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author:("Lee, hue")
1.  Up-Regulation of FOXM1 by E6 Oncoprotein through the MZF1/NKX2-1 Axis Is Required for Human Papillomavirus–Associated Tumorigenesis12 
Neoplasia (New York, N.Y.)  2014;16(11):961-971.
PURPOSE: Foxhead box M1 (FOXM1) expression has been shown to be linked with human papillomavirus (HPV) 16/18–infected cervical cancer. However, the mechanism underlying the induction of FOXM1 in HPV 16/18–infected cancers remains elusive. EXPERIMENTAL DESIGN: The mechanistic actions of FOXM1 induced by the E6/NKX2-1 axis in tumor aggressiveness were elucidated in cellular and animal models. The prognostic value of FOXM1 for overall survival (OS) and relapse-free survival (RFS) in HPV-positive oral and lung cancers was assessed using Kaplan-Meier and Cox regression models. RESULTS: Herein, FOXM1 expression is upregulated by E6-mediated NKX2-1 in HPV-positive cervical, oral, and lung cancer cells. Induction of FOXM1 by E6 through the MZF1/NKX2-1 axis is responsible for HPV-mediated soft agar growth, invasiveness, and stemness through activating Wnt/β-catenin signaling pathway. In a nude mice model, metastatic lung tumor nodules in HPV 18 E6-positive GNM or HPV 16 E6-positive TL-1–injected nude mice were markedly decreased in both cell types with E6 knockdown, FOXM1 knockdown, or treatment with FOXM1 inhibitor (thiostrepton). Among the four subgroup patients, the worst FOXM1 prognostic value for OS and RFS was observed in HPV 16/18–positive patients with tumors with high-expressing FOXM1. CONCLUSIONS: Induction of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis may be responsible for HPV 16/18–mediated tumor progression and poor outcomes in HPV-positive patients.
PMCID: PMC4240922  PMID: 25425970
2.  Diversity of Global Rice Markets and the Science Required for Consumer-Targeted Rice Breeding 
PLoS ONE  2014;9(1):e85106.
With the ever-increasing global demand for high quality rice in both local production regions and with Western consumers, we have a strong desire to understand better the importance of the different traits that make up the quality of the rice grain and obtain a full picture of rice quality demographics. Rice is by no means a ‘one size fits all’ crop. Regional preferences are not only striking, they drive the market and hence are of major economic importance in any rice breeding / improvement strategy. In this analysis, we have engaged local experts across the world to perform a full assessment of all the major rice quality trait characteristics and importantly, to determine how these are combined in the most preferred varieties for each of their regions. Physical as well as biochemical characteristics have been monitored and this has resulted in the identification of no less than 18 quality trait combinations. This complexity immediately reveals the extent of the specificity of consumer preference. Nevertheless, further assessment of these combinations at the variety level reveals that several groups still comprise varieties which consumers can readily identify as being different. This emphasises the shortcomings in the current tools we have available to assess rice quality and raises the issue of how we might correct for this in the future. Only with additional tools and research will we be able to define directed strategies for rice breeding which are able to combine important agronomic features with the demands of local consumers for specific quality attributes and hence, design new, improved crop varieties which will be awarded success in the global market.
PMCID: PMC3893639  PMID: 24454799
4.  The role of interleukin-10 in the progression of human papillomavirus-associated lung carcinoma 
Oncoimmunology  2013;2(9):e25854.
The secretion of interleukin-10 by both malignant and immune cells promotes the progression of lung tumors, hence negatively impacting on patient prognosis. As interleukin-10 mediates oncogenic effects through the PI3K/AKT signaling pathway, PI3K/AKT inhibitors might sensitize cancer cells to chemotherapy, thus favoring tumor regression and improving disease outcome.
PMCID: PMC3825731  PMID: 24244909
CIP2A; HPV; IL-10; IL-10R; lung cancer
5.  Correction: Human Papillomavirus Up-Regulates MMP-2 and MMP-9 Expression and Activity by Inducing Interleukin-8 in Lung Adenocarcinomas 
PLoS ONE  2013;8(6):10.1371/annotation/a50fa759-93fb-444d-9523-9d4a805ef898.
PMCID: PMC3681507
6.  Population-Based Study of Birth Prevalence and Factors Associated with Cleft Lip and/or Palate in Taiwan 2002–2009 
PLoS ONE  2013;8(3):e58690.
