Publications by authors named "Rahman Jamal"

142 Publications

Author Correction: Delineating colorectal cancer distribution, interaction, and risk prediction by environmental risk factors and serum trace elements.

Sci Rep 2021 Feb 23;11(1):4853. Epub 2021 Feb 23.

Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, W. Persekutuan, Malaysia.

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http://dx.doi.org/10.1038/s41598-021-83219-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902807PMC
February 2021

Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells.

Mol Biol Rep 2021 Feb 15;48(2):1493-1503. Epub 2021 Feb 15.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Medical Centre, Jalan Ya'acob Latiff, Bandar Tun Razak, 56000, Cheras, Kuala Lumpur, Malaysia.

Despite the advancements in primary brain tumour diagnoses and treatments, the mortality rate remains high, particularly in glioblastoma (GBM). Chemoresistance, predominantly in recurrent cases, results in decreased mean survival of patients with GBM. We aimed to determine the chemosensitisation and oncogenic characteristics of zinc finger protein 36-like 2 (ZFP36L2) in LN18 GBM cells via RNA interference (RNAi) delivery. We conducted a meta-analysis of microarray datasets and RNAi screening using pooled small interference RNA (siRNA) to identify the druggable genes responsive to GBM chemosensitivity. Temozolomide-resistant LN18 cells were used to evaluate the effects of gene silencing on chemosensitisation to the sub-lethal dose (1/10 of the median inhibitory concentration [IC50]) of temozolomide. ZFP36L2 protein expression was detected by western blotting. Cell viability, proliferation, cell cycle and apoptosis assays were carried out using commercial kits. A human apoptosis array kit was used to determine the apoptosis pathway underlying chemosensitisation by siRNA against ZFP36L2 (siZFP36L2). Statistical analyses were performed using one-way analysis of variance; p > 0.05 was considered significant. The meta-analysis and RNAi screening identified ZFP36L2 as a potential marker of GBM. ZFP36L2 knockdown significantly induced apoptosis (p < 0.05). Moreover, ZFP36L2 inhibition led to increased cell cycle arrest and decreased cell proliferation. Downstream analysis showed that the sub-lethal dose of temozolomide and siZFP26L2 caused major upregulation of BCL2-associated X, apoptosis regulator (BAX). ZFP36L2 has oncogenic and chemosensitive characteristics and may play an important role in gliomagenesis through cell proliferation, cell cycle arrest and apoptosis. This suggests that RNAi combined with chemotherapy treatment such as temozolomide may be a potential GBM therapeutic intervention in the future.
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http://dx.doi.org/10.1007/s11033-021-06144-zDOI Listing
February 2021

Parvimonas micra, Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer.

Sci Rep 2021 Feb 3;11(1):2925. Epub 2021 Feb 3.

UKM Medical Molecular Biology Institute (UMBI), UKM Medical Centre, Universiti Kebangsaan Malaysia, Jalan Yaa'cob Latiff, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.

Dysbiosis of the gut microbiome has been associated with the pathogenesis of colorectal cancer (CRC). We profiled the microbiome of gut mucosal tissues from 18 CRC patients and 18 non-CRC controls of the UKM Medical Centre (UKMMC), Kuala Lumpur, Malaysia. The results were then validated using a species-specific quantitative PCR in 40 CRC and 20 non-CRC tissues samples from the UMBI-UKMMC Biobank. Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were found to be over-represented in our CRC patients compared to non-CRC controls. These four bacteria markers distinguished CRC from controls (AUROC = 0.925) in our validation cohort. We identified bacteria species significantly associated (cut-off value of > 5 fold abundance) with various CRC demographics such as ethnicity, gender and CRC staging; however, due to small sample size of the discovery cohort, these results could not be further verified in our validation cohort. In summary, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were enriched in our local CRC patients. Nevertheless, the roles of these bacteria in CRC initiation and progression remains to be investigated.
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http://dx.doi.org/10.1038/s41598-021-82465-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859180PMC
February 2021

Long Non-Coding RNAs (lncRNAs) in Cardiovascular Disease Complication of Type 2 Diabetes.

Diagnostics (Basel) 2021 Jan 19;11(1). Epub 2021 Jan 19.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaa'cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia.

The discovery of non-coding RNAs (ncRNAs) has opened a new paradigm to use ncRNAs as biomarkers to detect disease progression. Long non-coding RNAs (lncRNA) have garnered the most attention due to their specific cell-origin and their existence in biological fluids. Type 2 diabetes patients will develop cardiovascular disease (CVD) complications, and CVD remains the top risk factor for mortality. Understanding the lncRNA roles in T2D and CVD conditions will allow the future use of lncRNAs to detect CVD complications before the symptoms appear. This review aimed to discuss the roles of lncRNAs in T2D and CVD conditions and their diagnostic potential as molecular biomarkers for CVD complications in T2D.
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http://dx.doi.org/10.3390/diagnostics11010145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835902PMC
January 2021

Extracellular Vesicles Derived From Colorectal Cancer Affects CD8 T Cells: An Analysis Based on Body Mass Index.

