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Biomedical subjects

Y L Kwong

Publications and source records attributed to Y L Kwong.

At least 19 recordsLinked to original sources
PubMed2006

Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells.

Epstein-Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC) and can be detected in early premalignant lesions of nasopharyngeal epithelium. The latent membrane protein 1 (LMP1) is an oncoprotein encoded by the EBV and is believed to play a role in transforming premalignant nasopharyngeal epithelial cells into cancer cells. RASSF1A is a tumor-suppressor gene commonly inactivated in many types of human cancer including NPC. In this study, we report a novel function of LMP1, in down-regulating RASSF1A expression in human epithelial cells. Downregulation of RASSF1A expression by LMP1 is dependent on the activation of intracellular signaling of NF-kappaB involving the C-terminal activating regions (CTARs) of LMP1. LMP1 expression also suppresses the transcriptional activity of the RASSF1A core promoter. RASSF1A stabilizes microtubules and regulates mitotic events. Aberrant mitotic spindles and chromosome aberrations are reported phenotypes in RASSF1A inactivated cells. In this study, we observed that LMP1 expression in human epithelial cells could induce aberrant mitotic spindles, disorganized interphase microtubules and aneuploidy. LMP1 expression could also suppress microtubule dynamics as exemplified by tracking movements of the growing tips of microtubules in live cells by transfecting EGFP-tagged EB1 into cells. The aberrant mitotic spindles and interphase microtubule organization induced by LMP1 could be rescued by transfecting RASSF1A expression plasmid into cells. Downregulation of RASSF1A expression by LMP1 may facilitate its role in transformation of premalignant nasopharyngeal epithelial cells into cancer cells.

Cell Line↗
PubMed2006

Molecular and cytogenetic changes involved in the immortalization of nasopharyngeal epithelial cells by telomerase.

Nasopharyngeal carcinoma (NPC) is a common disease in Hong Kong and southern provinces of China. EBV infection is believed to play a critical role in the development of NPC. Previous studies on the transformation mechanism of EBV genes were mostly performed in either NPC or nonnasopharyngeal epithelial cells which may not be representative of premalignant nasopharyngeal epithelial cells. Establishment of a representative cell system would greatly facilitate the elucidation of the role of EBV infection in the development of NPC. Using telomerase alone, we were able to establish an immortalized nasopharyngeal epithelial cell line from primary nonmalignant nasopharyngeal biopsies. The telomerase-immortalized nasopharyngeal epithelial cells are largely diploid in karyotype. Interestingly, this newly immortalized nasopharyngeal epithelial cell line, referred as NP460hTert, harbors genetic alterations previously identified in premalignant and malignant nasopharyngeal epithelial cells. These include inactivation of p16 by homozygous deletion of the p16(INK4A) locus and downregulation of RASSF1A expression. The deletion of the p16(INK4A) locus appears to be the most crucial event for the immortalization of nasopharyngeal epithelial cells by telomerase and precedes RASSF1A downregulation. In addition, detailed analysis of the cytogenetic changes by conventional cytogenetics, spectral karyotyping (SKY) and array-based CGH revealed a gain of a 17q21-q25 fragment on 11p15 chromosome in all NP460hTert cells which occurred before deletion of the p16(INK4A) locus. Gain of 17q has been previously reported in NPC. In addition, activation of NF-kappaB was observed in immortalized NP460hTert cells at the later population doublings, and may play a role in the survival of immortalized NP epithelial cells. Id1 which is commonly expressed in various human cancers, including NPC, was also upregulated in the immortalized NP460hTert cells. Thus, the establishment of an immortalized nasopharyngeal epithelial cell line harboring common genetic alterations present in premalignant and cancerous nasopharyngeal epithelial cells may provide a valuable cell system to examine for early events involved in NPC carcinogenesis, particularly in elucidating the role of EBV infection in NPC development.

Cell Proliferation↗
PubMed2006

Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation.