Facial cleft deformities, including cleft lip with or without cleft palate (CL/P) and cleft palate (CP), are common congenital birth anomalies, especially in Asia. This study aimed to analyze the prevalence of CL/P and CP and to identify associated factors in Taiwan.
This population-based epidemiological study retrospectively analyzed birth data obtained from the Department of Health in Taiwan for years 2002–2009. Frequency distribution, percentages and related predictors were investigated, and findings were presented by types of cleft deformities. Logistic regression analysis was performed to identify factors associated with cleft deformities.
Overall prevalence of cleft deformities among 1,705,192 births was 0.1% for CL/P and 0.04% for CP over the 8-year study period. Higher prevalence of CL/P or CP was observed with multiple pregnancies, being male for CL/P, being female for CP, gestational age ≤37 weeks and lower birth weight (<1.5 kg). Both CL/P and CP were significantly associated with gestational age <37 weeks and birth weight<1.5 kg (all P <0.0001). CL/P was significantly associated with multiple parities (P = 0.0004–0.002). Male newborns and female newborns were significantly associated with CL/P and CP, respectively (both P<0.0001).
Overall prevalence for congenital cleft deformities in study subjects was 0.1%, in keeping with high rates in Asia. Results suggest the need for awareness and early identification of those at high risk for cleft deformities, including newborns with gestational age <37 weeks, weighing <1.5 kg at birth and women with multiple parities, as a potential strategy to counter long-term adverse effects on speech and language in this population.
PMCID: PMC3608649  PMID: 23555592
7.  Human Papillomavirus Up-Regulates MMP-2 and MMP-9 Expression and Activity by Inducing Interleukin-8 in Lung Adenocarcinomas 
PLoS ONE  2013;8(1):e54423.
Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro-angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics.
PMCID: PMC3549962  PMID: 23349885
8.  Gender Difference in the Prognostic Role of Interleukin 6 in Oral Squamous Cell Carcinoma 
PLoS ONE  2012;7(11):e50104.
Interleukin 6 (IL6) plays an important role in immunoregulation and tumorigenesis in human cancers. Oral squamous cell carcinoma (OSCC) is a malignant tumor of the oral cavity with a male predominant tendency and a poor clinical prognosis. Due to the relatively few cases in females, the gender difference of prognostic markers for OSCC is seldom discussed.
In this study, we used immunohistochemical staining methods to investigate the associations between IL6 expression and the clinicopathological characteristics of OSCC. In addition, we collected 74 female and 263 male OSCC patients for evaluation.
High IL6 expression in tumor cells was significantly associated OSCC patient characteristics including female gender (P<0.001), high lymph node metastatic rate (P = 0.007), and poor tumor differentiation (P = 0.008). Tumor-expressed IL6 had prognostic role in male OSCC patients as defined by the log-rank test (P = 0.014), but not in female patients (P = 0.959). In male OSCC patients, high IL6 expression in tumor cells was associated with poor prognosis (P = 0.025) and a 1.454-fold higher death risk, as determined by Cox regression.
High IL6 expression in tumor cells was therefore significantly associated with aggressive clinical manifestations and might be an independent survival predictor, particularly in male OSCC patients.
PMCID: PMC3503757  PMID: 23185547
9.  The APE1 Asp/Asp Genotype and the Combination of APE1 Asp/Asp and hOGG1-Cys Variants Are Associated With Increased p53 Mutation in Non–Small Cell Lung Cancer 
Journal of Epidemiology  2012;22(6):537-542.
The hOGG1 Ser326Cys polymorphism is associated with lung cancer risk, but there are limited data regarding an association between the APE1 Asp148Glu polymorphism and lung cancer. Biological evidence shows that the hOGG1-Cys allele results in less DNA repair activity; however, this is not associated with p53 mutation in lung cancer. Therefore, we investigated whether an interaction between hOGG1 and APE1 is associated with the frequency of p53 mutation in lung cancer.
We studied 217 Taiwanese adults with primary lung cancer. DNA polymorphisms of hOGG1 and APE1 were determined by polymerase chain reaction (PCR)-based restriction fragment length polymorphism. Mutations in p53 exons 5–8 were detected by direct sequencing. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the risk of p53 mutation associated with polymorphisms of hOGG1 and APE1 in lung cancer.
