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Evaluation of serological transfusion-transmitted viral diseases and mutliplex nucleic acid testing in malaysian blood donors

Yaseen SG, Ahmed SA, Johan MF, Kiron R, Daher AM

Transfus Apher Sci, 2013 Dec;49(3):647-51.
PMID: 23890575 DOI: 10.1016/j.transci.2013.07.003

Transmission of infectious diseases is a recognized complication of blood transfusion and blood products. Nucleic acid testing (NAT) may contribute to improved efficiency of blood screening and thereby increase the safety margin for transfused blood.
Fulltext Guidelines for nucleic acid detection and analysis in hematological disorders

Hassan R, Husin A, Sulong S, Yusoff S, Johan MF, Yahaya BH, et al.

Malays J Pathol, 2015 Aug;37(2):165-73.
PMID: 26277676 MyJurnal
Mannose-binding lectin gene sequence data in Kelantan population

Zahidin MA, Mohd Noor NH, Johan MF, Abdullah AD, Zulkafli Z, Edinur HA

Sci Data, 2024 Apr 30;11(1):435.
PMID: 38688916 DOI: 10.1038/s41597-024-03274-4

The human mannose-binding lectin (MBL) gene encodes a polymorphic protein that plays a crucial role in the innate immune response. Human MBL deficiency is associated with immunodeficiencies, and its variants have been linked to autoimmune and infectious diseases. Despite this significance, gene studies concerning MBL sequencing are uncommon in Malaysia. Therefore, we aimed to preliminary described the human MBL sequencing dataset based on the Kelantan population. Blood samples were collected from 30 unrelated individuals and underwent DNA extraction, genotyping, and sequencing. The sequencing data generated 886 bp, which were deposited in GenBank (ON619541-ON619546). Allelic variants were identified and translated into six MBL haplotypes: HYPA, HYPB, LYPB, LXPB, HXPA, and LXPA. An evolutionary tree was constructed using the haplotype sequences. These findings contribute to the expansion of MBL information within the country, providing a valuable baseline for future research exploring the association between the gene and targeted diseases.
Fulltext Thymoquinone, as a Novel Therapeutic Candidate of Cancers

Almajali B, Al-Jamal HAN, Taib WRW, Ismail I, Johan MF, Doolaanea AA, et al.

Pharmaceuticals (Basel), 2021 Apr 16;14(4).
PMID: 33923474 DOI: 10.3390/ph14040369

To date, natural products are widely used as pharmaceutical agents for many human diseases and cancers. One of the most popular natural products that have been studied for anticancer properties is thymoquinone (TQ). As a bioactive compound of Nigella sativa, TQ has shown anticancer activities through the inhibition of cell proliferation, migration, and invasion. The anticancer efficacy of TQ is being investigated in several human cancers such as pancreatic cancer, breast cancer, colon cancer, hepatic cancer, cervical cancer, and leukemia. Even though TQ induces apoptosis by regulating the expression of pro- apoptotic and anti-apoptotic genes in many cancers, the TQ effect mechanism on such cancers is not yet fully understood. Therefore, the present review has highlighted the TQ effect mechanisms on several signaling pathways and expression of tumor suppressor genes (TSG). Data from relevant published experimental articles on TQ from 2015 to June 2020 were selected by using Google Scholar and PubMed search engines. The present study investigated the effectiveness of TQ alone or in combination with other anticancer therapeutic agents, such as tyrosine kinase inhibitors on cancers, as a future anticancer therapy nominee by using nanotechnology.
Fulltext Thymoquinone Enhances Apoptosis of K562 Chronic Myeloid Leukemia Cells through Hypomethylation of SHP-1 and Inhibition of JAK/STAT Signaling Pathway

Al-Rawashde FA, Al-Sanabra OM, Alqaraleh M, Jaradat AQ, Al-Wajeeh AS, Johan MF, et al.