BACKGROUND: E-cadherin methylation is important in gastric carcinogenesis. Reversing hypermethylation may halt the carcinogenic process. We have previously reported that Helicobacter pylori infection is associated with E-cadherin methylation in chronic gastritis patients. AIM: To examine if eradication of H pylori could reverse E-cadherin methylation. METHODS: Patients with dyspepsia and positive for H pylori infection, with a mucosal biopsy showing chronic active gastritis, were randomised to receive H pylori eradication therapy (group 1, n = 41) or no treatment (group 2, n = 40), and were followed up prospectively. Gastric mucosae were taken for methylation assay at week 0 (before treatment) and week 6 (after treatment). Archived specimens of intestinal metaplasia with H pylori infection (n = 22) and without (n = 19) were retrieved for methylation analysis. Methylation was assessed using methylation specific polymerase chain reaction and sequencing. RESULTS: Methylation at E-cadherin was detected in 46% (19/41) and 17% (7/41) of patients at weeks 0 and 6, respectively, in group 1 (p = 0.004); 78.9% (15/19) of specimens were unmethylated after eradication of H pylori. Mucosal biopsy showed chronic inactive gastritis in 35 patients, intestinal metaplasia in one, and normal mucosa in five at week 6. Methylation was detected in 47.5% (19/40) and 52.5% (21/40) of patients at weeks 0 and 6, respectively, in group 2 (P = 0.5). Gastric mucosal biopsy showed persistent chronic active gastritis in all cases. Methylation frequency did not differ in H pylori positive or negative intestinal metaplastic specimens (72.7% v 63%; p = 0.5). CONCLUSION: H pylori eradication therapy could reverse methylation in patients with chronic gastritis. This demonstrates an environmental effect on methylation.

Amoxicillin↗
PubMed2006

Serial analysis of JAK2 mutation in a patient who developed essential thrombocythemia after orthotopic liver transplantation.

A 52-year-old man developed essential thrombocythemia (ET) with JAK2 V617F mutation after orthotopic liver transplantation (OLT). Retrospective analysis showed that, despite a low platelet count, the JAK2 mutation was already found at presentation 14 months before OLT. The high platelet count that would have been typical of ET might be masked by the cirrhosis-related hypersplenism. Thrombocythemia became obvious after OLT. The patient subsequently developed blastic transformation 12 months afterward, a process probably accelerated by the immunosuppression required for the OLT.

Amino Acid Substitution↗
PubMed2005

Epigenetic inactivation of the CIP/KIP cell-cycle control pathway in acute leukemias.

Dysregulation of the cell cycle is important in oncogenesis. We analyzed the potential inactivation of the CIP/KIP family of the cyclin E/CDK/RB pathway by gene promoter hypermethylation in leukemias. The methylation-specific polymerase chain reaction (MSP) with primers for methylated (M-MSP) and unmethylated (U-MSP) alleles of the p21, p27, and p57 genes was used to study five leukemic cell lines, 50 acute myeloid leukemia (AML) samples, and 25 acute lymphoblastic leukemia (ALL) samples. p21 was hemizygously methylated in Raji and Jurkat but remained unmethylated in U937, HL60, and NB4. p27 was hemizygously methylated in Raji but unmethylated in the other cell lines. p57 was completely methylated in Raji and NB4, hemizygously methylated in U937, and unmethylated in HL60 and Jurkat. At diagnosis, p21 methylation was not detected in any case of AML or ALL. p27 methylation occurred in 2 (4%) AML patients and in 1 (4%) ALL patient. p57 methylation occurred in 1 (2%) AML patient and in 1 (4%) ALL patient. Therefore, methylation inactivation of the INK4/CDK/RB pathway in leukemia is infrequent. A review of the literature showed a marked variation in the frequencies of methylation of these genes, which might be attributable to difference in methodologies used to detect gene methylation.

Alleles↗
PubMed2005

Elevation of plasma osteopontin level in patients with undifferentiated nasopharyngeal carcinoma.