As expected, no association between hOGG1 polymorphism and p53 mutation was observed in this population. However, a higher risk of p53 mutation was found in participants with the APE1 Asp/Asp genotype than in those with the APE1-Glu allele (OR, 2.15; 95% CI, 1.19–3.87; P = 0.011). The risk of p53 mutation was also higher in participants with APE1 Asp/Asp plus hOGG1-Cys than in those with APE1-Glu plus hOGG1 Ser/Ser (OR, 3.72; 95% CI, 1.33–10.40; P = 0.012).
These results suggest that the APE1 Asp/Asp genotype and the combination of the APE1 Asp/Asp and hOGG1-Cys variants are associated with increased risk of p53 mutation in non–small cell lung cancer.
PMCID: PMC3798566  PMID: 23038158
hOGG1 Ser326Cys; APE1 Asp148Glu; p53 mutation; NSCLC
10.  Differential Impact of IL-10 Expression on Survival and Relapse between HPV16-Positive and -Negative Oral Squamous Cell Carcinomas 
PLoS ONE  2012;7(10):e47541.
Human papillomavirus (HPV) is a risk factor in a subset of oropharyngeal cancer; however, the contribution of HPV in the malignancy of oral squamous cell carcinomas (OSCC) is not fully understood in Taiwanese. Herein, 61 patients with no risk factors and 117 patients with one or more risk factors were enrolled in this study. HPV16/18 infection rate in non-smokers, non-drinkers and non-betel quid chewers was higher than their counterparts. The development of HPV-infected cancer has been shown to be associated with interleukin-10 (IL-10) expression. To this end, IL-10 mRNA expression in OSCC tumors was evaluated by real-time RT-PCR. Data showed that HPV-positive patients had higher IL-10 mRNA levels than in HPV-negative patients. Kaplan-Meier and Cox-regression analysis indicated that the prognostic significance of IL-10 mRNA on overall survival and relapse free survival was only observed in HPV-positive OSCC, but not in HPV-negative OSCC. Mechanistically, the elevation of IL-10 by E6 was responsible for increased colony formation and migration capability in OSCC cells. Therefore, we suggest that IL-10 induced by E6 promotes cell growth and migration capability and consequent poor survival and relapse in HPV-positive OSCC.
PMCID: PMC3485273  PMID: 23118878
11.  Human papilloma virus 16 E6 oncoprotein associated with p53 inactivation in colorectal cancer 
AIM: To investigate the association between human papilloma virus (HPV) infection and colorectal cancer.
METHODS: Sixty-nine patients with pathologically confirmed primary colorectal cancer including 6 stage I, 24 stage II, 21 stage III, and 18 stage IV patients were enrolled in this study to investigate whether HPV 16 could be involved in colorectal tumorigenesis. Nested-polymerase chain reaction (nested-PCR) was used to detect HPV16 DNA in colorectal tumor tissues and further confirmed by in situ hybridization (ISH). In addition, immunohistochemistry analysis was performed to examine the E6 oncoprotein in colorectal tumors. To verify whether E6 could inactivate the p53 transcriptional function, the levels of p21 and Mdm2 mRNA expression were evaluated by real-time reverse transcription (RT)-PCR.
RESULTS: Of the 69 colorectal tumors, HPV16 DNA was detected in 11 (16%) by nested-PCR, and HPV16 DNA was present in 8 of the 11 (73%) tumors which was confirmed by ISH. The presence of HPV16 DNA in colorectal tumors was not associated with patients’ clinical parameters including age, gender, smoking status, tumor site; however, HPV16 infection was more common in stage I patients than in late-stages patients (II, III and IV). We next asked whether HPV16 infection could be linked with colorectal cancer development. Immunohistochemical data indicated that 8 of the 11 HPV16 DNA-positive tumors had E6 oncoprotein expression. Moreover, we also observed that the adjacent normal tissues including endothelial cells, lymphocytes, fibroblasts, and gland cells in E6-positive tumors had E6 oncoprotein expression. In addition, 3 of the 4 (75%) E6-positive tumors carrying p53 wild-type had negative immunostaining, but one tumor had less p53 immunostaining. We further examined whether E6-positive and/or p53 mutated tumors reduce p53 transcriptional activity. Real-time RT-PCR analysis indicated that p21 and mdm2 mRNA expression levels in E6/p53-wildtype tumors were significantly lower than in their adjacent normal tissues; as expected, E6-positive/p53-mutated tumors had lower p21 and mdm2 mRNA expression levels compared with their adjacent normal tissues. These results clearly indicate that the E6 oncoprotein expressed in p53 wildtype tumors may reduce p21 and mdm2 expression via p53 inactivation.
