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Increased Expression of Phosphatidylinositol 3-Kinase p110α and Gene Amplification of PIK3CA in Nasopharyngeal Carcinoma

Yip WK, He PY, Abdullah MA, Yusoff S, Seow HF

Pathol Oncol Res, 2016 Apr;22(2):413-9.
PMID: 26581613 DOI: 10.1007/s12253-015-0007-8

Molecular alterations in PIK3CA oncogene that encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K p110α) are commonly found in human cancers. In this study, we examined the expression of PI3K p110α and PIK3CA gene amplification in 74 nasopharyngeal carcinoma (NPC) cases. Immunohistochemical staining demonstrated overexpression of PI3K p110α protein in 44.6% (33/74) of NPCs and 4.8% (2/42) of the adjacent normal nasopharyngeal mucosa. Copy number of PIK3CA gene was successfully analyzed in 51 of the total NPC cases and 19 non-malignant nasopharynx tissues by quantitative real-time PCR. Using mean + 2(standard deviation) of copy numbers in the non-malignant nasopharynx tissues as a cutoff value, PIK3CA copy number gain was found in 10 of 51 (19.6%) NPC cases. High PI3K p110α expression level was correlated with increased PIK3CA copy number (Spearman's rho =0.324, P = 0.02). PI3K p110α expression and PIK3CA copy number did not associate with Akt phosphorylation, and patient and tumor variables. This study suggests that PI3K p110α overexpression, which is attributed, at least in part, to PIK3CA gene amplification, may contribute to NPC pathogenesis. However, these molecular aberrations may not be responsible for activation of Akt signaling in NPC.
In vitro modulation of probiotic bacteria on the biofilm of Candida glabrata

Chew SY, Cheah YK, Seow HF, Sandai D, Than LT

Anaerobe, 2015 Aug;34:132-8.
PMID: 26028405 DOI: 10.1016/j.anaerobe.2015.05.009

A conspicuous new concept of pathogens living as the microbial societies in the human host rather than free planktonic cells has raised considerable concerns among scientists and clinicians. Fungal biofilms are communities of cells that possess distinct characteristic such as increased resistance to the immune defence and antimycotic agents in comparison to their planktonic cells counterpart. Therefore, inhibition of the biofilm may represent a new paradigm for antifungal development. In this study, we aim to evaluate the in vitro modulation of vulvovaginal candidiasis (VVC)-causing Candida glabrata biofilms using probiotic lactobacilli strains. Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 were shown to have completely inhibited C. glabrata biofilms and the results were corroborated by scanning electron microscopy (SEM), which revealed scanty structures of the mixed biofilms of C. glabrata and probiotic lactobacilli strains. In addition, biofilm-related C. glabrata genes EPA6 and YAK1 were downregulated in response to the probiotic lactobacilli challenges. The present study suggested that probiotic L. rhamnosus GR-1 and L. reuteri RC-14 strains inhibited C. glabrata biofilm by partially impeding the adherence of yeast cells and the effect might be contributed by the secretory compounds produced by these probiotic lactobacilli strains. Further investigations are required to examine and identify the biofilm inhibitory compounds and the mechanism of probiotic actions of these lactobacilli strains.
Expression of beta-catenin, COX-2 and iNOS in colorectal cancer: relevance of COX-2 adn iNOS inhibitors for treatment in Malaysia

Hong SK, Gul YA, Ithnin H, Talib A, Seow HF

Asian J Surg, 2004 Jan;27(1):10-7.
PMID: 14719508

BACKGROUND: Promising new pharmacological agents and gene therapy targeting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) could modulate treatment of colorectal cancer in the future. The aim of this study was to elucidate the expression fo beta-catenin and teh presence of COX-2 and iNOS in colorectal cancer specimens in Malaysia. This is a useful prelude to future studies investigating interventions directed towards COX-2 adn iNOS.
METHODS: A cross-section study using retrospective data over a 2-year period (1999-2000) involved 101 archival, formalin-fixed, paraffin-embedded tissue samples of colorectal cancers that were surgically resected in a tertiary referral.
RESULTS: COX-2 production was detected in adjacent normal tissue in 34 sample (33.7%) and in tumour tissue in 60 samples (59.4%). More tumours expressed iNOS (82/101, 81.2%) than COX-2. No iNOS expression was detected in adjacent normal tissue. Intense beta-catenin immunoreactivity at the cell-to-cell border. Poorly differentiated tumours had significantly lower total beta-catenin (p = 0.009) and COX-2 scores (p = 0.031). No significant relationships were established between pathological stage and beta-catenin, COX-2 and iNOS scores.
CONCLUSIONS: the accumulation of beta-catenin does not seem to be sufficient to activate pathways that lead to increased COX-2 and iNOS expression. A high proportion of colorectal cancers were found to express COX-2 and a significant number produced iNOS, suggesting that their inhibitors may be potentially useful as chemotherapeutic agents in the management of colorectal cancer.
Fulltext Basic fibroblast growth factor modulates cell cycle of human umbilical cord-derived mesenchymal stem cells

