Displaying publications 1 - 20 of 166 in total

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  1. Japanese encephalitis virus disrupts blood-brain barrier and modulates apoptosis proteins in THBMEC cells
    Al-Obaidi MMJ, Bahadoran A, Har LS, Mui WS, Rajarajeswaran J, Zandi K, et al.
    Virus Res, 2017 04 02;233:17-28.
    PMID: 28279803 DOI: 10.1016/j.virusres.2017.02.012
    Japanese encephalitis (JE) is a neurotropic flavivirus that causes inflammation in central nervous system (CNS), neuronal death and also compromises the structural and functional integrity of the blood-brain barrier (BBB). The aim of this study was to evaluate the BBB disruption and apoptotic process in Japanese encephalitis virus (JEV)-infected transfected human brain microvascular endothelial cells (THBMECs). THBMECs were overlaid by JEV with different MOIs (0.5, 1.0, 5.0 and 10.0) and monitored by electrical cell-substrate impedance sensing (ECIS) in a real-time manner in order to observe the barrier function of THBMECs. Additionally, the level of 43 apoptotic proteins was quantified in the virally infected cells with different MOIs at 24h post infection. Infection of THBMEC with JEV induced an acute reduction in transendothelial electrical resistance (TEER) after viral infection. Also, significant up-regulation of Bax, BID, Fas and Fasl and down-regulation of IGFBP-2, BID, p27 and p53 were observed in JEV infected THBMECs with 0.5 and 10 MOIs compared to uninfected cells. Hence, the permeability of THBMECs is compromised during the JEV infection. In addition high viral load of the virus has the potential to subvert the host cell apoptosis to optimize the course of viral infection through deactivation of pro-apoptotic proteins.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism
  2. Combined extract of Moringa oleifera and Centella asiatica modulates oxidative stress and senescence in hydrogen peroxide-induced human dermal fibroblasts
    Abdul Hisam EE, Rofiee MS, Khalid AM, Jalaluddin AF, Mohamad Yusof MI, Idris MH, et al.
    Turk J Biol, 2018;42(1):33-44.
    PMID: 30814868 DOI: 10.3906/biy-1708-23
    Moringa oleifera Lam. and Centella asiatica (L.) Urb. leaves have been previously reported to exhibit antioxidant activity. The objective of the present study is to determine the in vitro antioxidant activity of the combined extracts of M. oleifera and C. asiatica (TGT-PRIMAAGE) and its effect on hydrogen peroxide (H 2O2)-induced oxidative stress in human dermal fibroblasts. TGTPRIMAAGE acted on the mechanism of hydrogen transfer as it showed scavenging activity in the DPPH assay. This is due to the presence of phenolics and flavonoids in TGT-PRIMAAGE. TGT-PRIMAAGE effectively reduced cellular generation of reactive oxygen species induced by H O2. The activities of superoxide dismutase and catalase were also increased in cells treated with TGT-PRIMAAGE. 2 Treatment with TGT-PRIMAAGE showed significant reduction (P < 0.05) in the number of senescent cells. Significant reduction (P < 0.05) of malondialdehyde was also seen in cells treated with TGT-PRIMAAGE. The p53 protein level was reduced in TGT-PRIMAAGEtreated cells, which indicates its potential in protecting the cells from oxidative stress induced by H2O2.
    Matched MeSH terms: Tumor Suppressor Protein p53
  3. Fulltext Emerging Pathogenic and Prognostic Significance of Paired Box 3 (PAX3) Protein in Adult Gliomas
    Angelopoulou E, Paudel YN, Piperi C
    Transl Oncol, 2019 Jul 25;12(10):1357-1363.