Pharmaceuticals (Basel), 2023 Jun 15;16(6).
PMID: 37375831 DOI: 10.3390/ph16060884

The epigenetic silencing of tumor suppressor genes (TSGs) is critical in the development of chronic myeloid leukemia (CML). SHP-1 functions as a TSG and negatively regulates JAK/STAT signaling. Enhancement of SHP-1 expression by demethylation provides molecular targets for the treatment of various cancers. Thymoquinone (TQ), a constituent of Nigella sativa seeds, has shown anti-cancer activities in various cancers. However, TQs effect on methylation is not fully clear. Therefore, the aim of this study is to assess TQs ability to enhance the expression of SHP-1 through modifying DNA methylation in K562 CML cells. The activities of TQ on cell cycle progression and apoptosis were evaluated using a fluorometric-red cell cycle assay and Annexin V-FITC/PI, respectively. The methylation status of SHP-1 was studied by pyrosequencing analysis. The expression of SHP-1, TET2, WT1, DNMT1, DNMT3A, and DNMT3B was determined using RT-qPCR. The protein phosphorylation of STAT3, STAT5, and JAK2 was assessed using Jess Western analysis. TQ significantly downregulated the DNMT1 gene, DNMT3A gene, and DNMT3B gene and upregulated the WT1 gene and TET2 gene. This led to hypomethylation and restoration of SHP-1 expression, resulting in inhibition of JAK/STAT signaling, induction of apoptosis, and cell cycle arrest. The observed findings imply that TQ promotes apoptosis and cell cycle arrest in CML cells by inhibiting JAK/STAT signaling via restoration of the expression of JAK/STAT-negative regulator genes.
Identification and Quantification of Quercetin, A Major Constituent of Artocarpus altilis by Targeting Related Genes of Apoptosis and Cell Cycle: In Vitro Cytotoxic Activity Against Human Lung Carcinoma Cell Lines

Jalal TK, Khan AYF, Natto HA, Abdull Rasad MSB, Arifin Kaderi M, Mohammad M, et al.

Nutr Cancer, 2019;71(5):792-805.
PMID: 30614285 DOI: 10.1080/01635581.2018.1516790

Nine phenolic compounds were identified and quantified in Artocarpus altilia fruit. One of the main compounds was quercetin, which is the major class of flavonoids has been identified and quantified in pulp part of A. altilis fruit of methanol extract. The aim of this study was to evaluate in vitro cytotoxic assay. Inhibitory concentration 50% concentration was determined using trypan blue exclusion assay. Apoptosis induction and cell cycle regulation were studied by flow cytometric analysis. The expression of apoptosis and cell cycle-related regulatory genes were assessed by RT-qPCR study of the methanol extract of pulp part on human lung carcinoma (A549) cell line. A significant increase of cells at G2/M phases was detected (P
Fulltext Genotype-phenotype association of Hbe/β thalassemia disease and the role of genetic modifiers

HanafI S, Abdullah WZ, Adnan RA, Bahar R, Johan MF, Azman NF, et al.

Malaysian Journal of Paediatrics and Child Health, 2016;22(1):1-16.
MyJurnal

HbE/β-thalassemia is the most common severe form of thalassemia particularly in SEA region including Malaysia and globally, it comprised of a significant severe form of β-thalassemia disorder. It has various clinical manifestations ranging from very mild anemia to severe manifestation similar to beta thalassemia major. Many different syndromes are observed in HbE/β-thalassemia. Several genetic modifiers have been reported to play important role in contributing to phenotypic variability. The true reasons underlying this phenotypic variability remain unknown. The most reliable predictive factor of the disease phenotype is the nature of the beta globin gene mutation itself. However, the degree of severity is also believed to be affected by other genetic modifiers. For instance, high HbF level ameliorates the clinical severity of β thalassemia patients. Therefore, identification of these genetic modifiers is very important. The association of severe clinical manifestation and the specific β-globin gene mutation has been known. But the wide scope and other potential predictors have been only recently appreciated. This review therefore aimed to reveal the potential genetic modifiers of HbE/βthalassemia patients based on the previous reported studies. A better understanding on the mechanisms underlying the variety of phenotypes of this disease may lead to the direction for a better future management plans. This also promotes “personalized medicine” in patient care.
Fulltext Apoptotic induction in cCCRF-CEM and HL human leukemic cell lines by 5-azacitidine and trichostatin A

Aziee, S., Haiyuni, MY, Shafini, MY, Johan, MF, Al-Jamal, HAN, Abdul Wahab, R., et al.