CONCLUSION: These results suggest that HPV16 infection may be involved in a subset of colorectal cancer, and we suggest that the transmission of HPV to the colon and rectum might occur through peripheral blood lymphocytes.
PMCID: PMC3420003  PMID: 22912557
Human papilloma virus; Colorectal cancer; p53; p21; Blood lymphocytes
12.  Interleukin-10 Haplotype May Predict Survival and Relapse in Resected Non-Small Cell Lung Cancer 
PLoS ONE  2012;7(7):e39525.
IL-10 is associated with tumor malignancy via immune escape. We hypothesized that IL-10 haplotypes categorized by IL-10 promoter polymorphisms at –1082A>G, –819C>T, and –592C>A might influence IL-10 expression and give rise to non-small cell lung cancer (NSCLC) patients with poor outcomes and relapse. We collected adjacent normal tissues from 385 NSCLC patients to determine IL-10 haplotypes by direct sequencing and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Of the 385 tumors, 241 were available to evaluate IL-10 mRNA expression levels by real-time RT-PCR. The influence of IL-10 haplotypes on overall survival (OS) and relapse free survival (RFS) were determined by Kaplan-Meier and multivariate Cox regression analysis. The results showed that IL-10 mRNA levels were significantly higher in tumors with the non-ATA haplotype than with the ATA haplotype (P = 0.004). Patients with the non-ATA haplotype had shorter OS and RFS periods than did patients with the ATA haplotype. This may be associated with the observation that the number of tumor-infiltrating lymphocytes was decreased in the tumors with higher levels of IL-10. Consistently, T cells from the peripheral blood of the patients with non-ATA haplotype were more susceptible to apoptosis and less cytotoxic to tumor cells, compared to those from the patients with ATA haplotype. The results suggest that IL-10 can promote tumor malignancy via promoting T cell apoptosis and tumor cell survival, and IL-10 haplotype evaluated by PCR-RFLP or direct sequencing may be used to predict survival and relapse in resected NSCLC, helping clinicians to make appropriate decisions on treatment of the patients.
PMCID: PMC3407146  PMID: 22848356
13.  CYP1A1 protein activity is associated with allelic variation in pterygium tissues and cells 
Molecular Vision  2012;18:1937-1943.
A thymine/cytosine point mutation in the MSP I restriction site of cytochrome P450 1A1 (CYP1A1) has been linked to susceptibility to smoking-related cancers and is reported to result in increased enzyme activity. Therefore, we sought to determine whether allelic variation of CYP1A1 is associated with protein expression and protein activity in pterygium.
We collected 150 pterygium samples and 50 normal conjunctiva samples, which served as controls. DNA samples were extracted from blood cells and then subjected to real-time ploymerase chain reaction (PCR) to determine CYP1A1 genotype. CYP1A1 protein expression was determined by immunohistochemical staining with a monoclonal antibody for CYP1A1. Pterygium epithelial cells (PECs), cultured in a serum-free culture medium, real-time PCR, western blot and enzyme-linked immunosorbent assay (ELISA) were used to understand the effect of CYP1A1 allelic variation in protein expression and activity.
Forty-eight (33.3%) pterygium specimens tested positive for CYP1A1 protein expression. CYP1A1 protein expression was significantly greater in the pterygium group than in the control group (p<0.0001). In addition, CYP1A1 protein expression was associated with allelic variation. CYP1A1 protein expression was significantly greater in the m2/m2 group than in the m1/m1and m1/m2 groups (p=0.006). In the cell model, CYP1A1 protein expression and b[a]P 7,8-diol 9,10-epoxide (BPDE)-like DNA adducts increased in CYP1A1 m2/m2 (genotype T/T) PEC cells as compared with m1/m2 (genotype C/T) and m1/m1 (genotype C/C) cells.
CYP1A1 expression in pterygium correlates with allelic variation and can be used as an independent risk marker.