Ramasamy R, Tong CK, Yip WK, Vellasamy S, Tan BC, Seow HF

Cell Prolif, 2012 Apr;45(2):132-9.
PMID: 22309282 DOI: 10.1111/j.1365-2184.2012.00808.x

BACKGROUND: Mesenchymal stem cells (MSC) have great potential in regenerative medicine, immunotherapy and gene therapy due to their unique properties of self-renewal, high plasticity, immune modulation and ease for genetic modification. However, production of MSC at sufficient clinical scale remains an issue as in vitro generation of MSC inadequately fulfils the demand with respect to patients.
OBJECTIVES: This study has aimed to establish optimum conditions to generate and characterize MSC from human umbilical cord (UC-MSC).
MATERIALS AND METHODS: To optimize MSC population growth, basic fibroblast growth factor (bFGF) was utilized in culture media. Effects of bFGF on expansion kinetics, cell cycle, survival of UC-MSC, cytokine secretion, expression of early stem-cell markers and immunomodulation were investigated.
RESULTS: bFGF supplementation profoundly enhanced UC-MSC proliferation by reducing population doubling time without altering immunophenotype and immunomodulatory function of UC-MSC. However, cell cycle studies revealed that bFGF drove the cells into the cell cycle, as a higher proportion of cells resided in S phase and progressed into M phase. Consistent with this, bFGF was shown to promote expression of cyclin D proteins and their relevant kinases to drive UC-MSC to transverse cell cycle check points, thus, committing the cells to DNA synthesis. Furthermore, supplementation with bFGF changed the cytokine profiles of the cells and reduced their apoptotic level.
CONCLUSION: Our study showed that bFGF supplementation of UC-MSC culture enhanced the cells' growth kinetics without compromising their nature.
Overexpression of phospho-Akt correlates with phosphorylation of EGF receptor, FKHR and BAD in nasopharyngeal carcinoma

Yip WK, Leong VC, Abdullah MA, Yusoff S, Seow HF

Oncol Rep, 2008 Feb;19(2):319-28.
PMID: 18202777

The Akt pathway is one of the most common molecular alterations in various human malignancies. However, its involvement in nasopharyngeal carcinoma (NPC) tumorigenesis has not been well established. In this study, the status of Akt activation and expression of its upstream and downstream molecules was investigated in 64 NPC and 38 non-malignant nasopharyngeal tissues by immunohistochemistry. The hotspot mutations of PIK3CA, encoding the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), were also determined in 25 of these NPC tissues. No hotspot mutations were found in any of the samples tested. Akt was activated in 27 (42.2%) and 23 (35.9%) NPCs, as indicated by p-Akt (Thr308) and p-Akt (Ser473) immunoreactivity, respectively. PTEN loss did not correlate statistically with activated Akt. However, a positive correlation was observed between activated Akt and phospho-epidermal growth factor receptor (p-EGFR), suggesting that the EGFR signaling might be one of the upstream regulators of the Akt pathway. The phosphorylation of forkhead (FKHR) and Bcl-2 associated death domain (BAD), but not mammalian target of rapamycin and glycogen synthase kinase-3beta, was significantly correlated with Akt activation. This implies that Akt promotes cell proliferation (as estimated by Ki-67) and survival, at least, through the inactivation of FKHR and BAD in NPC. Our data revealed that the EGFR/PI3K/Akt signaling pathway is important in NPC pathogenesis and that PIK3CA hotspot mutations are rare in NPC.
Anti-proliferative and anti-invasive properties of a purified fraction from Streptomyces sp. H7372

