Displaying all 14 publications

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  1. Chin TF, Ibrahim K, Thirunavakarasu T, Azanan MS, Oh L, Lum SH, et al.
    Fetal Pediatr Pathol, 2018 Aug;37(4):243-253.
    PMID: 30273079 DOI: 10.1080/15513815.2018.1492054
    BACKGROUND: Survivors of childhood cancer are at risk of developing a second malignancy. One possible mechanism for neoplastic transformation of cells is through induction of persistent genomic instability. This study aims to seek evidence of chromosomal instability in long-term childhood leukemia survivors (CLS) in one of the largest pediatric academic oncology centers in South East Asia.

    METHODS: 50 asymptomatic (subjects have remained leukemia-free since treatment cessation) CLS and 50 healthy controls were recruited in this cross-sectional study. Of 50 CLS, 44 had acute lymphoblastic leukemia and 6 had acute myeloid leukemia. G-banded karyotyping was performed on unstimulated peripheral blood leukocytes of all subjects.

    RESULTS: CLS had significantly higher occurrence of karyotypic abnormalities compared to controls. Five CLS harbored six nonclonal abnormalities (mostly aneuploidy) while none were found in controls.

    CONCLUSION: Subpopulations with nonclonal chromosomal aberrations were present in peripheral blood leukocytes of our cohort of childhood leukemia long-term survivors.

    Matched MeSH terms: Genomic Instability/genetics*
  2. Alhaji SY, Ngai SC, Abdullah S
    Biotechnol Genet Eng Rev, 2019 Apr;35(1):1-25.
    PMID: 30514178 DOI: 10.1080/02648725.2018.1551594
    DNA methylation and histone modifications are vital in maintaining genomic stability and modulating cellular functions in mammalian cells. These two epigenetic modifications are the most common gene regulatory systems known to spatially control gene expression. Transgene silencing by these two mechanisms is a major challenge to achieving effective gene therapy for many genetic conditions. The implications of transgene silencing caused by epigenetic modifications have been extensively studied and reported in numerous gene delivery studies. This review highlights instances of transgene silencing by DNA methylation and histone modification with specific focus on the role of these two epigenetic effects on the repression of transgene expression in mammalian cells from integrative and non-integrative based gene delivery systems in the context of gene therapy. It also discusses the prospects of achieving an effective and sustained transgene expression for future gene therapy applications.
    Matched MeSH terms: Genomic Instability
  3. Langie SA, Koppen G, Desaulniers D, Al-Mulla F, Al-Temaimi R, Amedei A, et al.
    Carcinogenesis, 2015 Jun;36 Suppl 1:S61-88.
    PMID: 26106144 DOI: 10.1093/carcin/bgv031
    Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.
    Matched MeSH terms: Genomic Instability/drug effects*
  4. Salahshourifar I, Vincent-Chong VK, Chang HY, Ser HL, Ramanathan A, Kallarakkal TG, et al.
    Clin Oral Investig, 2015 Dec;19(9):2273-83.
    PMID: 25846277 DOI: 10.1007/s00784-015-1467-7
    OBJECTIVES: This study includes the direct sequencing of cornulin (CRNN) gene to elucidate the possible mechanism of CRNN downregulation and explore the genetic imbalances at 1q21.3 across oral squamous cell carcinoma (OSCC) samples.

    MATERIALS AND METHODS: In mutation screening of CRNN gene, gDNA from OSCC tissues were extracted, amplified, and followed by direct sequencing. OSCC samples were also subjected to fragment analysis on CRNN gene to investigate its microsatellite instability (MSI) and loss of heterozygosity (LOH). Immunohistochemistry was performed to validate CRNN downregulation in OSCC samples.

    RESULTS: No pathogenic mutation was found in CRNN gene, while high frequency of allelic imbalances was found at 1q21.3 region. MSI was found more frequent (25.3 %) than LOH (9.3 %). Approximately 22.6 % of cases had high MSI which reflects higher probability of inactivation of DNA mismatch repair genes. MSI showed significant association with no betel quid chewing (p = 0.003) and tongue subsite (p = 0.026). LOH was associated with ethnicity (p = 0.008) and advanced staging (p = 0.039). The LOH at 1q21.3 was identified to be as an independent prognostic marker in OSCC (HRR = 7.15 (95 % CI, 1.41-36.25), p = 0.018). Downregulation of CRNN was found among MSI-positive OSCCs and was associated with poor prognosis (p = 0.044).