Journal of Biomedical and Clinical Sciences, 2018;3(1):54-61.
MyJurnal

The aims of the study were to investigate the anti-cancer effects of 5-
Aza and TSA in two leukemic cell lines (CCRF-CEM and HL-60). Inhibition
concentration of 5-Aza and TSA were measured using trypan blue exclusion
assay. 5-Aza and TSA at IC50 were treated to both CCRF-CEM and HL-60 cell
lines for 4-6 days. To confirm the inhibition effects of these agents, Annexin-V
stained cells were analyzed using flow cytometry to evaluate the apoptotic
induction. The IC50 values of CCRF-CEM were 2.01±0.1µM and 2.65±0.3µM for
5-Aza- and TSA-treated, respectively. Whereas, the IC50 values of HL-60 were
1.98±0.2µM and 2.35±0.2µM for 5-Aza- and TSA-treated, respectively. To
further substantiate the findings, the time-dependent exposure of both drugs was
studied. CCRF-CEM cells were reduced to 49.4%±5.0, 49.4%±2.5 and
41.5%±5.6 by 5-Aza; 56.5%±7.0, 45.3%±4.2 and 40.2%±4.2 by TSA treatment
at first, third and sixth day. HL-60 cells were reduced to 72.0%±4.5, 51.0%±1.5
and 40.6%±2.6 by 5-Aza at first, third and sixth day. Meanwhile, HL-60 cells
reduced to 55.6%±4.5, 45.2%±4.0 and 36.3%±2.9 by TSA at first, second and
fourth day. Both cell lines were significantly inhibited (p
Enhanced induction of cell cycle arrest and apoptosis via the mitochondrial membrane potential disruption in human U87 malignant glioma cells by aloe emodin

Ismail S, Haris K, Abdul Ghani AR, Abdullah JM, Johan MF, Mohamed Yusoff AA

J Asian Nat Prod Res, 2013 Sep;15(9):1003-12.
PMID: 23869465 DOI: 10.1080/10286020.2013.818982

Aloe emodin, one of the active compounds found in Aloe vera leaves, plays an important role in the regulation of cell growth and death. It has been reported to promote the anti-cancer effects in various cancer cells by inducing apoptosis. However, the mechanism of inducing apoptosis by this agent is poorly understood in glioma cells. This research is to investigate the apoptosis and cell cycle arrest inducing by aloe emodin on U87 human malignant glioma cells. Aloe emodin showed a time- and dose-dependent inhibition of U87 cells proliferation and decreased the percentage of viable U87 cells via the induction of apoptosis. Characteristic morphological changes, such as the formation of apoptotic bodies, were observed with confocal microscope by Annexin V-FITC/PI staining, supporting our viability study and flow cytometry analysis results. Our data also demonstrated that aloe emodin arrested the cell cycle in the S phase and promoted the loss of mitochondrial membrane potential in U87 cells that indicated the early event of the mitochondria-induced apoptotic pathway.
Conformation sensitive gel electrophoresis for the detection of calreticulin mutations in BCR-ABL1-negative myeloproliferative neoplasms

Zakaria NA, Rosle NA, Siti Asmaa MJ, Aziee S, Haiyuni MY, Samat NA, et al.