Yip WK, Cheenpracha S, Chang LC, Ho CC, Seow HF

Int J Oncol, 2010 Nov;37(5):1229-41.
PMID: 20878070

Secondary metabolites from actinomycetes especially the genus Streptomyces may be one of the most important sources for novel anticancer agents. A purified fraction from a novel actinomycete strain, Streptomyces sp. H7372, was elucidated in breast cancer cells. We have isolated three purified fractions from a novel strain, Streptomyces sp. H7372. One of the fractions, designated as 31-2, exhibited the strongest growth-inhibitory effect and thereby was selected for further studies. 31-2 exerted a growth-inhibitory effect on a panel of 15 human cancer and 2 non-malignant cell lines. In MCF-7 and MDA-MB-231 breast cancer cells, 31-2 induced a cytostatic (anti-proliferative) effect without causing cytotoxicity (cell death). Our data suggest that the cytostasis resulted from cell cycle arrest at the G1 phase in MCF-7 cells and at the S phase in MDA-MB-231 cells. Western blot analysis demonstrated a modulation of phosphorylation of the Rb and CDC2 proteins and of CDK4, cyclin D1 and cyclin D3 in the 31-2-treated breast cancer cell lines. The protein levels of CDK2, CDK6, and PCNA were not affected by 31-2 treatment. 31-2 also exhibited an anti-invasive effect in MDA-MB-231 cells. However, this effect is not attributed to the modulation of proteolytic activity in MDA-MB-231 cells as the enzymatic degradation of type IV collagen was not affected by 31-2. The 31-2 is a potent cytostatic and anti-invasive agent and modulates the cell cycle pathway. Together, these results will have important implications in searching for novel approaches to treat cancer.
2-dodecanol (decyl methyl carbinol) inhibits hyphal formation and SIR2 expression in C. albicans

Lim CS, Wong WF, Rosli R, Ng KP, Seow HF, Chong PP

J Basic Microbiol, 2009 Dec;49(6):579-83.
PMID: 19810039 DOI: 10.1002/jobm.200900035

Candida albicans is capable of undergoing yeast-hypha transition to attain pathogenicity in humans. In this study, we investigated the differential expression of CaSIR2 via quantitative real-time PCR (qPCR), during yeast-hypha transition with and without the presence of 2-dodecanol. SIR2 transcript levels were found to be significantly enhanced after hyphal induction as compared to the yeast form. This study found that 2-dodecanol is able to inhibit hyphal development and block SIR2 up-regulation, even in hyphal-inducing growth conditions. We suggest that SIR2 may be involved in Candida albicans quorum-sensing and serum-induced yeast-hyphae transition via the Ras1-cAMP-Efg1 signalling cascade.
Generation of mesenchymal stem cell from human umbilical cord tissue using a combination enzymatic and mechanical disassociation method

Tong CK, Vellasamy S, Tan BC, Abdullah M, Vidyadaran S, Seow HF, et al.

Cell Biol Int, 2011 Mar;35(3):221-6.
PMID: 20946106 DOI: 10.1042/CBI20100326

MSCs (mesenchymal stem cells) promise a great potential for regenerative medicine due to their unique properties of self-renewal, high plasticity, modulation of immune response and the flexibility for genetic modification. Therefore, the increasing demand for cellular therapy necessitates a larger-scale production of MSC; however, the technical and ethical issues had put a halt on it. To date, studies have shown that MSC could be derived from human UC (umbilical cord), which is once considered as clinical waste. We have compared the two conventional methods which are classic enzymatic digestion and explant method with our newly tailored enzymatic-mechanical disassociation method to generate UC-MSC. The generated UC-MSCs from the methods above were characterized based on their immunophenotyping, early embryonic transcription factors expression and mesodermal differentiation ability. Our results show that enzymatic-mechanical disassociation method increase the initial nucleated cell yield greatly (approximately 160-fold) and maximized the successful rate of UC-MSC generation. Enzymatic-mechanical disassociation-derived UC-MSC exhibited fibroblastic morphology and surface markers expression of CD105, CD73, CD29, CD90 and MHC class I. Furthermore, these cells constitutively express early embryonic transcription factors (Nanog, Oct-4, Sox-2 and Rex-1), as confirmed by RT-PCR, indicating their multipotency and high self-renewal capacity. They are also capable of differentiating into osteoblasts and adipocytes when given an appropriate induction. The present study demonstrates a new and efficient approach in generating MSC from UC, hence serving as ideal alternative source of mesenchymal stem cell for clinical and research use.
Recurrent candidaemia in a neonate with Hirschsprung's disease: fluconazole resistance and genetic relatedness of eight Candida tropicalis isolates

Chong PP, Chieng DC, Low LY, Hafeez A, Shamsudin MN, Seow HF, et al.