    PMID: 31352198 DOI: 10.1016/j.tranon.2019.07.001
    Gliomas present the most common type of brain tumors in adults, characterized by high morbidity and mortality. In search of potential molecular targets, members of paired box (PAX) family have been found expressed in neural crest cells, regulating their proliferation, apoptosis, migration and differentiation. Recently, PAX3 overexpression has been implicated in glioma tumorigenesis by enhancing proliferation, increasing invasiveness and inducing resistance to apoptosis of glioma cells, while maintaining brain glioma stem cells (BGSCs) stemness. Although the oncogenic potential of PAX3 in gliomas is still under investigation, experimental evidence suggests that PAX3 function is mainly mediated through the canonical and non-canonical Wnt signaling pathway as well as through its interaction with GFAP and p53 proteins. In addition, PAX3 may contribute to the chemoresistance of glioma cells and modulates the effectiveness of novel experimental therapies. Further evidence indicates that PAX3 may represent a novel diagnostic and prognostic biomarker for gliomas, facilitating personalized treatment. This review addresses the emerging role of PAX3 in glioma diagnosis, prognosis and treatment, aiming to shed more light on the underlying molecular mechanisms that could lead to more effective treatment approaches.
    Matched MeSH terms: Tumor Suppressor Protein p53
  4. In vitro genotoxicity tests for polyhydroxybutyrate--a synthetic biomaterial
    Ali AQ, Kannan TP, Ahmad A, Samsudin AR
    Toxicol In Vitro, 2008 Feb;22(1):57-67.
    PMID: 17892925
    The aims of this study are to determine the mutagenicity of a locally produced polyhydroxybutyrate (PHB) using Salmonella mutagenicity test and to find out if PHB altered the expression of p53 and c-myc proto-oncogenes and bcl-xl and bcl-xs anti-apoptotic genes in the human fibroblast cell line, MRC-5. Different concentrations of PHB were incubated with special genotypic variants of Salmonella strains (TA1535, TA1537, TA1538, TA98 and TA100) carrying mutations in several genes both with and without metabolic activation (S9) and the test was assessed based on the number of revertant colonies. The average number of revertant colonies per plate treated with PHB was less than double as compared to that of negative control. For the gene expression analyses, fibroblast cell lines were treated with PHB at different concentrations and incubated for 1, 12, 24 and 48 h separately. The total RNA was isolated and analysed for the expression of p53, c-myc, bcl-xl and bcl-xs genes. The PHB did not show over or under expression of the genes studied. The above tests indicate that the locally produced PHB is non-genotoxic and does not alter the expression of the proto-oncogenes and anti-apoptotic genes considered in this study.
    Matched MeSH terms: Tumor Suppressor Protein p53/drug effects; Tumor Suppressor Protein p53/genetics
  5. Fulltext Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway
    Chan KM, Rajab NF, Siegel D, Din LB, Ross D, Inayat-Hussain SH
    Toxicol. Sci., 2010 Aug;116(2):533-48.
    PMID: 20498002 DOI: 10.1093/toxsci/kfq151
    Goniothalamin (GN), a styryl-lactone isolated from Goniothalamus andersonii, has been demonstrated to possess antirestenostic properties by inducing apoptosis on coronary artery smooth muscle cells (CASMCs). In this study, the molecular mechanisms of GN-induced CASMCs apoptosis were further elucidated. Apoptosis assessment based on the externalization of phosphatidylserine demonstrated that GN induces CASMCs apoptosis in a concentration-dependent manner. The GN-induced DNA damage occurred with concomitant elevation of p53 as early as 2 h, demonstrating an upstream signal for apoptosis. However, the p53 elevation in GN-treated CASMCs was independent of NAD(P)H: quinone oxidoreductase 1 and Mdm-2 expression. An increase in hydrogen peroxide and reduction in free thiols confirmed the role for oxidative stress in GN treatment. Pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK) that significantly abrogated GN-induced CASMCs apoptosis suggested the involvement of caspase(s). The role of apical caspase-2, -8, and -9 was then investigated, and sequential activation of caspase-2 and -9 but not caspase-8 leading to downstream caspase-3 cleavage was observed in GN-treated CASMCs. Reduction of ATP level and decrease in oxygen consumption further confirmed the role of mitochondria in GN-induced apoptosis in CASMCs. The mitochondrial release of cytochrome c was seen without mitochondrial membrane potential loss and was independent of cardiolipin. These data provide insight into the mechanisms of GN-induced apoptosis, which may have important implications in the development of drug-eluting stents.