PMCID: PMC3413426  PMID: 22876118
14.  Aqueous Extract from Hibiscus sabdariffa Linnaeus Ameliorate Diabetic Nephropathy via Regulating Oxidative Status and Akt/Bad/14-3-3γ in an Experimental Animal Model 
Several studies point out that oxidative stress maybe a major culprit in diabetic nephropathy. Aqueous extract of Hibiscus sabdariffa L. (HSE) has been demonstrated as having beneficial effects on anti-oxidation and lipid-lowering in experimental studies. This study aimed at investigating the effects of Hibiscus sabdariffa L. on diabetic nephropathy in streptozotocin induced type 1 diabetic rats. Our results show that HSE is capable of reducing lipid peroxidation, increasing catalase and glutathione activities significantly in diabetic kidney, and decreasing the plasma levels of triglyceride, low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL) value. In histological examination, HSE improves hyperglycemia-caused osmotic diuresis in renal proximal convoluted tubules (defined as hydropic change) in diabetic rats. The study also reveals that up-regulation of Akt/Bad/14-3-3γ and NF-κB-mediated transcription might be involved. In conclusion, our results show that HSE possesses the potential effects to ameliorate diabetic nephropathy via improving oxidative status and regulating Akt/Bad/14-3-3γ signaling.
PMCID: PMC3139510  PMID: 19965962
15.  Aqueous Extract of Shi-Liu-Wei-Liu-Qi-Yin Induces G2/M Phase Arrest and Apoptosis in Human Bladder Carcinoma Cells via Fas and Mitochondrial Pathway 
Shi-Liu-Wei-Liu-Qi-Yin (SLWLQY) was traditionally used to treat cancers. However, scientific evidence of the anticancer effects still remains undefined. In this study, we aimed to clarify the possible mechanisms of SLWLQY in treating cancer. We evaluated the effects of SLWLQY on apoptosis-related experiments inducing in TSGH-8301 cells by (i) 3-(4,5-dimethylthiazol-zyl)-2,5-diphenylterazolium bromide (MTT) for cytotoxicity; (ii) cell-cycle analysis and (iii) western blot analysis of the G2/M-phase and apoptosis regulatory proteins. Human bladder carcinoma TSGH-8301 cells were transplanted into BALB/c nude mice as a tumor model for evaluating the antitumor effect of SLWLQY. Treatment of SLWLQY resulted in the G2/M phase arrest and apoptotic death in a dose-dependent manner, accompanied by a decrease in cyclin-dependent kinases (cdc2) and cyclins (cyclin B1). SLWLQY stimulated increases in the protein expression of Fas and FasL, and induced the cleavage of caspase-3, caspase-9 and caspase-8. The ratio of Bax/Bcl2 was increased by SLWLQY treatment. SLWLQY markedly reduced tumor size in TSGH-8301 cells-xenografted tumor tissues. In the tissue specimen, SLWLQY up-regulated the expression of Fas, FasL and Bax proteins, and down-regulated Bcl2 as well as in in vitro assay. Our results showed that SLWLQY reduced tumor growth, caused cell-cycle arrest and apoptosis in TSGH-8301 cells via the Fas and mitochondrial pathway.
PMCID: PMC3135273  PMID: 19383839
16.  p53R2 expression as a prognostic biomarker in early stage non-small cell lung cancer 
Oncology Letters  2010;1(4):609-613.
p53R2 is a small subunit of ribonucleotide reductase (RR) which has 80% homology to hRRM2 and metastasis-suppressing potential. Previous reports suggested that the expression of p53R2 is used as a prognostic factor and chemotherapy response indicator in several types of cancer. This study aimed to elucidate the association of p53R2 expression and the clinicopathological characteristics of early stage non-small cell lung cancer (NSCLC). Immunohistochemistry was conducted on a tissue array including 92 early stage NSCLC samples. Correlations between p53R2 and clinicopathological factors, recurrence/metastasis and outcomes were analyzed. The analyses showed that there was no correlation between p53R2 expression and the clinicopathological factors. Among disease-free patients during follow-up, patients with p53R2(+) had a better outcome than those with p53R2(−) (P=0.022). By using Cox multivariate regression analysis, p53R2 (risk factor 3.801; 95% CI 1.004–9.454; P=0.044) served as a prognostic biomarker in the prediction of the survival rate for NSCLC patients. Detection of the RR subunit p53R2 may therefore be a useful prognostic marker in early stage NSCLC.