Front Cell Dev Biol 2020 26;8:564648. Epub 2020 Nov 26.

UKM Medical Molecular Biology Institute, UKM Medical Center, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Colorectal cancer (CRC) is one of the most widely diagnosed cancers worldwide. It has been shown that the body-mass index (BMI) of the patients could influence the tumor microenvironment, treatment response, and overall survival rates. Nevertheless, the mechanism on how BMI affects the tumorigenesis process, particularly the tumor microenvironment is still elusive. Herein, we postulate that extracellular vesicles (EVs) from CRC patients and non-CRC volunteers with different BMI could affect immune cells differently, in CD8 T cells particularly. We isolated the EVs from the archived serum of CRC patients with high and low BMI, as well as healthy controls with similar BMI status. The EVs were further characterized via electron microscopy, western blot and dynamic light scattering. Then, functional analysis was performed on CD8 T cells including apoptosis, cell proliferation, gene expression profiling and cytokine release upon co-incubation with the different EVs. Our results suggest that CRC-derived EVs were able to regulate the CD8 T cells. In some assays, low BMI EVs were functionally different than high BMI EVs. This study highlights the possible difference in the regulatory mechanism of cancer patients-derived EVs, especially on CD8 T cells.
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http://dx.doi.org/10.3389/fcell.2020.564648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726136PMC
November 2020

Seroprevalence of hepatitis B virus and hepatitis C virus infection among Malaysian population.

Sci Rep 2020 12 3;10(1):21009. Epub 2020 Dec 3.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Malaysia is a country with an intermediate endemicity for hepatitis B. As the country moves toward hepatitis B and C elimination, population-based estimates are necessary to understand the burden of hepatitis B and C for evidence-based policy-making. Hence, this study aims to estimate the prevalence of hepatitis B and C in Malaysia. A total of 1458 participants were randomly selected from The Malaysian Cohort (TMC) aged 35 to 70 years between 2006 and 2012. All blood samples were tested for hepatitis B and C markers including hepatitis B surface antigen (HBsAg), anti-hepatitis B core antibody (anti-HBc), antibodies against hepatitis C virus (anti-HCV). Those reactive for hepatitis C were further tested for HCV RNA genotyping. The sociodemographic characteristics and comorbidities were used to evaluate their associated risk factors. Descriptive analysis and multivariable analysis were done using Stata 14. From the samples tested, 4% were positive for HBsAg (95% CI 2.7-4.7), 20% were positive for anti-HBc (95% CI 17.6-21.9) and 0.3% were positive for anti-HCV (95% CI 0.1-0.7). Two of the five participants who were reactive for anti-HCV had the HCV genotype 1a and 3a. The seroprevalence of HBV and HCV infection in Malaysia is low and intermediate, respectively. This population-based study could facilitate the planning and evaluation of the hepatitis B and C control program in Malaysia.
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http://dx.doi.org/10.1038/s41598-020-77813-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713078PMC
December 2020

Delineating colorectal cancer distribution, interaction, and risk prediction by environmental risk factors and serum trace elements.

Sci Rep 2020 10 29;10(1):18670. Epub 2020 Oct 29.

Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, W. Persekutuan, Malaysia.

The burden of colorectal cancer (CRC) is increasing worldwide especially in developing countries. This phenomenon may be attributable to lifestyle, dietary and environmental risk factors. We aimed to determine the level of 25 trace elements, their interaction with environmental risk factors, and subsequently develop a risk prediction model for CRC (RPM CRC). For the discovery phase, we used a hospital-based case-control study (CRC and non-CRC patients) and in the validation phase we analysed pre-symptomatic samples of CRC patients from The Malaysian Cohort Biobank. Information on the environmental risk factors were obtained and level of 25 trace elements measured using the ICP-MS method. CRC patients had lower Zn and Se levels but higher Li, Be, Al, Co, Cu, As, Cd, Rb, Ba, Hg, Tl, and Pb levels compared to non-CRC patients. The positive interaction between red meat intake ≥ 50 g/day and Co ≥ 4.77 µg/L (AP 0.97; 95% CI 0.91, 1.03) doubled the risk of CRC. A panel of 24 trace elements can predict simultaneously and accurate of high, moderate, and low risk of CRC (accuracy 100%, AUC 1.00). This study provides a new input on possible roles for various trace elements in CRC as well as using a panel of trace elements as a screening approach to CRC.
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http://dx.doi.org/10.1038/s41598-020-75760-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596468PMC
October 2020

Prevalence of anaemia and associated risk factors amongst The Malaysian Cohort participants.