    Matched MeSH terms: Tumor Suppressor Protein p53/physiology*
  6. Correlations in survivin expression with the expression of p53 and bcl-2 in invasive ductal carcinoma of the breast
    Al-Joudi FS, Iskandar ZA, Imran AK
    Southeast Asian J. Trop. Med. Public Health, 2007 Sep;38(5):904-10.
    PMID: 18041310
    This work studied the correlations between survivin, bcl-2 and p53 in infiltrating ductal carcinoma of the breast. A total number of 382 cases were collected from 3 hospitals in northeastern Malaysia. Survivin, bcl-2 and p53 were detected by immunohistochemistry on samples prepared from tissue blocks. Significant correlations were found between tumor histological grades and tumor size and lymph node involvement. Highly significant statistical correlations (p<0.001) were found in expression of the markers under study. It is concluded that such significant correlations may imply that the alterations in the expression take place in a concerted fashion, implying that many of these cases may share common abnormalities.
    Matched MeSH terms: Tumor Suppressor Protein p53/biosynthesis*; Tumor Suppressor Protein p53/genetics
  7. Fulltext The relationship of p53 protein in meninigioma grading and their various influencing factors amongst neurosurgical patients in Hospital Kuala Lumpur
    Kantha R, Saffari HM, Suryati MY
    Med J Malaysia, 2007 Aug;62(3):194-6.
    PMID: 18246905 MyJurnal
    Meningioma, is the second most frequent intracranial tumor in Malaysia and are classified according to the World Health Organization classification. The relationship of p53 protein in the determination of meningioma grading and their influencing factors were studied via immunohistochemistry studies on 77 intracranial meningiomas (67 benign, 10 atypical). The higher the p53 reaction was correlated to the poorer the histological grade (19.4% in benign and 90% in atypical meningioma) (p < 0.001). Other variables like age, sex, ethnicity, demographic location, surgical clearance, midline shift and contrast enhancement of CT Scan Brain and clinical features were found not to be significant.
    Matched MeSH terms: Tumor Suppressor Protein p53*
  8. Fulltext P53 expression in colorectal carcinoma: the University of Malaya Medical Centre's experience
    Goh KSK, Ong TA, Peh SC, Yuen HL, Naicker M
    Med J Malaysia, 2004 Oct;59(4):515-21.
    PMID: 15779585
    Loss of P53 function is regarded as one of the critical steps in colorectal carcinogenesis. This study determines the P53 expression pattern of colorectal carcinoma in a cohort of 116 local patients. There was no significant relationship between overexpression of P53 with tumour stage (p=-0.209, chi square test) and grade (p=0.877, chi square test). Survival analysis using Kaplan-Meier procedure did not show significant relationship between P53 positivity with overall recurrence-free and survival outcome (p=0.3322 and 0.921 respectively; log rank test). Long-term follow-up may give a better evaluation on the prognostic value of P53 overexpression in colorectal carcinoma.
    Matched MeSH terms: Tumor Suppressor Protein p53/analysis*
  9. Fulltext P53 expression in invasive pancreatic adenocarcinoma and precursor lesions
    Norfadzilah MY, Pailoor J, Retneswari M, Chinna K, Noor LM
    Malays J Pathol, 2011 Dec;33(2):89-94.
    PMID: 22299208 MyJurnal
    Patients with pancreatic adenocarcinoma are known to have a high mortality rate. The 5-year survival rate still remains low even now compared to that of the 1960's despite new advances in management including surgery, chemotherapy, pathological classification and molecular diagnostic technologies. Precursors to invasive pancreatic adenocarcinoma have been identified in the last ten years that include mucinous cystic neoplasm, intraductal papillary mucinous neoplasm and pancreatic intraepithelial neoplasia. p53 protein accumulation in the nuclei is a common molecular event in most human neoplasms. Our objective is to investigate p53 expression in pancreatic adenocarcinoma and precursor lesions and their significance. The selected study material encompassed 31 invasive ductal adenocarcinoma, 15 mucinous cystic neoplasm and papillary mucinous neoplasm, and 27 cases of pancreatic intraepithelial neoplasia including grade 1, 2 and 3. Immunoscore was given for each case based on intensity of staining and percentage of cells positive and compared between precursor lesions and invasive adenocarcinoma. A score of 50 and above was considered significant. The results showed that p53 expression increased progressively and significantly with the grade of pancreatic intraepithelial neoplasia and adenocarcinoma (p-value < 0.001). These findings support the concept of multistep carcinogenesis in pancreatic adenocarcinoma and suggest that p53 inactivation occurs in the progression of precursors to pancreatic adenocarcinoma.
