Cancer Research Initiatives Foundation

Subang Jaya, Malaysia

Cancer Research Initiatives Foundation

Subang Jaya, Malaysia
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Suberi A.A.M.,University Tun Hussein Onn Malaysia | Zakaria W.N.W.,University Tun Hussein Onn Malaysia | Tomari R.,University Tun Hussein Onn Malaysia | Lim K.P.,Cancer Research Initiatives Foundation
IECBES 2016 - IEEE-EMBS Conference on Biomedical Engineering and Sciences | Year: 2016

The segmentation of Dendritic Cell (DC) from clumps of overlapping Peripheral Blood Mononuclear Cell (PBMC) in Phase Contrast Microscopy (PCM) images is notoriously challenging for an automated image analysis system. This problem is encountered due to the presence of shade off effect and halo region in the image. In order to improve the performance of DC classification, the methods in pre-processing are enhanced and analysed. The images undergo image normalization process to remove uneven illumination. Initially, Local Contrast Threshold (LCT) has been applied in preprocessing. However, it results in low performance of DC segmentation and identification. Therefore, a hybrid of low and high sigma in Gaussian kernel filtering with Local Adaptive Threshold (H-GLAT) through logical operator AND are proposed. Following that, halo removal is applied to eliminate halo region and post-processed by morphological operators to discriminate the cells from the background. The quantitative assessment demonstrates that proposed framework can successfully address these imaging artifact issues. The test results show that the H-GLAT method is better than the LCT that applied in previous work with classifier performance of 76%, 93.3% and 99.5% precision, recall and accuracy respectively. © 2016 IEEE.

Lau B.F.,University of Malaya | Abdullah N.,University of Malaya | Aminudin N.,University of Malaya | Lee H.B.,University of Malaya | Tan P.J.,Cancer Research Initiatives Foundation
Journal of Ethnopharmacology | Year: 2015

Ethnopharmacological relevance Several members of the genus Lignosus, which are collectively known as cendawan susu rimau (in Malay) or tigeŕs milk mushrooms (TMM), are regarded as important local medicine particularly by the indigenous communities in Malaysia. The mushroom sclerotia are purportedly effective in treating cancer, coughs, asthma, fever, and other ailments. The most commonly encountered Lignosus spp. in Malaysia was authenticated as Lignosus rhinocerotis (Cooke) Ryvarden (synonym: Polyporus rhinocerus), which is also known as hurulingzhi in China and has been used by Chinese physicians to treat liver cancer, gastric ulcers, and chronic hepatitis. In spite of growing interest in the therapeutic potential of TMM, there is no compilation of scientific evidence that supports the ethnomedicinal uses of these mushrooms. Therefore, the present review is intended (i) to provide a comprehensive, up-to-date overview of the ethnomedicinal uses, pharmacological activities, and cultivation of TMM in general and L. rhinocerotis in particular, (ii) to demonstrate how recent scientific findings have validated some of their traditional uses, and (iii) to identify opportunities for future research and areas to prioritize for TMM bioprospecting. Materials and methods A detailed literature search was conducted via library search (books, theses, reports, newspapers, magazines, and conference proceedings) and electronic search (Web of Science, PubMed, and Google Scholar) for articles published in peer-reviewed journals. These sources were scrutinized for information on TMM and specifically for L. rhinocerotis. Results Ethnomycological knowledge about TMM, with an emphasis on cultural associations and use as local medicine, has been comprehensively and systematically compiled for the first time. Some of the reported medicinal properties of TMM have been validated by scientific studies. The anti-tumor, immuno-modulatory, anti-inflammatory, anti-oxidative, anti-microbial, neurite outgrowth stimulation, and other pharmacological activities of L. rhinocerotis sclerotial extracts have been explored. The nature of sclerotial bioactive components, such as proteins, polysaccharides, and/or polysaccharide-protein complexes, has been identified, whereas the low-molecular-weight constituents remain poorly studied. The artificial cultivation of L. rhinocerotis via solid substrate and liquid fermentations successfully yielded fruiting bodies, sclerotium, mycelium, and culture broth that could be exploited as substitutes for the wild resources. The cultivated sclerotium and mycelium were shown to be safe from a toxicological point of view. Other research areas, e.g., chemical studies, genomics, and proteomics, have been employed to gain insights into the medicinal properties of TMM. Conclusions This review clarified the medicinal properties of TMM as recorded in various ethnomycological records, and it simultaneously highlighted the current efforts to provide scientific evidence by using various in vitro and in vivo models. Thus far, only the anti-tumor and immuno-modulatory effects of L. rhinocerotis sclerotial aqueous extracts have been extensively investigated, and other medicinal properties relevant to their traditional uses, e.g., anti-tussive and anti-pyretic properties, have yet to be validated. Further studies focusing on (i) the isolation and characterization of active components, (ii) the elucidation of their modes of action, and (iii) an evaluation of their safety and efficacy, when compared with the crude aqueous preparations, are warranted to accelerate potential drug discovery from TMM. © 2015 Elsevier Ireland Ltd. All rights reserved.