Ann Hematol 2020 Nov 25;99(11):2521-2527. Epub 2020 Sep 25.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.

This study was aimed at determining the prevalence of anaemia amongst the Malaysian Cohort participants and the associated risk factors. This was a cross-sectional study that involved 102,388 participants from The Malaysian Cohort (TMC) aged between 35 and 70 years old recruited from April 2006 to September 2012. Venous blood was taken for the full blood count. The prevalence of anaemia was 13.8% with majority having the microcytic-hypochromic type (59.7%). Comparison between the ethnic groups showed that Indians have the highest prevalence of anaemia (19.9%), followed by Malays (13.1%), and Chinese (12.0%). The prevalence of anaemia was substantially higher in females (20.1%) compared to males (4.9%). Amongst the female participants, the prevalence of anaemia was highest amongst those who were younger than 49 years old and decreased as the age increased. In contrast, the prevalence of anaemia in males increased with age. Gender, ethnicity, age, marital status, presence of platelet disorders and kidney disease were significant risk factors associated with anaemia and contributed to 14.9% of the risk of developing anaemia in this population. The prevalence of anaemia amongst the Malaysian Cohort participants is 13.8% with the majority having the microcytic and hypochromic type implying iron deficiency as the main cause. It is important that those who have anaemia be further investigated and treated.
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http://dx.doi.org/10.1007/s00277-020-04279-wDOI Listing
November 2020

Dengue epidemic in Malaysia: urban versus rural comparison of dengue immunoglobulin G seroprevalence among Malaysian adults aged 35-74 years.

Trans R Soc Trop Med Hyg 2020 11;114(11):798-811

UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, 56000, Malaysia.

Background: A periodic serosurvey of dengue seroprevalence is vital to determine the prevalence of dengue in countries where this disease is endemic. This study aimed to determine the prevalence of dengue immunoglobulin G (IgG) seropositivity among healthy Malaysian adults living in urban and rural areas.

Methods: A total of 2598 serum samples (1417 urban samples, 1181 rural samples) were randomly collected from adults ages 35-74 y. The presence of the dengue IgG antibody and neutralising antibodies to dengue virus (DENV) 1-4 was determined using enzyme-linked immunosorbent assay and the plaque reduction neutralisation test assay, respectively.

Results: The prevalence of dengue IgG seropositivity was 85.39% in urban areas and 83.48% in rural areas. The seropositivity increased with every 10-y increase in age. Ethnicity was associated with dengue seropositivity in urban areas but not in rural areas. The factors associated with dengue seropositivity were sex and working outdoors. In dengue IgG-positive serum samples, 98.39% of the samples had neutralising antibodies against DENV3, but only 70.97% of them had neutralising antibodies against DENV4.

Conclusion: The high seroprevalence of dengue found in urban and rural areas suggests that both urban and rural communities are vital for establishing and sustaining DENV transmission in Malaysia.
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http://dx.doi.org/10.1093/trstmh/traa056DOI Listing
November 2020

The Landscape of Tumor-Specific Antigens in Colorectal Cancer.

Vaccines (Basel) 2020 Jul 10;8(3). Epub 2020 Jul 10.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia.

Over the last few decades, major efforts in cancer research and treatment have intensified. Apart from standard chemotherapy approaches, immunotherapy has gained substantial traction. Personalized immunotherapy has become an important tool for cancer therapy with the discovery of immune checkpoint inhibitors. Traditionally, tumor-associated antigens are used in immunotherapy-based treatments. Nevertheless, these antigens lack specificity and may have increased toxicity. With the advent of next-generation technologies, the identification of new tumor-specific antigens is becoming more important. In colorectal cancer, several tumor-specific antigens were identified and functionally validated. Multiple clinical trials from vaccine-based and adoptive cell therapy utilizing tumor-specific antigens have commenced. Herein, we will summarize the current landscape of tumor-specific antigens particularly in colorectal cancer.
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http://dx.doi.org/10.3390/vaccines8030371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565947PMC
July 2020

Observational study on the current status of thalassaemia in Malaysia: a report from the Malaysian Thalassaemia Registry.

BMJ Open 2020 06 29;10(6):e037974. Epub 2020 Jun 29.

Department of Paediatrics, UKM Medical Centre, The National University of Malaysia, Jalan Yaacob Latif, Cheras, Kuala Lumpur, Malaysia

Objective: Thalassaemia is the most common inherited blood disorder in Malaysia. This study aims to report the current status of thalassaemia in Malaysia and provide a comprehensive understanding of the disease through data obtained from the Malaysian Thalassaemia Registry.