    Matched MeSH terms: Tumor Suppressor Protein p53/biosynthesis*
  10. Fulltext p53 and p21/WAF-1 overexpressions in prostatic adenocarcinoma
    Wan Muhaizan WM, Ahmad PK, Phang KS, Arni T
    Malays J Pathol, 2006 Dec;28(2):93-9.
    PMID: 18376798 MyJurnal
    This study was carried out to determine the role of p53 and p21 in the pathogenesis of prostatic adenocarcinoma and their association with tumour grade.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  11. Fulltext Mutational analysis of p53 and RB2/p130 genes in Malaysian nasopharyngeal carcinoma samples: a preliminary report
    Hoe SL, Sam CK
    Malays J Pathol, 2006 Jun;28(1):35-9.
    PMID: 17694957 MyJurnal
    This study reports the results of mutation detection of tumour suppressor genes, p53 and RB2/p130 genes in Malaysian nasopharyngeal carcinoma (NPC) studied by PCR-CSGE analysis and direct DNA sequencing method. Frequent sites of mutation in both genes (exons 5-8 of p53 and exons 19-21 of RB2/p130) were examined. Thirty-six NPC blood samples and three NPC cell lines were investigated for the presence of mutations. No mutation of p53 and RB2/p130 genes was identified in any of the blood samples. Nonetheless, there was an identical G-->4 C nucleotide change at codon 280 of p53 gene in all the cell lines. A larger study that includes biopsy tissues should be carried out to provide a more in-depth look into the pathogenesis of NPC in Malaysia.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics*
  12. RET and p53 expression in thyroid follicular adenoma: a study of 52 cases with 14 years follow-up
    Othman NH, Omar E, Mahmood MH, Madhavan M
    Malays J Pathol, 2005 Dec;27(2):91-8.
    PMID: 17191391
    Most previous studies on RET and p53 proteins have focused on thyroid papillary carcinoma. We investigated the role of RET and p53 protein expressions using immunohistochemistry on 52 cases of thyroid follicular adenomas and studied the follow-up records of these patients. The range of follow-up period was 3 to 14 years. The patients were between 15 and 71 years of age with a median age of 34.5 years. There were 46 females and 6 males. Except for 3 cases, all patients were Malays. The minimum volume of the tumour was 1000 mm3 and the maximum was 512,000 mm3 with a median of 270,000 mm3. Eleven (21.2%) cases showed RET expression. RET expression was not statistically significant when cross-tabulated against sex (p = 0.322), ethnicity (p = 0.518), age (p = 0.466) and symptom duration (p = 0.144). Six (11.5%) of 52 cases showed p53 immunopositivity. p53 expressions were also not significantly correlated to the clinical parameters above. There was no correlation between RET and p53 protein expressions. The only statistically significant finding was the association of tumour volume with duration of symptoms (p = 0.05). All patients are alive at the time of writing. 3 had recurrent goitre, 2 of these were diagnosed as colloid goitre while the third was a follicular lesion. One patient suffered from depression requiring anti-depressant treatment. In conclusion, unlike papillary carcinoma in which the roles of ret and p53 oncogenes are known, their roles in influencing the behaviour of follicular adenoma has not been ascertained.
    Matched MeSH terms: Tumor Suppressor Protein p53/biosynthesis*
  13. Fulltext p53: an overview of over two decades of study
    Cheah PL, Looi LM
    Malays J Pathol, 2001 Jun;23(1):9-16.