AIMS: We evaluated the clinicopathologic relevance of plasma osteopontin (OPN) level in nasopharyngeal carcinoma patients. METHODS: Seventy-two plasma samples were collected from patients with undifferentiated nasopharyngeal carcinoma (NPC) before radiotherapy. Plasma OPN level was determined by quantitative sandwich enzyme immunoassay. The plasma OPN level was evaluated for its clinicopathologic relevance. RESULTS: The mean plasma OPN level was significantly higher in NPC patients than in normal controls (184.66 vs 75.89 ng/ml, p<0.001). In addition, high OPN level was found in the patients with advanced cancer and was correlated with neck node metastasis (p<0.05). CONCLUSIONS: Our findings indicated a potential role of OPN in the pathogenesis and nodal metastasis of undifferentiated NPC.

Adult↗
PubMed2005

Autoimmune thyroid dysfunction after hematopoietic stem cell transplantation.

Autoimmune thyroid disease (AITD) may occur in patients after hematopoietic stem cell transplantation (HSCT). In all, 10 cases of AITD (seven allogeneic and three autologous HSCT) were diagnosed among 721 HSCT recipients, including two patients with sequential hyper- and hypothyroidism. The 5-year actuarial rates for AITD after allogeneic and autologous HSCT were 2.9 and 4%, respectively. Significant risk factors included HSCT for chronic myeloid leukemia, the HLA B46 and DR9 loci and the A2B46DR9 haplotype, while female donors showed trend to significance. On multivariate analysis, only female donors and HLA DR9 remained significant. For autologous HSCT, the associations with HLA B46 and DR9 were also significant. Only three donors had a family history of AITD. A review of other reported cases confirmed the predominance of female donors, although the other associations including graft-versus-host disease, familial AITD and other autoimmune phenomena might be related to reporting bias. Since the actuarial incidence of AITD from female donors with predisposing HLA alleles may be over 30%, susceptible recipients should be carefully monitored. Owing to the small number of reported cases and different HLA associations with AITD in different populations, our observations await confirmatory data from other registries.

Adult↗
PubMed2004

Absence of p300 gene promoter methylation in acute leukemia.

p300 is a widely expressed transcriptional coactivator, and is involved in DNA repair, cell growth, differentiation, and apoptosis. Recent data suggest that it may function as a tumor suppressor. We investigated the frequency of aberrant methylation of p300 promoter in seven leukemic cell lines, as well as in the diagnostic samples of 46 patients with acute myelocytic leukemia (11 with M1, 22 with M2, 3 with M4, and 1 with M5), 24 patients with acute promyelocytic leukemia, and 22 patients with acute lymphoblastic leukemia (3 with T-cell, 1 with pre-B, 2 with Burkitt, 2 with early B-precursors, and 14 with common). None of the cell lines and patient samples showed p300 gene methylation. Therefore, hypermethylation of p300 is not an important mechanism in leukemogenesis.

Apoptosis↗
PubMed2004

Epigenetic dysregulation of the Jak/STAT pathway by frequent aberrant methylation of SHP1 but not SOCS1 in acute leukaemias.

SOCS1 and SHP1 are negative regulators of the Jak/STAT signalling pathway that is implicated in leukaemogenesis. We studied if aberrant methylation of SOCS1 and SHP1 might be involved in the pathogenesis and prognostication of acute leukaemias by methylation-specific polymerase chain reaction (MSP). At diagnosis, methylation of SHP1 occurred more frequently in acute myeloid leukaemia (AML) (n=26, 52%) than acute lymphoblastic leukaemia (ALL) (n=6, 24%) (p=0.02). Methylation of SOCS1 was absent in both AML and ALL patients. SHP1 methylation was not associated with specific clinicopathologic features and had no prognostic impact on AML patients. Frequent methylation of SHP1, but not SOCS1, may be important in the pathogenesis, but not prognosis, of acute leukaemias.