Ng C.-H.,International Medical University | Wang W.-S.,University Tunku Abdul Rahman | Chong K.-V.,University Tunku Abdul Rahman | Win Y.-F.,University Tunku Abdul Rahman | And 5 more authors.
Dalton Transactions | Year: 2013

Chiral enantiomers [Cu(phen)(l-threo)(H2O)]NO31 and [Cu(phen)(d-threo)(H2O)]NO32 (threo = threoninate) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz.l- and d-[Cu(phen)(5MeOCA)(H2O)]NO3·xH 2O (3 and 4; phen = 1,10-phenanthroline; 5MeOCA = 5-methyloxazolidine-4-carboxylate; x = 0-3) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-Visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. Analysis of restriction enzyme inhibition by these four complexes revealed modulation of DNA binding selectivity by the type of ligand, ligand modification and chirality. Their interaction with bovine serum albumin was investigated by FL and electronic spectroscopy. With the aid of the crystal structure of BSA, spectroscopic evidence suggested their binding at the cavity containing Trp134 with numerous Tyr residues in subdomain IA. The products were more antiproliferative than cisplatin against cancer cell lines HK-1, MCF-7, HCT116, HSC-2 and C666-1 except HL-60, and were selective towards nasopharyngeal cancer HK-1 cells over normal NP69 cells of the same organ type. © 2013 The Royal Society of Chemistry.

Von S.-T.,University Tunku Abdul Rahman | Seng H.-L.,University of Technology Malaysia | Lee H.-B.,Cancer Research Initiatives Foundation | Ng S.-W.,University of Malaya | And 3 more authors.
Journal of Biological Inorganic Chemistry | Year: 2012

Abstract By inhibiting only two or three of 12 restriction enzymes, the series of [M(phen)(edda)] complexes [M(II) is Cu, Co, Zn; phen is 1,10-phenanthroline; edda is N,N0-ethylenediaminediacetate] exhibit DNA binding specificity. The Cu(II) and Zn(II) complexes could differentiate the palindromic sequences 50-CATATG-30 and 50-GTATAC-30, whereas the Co(II) analogue could not. This and other differences in their biological properties may arise from distinct differences in their octahedral structures. The complexes could inhibit topoisomerase I, stabilize or destabilize G-quadruplex, and lower the mitochondrial membrane potential of MCF7 breast cells. The pronounced stabilization of G-quadruplex by the Zn(II) complex may account for the additional ability of only the Zn(II) complex to induce cell cycle arrest in S phase. On the basis of the known action of anticancer compounds against the above-mentioned individual targets, we suggest the mode of action of the present complexes could involve multiple targets. Cytotoxicity studies with MCF10A and cisplatin-resistant MCF7 suggest that these complexes exhibit selectivity towards breast cancer cells over normal ones. © SBIC 2011.

Chang S.,U.S. National Cancer Institute | Wang R.-H.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Akagi K.,Ohio State University | Kim K.-A.,U.S. National Cancer Institute | And 16 more authors.
Nature Medicine | Year: 2011

BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors. © 2011 Nature America, Inc. All rights reserved.

Lim K.P.,University of Bristol | Lim K.P.,Cancer Research Initiatives Foundation | Cirillo N.,University of Bristol | Hassona Y.,University of Bristol | And 6 more authors.
Journal of Pathology | Year: 2011

Oral cancer is a highly aggressive malignancy with poor prognosis. This study examined the behaviour of fibroblast strains from normal oral mucosa, dysplastic epithelial tissue, and genetically stable (minimal copy number alterations-CNA; minimal loss of heterozygosity-LOH; wild-type p53; wild-type p16INK4A) and unstable (extensive CNA and LOH; inactivation of p53 and p16INK4A) oral squamous cell carcinoma (OSCC). Fibroblasts from genetically unstable OSCC relative to the other fibroblast subtypes grew more slowly and stimulated the invasion of a non-tumourigenic keratinocyte cell line into fibroblast-rich collagen gels. To understand these findings, genome-wide transcriptional profiles were generated using the GeneChip® cDNA whole transcript microarray platform. Principal component analysis showed that the fibroblasts could be distinguished according to the stage of tumour development. Tumour progression was associated with down-regulation of cell cycle- and cytokinesis-related genes and up-regulation of genes encoding transmembrane proteins including cell adhesion molecules. Gene expression was validated in independent fibroblast strains using qRT-PCR. Gene connectivity and interactome-transcriptome associations were determined using a systems biology approach to interrogate the gene expression data. Clusters of gene signatures were identified that characterized genetically unstable and stable OSCCs relative to each other and to fibroblasts from normal oral mucosa. The expression of highly connected genes associated with unstable OSCCs, including those that encode α-SMA and the integrin α6, correlated with poor patient prognosis in an independent dataset of head and neck cancer. The results of this study demonstrate that fibroblasts from unstable OSCCs represent a phenotypically distinguishable subset that plays a major role in oral cancer biology. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Phuah S.-Y.,Cancer Research Initiatives Foundation | Looi L.-M.,University of Malaya | Hassan N.,Cancer Research Initiatives Foundation | Hassan N.,University of Malaya | And 7 more authors.
Breast Cancer Research | Year: 2012