    PMID: 16329542
    p53 is the most commonly mutated gene in human cancers. It encodes a 53 kilodalton protein with several evolutionarily conserved domains viz sequence-specific DNA binding, tetramerisation, SH3 molecule binding, C-terminal and N-terminal. Existing in the cell at a very low level and in a relatively inactive form, p53 protein is increased and activated during periods of cellular stress. Unlike other proteins, the increase in protein level and its activation result from modification of the protein rather than genetic transcriptional or translational upregulation. Normally, Mdm2 protein interacts with p53 protein and effectively targets it for ubiquitin proteolysis within an autoregulatory feedback loop. Phosphorylation at the N-terminus reduces p53 interaction with Mdm2 with a resultant increase in p53 protein level. Modification at the C and N termini via phosphorylation or acetylation upregulates binding to specific DNA targets increasing transcription of these downstream genes. The net effect of p53 protein increase and activation lies in arrest of the cell in cycle which allows time for repair of the incurred damage or apoptosis or death of the cell. Failure of these normal protective and adaptive mechanisms caused by mutation of the p53 gene with product of an abnormal protein, loss of p53 protein through interaction with and degradation by HPV E6 protein or overexpressed Mdm2 etc. permits DNA-damaged cells to continue replicating. Left unchecked, this frequently contributes to tumourigenesis. Various methods have been devised to screen for mutations of the p53 gene, still the most common source of failed p53 mechanism. These include immunohistochemical detection of mutated proteins or identification of altered electrophoretic mobility of mutated p53 sequences. Sequencing of the gene nonetheless remains the most accurate method for determination of mutation. Major advances have been made in p53 research but the most meaningful probably lies in the promising results achieved in tumour therapy where introduction of wild type p53 gene has resulted in regression of non-small-cell lung cancer (NSCLC). Many other notable developments in this field include description of p53 homologues, "gain of function" mutants, p53 polymorphisms, angiogenesis-inhibiting properties of wild type p53 protein etc.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics*; Tumor Suppressor Protein p53/metabolism
  14. The correlation of EMT and p53 immunohistochemical markers with cisplatin resistance in muscle invasive bladder cancer patients: A single-centred study
    Paramanantham Y, B M Said NA, Mun KS
    Malays J Pathol, 2023 Apr;45(1):19-29.
    PMID: 37119243
    INTRODUCTION: Although epithelial-mesenchymal transition (EMT) and p53 have been established to play a pivotal role in the aggressiveness of muscle-invasive bladder cancer (MIBC), its pathological correlation to cisplatin treatment in the Malaysian patient cohort is lacking. This study aimed to evaluate the association of EMT markers, e-cadherin, vimentin and actin, as well as tumour suppressor gene, p53, in cisplatin-receiving MIBC patients.

    MATERIALS AND METHODS: Formalin-fixed paraffinembedded (FFPE) blocks of muscle-invasive bladder cancer patients receiving cisplatin-based chemotherapy between January 2010 to December 2020 were traced. Immunohistochemistry staining was performed on traced blocks using antibodies to e-cadherin, vimentin and actin, and p53.

    RESULTS: p53 and e-cadherin were stained positive in most cases (p=0.515 and 0.242 respectively), although e-cadherin showed stronger positive expression in pre-cisplatin receiving MIBC cases. All the cases stained negative for actin and vimentin except for faint staining observed in one pre-cisplatin case.

    CONCLUSION: Although this study does not show a significant correlation between EMT markers and p53 with cisplatin-responsiveness in MIBC patients, the results serve as preliminary findings on the heterogeneous outcomes of molecular staining in the Malaysian MIBC patient cohort.

    Matched MeSH terms: Tumor Suppressor Protein p53/therapeutic use
  15. Fulltext What We Know about the Molecular Genetics of Central Nervous System (CNS) Tumours in Malaysia
    Sulong S, Yusoff AA, Zainuddin N, Abdullah JM, Pannatil JG, Jaafar H, et al.
    Malays J Med Sci, 2004 Jan;11(1):37-43.