Int J Lab Hematol, 2021 Dec;43(6):1451-1457.
PMID: 34125992 DOI: 10.1111/ijlh.13628

INTRODUCTION: Calreticulin (CALR) mutations in myeloproliferative neoplasms (MPN) have been reported to be key markers in the molecular diagnosis, particularly in patients lacking JAK2 V617F mutation. In most current reports, CALR mutations were analysed by either allele-specific PCR (AS-PCR), or the more expensive quantitative real-time PCR, pyrosequencing and next-generation sequencing. Hence, we report the use of an alternative method, the conformation sensitive gel electrophoresis (CSGE) for the detection of CALR mutations in BCR-ABL1-negative MPN patients.
METHODS: Forty BCR-ABL1-negative MPN patients' DNA: 19 polycythemia vera (PV), 7 essential thrombocytosis (ET) and 14 primary myelofibrosis (PMF), were screened for CALR mutations by CSGE. PCR primers were designed to amplify sequences spanning between exons 8 and 9 to target the mutation hotspots in CALR. Amplicons displaying abnormal CSGE profiles by electrophoresis were directly sequenced, and results were analysed by BioEdit Sequence Alignment Editor v7.2.6. CSGE results were compared with AS-PCR and confirmed by Sanger sequencing.
RESULTS: CSGE identified 4 types of mutations; 2 PMF patients with either CALR type 1 (c.1099_1150del52) or type 2 (c.1155_1156insTTGTC), 1 ET patient with nucleotide deletion (c.1121delA) and insertion (c.1190insA) and 1 PV patient with p.K368del (c.1102_1104delAAG) and insertion (c.1135insA) inframe mutations. Three patients have an altered KDEL motif at the C-terminal of CALR protein. In comparison, AS-PCR only able to detect two PMF patients with mutations, either type 1 and type 2.
CONCLUSION: CSGE is inexpensive, sensitive and reliable alternative method for the detection of CALR mutations in BCR-ABL1-negative MPN patients.
Transcriptomic Profiles of MV4-11 and Kasumi 1 Acute Myeloid Leukemia Cell Lines Modulated by Epigenetic Modifiers Trichostatin A and 5-Azacytidine

Asmaa MJS, Al-Jamal HA, Hussein AR, Yahaya BH, Hassan R, Hussain FA, et al.

Int J Hematol Oncol Stem Cell Res, 2020 Jan 01;14(1):72-92.
PMID: 32337016

Background: Acute myeloid leukemia (AML) is the most common form of acute leukemias in adults which is clinically and molecularly heterogeneous. Several risk and genetic factors have been widely investigated to characterize AML. However, the concomitant epigenetic factors in controlling the gene expression lead to AML transformation was not fully understood. This study was aimed to identify epigenetically regulated genes in AML cell lines induced by epigenetic modulating agents, Trichostatin A (TSA) and 5-Azacytidine (5-Aza). Materials and Methods: MV4-11 and Kasumi 1 were treated with TSA and/or 5-Aza at IC50 concentration. Gene expression profiling by microarray was utilized using SurePrint G3 Human Gene Expression v3. Gene ontology and KEGG pathway annotations were analyzed by DAVID bioinformatics software using EASE enrichment score. mRNA expression of the differentially expressed genes were verified by quantitative real time PCR. Results: Gene expression analysis revealed a significant changes in the expression of 24,822, 15,720, 15,654 genes in MV4-11 and 12,598, 8828, 18,026 genes in Kasumi 1, in response to TSA, 5-Aza and combination treatments, respectively, compared to non-treated (p<0.05). 7 genes (SOCS3, TUBA1C, CCNA1, MAP3K6, PTPRC, STAT6 and RUNX1) and 4 genes (ANGPTL4, TUBB2A, ADAM12 and PTPN6) shown to be predominantly expressed in MV4-11 and Kasumi 1, respectively (EASE<0.1). The analysis also revealed phagosome pathway commonly activated in both cell lines. Conclusion: Our data showed a distinct optimal biological characteristic and pathway in different types of leukemic cell lines. These finding may help in the identification of cell-specific epigenetic biomarker in the pathogenesis of AML.
Fulltext Clinical and Laboratory Features of JAK2 V617F, CALR, and MPL Mutations in Malaysian Patients with Classical Myeloproliferative Neoplasm (MPN)

