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Biomedical subjects

J T Chang

Publications and source records attributed to J T Chang.

At least 19 recordsLinked to original sources
PubMed2006

Compensation and specificity of function within the E2F family.

Functions encoded by single genes in lower organisms are often represented by multiple related genes in the mammalian genome. An example is the retinoblastoma and E2F families of proteins that regulate transcription during the cell cycle. Analysis of gene function using germline mutations is often confounded by overlapping function resulting in compensation. Indeed, in cells deleted of the E2F1 or E2F3 genes, there is an increase in the expression of the other family member. To avoid complications of compensatory effects, we have used small-interfering RNAs that target individual E2F proteins to generate a temporary loss of E2F function. We find that both E2F1 and E2F3 are required for cells to enter the S phase from a quiescent state, whereas only E2F3 is necessary for the S phase in growing cells. We also find that the acute loss of E2F3 activity affects the expression of genes encoding DNA replication and mitotic activities, whereas loss of E2F1 affects a limited number of genes that are distinct from those regulated by E2F3. We conclude that the long-term loss of E2F activity does lead to compensation by other family members and that the analysis of acute loss of function reveals specific and distinct roles for these proteins.

Animals↗
PubMed2006

DSG3 is overexpressed in head neck cancer and is a potential molecular target for inhibition of oncogenesis.

To identify genes that could potentially serve as molecular therapeutic markers for human head and neck cancer (HNC), we employed differential display analysis to compare the gene expression profiles between HNC and histopathologically normal epithelial tissues. Using reverse transcription-polymerase chain reaction and Western blot analysis, desmoglein 3 (DSG3) was identified as being differentially expressed at both the RNA and protein levels. Of 56 patients assayed, 34 (61%) had overexpression of DSG3, which correlated statistically with T stage (P=0.009), N stage (P=0.047), overall stage (P=0.011), tumor depth (P=0.009) and extracapsular spread in lymph nodes (P=0.044), suggesting that DSG3 participates in carcinogenesis of HNC. Consistent with the clinical findings, inhibition of DSG3 by RNA interference (RNAi) significantly reduced cell growth and colony formation to 57-21% in three HNC cell lines. Use of an in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also inhibited to 30-48% in three cell lines tested. An in vivo xenograft study showed that administration of DSG3-RNAi plasmid significantly inhibited tumor growth for 2 months in BALB/C nude mice. In conclusion, DSG3 is identified overexpressed in HNC, with the degree of overexpression associated with clinicopathologic features of the tumor. Inhibition of DSG3 significantly suppresses carcinogenic potential in cellular and in vivo animal studies. These findings suggest that DSG3 is a potential molecular target in the development of adjuvant therapy for HNC.

Animals↗
PubMed2006

hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells.

Telomerase activity is suppressed in normal somatic tissues but is activated in most cancer cells. We have previously found that all six telomerase subunit proteins, including hTERT and hsp90 are needed for full enzyme activity. Telomerase activity has been reported to be upregulated by protein kinase C (PKC), but the mechanism is not clear. In this study, we examined how PKC regulates telomerase activity in head and neck cancer cells. PKC inhibitor, bisindolylmaleimide I (BIS), inhibited telomerase activity but had no effect on the expressions of telomerase core subunits. RNA interference (RNAi) and in vitro phosphorylation studies revealed that PKC isoforms alpha, beta, delta, epsilon, zeta specifically involved in telomerase regulation, and the phosphorylation target was on hTERT. Treatment with the hsp-90 inhibitor novobiocin dissociated hsp90 and hTERT as revealed by immunoprecipitation and immunoblot analysis and reduced telomerase activity. Treatment with the PKC activator SC-10 restored the association of hsp90 and hTERT and reactivate telomerase, suggesting that hTERT phosphorylation by PKC is essential for telomerase holoenzyme integrity and function. Analysis on clinical normal and tumour tissues reveal that the expressions of PKC alpha, beta, delta, epsilon, zeta were higher in the tumour tissues, correlated with telomerase activity. Disruption of PKC phosphorylation by BIS significantly increased chemosensitivity to cisplatin. In conclusion, PKC isoenzymes alpha, beta, delta, epsilon, zeta regulate telomerase activity in head and neck cancer cells by phosphorylating hTERT. This phosphorylation is essential for telomerase holoenzyme assembly, leading to telomerase activation and oncogenesis. Manipulation of telomerase activity by PKC inhibitors is worth exploring as an adjuvant therapeutic approach.