J Med Microbiol, 2006 Apr;55(Pt 4):423-428.
PMID: 16533990 DOI: 10.1099/jmm.0.46045-0

The incidence of candidaemia among immunocompromised patients in Malaysia is increasing at an alarming rate. Isolation of clinical strains that are resistant to fluconazole has also risen markedly. We report here the repeated isolation of Candida tropicalis from the blood of a neonatal patient with Hirschsprung's disease. In vitro fluconazole susceptibility tests of the eight isolates obtained at different time points showed that seven of the isolates were resistant and one isolate was scored as susceptible dose-dependent. Random amplification of polymorphic DNA fingerprinting of the isolates using three primers and subsequent phylogenetic analysis revealed that these isolates were highly similar strains having minor genetic divergence, with a mean pairwise similarity coefficient of 0.893+/-0.041. The source of the infectious agent was thought to be the central venous catheter, as culture of its tip produced fluconazole-resistant C. tropicalis. This study demonstrates the utility of applying molecular epidemiology techniques to complement traditional mycological culture and drug susceptibility tests for accurate and appropriate management of recurrent candidaemia and highlights the need for newer antifungals that can combat the emergence of fluconazole-resistant C. tropicalis strains.
HLA-A and breast cancer in West Peninsular Malaysia

Leong PP, Muhammad R, Ibrahim N, Cheong SK, Seow HF

Med Oncol, 2011 Mar;28(1):51-6.
PMID: 20069393 DOI: 10.1007/s12032-009-9414-6

Breast cancer is the most common malignancy among females in Malaysia. Attempts have been made to investigate the association between breast cancer and human leukocyte antigen (HLA) types. However, data from those previous studies are highly variable. The aim of this study is to investigate the association between HLA-A types and clinicopathological factors in breast cancer. The frequencies of HLA-A type in 59 female patients with infiltrating ductal of the breast were determined by polymerase chain reaction method. HLA-A2/A30 and A2/A31 haplotype (5.1%; P = 0.045) as well as HLA-A30 (5.1%, P = 0.045) and A31 (6.8%; P = 0.020) allele were significant higher in the patients than controls (0%). HLA-A24 allele was negatively related to lymph node metastasis (r = -0.316; P = 0.021) whereas, A26 (r = -0.430; P = 0.001) and A36 (r = -0.430; P = 0.001) alleles were negatively correlated to distant metastasis in breast cancer. Negative correlations between HLA-A26/A36 (r = -0.430; P = 0.001), A2/A11 (r = -0.276; P = 0.044), A24/A34 (r = -0.430; P = 0.001) haplotypes and distant metastasis were identified. Interestingly, Her2 expression in breast carcinoma was negatively correlated to A11/24 haplotypes (r = -0.294; P = 0.034) but positively correlated to homozygous HLA-A24 (r = 0.396; P = 0.040). In conclusion, HLA-A2, -A30 and A31 were associated with breast cancer.
Association between polymorphisms of interleukin-17A G197A and interleukin-17F A7488G and risk of colorectal cancer

Samiei G, Yip WK, Leong PP, Jabar MF, Dusa NM, Mohtarrudin N, et al.

J Cancer Res Ther, 2018 Jun;14(Supplement):S299-S305.
PMID: 29970680 DOI: 10.4103/0973-1482.235345

Background: Interleukin (IL)-17A and IL-17F are inflammatory cytokines mainly produced by T helper 17 cells. IL-17A is known to be protumorigenic while IL-17F has a protective role in cancer. A number of studies have been conducted to determine the association between polymorphisms of IL-17AG197A (rs2275913) and IL-17FA7488G (rs763780) and risk of cancers. No studies have yet to be conducted to genotype the IL-17AG197A polymorphism in colorectal cancer (CRC).
Objective: To assess the association of IL-17AG197A and IL-17FA7488G polymorphisms with CRC risk.
Materials and Methods: We performed the genotyping by polymerase chain reaction-restriction fragment length polymorphism method on blood samples from 80 healthy individuals and paraffin-embedded tumor tissues from 70 CRC patients.
Results: Our study showed that IL-17A197AA genotype was significantly associated with an increased CRC risk with odds ratios of 6.08 (95% confidence interval [CI]: 2.25-16.42, P < 0.001) and 2.80 (95% CI: 1.23-6.35, P = 0.014), in comparison with GG and AG genotypes, respectively. However, IL-17FA7488G polymorphism was not significantly associated with CRC risk (P = 0.102). No significant association of IL-17AG197A and IL-17FA7488G polymorphisms with patient and tumor variables was found.
Conclusion: This report from Malaysia shows the relationship of IL-17A197AA genotype with susceptibility to CRC.
Fulltext Effect of the miR-96-5p inhibitor and mimic on the migration and invasion of the SW480-7 colorectal cancer cell line