Acute Disease↗
PubMed2004

Transformation of diffuse large B-cell lymphoma into pre-B acute lymphoblastic leukemia: clinicopathologic features and clonal relationship.

A patient with fibrosing alveolitis developed a diffuse large B-cell (DLBC) lymphoma that expressed CD20 and CD30. After an initial response, the lymphoma relapsed and was salvaged with further chemotherapy. After another remission of 3 years, a pre-B-cell acute lymphoblastic leukemia (ALL), which expressed CD10, CD19, CD22, CD79a, CD34 and terminal deoxyribonucleotidyl transferase, developed and led to death. Molecular analysis of the immunoglobulin heavy-chain gene showed that the initial lymphoma and its relapse were clonally related. At leukemic relapse, 2 clones related to the initial and relapsed lymphoma clones were present. DLBC lymphomas arise from post-follicle center B cells, whereas ALL arises from pregerminal B cells. Therefore, a direct transformation of DLBC lymphoma to ALL appears unlikely. The overall features suggest instead separate lymphoma and leukemic evolution from a common mutated B-cell precursor rather than transformation of DLBC lymphoma to ALL.

Aged↗
PubMed2004

Methylation profiling in multiple myeloma.

BACKGROUND: We analysed the methylation status of a panel of 10 genes including p15, p16, DAPK, p73, VHL, E-CAD, MGMT, RARbeta, RIZ1, and ER. METHODS: The gene promoter methylation status was studied by methylation-specific polymerase chain reaction (MSP) with primers for methylated (M-MSP) and unmethylated (U-MSP) DNA in the bone marrow of 13 patients with myeloma, and one patient with plasmacytoma. RESULT: None of the 10 genes tested were methylated in eight normal bone marrow samples. For the positive control, the sensitivity of M-MSP ranged from 1 x 10(-2) for E-CAD and MGMT, to 1 x 10(-4) for p73. Of the eight diagnostic myeloma marrow samples, hypermethylation of p15, p16, E-CAD, DAPK and ER occurred in six (75%), four (50%), seven (87.5%), eight (100%), and six (75%) patients. Similarly, of the five samples from patients who progressed from plateau phase, hypermethylation of p15, p16, E-CAD, DAPK, and ER occurred in five (80%), two (40%), five (100%), five (100%), and three (60%). None of the cases had hypermethylation of RIZ1, p73, VHL, RARbeta, and MGMT. At diagnosis, all patients had concurrent hypermethylation of at least three genes, and five (62%) had concurrent methylation of four or more genes. One patient with plasmacytoma had methylation of E-CAD, ER, and DAPK. CONCLUSION: p15, p16, ER, DAPK, and E-CAD (but not RARbeta, p73, VHL, RIZ1, and MGMT) were frequently methylated in MM at both diagnosis and disease progression. Future studies of larger scale are needed to identify the genes responsible for disease progression.

Base Sequence↗
PubMed2004

Liver graft-versus-host disease after donor lymphocyte infusion for relapses of hematologic malignancies post allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is the commonest complication after donor lymphocyte infusion (DLI). In 19 patients undergoing DLI for relapses of hematologic malignancies post hematopoietic stem cell transplantation (HSCT), 11 developed GVHD, of whom nine had isolated liver involvement, and two had liver and skin involvement. The clinical diagnosis of liver GVHD was hepatitic in six patients (55%) and classical in five patients (45%). Patients with GVHD post-DLI showed a different clinical pattern when compared to a cohort of 106 cases of GVHD post-HSCT, in having significantly more isolated liver involvement (9/11 vs 17/106, P<0.001), and less skin (2/11 vs 80/106, P<0.001) and gut (0/11 vs 28/106, P<0.001) involvement. However, liver GVHD post-DLI and post-HSCT had comparable patient characteristics, underlying diseases, clinical subtypes (classical and hepatitic) and response to treatment.

Adolescent↗