    PMID: 22977358 MyJurnal
    The new millennium has been regarded as a genomic era. A lot of researchers and pathologists are beginning to understand the scientific basis of molecular genetics and relates with the progression of the diseases. Central nervous system (CNS) tumours are among the most rapidly fatal of all cancers. It has been proposed that the progression of malignant tumours may result from multi-step of genetic alterations, including activation of oncogenes, inactivation of tumour suppressor genes and also the presence of certain molecular marker such as telomerase activity. In this paper, we review some recent data from the literature, including our own studies, on the molecular genetics analysis in CNS tumours. Our studies have shown that two types of tumour suppressor genes, p53 and PTEN were involved in the development of these tumours but not in p16 gene among the patients from Hospital Universiti Sains Malaysia (HUSM). Telomerase activity also has been detected in various types of CNS tumours. Thus, it is important to assemble all data which related to this study and may provide as a vital information in a new approach to neuro-oncology studies in Malaysia.
    Matched MeSH terms: Tumor Suppressor Protein p53
  16. Human Papillomavirus Infection, p16INK4a Expression and Genetic Alterations in Vietnamese Cervical Neuroendocrine Cancer
    Van Ta T, Nguyen QN, Truong VL, Tran TT, Nguyen HP, Vuong LD
    Malays J Med Sci, 2019 Sep;26(5):151-157.
    PMID: 31728128 DOI: 10.21315/mjms2019.26.5.15
    Neuroendocrine cervical cancer is a rare subtype of cervical cancer with a highly aggressive malignancy. This study was conducted to analyse the human papillomavirus (HPV) infection and molecular abnormalities in Vietnamese neuroendocrine carcinomas of the uterine cervix. HPV genotyping and p53 mutations were examined using polymerase chain reaction (PCR)-based direct sequencing. Mutations of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and v-Raf murine sarcoma viral oncogene homolog B (BRAF) were identified using commercial kits. Four high-risk HPV genotypes were identified in 26 (86.7%) out of a total of 30 tumours. The prevalence of HPV 16, 18, 31 and 45 was 20.0%, 50.0%, 20.0% and 36.7%, respectively. Overexpression of p16INK4a was observed in 93.3% of cases and was significantly correlated with high-risk HPV infections. Furthermore, p53 and NRAS mutations were detected in five (16.7%) and one (3.3%) cases, respectively, whereas no EGFR, KRAS or BRAF mutations were observed. These results demonstrate that high-risk HPV infection may be an important oncogenic factor for the development and progression of cervical neuroendocrine carcinoma.
    Matched MeSH terms: Tumor Suppressor Protein p53
  17. Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications
    McCart Reed AE, Kalaw E, Nones K, Bettington M, Lim M, Bennett J, et al.
    J Pathol, 2019 02;247(2):214-227.
    PMID: 30350370 DOI: 10.1002/path.5184
    Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics
  18. Practical Considerations for Using RNA Sequencing in Management of B-Lymphoblastic Leukemia: Malaysia-Singapore Acute Lymphoblastic Leukemia 2020 Implementation Strategy
    Ni Chin WH, Li Z, Jiang N, Lim EH, Suang Lim JY, Lu Y, et al.
    J Mol Diagn, 2021 10;23(10):1359-1372.
    PMID: 34365011 DOI: 10.1016/j.jmoldx.2021.07.013
    Despite the immense genetic heterogeneity of B-lymphoblastic leukemia [or precursor B-cell acute lymphoblastic leukemia (B-ALL)], RNA sequencing (RNA-Seq) could comprehensively interrogate its genetic drivers, assigning a specific molecular subtype in >90% of patients. However, study groups have only started to use RNA-Seq. For broader clinical use, technical, quality control, and appropriate performance validation are needed. We describe the development and validation of an RNA-Seq workflow for subtype classification, TPMT/NUDT15/TP53 variant discovery, and immunoglobulin heavy chain (IGH) disease clone identification for Malaysia-Singapore acute lymphoblastic leukemia (ALL) 2020. We validated this workflow in 377 patients in our preceding Malaysia-Singapore ALL 2003/Malaysia-Singapore ALL 2010 studies and proposed the quality control measures for RNA quality, library size, sequencing, and data analysis using the International Organization for Standardization 15189 quality and competence standard for medical laboratories. Compared with conventional methods, we achieved >95% accuracy in oncogene fusion identification, digital karyotyping, and TPMT and NUDT15 variant discovery. We found seven pathogenic TP53 mutations, confirmed with Sanger sequencing, which conferred a poorer outcome. Applying this workflow prospectively to the first 21 patients in Malaysia-Singapore ALL 2020, we identified the genetic drivers and IGH disease clones in >90% of patients with concordant TPMT, NUDT15, and TP53 variants using PCR-based methods. The median turnaround time was 12 days, which was clinically actionable. In conclusion, RNA-Seq workflow could be used clinically in management of B-cell ALL patients.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics*
  19. Fulltext Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53
    Abd-Aziz N, Stanbridge EJ, Shafee N
    J Gen Virol, 2016 Dec;97(12):3174-3182.