PMCID: PMC3436342  PMID: 22966352
p53R2; ribonucleotide reductase; non-small cell lung cancer; early stage
17.  PIK3CA Mutations and Copy Number Gains in Human Lung Cancers 
Cancer research  2008;68(17):6913-6921.
We investigated the frequency and function of mutations and increased copy number of the PIK3CA gene in lung cancers. PIK3CA mutations are one of the most common gene changes present in human cancers. We analyzed the mutational status of exons 9 and 20 and gene copy number of PIK3CA using 86 non–small cell lung cancer (NSCLC) cell lines, 43 small cell lung cancer (SCLC) cell lines, 3 extrapulmonary small cell cancer (ExPuSC) cell lines, and 691 resected NSCLC tumors and studied the relationship between PIK3CA alterations and mutational status of epidermal growth factor receptor (EGFR) signaling pathway genes (EGFR, KRAS, HER2, and BRAF). We also determined PIK3CA expression and activity and correlated the findings with effects on cell growth. We identified mutations in 4.7% of NSCLC cell lines and 1.6% of tumors of all major histologic types. Mutations in cell lines of small cell origin were limited to two ExPuSC cell lines. PIK3CA copy number gains were more frequent in squamous cell carcinoma (33.1%) than in adenocarcinoma (6.2%) or SCLC lines (4.7%). Mutational status of PIK3CA was not mutually exclusive to EGFR or KRAS. PIK3CA alterations were associated with increased phosphatidylinositol 3-kinase activity and phosphorylated Akt expression. RNA interference–mediated knockdown of PIK3CA inhibited colony formation of cell lines with PIK3CA mutations or gains but was not effective in PIK3CA wild-type cells. PIK3CA mutations or gains are present in a subset of lung cancers and are of functional importance.
PMCID: PMC2874836  PMID: 18757405
18.  Long-term results of intensity-modulated radiotherapy concomitant with chemotherapy for hypopharyngeal carcinoma aimed at laryngeal preservation 
BMC Cancer  2010;10:102.
The objective of this retrospective study is to investigate laryngeal preservation and long-term treatment results in hypopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) combined with chemotherapy.
Twenty-seven patients with hypopharyngeal carcinoma (stage II-IV) were enrolled and underwent concurrent chemoradiotherapy. The chemotherapy regimens were monthly cisplatin and 5-fluorouracil for six patients and weekly cisplatin for 19 patients. All patients were treated with IMRT with simultaneous integrated boost technique. Acute and late toxicities were recorded based on CTCAE 3.0 (Common Terminology Criteria for Adverse Events).
The median follow-up time for survivors was 53.0 months (range 36-82 months). The initial complete response rate was 85.2%, with a laryngeal preservation rate of 63.0%. The 5-year functional laryngeal, local-regional control, disease-free and overall survival rates were 59.7%, 63.3%, 51.0% and 34.8%, respectively. The most common greater than or equal to grade 3 acute and late effects were dysphagia (63.0%, 17 of 27 patients) and laryngeal stricture (18.5%, 5 of 27 patients), respectively. Patients belonging to the high risk group showed significantly higher risk of tracheostomy compared to the low risk group (p = 0.014).
After long-term follow-up, our results confirmed that patients with hypopharyngeal carcinoma treated with IMRT concurrent with platinum-based chemotherapy attain high functional laryngeal and local-regional control survival rates. However, the late effect of laryngeal stricture remains a problem, particularly for high risk group patients.
PMCID: PMC3087314  PMID: 20298550
19.  An association between BPDE-like DNA adduct levels and CYP1A1 and GSTM1 polymorphisma in pterygium 
Molecular Vision  2010;16:623-629.
Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), an ultimate metabolite of benzo[a]pyrene, attacks deoxyguanosine to form a BPDE-N2-dG adduct resulting in p53 mutations. Both cytochrome P4501A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) have been demonstrated to be involved in the metabolism of polycyclic aromatic hydrocarbons. The relationship between BPDE-like DNA adduct levels and CYP1A1 and GSTM1 gene polymorphisms in pterygium is not clear. Therefore, BPDE-like DNA adducts and CYP1A1 and GSTM1 polymorphisms were detected in this study to provide more molecular evidence to understand the cause of BPDE-like DNA adduct formation in pterygium.