Design: Data were extracted from the Malaysian Thalassaemia Registry, a web-based system accessible to enrolled users through www.mytalasemia.net.my.

Setting: The Malaysian Thalassaemia Registry data was recorded from reports obtained from 110 participating government and university hospitals in Malaysia.

Participants: The patients were those attending the 110 participating hospitals for thalassaemia treatment.

Intervention: Data were collected from the Malaysian Thalassaemia Registry from 2007 until the fourth quarter of 2018.

Primary Outcome Measure: 7984 out of 8681 patients with thalassaemia registered in the Malaysian Thalassaemia Registry were reported alive.

Results: Majority of the patients were reported in the state of Sabah (22.72%); the largest age group affected was 5.0-24.9 years old (64.45%); the largest ethnic group involved was Malay (63.95%); and the major diagnosis was haemoglobin E/β-thalassaemia (34.37%). From the 7984 patients, 56.73% were on regular blood transfusions and 61.72% were on chelation therapy. A small fraction (14.23%) has undergone splenectomy, while the percentage of patients with severe iron overload (serum ferritin ≥5000 µg/L) reduced over time. However, cardiac complications are still the main cause of death in patients with thalassaemia.

Conclusion: Data gathered into the registry can be used to understand the progression of the disorder, to monitor iron overload management and to improve the outcomes of treatment, to enhance preventive strategies, reduce healthcare burden and improve the quality of life. Sustainability of the Malaysian Thalassaemia Registry is important for surveillance of thalassaemia management in the country and help the national health authorities to develop more effective policies.
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http://dx.doi.org/10.1136/bmjopen-2020-037974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328811PMC
June 2020

Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells.

Int J Mol Med 2020 Aug 28;46(2):685-699. Epub 2020 May 28.

UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumour that commonly exhibits resistance to treatment. The tumour is highly heterogenous and complex kinomic alterations have been reported leading to dysregulation of signalling pathways. The present study aimed to investigate the novel kinome pathways and to identify potential therapeutic targets in GBM. Meta‑analysis using Oncomine identified 113 upregulated kinases in GBM. RNAi screening was performed on identified kinases using ON‑TARGETplus siRNA library on LN18 and U87MG. Tousled‑like kinase 1 (TLK1), which is a serine/threonine kinase was identified as a potential hit. In vitro functional validation was performed as the role of TLK1 in GBM is unknown. TLK1 knockdown in GBM cells significantly decreased cell viability, clonogenicity, proliferation and induced apoptosis. TLK1 knockdown also chemosensitised the GBM cells to the sublethal dose of temozolomide. The downstream pathways of TLK1 were examined using microarray analysis, which identified the involvement of DNA replication, cell cycle and focal adhesion signalling pathways. In vivo validation of the subcutaneous xenografts of stably transfected sh‑TLK1 U87MG cells demonstrated significantly decreased tumour growth in female BALB/c nude mice. Together, these results suggested that TLK1 may serve a role in GBM survival and may serve as a potential target for glioma.
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http://dx.doi.org/10.3892/ijmm.2020.4619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307829PMC
August 2020

Integrative meta-analysis for the identification of hub genes in chemoresistant colorectal cancer.

Biomark Med 2020 05 28;14(7):525-537. Epub 2020 May 28.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia.

Finding a new target or a new drug to overcome chemoresistance is difficult due to the heterogenous nature of cancer. Meta-analysis was performed to combine the analysis of different microarray studies to get a robust discovery. m Herein, we analyzed three microarray datasets on combination of folinic acid, fluorouracil, and oxaliplatin drugs (FOLFOX) resistance that fit our inclusion/exclusion criteria and performed a meta-analysis using the OmiCC system. We identified several deregulated genes and we discovered as a hub gene. We performed functional validation and observed that by targeting HNF4A, HCT116 cells were more sensitive toward both oxaliplatin and 5-fluorouracil significantly.  Our findings show that HNF4A could be a potential target in overcoming FOLFOX chemoresistance in colorectal cancer.
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http://dx.doi.org/10.2217/bmm-2019-0241DOI Listing
May 2020

Genome-Wide Open Chromatin Methylome Profiles in Colorectal Cancer.

Biomolecules 2020 05 5;10(5). Epub 2020 May 5.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia.