He PY, Yip WK, Jabar MF, Mohtarrudin N, Dusa NM, Seow HF

Oncol Lett, 2019 Aug;18(2):1949-1960.
PMID: 31423265 DOI: 10.3892/ol.2019.10492

The objectives of the present study were to identify the aberrant expression of microRNA (miRNA) in colorectal carcinoma (CRC) tissues from published miRNA profiling studies and to investigate the effects of the identified miRNA inhibitor and mimic miR-96-5p on CRC cell migration and invasion. The altered expression of the regulators of cytoskeleton mRNA in miR-96-5p inhibitor-transfected cells was determined. The miR-96-5p expression level in five CRC cell lines, HCT11, CaCo2, HT29, SW480 and SW620, and 26 archived paraffin-embedded CRC tissues were also investigated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR). Cell viability in response to the miR-96-5p inhibitor and mimic transfections was determined by an MTT assay. A Matrigel invasion assay was conducted to select the invasive subpopulation designated SW480-7, by using the parental cell line SW480. The effects of miR-96-5p mimic- or inhibitor-transfected SW480-7 cells on cell migration and invasion were evaluated using the Transwell and Matrigel assays, and the change in expression of the regulators of cytoskeleton mRNAs was identified by Cytoskeleton Regulators RT2-Profiler PCR array followed by validation with RT-qPCR. CRC tissues exhibited a significant increase in miR-96-5p expression, compared with their matched normal adjacent tissues, indicating an oncogenic role for miR-96-5p. The results demonstrated that the miR-96-5p inhibitor decreased the migration of SW480-7 cells, but had no effect on invasion. This may be due to the promotion of cell invasion by Matrigel, which counteracts the blockade of cell invasion by the miR-96-5p inhibitor. The miR-96-5p mimic enhanced SW480-7 cell migration and invasion, as expected. It was determined that there was a >2.5 fold increase in the expression of genes involved in cytoskeleton regulation, myosin light chain kinase 2, pleckstrin homology like domain family B member 2, cyclin A1, IQ motif containing GTPase activating protein 2, Brain-specific angiogenesisinhibitor 1-associated protein 2 and microtubule-actin crosslinking factor 1, in miR-96-5p inhibitor-transfected cells, indicating that they are negative regulators of cell migration. In conclusion, the miR-96-5p inhibitor blocked cell migration but not invasion, and the latter may be due to the counteraction of Matrigel, which has been demonstrated to stimulate cell invasion.
Phenotyping of lymphocytes expressing regulatory and effector markers in infiltrating ductal carcinoma of the breast

Leong PP, Mohammad R, Ibrahim N, Ithnin H, Abdullah M, Davis WC, et al.

Immunol Lett, 2006 Feb 15;102(2):229-36.
PMID: 16246429

Dysfunction of the host immune system in cancer patients can be due to a number of reasons including suppression of tumour associated antigen reactive lymphocytes by regulatory T (Treg) cells. In this study, we used flow cytometry to determine the phenotype and relative abundance of the tumour infiltrating lymphocytes (TILs) from 47 enzymatically dissociated tumour specimens from patients with infiltrating ductal carcinoma (IDC) of the breast. The expression of both effector and regulatory markers on the TILs were determined by using a panel of monoclonal antibodies. Analysis revealed CD8(+) T cells (23.4+/-2.1%) were predominant in TILs, followed by CD4(+) T cells (12.6+/-1.7%) and CD56(+) natural killer cells (6.4+/-0.7%). The CD4(+)/CD8(+) ratio was 0.8+/-0.9%. Of the CD8(+) cells, there was a higher number (68.4+/-3.5%) that expressed the effector phenotype, namely, CD8(+)CD28(+) and about 46% of this subset expressed the activation marker, CD25. Thus, a lower number of infiltrating CD8(+) T cells (31.6+/-2.8%) expressed the marker for the suppressor phenotype, CD8(+)CD28(-). Of the CD4(+) T cells, 59.6+/-3.9% expressed the marker for the regulatory phenotype, CD4(+)CD25(+). About 43.6+/-3.8% CD4(+)CD25(+) subset co-expressed both the CD152 and FOXP3, the Treg-associated molecules. A positive correlation was found between the presence of CD4(+)CD25(+) subset and age (> or =50 years old) (r=0.51; p=0.045). However, no significant correlation between tumour stage and CD4(+)CD25(+) T cells was found. In addition, we also found that the CD4(+)CD25(-) subset correlated with the expression of the nuclear oestrogen receptor (ER)-alpha in the tumour cells (r=0.45; p=0.040). In conclusion, we detected the presence of cells expressing the markers for Tregs (CD4(+)CD25(+)) and suppressor (CD8(+)CD28(-)) in the tumour microenvironment. This is the first report of the relative abundance of Treg co-expressing CD152 and FOXP3 in breast carcinoma.
Expression of interleukin-18, interferon-gamma and interleukin-10 in hepatocellular carcinoma

Chia CS, Ban K, Ithnin H, Singh H, Krishnan R, Mokhtar S, et al.