Cell Transformation, Neoplastic↗
PubMed2004

False positive fluorine-18 fluorodeoxy-D-glucose positron emission tomography finding caused by osteoradionecrosis in a nasopharyngeal carcinoma patient.

Nasopharyngeal carcinoma (NPC) is treated by radiotherapy with or without chemotherapy. It is not uncommon to find the residual/recurrent lesion in the skull base area. For patients who had received radiotherapy, it is difficult to differentiate the skull base tumour from post-treatment change in the CT or MRI. (18)F-2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) provides an alternative diagnostic choice in this situation for head and neck cancer including NPC especially when there is inconclusive CT/MRI finding. This report of an NPC patient who received radiotherapy 18 months previously, describes the misdiagnosis of tumour recurrence at the skull base found in both MRI and FDG PET scan. Histopathological studies showed osteoradionecrosis of the debrided tissue and follow-up PET showed complete regression of the skull base lesion. Therefore, a false positive result in FDG PET caused by osteoradionecrosis was confirmed. To the best of our knowledge, this is the first case report in the literature.

Adult↗
PubMed2003

Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis.

Although several studies have found overexpression of epidermal growth factor receptor (EGFR) proteins EGFR and Her-2 in head and neck cancers, the clinical relevance of the finding varies. We examined the expression and clinical association of these molecules with oral squamous cell carcinoma in an area where betel chewing is prevalent. EGFR and Her-2 proteins were measured in 59 paired (grossly normal and cancer) tissues by an enzyme immunoassy method. The cutoff value for gene overexpression was defined as the level of mean expression in normal tissue plus two s.d. A total of 59% of the patients consumed alcohol, 90% smoked tobacco, and 90% chewed betel quid. Of the patients assayed, 34 (58%) and 24 (41%) had EGFR and Her-2 overexpression, with average 3.5- and 1.5-fold elevations. EGFR overexpression has been shown to be statistically associated with T stage, N stage, overall TMN stage, primary tumour depth, lymph node extra-capsular spread, and poor survival. Her-2 overexpression, however, did not demonstrate a similar association with clinicopathological parameters or therapeutic outcome. On multivariant analysis, EGFR overexpression (P=0.041) and N stage (P=0.024) were the only independent factors for overall survival. These results indicate that the molecular targeting therapy to EGFR may be a treatment for oral cavity cancer in the betel quid-chewing prevalent area.

Adult↗
PubMed2001

Isolated paraaortic lymph node recurrence after definitive irradiation for cervical carcinoma.

PURPOSE: To evaluate the clinical features of isolated paraaortic lymph node (PALN) recurrence after definitive radiotherapy, and analyze the prognostic factors and effect of salvage treatment. METHODS AND MATERIALS: Of a total 876 patients who received pelvic radiotherapy after the diagnosis of primary cervical carcinoma, 26 were found to have isolated PALN recurrence as the first recurrent site, and these patients enrolled in this study. Only those with primary-site carcinoma controlled and who were free of other distant metastases were eligible. Nineteen of the 26 patients accepted salvage therapy. Fourteen patients accepted concurrent chemoradiation (CCRT), 1 accepted radiation to the paraaortic region, and 4 accepted chemotherapy alone. Clinical parameters evaluated included tumor markers (SCC and CEA) and image studies. RESULTS: Seven of the 26 patients were alive and disease-free. All 7 survivors had salvage treatment with radiation to the paraaortic region and concurrent cisplatin-based chemotherapy. None of the patients receiving chemotherapy or radiation alone enjoyed long-term, disease-free survival. The 5-year survival rate for isolated PALN recurrence of the 14 patients who accepted salvage concurrent chemoradiation (CCRT) was 51.2%. The presence of a clinical symptom at the time of PALN recurrence was analyzed. Seven of the 12 asymptomatic patients and none of the 14 symptomatic patients survived without disease after salvage treatment. The SCC levels at recurrence showed a statistically significant relationship to disease-free survival. CONCLUSIONS: An SCC level of < or = 4 ng/ml and a lack of symptoms at the time of recurrence were good prognostic factors in isolated PALN recurrence after primary radiation therapy. In addition to concurrent CCRT, periodical surveillance with tumor markers and imaging studies allowed early detection and salvage of those patients.