The methylome of open chromatins was investigated in colorectal cancer (CRC) to explore cancer-specific methylation and potential biomarkers. Epigenome-wide methylome of open chromatins was studied in colorectal cancer tissues using the Infinium DNA MethylationEPIC assay. Differentially methylated regions were identified using the ChAMP Bioconductor. Our stringent analysis led to the discovery of 2187 significant differentially methylated open chromatins in CRCs. More hypomethylated probes were observed and the trend was similar across all chromosomes. The majority of hyper- and hypomethylated probes in open chromatin were in chromosome 1. Our unsupervised hierarchical clustering analysis showed that 40 significant differentially methylated open chromatins were able to segregate CRC from normal colonic tissues. Receiver operating characteristic analyses from the top 40 probes revealed several significant, highly discriminative, specific and sensitive probes such as cg26256223, cg01328892, and cg11513637, among others. cg26256223 hypermethylation is associated with reduced gene expression in the CRC. This study reports many open chromatin loci with novel differential methylation statuses, some of which with the potential as candidate markers for diagnostic purposes.
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http://dx.doi.org/10.3390/biom10050719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277229PMC
May 2020

Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine.

Biomolecules 2020 03 20;10(3). Epub 2020 Mar 20.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia.

Global statistics have placed colorectal cancer (CRC) as the third most frequently diagnosed cancer and the fourth principal cause of cancer-related deaths worldwide. Improving survival for CRC is as important as early detection. Personalized medicine is important in maximizing an individual's treatment success and minimizing the risk of adverse reactions. Approaches in achieving personalized therapy in CRC have included analyses of specific genes with its clinical implications. Tumour genotyping via next-generation sequencing has become a standard practice to guide clinicians into predicting tumor behaviour, disease prognosis, and treatment response. Nevertheless, better prognostic markers are necessary to further stratify patients for personalized treatment plans. The discovery of new markers remains indispensable in providing the most effective chemotherapy in order to improve the outcomes of treatment and survival in CRC patients. This review aims to compile and discuss newly discovered, less frequently mutated genes in CRC. We also discuss how these mutations are being used to assist therapeutic decisions and their potential prospective clinical utilities. In addition, we will summarize the importance of profiling the large genomic rearrangements, gene amplification, and large deletions and how these alterations may assist in determining the best treatment option for CRC patients.
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http://dx.doi.org/10.3390/biom10030476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175115PMC
March 2020

Interactions Among Non-Coding RNAs in Diabetic Nephropathy.

Front Pharmacol 2020 3;11:191. Epub 2020 Mar 3.

UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Diabetic Nephropathy (DN) is the most common cause of End-stage renal disease (ESRD). Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden. Recent findings showed that noncoding RNAs (ncRNAs) play an important role in DN progression, potentially can be used as biomarkers and therapeutic targets. NcRNAs refers to the RNA species that do not encode for any protein, and the most known ncRNAs are the microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs). Dysregulation of these ncRNAs was reported before in DN patients and animal models of DN. Importantly, there are some interactions between these ncRNAs to regulate the crucial steps in DN progression. Here, we aimed to discuss the reported ncRNAs in DN and their interactions with critical genes in DN progression. Elucidating these ncRNAs regulatory network will allow for a better understanding of the molecular mechanisms in DN and how they can act as new biomarkers for DN and also as the potential targets for treatment.
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http://dx.doi.org/10.3389/fphar.2020.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062796PMC
March 2020

Association between MIR499A rs3746444 polymorphism and breast cancer susceptibility: a meta-analysis.

Sci Rep 2020 02 26;10(1):3508. Epub 2020 Feb 26.

UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Numerous studies have investigated the association of MIR499A rs3746444 polymorphism with breast cancer susceptibility, but the results have been inconsistent. In this work, we performed a meta-analysis to obtain a more reliable estimate of the association between the polymorphism and susceptibility to breast cancer. A comprehensive literature search was conducted on PubMed, Scopus, Web of Science (WoS), China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases up to January 2020. A total of 14 studies involving 6,797 cases and 8,534 controls were included for analysis under five genetic models: homozygous (GG vs. AA), heterozygous (AG vs. AA), dominant (AG + GG vs. AA), recessive (GG vs. AA + AG) and allele (G vs. A). A statistically significant association was observed between the polymorphism and an increased breast cancer susceptibility under all genetic models (homozygous, OR = 1.33, 95% CI = 1.03-1.71, P = 0.03; heterozygous, OR = 1.08, 95% CI = 1.00-1.16, P = 0.04; dominant, OR = 1.15, 95% CI = 1.02-1.30; P = 0.03; recessive, OR = 1.35, 95% CI = 1.06-1.72, P = 0.01; allele, OR = 1.12, 95% CI = 1.00-1.26, P = 0.04). Subgroup analysis based on ethnicity suggested that significant association was present only among Asians, but not Caucasians. In conclusion, MIR499A rs3746444 polymorphism was significantly associated with breast cancer susceptibility among Asians, suggesting its potential use as a genetic risk marker in this population.
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http://dx.doi.org/10.1038/s41598-020-60442-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044335PMC
February 2020

Circular RNAs: Potential Regulators of Treatment Resistance in Human Cancers.