Immunol Lett, 2002 Dec 03;84(3):163-72.
PMID: 12413732

This is the first report on the detection of IL-18, IFN-gamma and IL-10 proteins in hepatocelllular carcinoma. In the apparently normal surrounding tissue, 13 out of 17 paired specimens showed positive immunoreactivity to IL-18 (76.5%) compared with six out of 17 in the tumour portion (35.3% of specimens). Thus, a significantly higher number of IL-18 positive specimens was found in the hepatocytes of apparently normal surrounding tissue compared with the tumour (P=0.018). In contrast, the number of specimens with positive immunoreactivity to the antibody against the Th1 cytokine, IFN-gamma expression in the hepatocytes was lower. Only one specimen from the apparently normal surrounding tissue (one out of 17; 5.9%) and three other specimens from the tumour portion (three out of 17; 17.6%) had positive immunoreactivity. Similarly, the expression of the Th2 cytokine, IL-10 in normal (four out of 17; 23.5%) and tumour portions (five out of 17; 29.4%) was also low. Thus, there did not appear to be predominant Th2 immune response as denoted by IL-10 expression. Using the Spearman correlation rank test, a significant correlation between IL-18 expression in the apparently normal surrounding tissue and high alpha-foetoprotein (AFP) levels of >350 IU/l. No correlation between IL-18 expression in the tumour portion and clinicopathological factors was found. There was also no correlation found between IL-18 and the other cytokines, namely, IFN-gamma and IL-10 expression These new findings provide additional information on the type of cytokines expressed in the tumour microenvironment and give a further insight into the role of cytokines in the pathogenesis of cancer which is critical for the development of effective immunotherapeutic approaches for cancer therapy in the future.
Seroprevalence of antibodies to hepatitis E virus in the normal blood donor population and two aboriginal communities in Malaysia

Seow HF, Mahomed NM, Mak JW, Riddell MA, Li F, Anderson DA

J Med Virol, 1999 Oct;59(2):164-8.
PMID: 10459151

The prevalence of antibodies to hepatitis E virus (HEV) has been examined in many countries, but such studies have generally been limited to majority populations such as those represented in healthy blood donors or cross sections of urban populations. Due to its major route of enteric transmission, large differences in HEV prevalence might be expected between populations in the same country but with different living conditions. Using an ELISA based on GST-ORF2.1 antigen, the prevalence of IgG-class antibodies to HEV was examined in three distinct populations in Malaysia: the normal (urban) blood donor population and two aboriginal communities located at Betau, Pahang and Parit Tanjung, Perak. IgG anti-HEV was detected in 45 (44%) of 102 samples from Betau and 15 (50%) of 30 samples from Parit Tanjung, compared to only 2 (2%) of 100 normal blood donors. The distribution of sample ELISA reactivities was also consistent with ongoing sporadic infection in the aboriginal communities, while there was no significant relationship between HEV exposure and age, sex, or malaria infection. The high prevalence of antibodies to HEV in the two aboriginal communities indicates that this group of people are at high risk of exposure to HEV compared to the general blood donors, and the results suggest that studies of HEV seroprevalence within countries must take into account the possibility of widely varying infection rates between populations with marked differences in living conditions.
Carica papaya increases regulatory T cells and reduces IFN-γ+ CD4+ T cells in healthy human subjects

Abdullah M, Chai PS, Loh CY, Chong MY, Quay HW, Vidyadaran S, et al.

Mol Nutr Food Res, 2011 May;55(5):803-6.
PMID: 21520494 DOI: 10.1002/mnfr.201100087

Fruit and vegetables have therapeutic potential as they dampen inflammation, have no known side-effects and as whole foods have prospective additive and synergistic benefits. Th1 (IFN-γ(+) CD4(+))/Th2 (IL-4(+)CD4(+)) T cells play a vital role in mediating inflammatory responses and may be regulated by regulatory T cells (Tregs). Effects of Carica papaya on cells of healthy individuals were determined using flow cytometry methods. Significant down-regulation of IFN-γ(+) CD4(+) (p=0.03, n=13), up-regulation of IL-4(+) CD4(+) (p=0.04, n=13) T cells and up-regulation of CD3(+) CD4(+) CD25(+) CD127(-) (p=0.001, n=15) Tregs were observed after papaya consumption. In vitro cultures showed up-regulation of Tregs in male subjects and was significantly associated with levels of IL-1β in culture supernatants (R(2) =0.608, p=0.04, n=12). Other inflammatory cytokines were significantly suppressed. Papaya consumption may exert an anti-inflammatory response mediated through Tregs and have potential in alleviating inflammatory conditions.
Genotyping and drug resistance profile of Candida spp. in recurrent and one-off vaginitis, and high association of non-albicans species with non-pregnant status

Chong PP, Abdul Hadi SR, Lee YL, Phan CL, Tan BC, Ng KP, et al.