Adult↗
PubMed2001

Expression and permeation properties of the K(+) channel Kir7.1 in the retinal pigment epithelium.

Bovine Kir7.1 clones were obtained from a retinal pigment epithelium (RPE)-subtracted cDNA library. Human RPE cDNA library screening resulted in clones encoding full-length human Kir7.1. Northern blot analysis indicated that bovine Kir7.1 is highly expressed in the RPE. Human Kir7.1 channels were expressed in Xenopus oocytes and studied using the two-electrode voltage-clamp technique. The macroscopic Kir7.1 conductance exhibited mild inward rectification and an inverse dependence on extracellular K+ concentration ([K+]o). The selectivity sequence based on permeability ratios was K+ (1.0) approximately Rb+ (0.89) > Cs+ (0.013) > Na+ (0.003) approximately Li+ (0.001) and the sequence based on conductance ratios was Rb+ (9.5) >> K+ (1.0) > Na+ (0.458) > Cs+ (0.331) > Li+ (0.139). Non-stationary noise analysis of Rb+ currents in cell-attached patches yielded a unitary conductance for Kir7.1 of approximately 2 pS. In whole-cell recordings from freshly isolated bovine RPE cells, the predominant current was a mild inwardly rectifying K+ current that exhibited an inverse dependence of conductance on [K+]o. The selectivity sequence based on permeability ratios was K+ (1.0) approximately Rb+ (0.89) > Cs+ (0.021) > Na+ (0.003) approximately Li+ (0.002) and the sequence based on conductance ratios was Rb+ (8.9) >> K+ (1.0) > Na+ (0.59) > Cs+ (0.23) > Li+ (0.08). In cell-attached recordings with Rb+ in the pipette, inwardly rectifying currents were observed in nine of 12 patches of RPE apical membrane but in only one of 13 basolateral membrane patches. Non-stationary noise analysis of Rb+ currents in cell-attached apical membrane patches yielded a unitary conductance for RPE Kir of approximately 2 pS. On the basis of this molecular and electrophysiological evidence, we conclude that Kir7.1 channel subunits comprise the K+ conductance of the RPE apical membrane.

Animals↗
PubMed2001

Basic microarray analysis: grouping and feature reduction.

DNA microarray technologies are useful for addressing a broad range of biological problems - including the measurement of mRNA expression levels in target cells. These studies typically produce large data sets that contain measurements on thousands of genes under hundreds of conditions. There is a critical need to summarize this data and to pick out the important details. The most common activities, therefore, are to group together microarray data and to reduce the number of features. Both of these activities can be done using only the raw microarray data (unsupervised methods) or using external information that provides labels for the microarray data (supervised methods). We briefly review supervised and unsupervised methods for grouping and reducing data in the context of a publicly available suite of tools called CLEAVER, and illustrate their application on a representative data set collected to study lymphoma.

Algorithms↗
PubMed2001

Methodology standards associated with quality reporting in clinical studies in pediatric surgery journals.