    CONCLUSION: This study showed a significant correlation between LOH/MSI at 1q21.3 with clinical outcomes and that downregulation of CRNN gene could be considered as a prognostic marker of OSCC.

    CLINICAL RELEVANCE: Insights of the downregulation mode of CRNN gene lays the basis of drug development on this gene as well as revealing its prognostic value.

    Matched MeSH terms: Genomic Instability*
  5. Yong KW, Choi JR, Dolbashid AS, Wan Safwani WKZ
    Regen Med, 2018 03;13(2):219-232.
    PMID: 29509072 DOI: 10.2217/rme-2017-0078
    An outstanding amount of resources has been used in research on manipulation of human stem cells, especially mesenchymal stem cells (MSCs), for various clinical applications. However, human MSCs have not been fully utilized in clinical applications due to restrictions with regard to their certain biosafety and bioefficacy concerns, for example, genetic abnormality, tumor formation, induction of host immune response and failure of homing and engraftment. This review summarizes the biosafety and bioefficacy assessment of human MSCs in terms of genetic stability, tumorigenicity, immunogenicity, homing and engraftment. The strategies used to reduce the biosafety concerns and improve the bioefficacy of human MSCs are highlighted. In addition, the approaches that can be implemented to improve their biosafety and bioefficacy assessment are briefly discussed.
    Matched MeSH terms: Genomic Instability
  6. Nimmo IC, Barbrook AC, Lassadi I, Chen JE, Geisler K, Smith AG, et al.
    Elife, 2019 07 18;8.
    PMID: 31317866 DOI: 10.7554/eLife.45292
    Coral reefs are some of the most important and ecologically diverse marine environments. At the base of the reef ecosystem are dinoflagellate algae, which live symbiotically within coral cells. Efforts to understand the relationship between alga and coral have been greatly hampered by the lack of an appropriate dinoflagellate genetic transformation technology. By making use of the plasmid-like fragmented chloroplast genome, we have introduced novel genetic material into the dinoflagellate chloroplast genome. We have shown that the introduced genes are expressed and confer the expected phenotypes. Genetically modified cultures have been grown for 1 year with subculturing, maintaining the introduced genes and phenotypes. This indicates that cells continue to divide after transformation and that the transformation is stable. This is the first report of stable chloroplast transformation in dinoflagellate algae.
    Matched MeSH terms: Genomic Instability
  7. Liu C, Hirakawa H, Tanaka K, Mohd Saaya F, Nenoi M, Fujimori A, et al.
    Dose Response, 2019 03 04;17(1):1559325819833840.
    PMID: 30858771 DOI: 10.1177/1559325819833840
    Radiotherapy (RT) treats cancer effectively with high doses of ionizing radiation (IR) to killing cancer cells and shrinking tumors while bearing the risk of developing different side effects, including secondary cancer, which is most concerning for long-term health consequences. Genomic instability (GI) is a characteristic of most cancer cells, and IR-induced GI can manifest as delayed homologous recombination (HR). Radioadaptive response (RAR) is capable of reducing genotoxicity, cell transformation, mutation, and carcinogenesis, but the rational evidence describing its contributions to the reduction of radiation risk, in particular, carcinogenesis, remains fragmented. In this work, to investigate the impact of RAR on high-dose, IR-induced GI measured as delayed HR, the frequency of recombinant cells was comparatively studied under RAR-inducible and -uninducible conditions in the nucleated cells in hematopoietic tissues (bone marrow and spleen) using the Rosa26 Direct Repeat-green fluorescent protein (RaDR-GFP) homozygote mice. Results demonstrated that the frequency of recombinant cells was significantly lower in hematopoietic tissues under RAR-inducible condition. These findings suggest that reduction in delayed HR may be at least a part of the mechanisms underlying decreased carcinogenesis by RAR, and application of RAR would contribute to a more rigorous and scientifically grounded system of radiation protection in RT.
    Matched MeSH terms: Genomic Instability
  8. Ooi TC, Chan KM, Sharif R
    Nutr Cancer, 2017 Feb-Mar;69(2):201-210.
    PMID: 28094570 DOI: 10.1080/01635581.2017.1265132