Infect Genet Evol, 2007 Jul;7(4):449-56.
PMID: 17324639

Recurrent vulvovaginal candidiasis affects women worldwide and the resistance to azole drugs may be an important factor. The extent of strain-to-strain variation within a species and its relationship to the ability of the organism to colonize the vulvovaginal mucosa is not well established. The aims of this study were to compare: (i) the genotypes of Candida strains in sequential infections in patients with recurrent vaginitis, (ii) the genotypes of strains in patients with only one episode of infection in a period of 1 year and (iii) determine the in vitro antifungal susceptibilities of strains that cause recurrent vaginitis. Fifty-one cultured specimens from six distinct Candida species were genotyped via random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) method using the ERIC1 and ERIC2 primers (ERIC, enterobacterial repetitive intergenic consensus). Statistical analyses allowed three different scenarios to be discerned for recurrent cases: (i) strain maintenance without genetic variation, (ii) strain maintenance with minor genetic variation and (iii) outright strain replacement. The genetic relatedness between strains from patients with recurrent vaginitis and patients with single episode of vaginitis were demonstrated by the dendogramme and the mean pairwise similarity coefficient S(AB) for the intergroup comparison was 0.223. However, intragroup genetic relatedness was slightly higher than intergroup comparison, with mean S(AB) of 0.261 and 0.331 for Groups I and II, respectively. A high proportion of Group I isolates (87.5%) causing recurrent infections were resistant to ketoconazole, whereas 41.7% of these isolates were cross-resistant to both clotrimazole and ketoconazole as shown by the in vitro antifungal susceptibility test, especially for C. glabrata isolates. Pregnancy status of patients displayed a highly significant association with C. albicans species whereas non-albicans species had a markedly higher prevalence in non-pregnant patients (p<0.001). These results may have a profound impact on the management of vaginal candidiasis, especially in recurrent cases.
Inhibition of cell migration and invasion by miR‑29a‑3p in a colorectal cancer cell line through suppression of CDC42BPA mRNA expression

He PY, Yip WK, Chai BL, Chai BY, Jabar MF, Dusa N, et al.

Oncol Rep, 2017 Dec;38(6):3554-3566.
PMID: 29039592 DOI: 10.3892/or.2017.6037

The objective of this study was to determine the effect of miR‑29a‑3p inhibitor on the migration and invasion of colorectal cancer cell lines (CRC) and the underlying molecular mechanisms. miR‑29a‑3p was detected using reverse transcription-quantitative polymerase chain reaction (RT‑qPCR) in the CRC cell lines HCT11, CaCo2, HT29, SW480 and SW620. An invasive subpopulation designated SW480‑7 was derived from the parental cell line, detected by Transwell and Transwell Matrigel assays. Cytoskeleton Regulators RT2 profiler PCR array and western blot analysis were utilized to identify the alterations in expression of downstream mRNAs. siRNA against CDC42BPA was transfected into SW480‑7 and effects on cell migration and invasion were investigated. Data obtained showed that miR‑29a‑3p was detected in these five CRC cell lines. miR‑29a‑3p inhibitor had no effect on viability but stimulated cell migration and invasion of SW480‑7 cells. In contrast, miR‑29a‑3p mimic suppressed cell migration and invasion. TargetScan miRBD and DIANA were employed to identify the potential direct target genes of miR‑29a‑3p in the Cytoskeleton Regulators RT2-Profiler PCR array. Cytoskeleton Regulators RT2-Profiler PCR array data showed that 3 out of the 5 predicted targets genes, CDC42BPA (2.33-fold), BAIAP2 (1.79-fold) and TIAM1 (1.77-fold), in the array were upregulated by miR‑29a‑3p. A significant increase in expression IQGAP2, PHLDB2, SSH1 mRNAs and downregulation of PAK1 mRNA was also detected with miR‑29a‑3p inhibition. Increase in CDC42BPA, SSH1 and IQGAP2 mRNA expression correlated with increased protein level in miR‑29a‑3p transfected SW-480-7 cells. Silencing of CDC42BPA (an enhancer of cell motility) partially abolished miR‑29a‑3p inhibitor-induced stimulation of cell migration and invasion. miR‑29a‑3p expression in stage II and III CRC is relatively lower than that of stage I CRC. However, the data need to be interpreted with caution due to the small sample size. In conclusion, inhibition of miR‑29a‑3p stimulates SW480‑7 cell migration and invasion and downstream expression IQGAP2, PHLDB2, SSH1 mRNAs are upregulated whilst PAK1 mRNA is downregulated. Silencing of CDC42BPA expression partially reduces miR29a‑3p inhibitor-induced migration and invasion of SW480‑7 cells.
Apoptosis induced by para-phenylenediamine involves formation of ROS and activation of p38 and JNK in chang liver cells