BACKGROUND/PURPOSE: Reports of clinical trials often lack adequate descriptions of design and analysis; recent attention has focused on improving this omission so readers can properly assess the strength of the findings and draw their own conclusions. Similar analysis of study design and methodologic standards associated with quality reporting has not been carried out for pediatric surgery journals. METHODS: All studies (n = 642) published in 1998 in Journal of Pediatric Surgery (JPS) and Pediatric Surgery International (PSI), were reviewed for demographic data and study design. The frequency of reporting of 11 basic elements of design and analysis was evaluated in randomized clinical trials (RCT), nonrandomized clinical trials (NRCT), and retrospective cohorts (RC) from JPS by consensus of 2 assessors. RESULTS: Of the 642 studies, 17% of articles (111 of 642) were classified as clinical studies. Sixty-three were comparative studies and consisted of RC (n = 48), NRCT (n = 12), and RCT (n = 3). Two-thirds of articles published were either case reports or case series (431 of 642), and 16% were basic science articles. Demographic analysis showed a wide range of topics addressed, 4 authors per article, and multiple country of origin of authors. More than 66% of all RCT in JPS reported on eligibility criteria, admission before allocation, random allocation, method of randomization, patients' blindness to treatment, treatment complications, statistical analyses, statistical methods, loss to follow-up, and statistical methods; 2 elements of design and analysis, however, were poorly reported: blind assessment of outcome (33%) and power (17%). CONCLUSIONS: There were few randomized, controlled trials in pediatric surgery journals, and further attention should be given to evaluate the causal factors. Nine elements of quality reporting were well reported; however, 2 others were poorly reported; this may improve if editors of pediatric surgical journals provide authors with guidelines on how to report clinical trial design and analysis.

Authorship↗
PubMed2001

Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese.

p53 mutations are etiologically associated with the development of oral squamous cell carcinomas (OSCCs) or are associated with exposure to specific carcinogens. In this study, we used PCR-single strand conformation polymorphism and DNA sequencing to analyze the conserved regions of the p53 gene (exons 5-9) in OSCC tumor specimens from 187 patients with varied histories of betel quid, tobacco and alcohol use. Ninety-one of the 187 OSCCs (48.66%) showed p53 gene mutations at exons 5-9. The incidence of p53 mutations was not associated with age, sex, TNM stage, status of cigarette smoking or betel quid chewing. However, alcohol drinkers exhibited a significantly higher incidence (57/101, 56.44%) of p53 mutations than non-users (39.53%, 34/86) (P = 0.02). The effect of alcohol on the incidence of p53 mutations was still statistically significant (RR = 2.24; 95% CI, 1.21-4.15) after adjustment for cigarette smoking and betel quid (BQ) chewing. G:C to A:T transitions were the predominant mutations observed and associated with BQ and tobacco use. Alcohol drinking could enhance these transitions. After adjustment for cigarette smoking and BQ chewing, alcohol drinking still showed an independent effect on G:C to A:T transitions (RR = 2.41; 95% CI, 1.01-5.74). These findings strongly suggest an important contributive role of tobacco carcinogens to p53 mutation in this series of Taiwanese OSCCs and alcohol might enhance these mutagenic effects. As safrole-DNA adducts have been detected in 77% (23/30) of the OSCC tissues from Taiwanese oral cancer patients with a BQ chewing history, we cannot rule out the possibility that safrole or other carcinogens present in the BQ may cause a similar pattern of mutagenesis. Determination of the role of safrole and other carcinogens present in BQ on the pattern of p53 gene mutation in OSCC will require further study.

Adult↗
PubMed2001

Poor prognosis in nasopharyngeal cancer patients with low glucose-6-phosphate-dehydrogenase activity.

Nasopharyngeal carcinoma (NPC) is endemic among well-defined ethnic groups in several world regions, such as Southeastern China and Taiwan. Glucose-6-phosphate-dehydrogenase (G6PD)- deficiency, a sex-linked disorder, is one of the most common enzymopathies in Taiwan. The major role of G6PD is to generate NADPH to protect cells from oxidative damage, which is a major contributing factor to certain degenerative diseases, such as aging and cancer. In view of the coincidence of epidemic distribution of NPC and G6PD deficiency, as well as the house-keeping function of G6PD in cellular oxidative defense, we investigated the correlation of G6PD activity with NPC. The stage of NPC was classified by AJCC (1997) criteria. G6PD levels were determined in 108 NPC male patients and 75 healthy male individuals. The mean G6PD level of NPC patients was 218.9 U/10(12) RBC or 7.53 U/g hemoglobin (Hb), being much lower than in normal individuals (260.6 U/10(12) erythrocytes (RBC) or 8.92 U / gHb). The level of G6PD activity had no correlation with tumor stage or lymph node or distant metastasis, but was significantly correlated with tumor recurrence (P = 0.004 when using G6PD = 130 U/10(12) RBC as cutoff value). These results indicated that low G6PD activity in patients with NPC is associated with poor prognosis.