    PMID: 27902314 DOI: 10.1099/jgv.0.000623
    Newcastle disease virus (NDV) is a candidate agent for oncolytic virotherapy. Despite its potential, the exact mechanism of its oncolysis is still not known. Recently, we reported that NDV exhibited an increased oncolytic activity in hypoxic cancer cells. These types of cells negatively affect therapeutic outcome by overexpressing pro-survival genes under the control of the hypoxia-inducible factor (HIF). HIF-1 is a heterodimeric transcriptional factor consisting of a regulated α (HIF-1α) and a constitutive β subunit (HIF-1β). To investigate the effects of NDV infection on HIF-1α in cancer cells, the osteosarcoma (Saos-2), breast carcinoma (MCF-7), colon carcinoma (HCT116) and fibrosarcoma (HT1080) cell lines were used in the present study. Data obtained showed that a velogenic NDV infection diminished hypoxia-induced HIF-1α accumulation, leading to a decreased activation of its downstream target gene, carbonic anhydrase 9. This NDV-induced downregulation of HIF-1α occurred post-translationally and was partially abrogated by proteasomal inhibition. The process appeared to be independent of the tumour suppressor protein p53. These data revealed a correlation between NDV infection and HIF-1α downregulation, which highlights NDV as a promising agent to eliminate hypoxic cancer cells.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism*
  20. Bursal transcriptome profiling of different inbred chicken lines reveals key differentially expressed genes at 3 days post-infection with very virulent infectious bursal disease virus
    Farhanah MI, Yasmin AR, Mat Isa N, Hair-Bejo M, Ideris A, Powers C, et al.
    J Gen Virol, 2018 Jan;99(1):21-35.
    PMID: 29058656 DOI: 10.1099/jgv.0.000956
    Infectious bursal disease is a highly contagious disease in the poultry industry and causes immunosuppression in chickens. Genome-wide regulations of immune response genes of inbred chickens with different genetic backgrounds, following very virulent infectious bursal disease virus (vvIBDV) infection are poorly characterized. Therefore, this study aims to analyse the bursal tissue transcriptome of six inbred chicken lines 6, 7, 15, N, O and P following infection with vvIBDV strain UK661 using strand-specific next-generation sequencing, by highlighting important genes and pathways involved in the infected chicken during peak infection at 3 days post-infection. All infected chickens succumbed to the infection without major variations among the different lines. However, based on the viral loads and bursal lesion scoring, lines P and 6 can be considered as the most susceptible lines, while lines 15 and N were regarded as the least affected lines. Transcriptome profiling of the bursa identified 4588 genes to be differentially expressed, with 2985 upregulated and 1642 downregulated genes, in which these genes were commonly or uniquely detected in all or several infected lines. Genes that were upregulated are primarily pro-inflammatory cytokines, chemokines and IFN-related. Various genes that are associated with B-cell functions and genes related to apoptosis were downregulated, together with the genes involved in p53 signalling. In conclusion, bursal transcriptome profiles of different inbred lines showed differential expressions of pro-inflammatory cytokines and chemokines, Th1 cytokines, JAK-STAT signalling genes, MAPK signalling genes, and their related pathways following vvIBDV infection.
    Matched MeSH terms: Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/immunology
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