    Cancer is one of the major causes of death worldwide, and the incidence and mortality rates of cancer are expected to rise tremendously in the near future. Despite a better understanding of cancer biology and advancement in cancer management, current strategies in cancer treatment remain costly and ineffective. Hence, instead of putting more efforts to search for new cancer cures, attention has now been shifted to the development of cancer chemopreventive agents as a preventive measure for cancer formation. It is well known that neoplastic transformation of cells is multifactorial, and the occurrence of oxidative stress, chronic inflammation, and genomic instability events has been implicated in the carcinogenesis of cells. Zinc l-carnosine (ZnC), which is clinically used as gastric ulcer treatment in Japan, has been suggested to have the potential in preventing cancer development. Multiple studies have revealed that ZnC possesses potent antioxidant, anti-inflammatory, and genomic stability enhancement effects. Thus, this review provides some mechanistic insight into the antioxidant, anti-inflammatory, and genomic stability enhancement effects of ZnC in relevance to its chemopreventive potential.
    Matched MeSH terms: Genomic Instability
  9. Dhakal S, Kushairi N, Phan CW, Adhikari B, Sabaratnam V, Macreadie I
    Int J Mol Sci, 2019 Oct 14;20(20).
    PMID: 31615073 DOI: 10.3390/ijms20205090
    Ageing is an inevitable fundamental process for people and is their greatest risk factor for neurodegenerative disease. The ageing processes bring changes in cells that can drive the organisms to experience loss of nutrient sensing, disrupted cellular functions, increased oxidative stress, loss of cellular homeostasis, genomic instability, accumulation of misfolded protein, impaired cellular defenses and telomere shortening. Perturbation of these vital cellular processes in neuronal cells can lead to life threatening neurological disorders like Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Lewy body dementia, etc. Alzheimer's Disease is the most frequent cause of deaths in the elderly population. Various therapeutic molecules have been designed to overcome the social, economic and health care burden caused by Alzheimer's Disease. Almost all the chemical compounds in clinical practice have been found to treat symptoms only limiting them to palliative care. The reason behind such imperfect drugs may result from the inefficiencies of the current drugs to target the cause of the disease. Here, we review the potential role of antioxidant polyphenolic compounds that could possibly be the most effective preventative strategy against Alzheimer's Disease.
    Matched MeSH terms: Genomic Instability
  10. Sharif R, Thomas P, Zalewski P, Fenech M
    Mol Nutr Food Res, 2015 Jun;59(6):1200-12.
    PMID: 25755079 DOI: 10.1002/mnfr.201400784
    An increased intake of Zinc (Zn) may reduce the risk of degenerative diseases but may prove to be toxic if taken in excess. This study aimed to investigate whether zinc carnosine supplement can improve Zn status, genome stability events, and Zn transporter gene expression in an elderly (65-85 years) South Australian cohort with low plasma Zn levels.
    Matched MeSH terms: Genomic Instability/drug effects*
  11. Wen WX, Leong CO
    PLoS One, 2019;14(4):e0215381.
    PMID: 31022191 DOI: 10.1371/journal.pone.0215381
    Immune checkpoint inhibitors have demonstrated effective anti-tumour response in cancer types with high mutation burden (e.g. melanoma) and in subset of cancers with features of genomic instability (e.g. mismatch-repair deficiency). One possible explanation for this effect is the increased expression of immune checkpoint molecules and pre-existing adaptive immune response in these cancers. Given that BRCA1 and BRCA2 are integral in maintaining genomic integrity, we hypothesise that the inactivation of these genes may give rise to breast cancers with such immunogenic phenotype. Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability, expression of PD-L1 and PD-1, landscape of inferred tumour-infiltrating immune cells, and T-cell inflamed signature in breast cancers. Here, we report that BRCA1 and BRCA2-deficient breast cancers were associated with features of genomic instability including increased mutation burden. Interestingly, BRCA1-, but not BRCA2-, deficient breast cancers were associated with increased expression of PD-L1 and PD-1, higher abundance of tumour-infiltrating immune cells, and enrichment of T cell-inflamed signature. The differences in immunophenotype between BRCA1- and BRCA2-deficient breast cancers can be attributed, in part, to PTEN gene mutation. Therefore, features of genomic instability such as that mediated by BRCA1- and BRCA2- deficiency in breast cancer were necessary, but not always sufficient, for yielding T cell-inflamed tumour microenvironment, and by extension, predicting clinical benefit from immunotherapy.
    Matched MeSH terms: Genomic Instability/immunology