Zulkeflee RH, Zulkafli Z, Johan MF, Husin A, Islam MA, Hassan R

Int J Environ Res Public Health, 2021 Jul 16;18(14).
PMID: 34300032 DOI: 10.3390/ijerph18147582

Mutations of JAK2V617F, CALR, and MPL genes confirm the diagnosis of myeloproliferative neoplasm (MPN). This study aims to determine the genetic profile of JAK2V617F, CALR exon 9 Type 1 (52 bp deletion) and Type 2 (5 bp insertion), and MPL W515 L/K genes among Malaysian patients and correlate these mutations with clinical and hematologic parameters in MPN. Mutations of JAK2V617F, CALR, and MPL were analyzed in 159 Malaysian patients using allele-specific polymerase chain reaction, including 76 polycythemia vera (PV), 41 essential thrombocythemia (ET), and 42 primary myelofibrosis (PMF) mutations, and the demographics of the patients were retrieved. The result showed that 73.6% JAK2V617F, 5.66% CALR, and 27.7% were triple-negative mutations. No MPL W515L/K mutation was detected. In ET and PMF, the predominance type was the CALR Type 1 mutation. In JAK2V617F mutant patients, serum LDH was significantly higher in PMF compared to PV and ET. PV has a higher risk of evolving to post PV myelofibrosis compared to ET. A thrombotic event at initial diagnosis of 40.9% was high compared to global incidence. Only one PMF patient had a CALR mutation that transformed to acute myeloid leukemia. JAK2V617F and CALR mutations play an important role in diagnostics. Hence, every patient suspected of having a myeloproliferative neoplasm should be screened for these mutations.
Fulltext Reduced hepcidin expression enhances iron overload in patients with HbE/β-thalassemia: Α comparative cross-sectional study

Saad HKM, Taib WRW, Ismail I, Johan MF, Al-Wajeeh AS, Al-Jamal HAN

Exp Ther Med, 2021 Dec;22(6):1402.
PMID: 34675995 DOI: 10.3892/etm.2021.10838

Iron homeostasis is regulated by hepcidin (HEPC) that controls the dietary iron absorption and iron recycling. HEPC deficiency contributes to iron overload in β-thalassemia patients. The present study aimed to investigate the correlation between HEPC concentration and serum iron status among hemoglobin E (HbE)/β-thalassemia patients and their parents (HbE trait and β-thalassemia trait) compared with healthy controls. This study is a comparative cross-sectional study in which iron profile and HEPC level were examined in 65 HbE/β-thalassemia patients (pretransfusion) and 65 parents at the Hospital Sultanah Nur Zahirah and in 130 students as healthy controls from Univesiti Sultan Zainal Abidin, Terengganu, Malaysia. Furthermore, six samples from each group (HbE/β-thalassemia patients, parents and healthy controls) were randomly selected for gene expression analysis of HEPC and ferroportin1 (FPN1) using reverse transcription quantitative PCR. The results demonstrated that serum HEPC level were significantly decreased in HbE/β-thalassemia patients and their parents (P<0.001) compared with healthy controls. In addition, the gene expression analysis showed a dramatically downregulated HEPC in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. However, there was a marked upregulation of FPN1 in HbE/β-thalassemia patients and their parents (P=0.001) compared with healthy controls. Iron profiling results revealed a significantly increased serum ferritin in HbE/β-thalassemia patients and their parents compared with healthy controls (P<0.001). In summary, the present study demonstrated that HEPC expression level and serum level were significantly decreased in HbE/β-thalassemia patients and their parents, which was combined with a marked increased FPN1 expression level and serum ferritin level compared with healthy volunteers. These findings supported the hypothesis that downregulated HEPC could lose its function as a negative regulator of FPN1, resulting in iron overload in HbE/β-thalassemia patients. Subsequently, assessing HEPC and FPN1 gene expression may be a useful tool to determine the risk of iron toxicity in patients with HbE/β-thalassemia and their parents, and could therefore be considered as a therapeutic target in the management of iron burden in these patients.
Fulltext Worldwide Prevalence of Epstein-Barr Virus in Patients with Burkitt Lymphoma: A Systematic Review and Meta-Analysis