In this study, immunohistochemical staining using a polyclonal antibody on BPDE-like DNA adducts was performed on 103 pterygial specimens. For the analysis of CYP1A1 and GSTM1 polymorphisms, DNA samples were extracted from epithelial cells and then subjected to restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) for the determination of mutation and genotype of CYP1A1 and GSTM1.
BPDE-like DNA adducts were detected in 33.0% (34/103) of the pterygium samples. The differences in DNA adduct levels were associated with the genetic polymorphisms of CYP1A1 but not GSTM1. Additionally, the risk of BPDE-like DNA adduct formation for patients with CYP1A1 m1/m2 (C/T) andm2/m2 (T/T) was 9.675 fold higher than that of patients with CYP1A1 m1/m1 (C/C) types (p=0.001, 95% Confidence Interval 2.451–38.185).
Our data provide evidence that the BPDE-like DNA adduct formation in pterygium samples was associated with CYP1A1 polymorphisms.
PMCID: PMC2852619  PMID: 20700368
20.  XRCC1, but not APE1 and hOGG1 gene polymorphisms is a risk factor for pterygium 
Molecular Vision  2010;16:991-996.
Epidemiological evidence suggests that UV irradiation plays an important role in pterygium pathogenesis. UV irradiation can produce a wide range of DNA damage. The base excision repair (BER) pathway is considered the most important pathway involved in the repair of radiation-induced DNA damage. Based on previous studies, single-nucleotide polymorphisms (SNPs) in 8-oxoguanine glycosylase-1 (OGG1), X-ray repair cross-complementing-1 (XRCC1), and AP-endonuclease-1 (APE1) genes in the BER pathway have been found to affect the individual sensitivity to radiation exposure and induction of DNA damage. Therefore, we hypothesize that the genetic polymorphisms of these repair genes increase the risk of pterygium.
XRCC1, APE1, and hOGG1 polymorphisms were studied using fluorescence-labeled Taq Man probes on 83 pterygial specimens and 206 normal controls.
There was a significant difference between the case and control groups in the XRCC1 genotype (p=0.038) but not in hOGG1 (p=0.383) and APE1 (p=0.898). The odds ratio of the XRCC1 A/G polymorphism was 2.592 (95% CI=1.225–5.484, p=0.013) and the G/G polymorphism was 1.212 (95% CI=0.914–1.607), compared to the A/A wild-type genotype. Moreover, individuals who carried at least one C-allele (A/G and G/G) had a 1.710 fold increased risk of developing pterygium compared to those who carried the A/A wild type genotype (OR=1.710; 95% CI: 1.015–2.882, p=0.044). The hOGG1 and APE1 polymorphisms did not have an increased odds ratio compared with the wild type.
XRCC1 (Arg399 Glu) is correlated with pterygium and might become a potential marker for the prediction of pterygium susceptibility.
PMCID: PMC2890553  PMID: 20577654
21.  CYP1A1 gene polymorphisms as a risk factor for pterygium 
Molecular Vision  2010;16:1054-1058.
Both cytochrome P4501A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) have been demonstrated to be involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs). BaP 7,8-diol 9,10-epoxide (BPDE), an ultimate metabolite of benzo(a)pyrene (BaP), attacks deoxyguanosine to form a BPDE-N2-dG adduct resulting in p53 gene mutations. Our previous report indicated that BPDE-like DNA adduct levels in pterygium were associated with CYP1A1 gene polymorphisms. Therefore, we hypothesize that the genetic polymorphisms of CYP1A1 and GSTM1 increase the risk for pterygium.
Two hundred-five pterygial specimens and 206 normal controls were collected in this study. For the analysis of CYP1A1 and GSTM1 gene polymorphisms, DNA samples were extracted from blood cells and then subjected to restriction fragment length polymorphism and polymerase chain reaction for the determination of mutation and genotype of CYP1A1 and GSTM1.
There was a significant difference between the case and control groups in the CYP1A1 genotype (p=0.0161) but not in GSTM1 (p=1.000). The odds ratio of the CYP1A1 m1/m2 polymorphism was 1.327 (95% CI=0.906–2.079, p=0.135) and the m2/m2 polymorphism was 1.647 (95% CI=1.154–2.350, p=0.006), compared to the m1/m1 wild-type genotype. The GSTM1 polymorphisms did not have an increased odds ratio compared with the wild type.
In conclusion, a CYP1A1 polymorphism is correlated with pterygium and might become a marker for the prediction of pterygium susceptibility.