Front Genet 2019 28;10:1369. Epub 2020 Jan 28.

UKM Medical Molecular Biology Institute (UMBI), UKM Medical Center, Kuala Lumpur, Malaysia.

Circular RNAs (circRNAs) which were once considered as "junk" are now in the spotlight as a potential player in regulating human diseases, especially cancer. With the development of high throughput technologies in recent years, the full potential of circRNAs is being uncovered. CircRNAs possess some unique characteristics and advantageous properties that could benefit medical research and clinical applications. CircRNAs are stable with covalently closed loops that are resistant to ribonucleases, have disease stage-specific expressions and are selectively abundant in different types of tissues. Interestingly, the presence of circRNAs in different types of treatment resistance in human cancers was recently observed with the involvement of a few key pathways. The activation of certain pathways by circRNAs may give new insights to treatment resistance management. The potential usage of circRNAs from this aspect is very much in its infancy stage and has not been fully validated. This mini-review attempts to highlight the possible role of circRNAs as regulators of treatment resistance in human cancers based on its intersection molecules and cancer-related regulatory networks.
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http://dx.doi.org/10.3389/fgene.2019.01369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997550PMC
January 2020

Retention of Somatic Memory Associated with Cell Identity, Age and Metabolism in Induced Pluripotent Stem (iPS) Cells Reprogramming.

Stem Cell Rev Rep 2020 04;16(2):251-261

UKM Medical Molecular Biology Institute, National University of Malaysia, Bangi, Malaysia.

The discovery of induced pluripotent stem (iPS) cells in 2006 marked a major breakthrough in regenerative medicine, enabling reversal of terminally differentiated somatic cells into pluripotent stem cells. The embryonic stem (ES) cells-like pluripotency and unlimited self-renewal capability of iPS cells have granted them enormous potential in many applications, particularly regenerative therapy. Unlike ES cells, however, iPS cells exhibit somatic memories which were carried over from the tissue of origin thus limited its translation in clinical applications. This review provides an updated overview of the retention of various somatic memories associated with the cellular identity, age and metabolism of tissue of origin in iPS cells. The influence of cell types, stage of maturation, age and various other factors on the retention of somatic memory has been discussed. Recent evidence of somatic memory in the form of epigenetic, transcriptomic, metabolic signatures and its functional manifestations in both in vitro and in vivo settings also have been reviewed. The increasing number of studies which had adopted isogenic cell lines for comparisons in recent years had facilitated the identification of genuine somatic memories. These memories functionally affect iPS cells and its derivatives and are potentially tumorigenic thus, raising concerns on their safety in clinical application. Various approaches for memory erasure had since being reported and their efficacies were highlighted in this review.
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http://dx.doi.org/10.1007/s12015-020-09956-xDOI Listing
April 2020

Colorectal screening using the immunochemical faecal occult blood test kit among the Malaysian cohort participants.

Cancer Epidemiol 2020 04 20;65:101656. Epub 2020 Feb 20.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.canep.2019.101656DOI Listing
April 2020

Simultaneous analysis of 25 trace elements in micro volume of human serum by inductively coupled plasma mass spectrometry (ICP-MS).

Pract Lab Med 2020 Jan 16;18:e00142. Epub 2019 Oct 16.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, 56000 Cheras, W. Persekutuan, Kuala Lumpur, Malaysia.

Introduction: In recent years, trace elements have gained importance as biomarkers in many chronic diseases. Unfortunately, the requirement for sample volume increases with the extent of investigation either for diagnosis or elucidating the mechanism of the disease. Here, we describe the method development and validation for simultaneous determination of 25 trace elements (lithium [Li], beryllium [Be], magnesium [Mg], aluminium [Al], vanadium [V], chromium [Cr], manganese [Mn], iron [Fe], cobalt [Co], nickel [Ni], copper [Cu], zinc [Zn], gallium [Ga], arsenic [As], selenium [Se], rubidium [Rb], strontium [Sr], silver [Ag], cadmium [Cd], caesium [Cs], barium [Ba], mercury [Hg], thallium [Tl], lead [Pb], uranium [U]) using only 20 μL of human serum.

Methods: Serum samples were digested with nitric acid and hydrochloric acid (ratio 1:1, v/v) and analysed by inductively coupled plasma-mass spectrometry (ICP-MS). Seronorm®, a human-derived serum control material was used as quality control samples.

Results: The coefficient of variations for both intra- and inter-day precisions were consistently <15% for all elements. The validated method was later tested on 30 human serum samples to evaluate its applicability.

Conclusion: We have successfully developed and validated a precise and accurate analytical method for determining 25 trace elements requiring very low volume of human serum.
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http://dx.doi.org/10.1016/j.plabm.2019.e00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838531PMC
January 2020

Extracellular Vesicle-derived circular RNAs confers chemoresistance in Colorectal cancer.