Al-Khreisat MJ, Ismail NH, Tabnjh A, Hussain FA, Mohamed Yusoff AA, Johan MF, et al.

Diagnostics (Basel), 2023 Jun 15;13(12).
PMID: 37370963 DOI: 10.3390/diagnostics13122068

Burkitt lymphoma (BL) is a form of B-cell malignancy that progresses aggressively and is most often seen in children. While Epstein-Barr virus (EBV) is a double-stranded DNA virus that has been linked to a variety of cancers, it can transform B lymphocytes into immortalized cells, as shown in BL. Therefore, the estimated prevalence of EBV in a population may assist in the prediction of whether this population has a high risk of increased BL cases. This systematic review and meta-analysis aimed to estimate the prevalence of Epstein-Barr virus in patients with Burkitt lymphoma. Using the appropriate keywords, four electronic databases were searched. The quality of the included studies was assessed using the Joanna Briggs Institute's critical appraisal tool. The results were reported as percentages with a 95% confidence interval using a random-effects model (CI). PROSPERO was used to register the protocol (CRD42022372293), and 135 studies were included. The prevalence of Epstein-Barr virus in patients with Burkitt lymphoma was 57.5% (95% CI: 51.5 to 63.4, n = 4837). The sensitivity analyses demonstrated consistent results, and 65.2% of studies were of high quality. Egger's test revealed that there was a significant publication bias. EBV was found in a significantly high proportion of BL patients (more than 50% of BL patients). This study recommends EBV testing as an alternative for predictions and the assessment of the clinical disease status of BL.
An Epidemiology Study of Adult Immune Thrombocytopenia Patients in a Teaching Hospital in Northeastern Malaysia

Zahidin MA, Abdul Razak NI, Mohd Noor NH, Johan MF, Zulkafli Z, Abdullah AD, et al.

Cureus, 2023 Nov;15(11):e48533.
PMID: 38073971 DOI: 10.7759/cureus.48533

Immune thrombocytopenia (ITP) has been comprehensively studied and understood in Western Europe and various Asia-Pacific regions. However, the epidemiological and clinical-laboratory aspects of ITP in Malaysia remain limited and not well documented. Therefore, this study aims to evaluate the incidence and clinical parameters of ITP using 20-year retrospective data. Medical records for 205 consecutive adult patients with ITP between January 2000 and December 2022 were analyzed. A p-value of <0.05 is considered statistically significant. The majority were Malays (n=192, 93.7%) and females (n=150, 73.2%), with a male-to-female ratio of 1:2.73. One hundred thirty-two (64.4%) and 73 (35.6%) patients were diagnosed with primary ITP (pITP) and secondary ITP (sITP), respectively. Systemic lupus erythematosus (SLE) (n=23, 35.9%), antiphospholipid syndrome (APS) (n=5, 7.8%), and familial thrombocytopenia (n=5, 7.8%) were the top 3 comorbid conditions for ITP. The overall incidence was 1.80/100,000 person-years (95% confidence interval (CI): 1.56-2.07), and the incidences were higher in females than in males with pITP (1.78/100,000 person-years versus 0.70/100,000 person-years) and sITP (0.86/100,000 person-years versus 0.26/100,000 person-years). The median age for patients with pITP was significantly higher than for those with sITP (median: 44 versus 37 years, respectively) (p=0.026). However, there was no statistically significant difference in white blood cell (WBC) counts, hemoglobin (HB) counts, platelet (PLT) counts, absolute neutrophil counts (ANC), or hematocrit (HCT) counts between those with pITP and sITP at the time of diagnosis. The current study provides an overview of ITP epidemiology in northeastern Malaysia. We emphasize the critical need for further additional research, particularly at the state and national levels in the future.
Fulltext The Prevalence of TET2 Gene Mutations in Patients with BCR-ABL-Negative Myeloproliferative Neoplasms (MPN): A Systematic Review and Meta-Analysis