Introduction: Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors.Methods: Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and included in a modified Manchester scoring method.Results: Our study in an Asian series of TNBC patients demonstrated that 27 (24.5%) of 110 patients have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110). We found that among women diagnosed with breast cancer aged 36 to 50 years but with no family history of breast or ovarian cancer, the prevalence of BRCA1 and BRCA2 mutations was similar in TNBC (8.5%) and non-TNBC patients (6.7%). By contrast, in women diagnosed with breast cancer, younger than 35 years, with no family history of these cancers, and in women with a family history of breast cancer, the prevalence of mutations was higher in TNBC compared with non-TNBC (28.0% and 9.9%; P = 0.045; and 42.1% and 14.2%; P < 0.0001, respectively]. Finally, we found that incorporation of estrogen-receptor and TNBC status improves the sensitivity of the Manchester Scoring method (42.9% to 64.3%), and furthermore, incorporation of PTEN status further improves sensitivity (42.9% to 85.7%).Conclusions: We found that TNBC is an important criterion for highlighting women who may benefit from genetic testing, but that this may be most useful for women with early-onset breast cancer (35 years or younger) or with a family history of cancers. Furthermore, addition of TNBC and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context, where risk-assessment models underestimate the number of mutation carriers. © 2012 Phuah et al.; licensee BioMed Central Ltd.

Tan P.J.,Cancer Research Initiatives Foundation | Appleton D.R.,University of Malaya | Appleton D.R.,University Putra Malaysia | Mustafa M.R.,University of Malaya | Lee H.B.,Cancer Research Initiatives Foundation
Phytochemical Analysis | Year: 2012

Introduction Photodynamic therapy is a treatment modality that involves site-directed generation of cytotoxic reactive oxygen species by light-activated photosensitisers. Objective In order to rapidly identify new photosensitisers from natural extracts, we developed a liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS) method to rapidly identify plant extracts that contain photosensitisers, particularly those possessing a cyclic tetrapyrrole structure. Method Six previously isolated compounds (1-6) were identified in bioactive fractions derived from 15 plant extracts on the basis of their chromatographic retention times, UV-visible profiles, accurate mass and fragmentation patterns. Results Samples containing uncommon photosensitisers were rapidly identified using this method, and subsequent scale-up isolation efforts led to two new compounds (7 and 8) which were confirmed to be active photosensitisers in a photo-cytotoxicity assay. Conclusion This method serves as a useful tool in prioritising samples that may contain new photosensitisers out of a larger group of photo-cytotoxic natural products extracts. © 2011 John Wiley & Sons, Ltd.

Lee D.S.C.,Cancer Research Initiatives Foundation | Yoon S.-Y.,Cancer Research Initiatives Foundation | Looi L.M.,University of Malaya | Kang P.,Cancer Research Initiatives Foundation | And 9 more authors.
Breast Cancer Research | Year: 2012

Introduction: Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing.Methods: A total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.Results: We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.Conclusions: Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers. © 2012 Lee et al.; licensee BioMed Central Ltd.

Yoon S.-Y.,Cancer Research Initiatives Foundation | Thong M.-K.,University of Malaya | Taib N.A.M.,University of Malaya | Yip C.-H.,University of Malaya | And 2 more authors.
Familial Cancer | Year: 2011

Genetic counseling (GC) and genetic testing are vital risk management strategies in hereditary breast and ovarian cancer (HBOC) syndromes. Hitherto, cancer genetic testing amongst Asians has been described only in developed and high-income Asian countries. We studied the uptake and acceptance of GC and genetic testing services to Asian BRCA carriers in a middle-income country. A total of 363 patients were tested by full sequencing and large rearrangement analysis of both BRCA1 and BRCA2 genes in the Malaysian Breast Cancer (MyBrCa) Genetic Study. Of these, 49 index patients (13.5%) were found to carry deleterious mutations. GC pre- and post- result disclosures were provided and these groups of patients and their families were studied. GC and genetic testing were accepted by 82% of Malaysian patients at high risk for HBOC syndromes. However, risk assessment was limited by large, geographically dispersed, often polygamous or polyandrous families, and the lack of complete cancer registry. Cultural taboos about cancer diagnoses, social marginalization and lack of regulatory control of genetic discrimination were significant concerns. Only 78% of index patients informed their families of their risks and 11% of relatives came forward when offered free counseling and testing. Even when GC and genetic testing are provided at no cost, there remain significant societal and regulatory barriers to effective cancer genetic services in this underserved Asian population. Families believe there is a need for regulatory protection against genetic discrimination. Further studies are needed in the area of increasing awareness about the potential benefits of GC and genetic testing in Asians. © 2011 Springer Science+Business Media B.V.

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