Adult↗
PubMed2001

Including biological literature improves homology search.

Annotating the tremendous amount of sequence information being generated requires accurate automated methods for recognizing homology. Although sequence similarity is only one of many indicators of evolutionary homology, it is often the only one used. Here we find that supplementing sequence similarity with information from biomedical literature is successful in increasing the accuracy of homology search results. We modified the PSI-BLAST algorithm to use literature similarity in each iteration of its database search. The modified algorithm is evaluated and compared to standard PSI-BLAST in searching for homologous proteins. The performance of the modified algorithm achieved 32% recall with 95% precision, while the original one achieved 33% recall with 84% precision; the literature similarity requirement preserved the sensitive characteristic of the PSI-BLAST algorithm while improving the precision.

Algorithms↗
PubMed2000

Requirements for the maintenance of Th1 immunity in vivo following DNA vaccination: a potential immunoregulatory role for CD8+ T cells.

Protective immunity against Leishmania major generated by DNA encoding the LACK (Leishmania homologue of receptor for activated C kinase) Ag has been shown to be more durable than vaccination with LACK protein plus IL-12. One mechanism to account for this may be the selective ability of DNA vaccination to induce CD8+ IFN-gamma-producing T cells. In this regard, we previously reported that depletion of CD8+ T cells in LACK DNA-vaccinated mice abrogated protection when infectious challenge was done 2 wk postvaccination. In this study, we extend these findings to study the mechanism by which CD8+ T cells induced by LACK DNA vaccination mediate both short- and long-term protective immunity against L. major. Mice vaccinated with LACK DNA and depleted of CD8+ T cells at the time of vaccination or infection were unable to control infection when challenge was done 2 or 12 wk postvaccination. Remarkably, it was noted that depletion of CD8+ T cells in LACK DNA-vaccinated mice was associated with a striking decrease in the frequency of LACK-specific CD4+ IFN-gamma-producing T cells both before and after infection. Moreover, data are presented to suggest a mechanism by which CD8+ T cells exert this regulatory role. Taken together, these data provide additional insight into how Th1 cells are generated and sustained in vivo and suggest a potentially novel immunoregulatory role for CD8+ T cells following DNA vaccination.

Animals↗
PubMed2000

The effect of nodal status on determinants of initial treatment response and patterns of relapse-free survival in nasopharyngeal carcinoma.

PURPOSE: To study the effect of regional nodal status on predictors of treatment response, failure patterns, and the time-dependent nature of the various pattern of relapse via a hazard function analysis. METHODS AND MATERIALS: We reviews tumor control data of 496 patients with nasopharyngeal carcinoma (NPC) to whom a radical course of radiotherapy (RT) with or without induction chemotherapy (CT) was given. All alive patients had a median follow-up period of 131 months. Primary tumor (T) and nodal (N) status were staged according to the TNM system of the American Joint Committee. Remote after-loading brachytherapy may be added to teletherapy in T1-2 lesions while induction CT could be given for N3 and/or T4 lesions. Hazard function analysis over 1-year interval was carried out for locoregional or distant relapse. RESULTS: T stage and brachytherapy were two independent predictors for complete response (CR) at the primary site irrespective of nodal status, whereas N stage and brachytherapy are major determinants for regional CR in node (+) patients. Multivariate analysis revealed that contributors to a relatively long disease-free interval in (1) node (-) patients were for locoregional relapse, induction CT(-) (p = 0.0062) or brachytherapy (+) (p = 0.0268) and for distant relapse, none; (2) node (+) patients were for locoregional relapse, early T stage (p = 0.0377) or regional CR (p = 0.0075) and for distant relapse, induction CT(-) (p = 0.0001) or regional CR (p = 0.0001). In node (-) or (+) patients, primary CR rate yield no independent prognostic value on various types of disease-free survival. Hazard function analysis for relapse revealed that hazard rates are in general negatively correlated with time, being highest at the first year post-treatment, decreasing from time to time, and approaching zero after a longer follow-up period in patients with locoregional CR than in patients without. CONCLUSION: Nodal status had no significant impact on predictors of primary CR, whereas in node (+) patients regional CR rate had an independent value in predicting disease-free survival to locoregional and distant relapse. Hazard function analysis revealed a decreasing hazard rate over a protracted post-treatment time in primary and regional CR patients. This indicates the continued risk of late recurrence in this subset of patients for whom long-term observation is recommended.