Chia YC, Islam MA, Hider P, Woon PY, Johan MF, Hassan R, et al.

Cancers (Basel), 2021 Jun 20;13(12).
PMID: 34203097 DOI: 10.3390/cancers13123078

Multiple recurrent somatic mutations have recently been identified in association with myeloproliferative neoplasms (MPN). This meta-analysis aims to assess the pooled prevalence of TET2 gene mutations among patients with MPN. Six databases (PubMed, Scopus, ScienceDirect, Google Scholar, Web of Science and Embase) were searched for relevant studies from inception till September 2020, without language restrictions. The eligibility criteria included BCR-ABL-negative MPN adults with TET2 gene mutations. A random-effects model was used to estimate the pooled prevalence with 95% confidence intervals (CIs). Subgroup analyses explored results among different continents and countries, WHO diagnostic criteria, screening methods and types of MF. Quality assessment was undertaken using the Joanna Briggs Institute critical appraisal tool. The study was registered with PROSPERO (CRD42020212223). Thirty-five studies were included (n = 5121, 47.1% female). Overall, the pooled prevalence of TET2 gene mutations in MPN patients was 15.5% (95% CI: 12.1-19.0%, I2 = 94%). Regional differences explained a substantial amount of heterogeneity. The prevalence of TET2 gene mutations among the three subtypes PV, ET and MF were 16.8%, 9.8% and 15.7%, respectively. The quality of the included studies was determined to be moderate-high among 83% of the included studies. Among patients with BCR-ABL-negative MPN, the overall prevalence of TET2 gene mutations was 15.5%.
Fulltext The Role of Epigenetics in the Development and Progression of Multiple Myeloma

Ismail NH, Mussa A, Zakaria NA, Al-Khreisat MJ, Zahidin MA, Ramli NN, et al.

Biomedicines, 2022 Oct 31;10(11).
PMID: 36359286 DOI: 10.3390/biomedicines10112767

Multiple myeloma (MM) is an exceptionally complicated and heterogeneous disease that is caused by the abnormal proliferation of malignant monoclonal plasma cells initiated in the bone marrow. In disease progression, a multistep process including differentiation, proliferation, and invasion is involved. Despite great improvement in treatment outcomes in recent years due to the substantial discovery of novel therapeutic drugs, MM is still regarded as an incurable disease. Patients with MM are afflicted by confronting remission periods accompanied by relapse or progression outcomes, which inevitably progress to the refractory stage. In this regard, MM may need new medications or modifications in therapeutic strategies to overcome resistance. A variety of genetic abnormalities (e.g., point mutations, translocations, and deletions) and epigenetic changes (e.g., DNA methylation, histone modification, and non-coding RNA) contribute to the pathogenesis and development of MM. Here, we review the significant roles of epigenetic mechanisms in the development and progression of MM. We also highlight epigenetic pathways as potential novel treatment avenues for MM, including their interplay, use of epigenetic inhibitors, and major involvement in immuno-oncology.
Fulltext Anticancer activity of grassy Hystrix brachyura bezoar and its mechanisms of action: An in vitro and in vivo based study

Khan AYF, Ahmed QU, Narayanamurthy V, Razali S, Asuhaimi FA, Saleh MSM, et al.