Sci Rep 2019 11 11;9(1):16497. Epub 2019 Nov 11.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

Chemo-resistance is associated with poor prognosis in colorectal cancer (CRC), with the absence of early biomarker. Exosomes are microvesicles released by body cells for intercellular communication. Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loops and enriched in exosomes. Crosstalk between circRNAs in exosomes and chemo-resistance in CRC remains unknown. This research aims to identify exosomal circRNAs associated with FOLFOX-resistance in CRC. FOLFOX-resistant HCT116 CRC cells (HCT116-R) were generated from parental HCT116 cells (HCT116-P) using periodic drug induction. Exosomes were characterized using transmission electron microscopy (TEM), Zetasizer and Western blot. Our exosomes were translucent cup-shaped structures under TEM with differential expression of TSG101, CD9, and CD63. We performed circRNAs microarray using exosomal RNAs from HCT116-R and HCT116-P cells. We validated our microarray data using serum samples. We performed drug sensitivity assay and cell cycle analysis to characterize selected circRNA after siRNA-knockdown. Using fold change >2 and p < 0.05, we identified 105 significantly upregulated and 34 downregulated circRNAs in HCT116-R exosomes. Knockdown of circ_0000338 improved the chemo-resistance of CRC cells. We have proposed that circ_0000338 may have dual regulatory roles in chemo-resistant CRC. Exosomal circ_0000338 could be a potential biomarker for further validation in CRC.
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http://dx.doi.org/10.1038/s41598-019-53063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848089PMC
November 2019

Prevalence and Histopathological Characteristics of Mutant Aldosterone-Producing Adenomas in a Multi-Ethnic Malaysian Cohort.

Front Endocrinol (Lausanne) 2019 4;10:666. Epub 2019 Oct 4.

Department of Medicine, The National University of Malaysia (UKM) Medical Centre, Kuala Lumpur, Malaysia.

Studies on excised adrenals from primary aldosteronism patients have found that somatic mutations in frequently cause excess aldosterone production in the culprit aldosterone-producing adenoma (APA). mutant APAs were reported to be peculiarly overrepresented among young females and in Oriental cohorts, compared to their older male, or Caucasian counterparts. These larger APAs were also reported to have similarities with the zona fasciculata (ZF) in the adrenal both from the steroid production profile and the morphology of the cell. We therefore aimed to corroborate these findings by characterizing the APAs from a multi-ethnic Malaysian cohort. The prevalence of mutations was estimated through targeted DNA sequencing of in 54 APAs. Confirmation of APA sample acquisition was performed by CYP11B2 immunohistochemistry (IHC) staining. The ZF steroid production profile was based on the ZF enzyme CYP17A1 IHC staining, and ZF cell morphology was based on a high cytoplasm to nucleus ratio. Seventeen (31.5%) APAs studied, harbored a mutation. No female over-representation was seen in this cohort though females were found to have a higher expression of CYP11B2 than males ( = 0.009; Mann-Whitney test). Age at adrenalectomy correlated negatively with the percentage of ZF-like cells in the APA ( = 0.01; Spearman's rho) but not with the genotype. mutant APAs had a high percentage of ZF-like cells (and high CYP17A1 expression) but so did the wild-type APAs. In summary, prevalence of mutant APAs in this cohort was similar to other Caucasian cohorts, however, over-representation of females did not occur, which is similar to some studies in Oriental cohorts.
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http://dx.doi.org/10.3389/fendo.2019.00666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787170PMC
October 2019

Plasma/serum proteomics: depletion strategies for reducing high-abundance proteins for biomarker discovery.

Bioanalysis 2019 Oct 16;11(19):1799-1812. Epub 2019 Oct 16.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, UKM Medical Centre, Jalan Yaacob Latiff, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia.

Plasma and serum are widely used for proteomics-based biomarker discovery. However, analysis of these biofluids is highly challenging due to the complexity and wide dynamic range of their proteomes. Notably, highly abundant proteins tend to obscure the detection of potential biomarkers that are usually of lower concentrations. Among the strategies to resolve this problem are: depletion of high-abundance proteins, enrichment of low abundant proteins of interest and prefractionation. In this review, we focus on current and emerging depletion techniques used to enhance the detection and identification of the less abundant proteins in plasma and serum. We discuss the applications and contributions of these methods to proteomics analysis of plasma and serum alongside their limitations and future perspectives.
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http://dx.doi.org/10.4155/bio-2019-0145DOI Listing
October 2019

Cancer-Derived Exosomes as Effectors of Key Inflammation-Related Players.

Front Immunol 2019 4;10:2103. Epub 2019 Sep 4.