Adult↗
PubMed2000

CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo.

The mechanism of action of microbial adjuvants in promoting the differentiation of autoimmune effector cells remains to be elucidated. We demonstrate that CpG-containing oligodeoxynucleotides (ODN) can completely substitute for heat-killed mycobacteria in the priming of encephalitogenic myelin-reactive T cells in vivo. The adjuvanticity of the CpG ODN was secondary to their direct ability to induce IL-12 or to act synergistically with endogenous IL-12 to promote Th1 differentiation and encephalitogenicity. T cells primed in the absence of CpG with Ag and IFA alone appeared to be in a transitional state and had not undergone differentiation along a conventional Th pathway. Unlike Th2 cells, they expressed low levels of the IL-12R beta 2 subunit and retained the ability to differentiate into encephalitogenic effectors when reactivated in vitro under Th1-polarizing conditions. These results support the use of CpG ODN as adjuvants but also suggest that they could potentially trigger autoimmune disease in a susceptible individual.

Adjuvants, Immunologic↗
PubMed2000

Role of costimulation in the induction of the IL-12/IL-12 receptor pathway and the development of autoimmunity.

Costimulation mediated by the interactions of the B7 Ags (CD80/CD86) on APC with CD28 on the responding T cell regulates the magnitude of the immune response and may influence Th1/Th2 development. The IL-12Rbeta2 subunit plays a critical role in maintaining IL-12 responsiveness and controlling Th1 lineage commitment. We demonstrate that IL-2 and IL-12 resulting from CD28/B7 interactions both play a critical role in the induction of expression of the IL-12Rbeta2 subunit and as a result the differentiation of pathogenic autoreactive effector cells. These findings suggest that targeting IL-2 and IL-12 simultaneously may be effective in the treatment of Th1-mediated autoimmunity.

Abatacept↗
PubMed2000

The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor beta2 subunit.

IL-18 was originally described as a cytokine which induced IFN-gamma production by established Th1 cells in an IL-12-independent manner. However, subsequent studies demonstrated that exogenous IL-18 in the absence of IL-12 failed to drive Th1 differentiation of naive cells and induced IFN-gamma from established Th1 cells only in combination with IL-12. We have examined the role of endogenous IL-18 in controlling Th1 lineage commitment. When naive TCR-transgenic T cells were stimulated with antigen, anti-IL-18 antibodies resulted in partial inhibition of IFN-gamma production, but did not inhibit Th1 differentiation. To distinguish whether the inhibitory effect of anti-IL-18 antibodies was mediated directly by blocking IFN-gamma production or indirectly by blocking IL-12Rbeta2 up-regulation, naive T cells from IL-12 - / - mice were stimulated with anti-CD3 and IL-18. These cells failed to produce IFN-gamma, but markedly up-regulated IL-12Rbeta2 expression. We propose that the major effect of IL-18 on Th1 development is mediated by up-regulation of IL-12Rbeta2 expression, thereby enhancing IL-12-mediated signaling. The enhancement of IL-12Rbeta2 expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development.

Amino Acid Sequence↗