Chye SM, Tiong YL, Yip WK, Koh RY, Len YW, Seow HF, et al.

Environ Toxicol, 2014 Sep;29(9):981-90.
PMID: 23172806 DOI: 10.1002/tox.21828

para-Phenylenediamine (p-PD) is a suspected carcinogen, but it has been widely used as a component in permanent hair dyes. In this study, the mechanism of p-PD-induced cell death in normal Chang liver cells was investigated. The results demonstrated that p-PD decreased cell viability in a dose-dependent manner. Cell death via apoptosis was confirmed by enhanced DNA damage and increased cell number in the sub-G1 phase of the cell cycle, using Hoechst 33258 dye staining and flow cytometry analysis. Apoptosis via reactive oxygen species generation was detected by the dichlorofluorescin diacetate staining method. Mitogen-activated protein kinase (MAPK) activation was assessed by western blot analysis and revealed that p-PD activated not only stress-activated protein kinase (SAPK)/c-Jun N-terminal kinases (JNK) and p38 MAPK but also extracellular signal-regulated kinase (ERK). Cytotoxicity and apoptosis induced by p-PD were markedly enhanced by ERK activation and selectively inhibited by ERK inhibitor PD98059, thus indicating a negative role of ERK. In contrast, inhibition of p38 MAPK activity with the p38-specific inhibitor SB203580 moderately inhibited cytotoxicity and apoptosis induction by p-PD. Similarly, SP600125, an inhibitor of SAPK/JNK, moderately inhibited cytotoxicity and apoptosis induced by p-PD, thus implying that p38 MAPK and SAPK/JNK had a partial role in p-PD-induced apoptosis. Western blot analysis revealed that p-PD significantly increased phosphorylation of p38 and SAPK/JNK and decreased phosphorylation of ERK. In conclusion, the results demonstrated that SAPK/JNK and p38 cooperatively participate in apoptosis induced by p-PD and that a decreased ERK signal contributes to growth inhibition or apoptosis.
Fulltext Circulating miRNAs in Type 2 Diabetic Patients with and without Albuminuria in Malaysia

Zahari Sham SY, Ng CT, Azwar S, Yip WK, Abdullah M, Thevandran K, et al.

Kidney Blood Press Res, 2022;47(2):81-93.
PMID: 35158353 DOI: 10.1159/000518866

INTRODUCTION: Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease. Dysregulation of circulating miRNAs has been reported, suggesting their pathological roles in DKD. This study aimed to investigate differentially expressed miRNAs in the sera of type 2 diabetes mellitus (T2DM) patients with and without albuminuria in a selected Malaysian population.
METHOD: Forty-one T2DM patients on follow-up at a community clinic were divided into normo-(NA), micro-(MIC), and macroalbuminuria (MAC) groups. Differential levels of miRNAs in 12 samples were determined using the pathway-focused (human fibrosis) miScript miRNA qPCR array and was validated in 33 samples, using the miScript custom qPCR array (CMIHS02742) (Qiagen GmbH, Hilden, Germany).
RESULTS: Trends of upregulation of 3 miRNAs in the serum, namely, miR-874-3p, miR-101-3p, and miR-145-5p of T2DM patients with MAC compared to those with NA. Statistically significant upregulation of miR-874-3p (p = 0.04) and miR-101-3p (p = 0.01) was seen in validation cohort. Significant negative correlations between the estimated glomerular filtration rate (eGFR) and miR-874-3p (p = 0.05), miR-101-3p (p = 0.03), and miR-145-5p (p = 0.05) as well as positive correlation between miR-874-3p and age (p = 0.03) were shown by Pearson's correlation coefficient analysis.
CONCLUSION: Upregulation of previously known miRNA, namely, miR-145-5p, and possibly novel ones, namely, miR-874-3p and miR-101-3p in the serum of T2DM patients, was found in this study. There was a significant correlation between the eGFR and these miRNAs. The findings of this study have provided encouraging evidence to further investigate the putative roles of these differentially expressed miRNAs in DKD.

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