Biomed Pharmacother, 2019 Jun;114:108841.
PMID: 30981106 DOI: 10.1016/j.biopha.2019.108841

Porcupine bezoar (PB) is a calcified undigested material generally found in porcupine's (Hystrix brachyura) gastrointestinal tract. The bezoar is traditionally used in South East Asia and Europe for the treatment of cancer, poisoning, dengue, typhoid, etc. However, limited scientific studies have been performed to verify its anticancer potential to substantiate its traditional claims in the treatment of cancers. Hence, this study was aimed at investigating the in vitro and in vivo anticancer properties of two grassy PB aqueous extract (PB-A and PB-B) using A375 cancer cell line and zebrafish model, respectively. This paper presents the first report on in vitro A375 cell viability assay, apoptosis assay, cell cycle arrest assay, migration assay, invasion assay, qPCR experimental assay and in vivo anti-angiogenesis assay using the grassy PBs. Experimental findings revealed IC50 value are 26.59 ± 1.37 μg/mL and 30.12 ± 3.25 μg/mL for PB-A and PB-B respectively. PBs showed anti-proliferative activity with no significant cytotoxic effect on normal human dermal fibroblast (NHDF). PBs were also found to induce apoptosis via intrinsic pathway and arrest cell cycle at G2/M phase. Additionally, the findings indicated its ability to debilitate migration and invasion of A375 cells. Further evaluation using embryo zebrafish model revealed LC50 = 450.0 ± 2.50 μg/mL and 58.7 ± 5.0 μg/mL for PB-A and PB-B which also exerted anti-angiogenesis effect in zebrafish. Moreover, stearic acid, ursodeoxycholic acid and pregnenolone were identified as possible metabolites that might contribute to the anticancer effect of the both PBs. Overall, this study demonstrated that PB-A and PB-B possess potential in vitro and in vivo anticancer effects which are elicited through selective cytotoxic effect, induction of apoptosis, inhibition of migration and invasion and anti-angiogenesis. This study provides scientific evidence that the porcupine bezoar do possess anti-cancer efficacy and further justifies its traditional utility. However, more experiments with higher vertebrae models are still warranted to validate its traditional claims as an anticancer agent.
Fulltext The first Malay database toward the ethnic-specific target molecular variation

Halim-Fikri H, Etemad A, Abdul Latif AZ, Merican AF, Baig AA, Annuar AA, et al.

BMC Res Notes, 2015;8:176.
PMID: 25925844 DOI: 10.1186/s13104-015-1123-y

The Malaysian Node of the Human Variome Project (MyHVP) is one of the eighteen official Human Variome Project (HVP) country-specific nodes. Since its inception in 9(th) October 2010, MyHVP has attracted the significant number of Malaysian clinicians and researchers to participate and contribute their data to this project. MyHVP also act as the center of coordination for genotypic and phenotypic variation studies of the Malaysian population. A specialized database was developed to store and manage the data based on genetic variations which also associated with health and disease of Malaysian ethnic groups. This ethnic-specific database is called the Malaysian Node of the Human Variome Project database (MyHVPDb).
Fulltext Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia

Al-Jamal HA, Mat Jusoh SA, Hassan R, Johan MF

BMC Cancer, 2015;15:869.
PMID: 26547689 DOI: 10.1186/s12885-015-1695-x

Tumor-suppressor genes are inactivated by methylation in several cancers including acute myeloid leukemia (AML). Src homology-2 (SH2)-containing protein-tyrosine phosphatase 1 (SHP-1) is a negative regulator of the JAK/STAT pathway. Transcriptional silencing of SHP-1 plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced SHP-1. Lestaurtinib (CEP-701) is a multi-targeted tyrosine kinase inhibitor that potently inhibits FLT3 tyrosine kinase and induces hematological remission in AML patients harboring the internal tandem duplication of the FLT3 gene (FLT3-ITD). However, the majority of patients in clinical trials developed resistance to CEP-701. Therefore, the aim of this study, was to assess the effect of re-expression of SHP-1 on sensitivity to CEP-701 in resistant AML cells.

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