  12. Haque N, Rahman MT, Abu Kasim NH, Alabsi AM
    ScientificWorldJournal, 2013;2013:632972.
    PMID: 24068884 DOI: 10.1155/2013/632972
    Cell-based regenerative therapies, based on in vitro propagation of stem cells, offer tremendous hope to many individuals suffering from degenerative diseases that were previously deemed untreatable. Due to the self-renewal capacity, multilineage potential, and immunosuppressive property, mesenchymal stem cells (MSCs) are considered as an attractive source of stem cells for regenerative therapies. However, poor growth kinetics, early senescence, and genetic instability during in vitro expansion and poor engraftment after transplantation are considered to be among the major disadvantages of MSC-based regenerative therapies. A number of complex inter- and intracellular interactive signaling systems control growth, multiplication, and differentiation of MSCs in their niche. Common laboratory conditions for stem cell culture involve ambient O₂ concentration (20%) in contrast to their niche where they usually reside in 2-9% O₂. Notably, O₂ plays an important role in maintaining stem cell fate in terms of proliferation and differentiation, by regulating hypoxia-inducible factor-1 (HIF-1) mediated expression of different genes. This paper aims to describe and compare the role of normoxia (20% O₂) and hypoxia (2-9% O₂) on the biology of MSCs. Finally it is concluded that a hypoxic environment can greatly improve growth kinetics, genetic stability, and expression of chemokine receptors during in vitro expansion and eventually can increase efficiency of MSC-based regenerative therapies.
    Matched MeSH terms: Genomic Instability
  13. Ohba K, Ichiyama K, Yajima M, Gemma N, Nikaido M, Wu Q, et al.
    PLoS One, 2014;9(5):e97787.
    PMID: 24858917 DOI: 10.1371/journal.pone.0097787
    High prevalence of infection with high-risk human papilloma virus (HPV) ranging from 25 to 100% (average 31%) was observed in breast cancer (BC) patients in Singapore using novel DNA chip technology. Early stage of BC demonstrated higher HPV positivity, and BC positive for estrogen receptor (ER) showed significantly higher HPV infection rate. This unique association of HPV with BC in vivo prompted us to investigate a possible involvement of HPV in early stages of breast carcinogenesis. Using normal breast epithelial cells stably transfected with HPV-18, we showed apparent upregulation of mRNA for the cytidine deaminase, APOBEC3B (A3B) which is reported to be a source of mutations in BC. HPV-induced A3B overexpression caused significant γH2AX focus formation, and DNA breaks which were cancelled by shRNA to HPV18 E6, E7 and A3B. These results strongly suggest an active involvement of HPV in the early stage of BC carcinogenesis via A3B induction.
    Matched MeSH terms: Genomic Instability
  14. Goh KM, Gan HM, Chan KG, Chan GF, Shahar S, Chong CS, et al.
    PLoS One, 2014;9(6):e90549.
    PMID: 24603481 DOI: 10.1371/journal.pone.0090549
    Species of Anoxybacillus are widespread in geothermal springs, manure, and milk-processing plants. The genus is composed of 22 species and two subspecies, but the relationship between its lifestyle and genome is little understood. In this study, two high-quality draft genomes were generated from Anoxybacillus spp. SK3-4 and DT3-1, isolated from Malaysian hot springs. De novo assembly and annotation were performed, followed by comparative genome analysis with the complete genome of Anoxybacillus flavithermus WK1 and two additional draft genomes, of A. flavithermus TNO-09.006 and A. kamchatkensis G10. The genomes of Anoxybacillus spp. are among the smaller of the family Bacillaceae. Despite having smaller genomes, their essential genes related to lifestyle adaptations at elevated temperature, extreme pH, and protection against ultraviolet are complete. Due to the presence of various competence proteins, Anoxybacillus spp. SK3-4 and DT3-1 are able to take up foreign DNA fragments, and some of these transferred genes are important for the survival of the cells. The analysis of intact putative prophage genomes shows that they are highly diversified. Based on the genome analysis using SEED, many of the annotated sequences are involved in carbohydrate metabolism. The presence of glycosyl hydrolases among the Anoxybacillus spp. was compared, and the potential applications of these unexplored enzymes are suggested here. This is the first study that compares Anoxybacillus genomes from the aspect of lifestyle adaptations, the capacity for horizontal gene transfer, and carbohydrate metabolism.
    Matched MeSH terms: Genomic Instability
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