PMCID: PMC2893055  PMID: 20596254
22.  CyclinD1 protein expressed in pterygia is associated with β-catenin protein localization 
Molecular Vision  2010;16:2733-2738.
The Wnt (Wg/Wnt) signaling cascade plays an important role in tumorigenesis. Our previous report indicated that aberrant localization of β-catenin proteins was a feature of pterygia. Therefore, this study aimed to analyze the association of β-catenin protein and expression of a downstream gene, cyclin D1, in pterygial tissues.
Using immunohistochemistry, β-catenin and cyclin D1 protein expression was studied, in 150 pterygial specimens and 30 normal conjunctivas.
Seventy-three (48.7%) and 60 (40.0%) pterygial specimens tested positive for β-catenin and cyclin D1 protein expression, respectively. Cyclin D1protein expression was significantly higher in β-catenin-nuclear/cytoplasmic positive groups than in β-catenin membrane positive and negative groups (p<0.0001). In addition, cyclin D1 expression was significantly higher in the fleshy group than in the atrophic and intermediate groups (p=0.006).
Our study demonstrated that β-catenin expressed in nuclei/cytoplasm increases cyclinD1 protein expression, which invokes pterygial cell proliferation.
PMCID: PMC3003710  PMID: 21179427
23.  HPV infection and p53 inactivation in pterygium 
Molecular Vision  2009;15:1092-1097.
Our recent report indicated that tumor suppressor gene (p53) mutations and protein aberrant expression were detected in pterygium. Inactivation of p53 by Human papillomavirus (HPV) 16/18 E6 plays a crucial role in cervical tumorigenesis. In this study, we further speculate that p53 inactivation may be linked with HPV infection in pterygium pathogenesis. To investigate the involvement of HPV 16/18 E6 in p53 inactivation in pterygium, the association between HPV 16 or HPV 18 infection, the HPV E6 oncoprotein, and p53 protein expression was analyzed in this study.
HPV 16/18 infection was detected by nested-polymerase chain reaction (nested-PCR), the p53 mutation was detected by direct sequencing, and the p53 and the HPV 16/18 E6 proteins were studied using immunohistochemistry on 129 pterygial specimens and 20 normal conjunctivas.
The HPV 16/18 was detected in 24% of the pterygium tissues (31 of 129) but not in the normal conjunctiva, and the HPV16/18 E6 oncoprotein was detected in 48.3% of HPV 16/18 DNA-positive pterygium tissues (15 of 31). In addition, p53 protein negative expression in pterygium was correlated with HPV16/18 E6 oncoprotein expression but not with a p53 mutation.
HPV 16/18 E6 contributes to HPV-mediated pterygium pathogenesis as it is partly involved in p53 inactivation and is expressed in HPV DNA-positive pterygium.
PMCID: PMC2690956  PMID: 19503739
24.  Cyclooxygenase 2 expression in pterygium 
Molecular Vision  2007;13:635-638.
Following the recent discovery of an abnormal expression of the p53 gene in the epithelium in pterygium, some researchers felt that pterygium is a tumor rather than a degenerative disease. Ultraviolet (UV) radiation has been reported to be associated with pterygium formation, however the mechanism whereby UV induces uncontrolled proliferation in pterygial cells is unclear. Because cyclooxygenase 2 (COX 2) was reported to exist and play an important role in UV-related cutaneous carcinogenesis, it is logical to suspect that COX 2 existed in pterygium. This study was designed to investigate the expression of COX 2 in pterygium.
Immunohistochemical staining using a monoclonal antibody to COX 2 was performed on 90 pterygial specimens, 40 normal conjunctiva, and 5 normal limbus.
In the pterygium group, 75 (83.3%) specimens stained positive for COX 2. The staining was limited to the cytoplasm of the epithelial layer and predominantly over the basal epithelial layer. No substantial staining was visible in the subepithelial fibrovascular layers. All specimens were negative in the normal conjunctiva and limbus group.
The present study showed COX 2 existed in pterygium. Given the role of COX 2 in cutaneous tumor carcinogenesis, we suggest COX 2 may also play a role in pterygium formation. This study could be used as the basis for future surveys of the causal relationship between COX 2 and pterygium as well as the effect of COX 2 inhibitor in preventing primary or recurrent pterygium.
PMCID: PMC2669508  PMID: 17515883

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