UKM Medical Centre, UKM Medical Molecular Biology Institute, Kuala Lumpur, Malaysia.

Exosomes, a category of small lipid bilayer extracellular vesicles that are naturally secreted by many cells (both healthy and diseased), carry cargo made up of proteins, lipids, DNAs, and RNAs; all of which are functional when transferred to their recipient cells. Numerous studies have demonstrated the powerful role that exosomes play in the mediation of cell-to-cell communication to induce a pro-tumoral environment to encourage tumor progression and survival. Recently, considerable interest has developed in regard to the role that exosomes play in immunity; with studies demonstrating the ability of exosomes to either metabolically alter immune players such as dendritic cells, T cells, macrophages, and natural killer cells. In this review, we summarize the recent literature on the function of exosomes in regulating a key process that has long been associated with the progression of cancer-inflammation and immunity.
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http://dx.doi.org/10.3389/fimmu.2019.02103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737008PMC
November 2020

Validation of immunogenic PASD1 peptides against HLA-A*24:02 colorectal cancer.

Immunotherapy 2019 10 3;11(14):1205-1219. Epub 2019 Sep 3.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

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.
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http://dx.doi.org/10.2217/imt-2019-0073DOI Listing
October 2019

Proteogenomics: From next-generation sequencing (NGS) and mass spectrometry-based proteomics to precision medicine.

Clin Chim Acta 2019 Nov 14;498:38-46. Epub 2019 Aug 14.

UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia.

One of the best-established area within multi-omics is proteogenomics, whereby the underpinning technologies are next-generation sequencing (NGS) and mass spectrometry (MS). Proteogenomics has contributed significantly to genome (re)-annotation, whereby novel coding sequences (CDS) are identified and confirmed. By incorporating in-silico translated genome variants in protein database, single amino acid variants (SAAV) and splice proteoforms can be identified and quantified at peptide level. The application of proteogenomics in cancer research potentially enables the identification of patient-specific proteoforms, as well as the association of the efficacy or resistance of cancer therapy to different mutations. Here, we discuss how NGS/TGS data are analyzed and incorporated into the proteogenomic framework. These sequence data mainly originate from whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-Seq. We explain two major strategies for sequence analysis i.e., de novo assembly and reads mapping, followed by construction of customized protein databases using such data. Besides, we also elaborate on the procedures of spectrum to peptide sequence matching in proteogenomics, and the relationship between database size on the false discovery rate (FDR). Finally, we discuss the latest development in proteogenomics-assisted precision oncology and also challenges and opportunities in proteogenomics research.
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http://dx.doi.org/10.1016/j.cca.2019.08.010DOI Listing
November 2019

Transcriptome analysis reveals the molecular mechanisms of combined gamma-tocotrienol and hydroxychavicol in preventing the proliferation of 1321N1, SW1783, and LN18 glioma cancer cells.

J Physiol Biochem 2019 Nov 14;75(4):499-517. Epub 2019 Aug 14.

Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Ya'acob, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.

Gamma-tocotrienol (GTT) and hydroxychavicol (HC) exhibit anticancer activity in glioma cancer cells, where the combination of GTT + HC was shown to be more effective than single agent. The aim of this study was to determine the effect of GTT + HC by measuring the cell cycle progression, migration, invasion, and colony formation of glioma cancer cells and elucidating the changes in gene expression mitigated by GTT + HC that are critical to the chemoprevention of glioma cell lines 1321N1 (grade II), SW1783 (grade III), and LN18 (grade IV) using high-throughput RNA sequencing (RNA-seq). Results of gene expression levels and alternative splicing transcripts were validated by qPCR. Exposure of glioma cancer cells to GTT + HC for 24 h promotes cell cycle arrest at G2M and S phases and inhibits cell migration, invasion, and colony formation of glioma cancer cells. The differential gene expression induced by GTT + HC clustered into response to endoplasmic reticulum (ER) stress, cell cycle regulations, apoptosis, cell migration/invasion, cell growth, and DNA repair. Subnetwork analysis of genes altered by GTT + HC revealed central genes, ATF4 and XBP1. The modulation of EIF2AK3, EDN1, and FOXM1 were unique to 1321N1, while CSF1, KLF4, and FGF2 were unique to SW1783. PLK2 and EIF3A gene expressions were only altered in LN18. Moreover, GTT + HC treatment dynamically altered transcripts and alternative splicing expression. GTT + HC showed therapeutic potential against glioma cancer as evident by the inhibition of cell cycle progression, migration, invasion, and colony formation of glioma cancer cells, as well as the changes in gene expression profiles with key targets in ER unfolded protein response pathway, apoptosis, cell cycle, and migration/invasion.
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http://dx.doi.org/10.1007/s13105-019-00699-zDOI Listing
November 2019