of UC patients received biologic therapy.

    CONCLUSION: The incidence of IBD is rising in Malaysia, especially in the last one decade. This might be associated with the urbanization and changing diets. Public and clinicians' awareness of this emerging disease in Malaysia is important for the timely detection and management.

  8. Muhammad Nawawi KN, Mokhtar NM, Wong Z, Mohd Azman ZA, Hsin Chew DC, Rehir R, et al.
    PeerJ, 2021;9:e12425.
    PMID: 34820182 DOI: 10.7717/peerj.12425
    Background: The incidence rate of colorectal cancer (CRC) in Asian countries is increasing. Furthermore, recent studies have shown a concerning rise in the incidence of CRC among younger patients aged less than 50 years. This study aimed to analyze the incidence trends and clinicopathological features in patients with early-onset CRC (EOCRC) and later-onset CRC (at age ≥ 50 years).

    Methods: A retrospective analysis was performed on 946 patients with CRC diagnosed from 1997 to 2017 at Universiti Kebangsaan Malaysia Medical Centre. The time trend was assessed by dividing the two decades into four 5-year periods. The mean age-standardized and age-specific incidence rates were calculated by using the 5-year cumulative population of Kuala Lumpur and World Health Organization standard population. The mean incidence was expressed per 100,000 person-years.

    Results: After a stable (all age groups) CRC incidence rate during the first decade (3.00 per 100,000 and 3.85 per 100,000), it sharply increased to 6.12 per 100,000 in the 2008-2012 period before decreasing to 4.54 per 100,000 in the 2013-2017 period. The CRC incidence trend in later-onset CRC showed a decrease in the 2013-2017 period. Contrariwise, for age groups of 40-44 and 45-49 years, the trends showed an increase in the latter 15 years of the study period (40-44 years: 1.44 to 1.92 to 2.3 per 100,000; 45-49 years: 2.87 to 2.94 to 4.01 per 100,000). Malays' EOCRC incidence rate increased from 2008-2012 to 2013-2017 for both the age groups 40-44 years (1.46 to 2.89 per 100,000) and 45-49 years (2.73 to 6.51 per 100,000). Nearly one-fifth of EOCRC cases were diagnosed at an advanced stage (Dukes D: 19.9%), and the majority of them had rectal cancer (72.8%).

    Conclusion: The incidence of EOCRC increased over the period 1997-2017; the patients were predominantly Malays, diagnosed at a later stage, and with cancer commonly localized in the rectal region. All the relevant stakeholders need to work on the management and prevention of CRC in Malaysia.

  9. Mohd Yunos RI, Ab Mutalib NS, Khoo JS, Saidin S, Ishak M, Syafruddin SE, et al.
    Front Mol Biosci, 2022;9:997747.
    PMID: 36866106 DOI: 10.3389/fmolb.2022.997747
    The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/β-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.
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