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1.  Significance of DNMT3b in Oral Cancer 
PLoS ONE  2014;9(3):e89956.
The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 –DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy.
doi:10.1371/journal.pone.0089956
PMCID: PMC3953114  PMID: 24625449
2.  The role of IL-6 in the radiation response of prostate cancer 
Background
Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study.
Material and methods
The murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model.
Results
HR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT-induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.
Conclusion
These data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer.
doi:10.1186/1748-717X-8-159
PMCID: PMC3717100  PMID: 23806095
IL-6; Irradiation; Prostate cancer
3.  IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus 
Molecular Cancer  2013;12:26.
Background
The identification of potential tumor markers can improve therapeutic planning and patient management. The aim of this study was to highlight the significance of IL-6 in esophageal squamous cell carcinoma (SCC).
Methods
We retrospectively analyzed the clinical outcomes of 173 patients with esophageal SCC, and examined the correlation between IL-6 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T was selected for cellular and animal experiments to investigate changes in tumor behavior and treatment response after manipulation of IL-6 expression.
Results
In clinical outcome analysis, positive IL-6 staining and poor treatment response was significantly associated with shorter survival. Furthermore, the frequency of IL-6 immunoreactivity was significantly higher in esophageal cancer specimens than in non-malignant epithelium, and this staining was positively linked to the development of distant metastasis (p = 0.0003) and lower treatment response rates (p = 0.0001).By ELISA analysis, IL-6 serum levels were significantly elevated in patients developing disease failure.When IL-6 expression was inhibited, aggressive tumor behavior and radiation resistance could be overcome in vitro and in vivo. The underlying changes included increased cell death, less epithelial-mesenchymal transition and attenuated STAT3 activation. IL-6 inhibition was also associated with attenuated angiogenesis in tumor-bearing mice.
Conclusions
IL-6 was significantly associated with poor prognosis in patients with esophageal cancer. Targeting this cytokine could be a promising strategy for treatment of esophageal cancer, as evidenced by inhibition of aggressive tumor behavior and treatment resistance.
doi:10.1186/1476-4598-12-26
PMCID: PMC3667147  PMID: 23561329
IL-6, Esophageal squamous cell carcinoma; Prognosis
4.  Normal tissue complication probability model parameter estimation for xerostomia in head and neck cancer patients based on scintigraphy and quality of life assessments 
BMC Cancer  2012;12:567.
Background
With advances in modern radiotherapy (RT), many patients with head and neck (HN) cancer can be effectively cured. However, xerostomia is a common complication in patients after RT for HN cancer. The purpose of this study was to use the Lyman–Kutcher–Burman (LKB) model to derive parameters for the normal tissue complication probability (NTCP) for xerostomia based on scintigraphy assessments and quality of life (QoL) questionnaires. We performed validation tests of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines against prospectively collected QoL and salivary scintigraphic data.
Methods
Thirty-one patients with HN cancer were enrolled. Salivary excretion factors (SEFs) measured by scintigraphy and QoL data from self-reported questionnaires were used for NTCP modeling to describe the incidence of grade 3+ xerostomia. The NTCP parameters estimated from the QoL and SEF datasets were compared. Model performance was assessed using Pearson’s chi-squared test, Nagelkerke’s R2, the area under the receiver operating characteristic curve, and the Hosmer–Lemeshow test. The negative predictive value (NPV) was checked for the rate of correctly predicting the lack of incidence. Pearson’s chi-squared test was used to test the goodness of fit and association.
Results
Using the LKB NTCP model and assuming n=1, the dose for uniform irradiation of the whole or partial volume of the parotid gland that results in 50% probability of a complication (TD50) and the slope of the dose–response curve (m) were determined from the QoL and SEF datasets, respectively. The NTCP-fitted parameters for local disease were TD50=43.6 Gy and m=0.18 with the SEF data, and TD50=44.1 Gy and m=0.11 with the QoL data. The rate of grade 3+ xerostomia for treatment plans meeting the QUANTEC guidelines was specifically predicted, with a NPV of 100%, using either the QoL or SEF dataset.
Conclusions
Our study shows the agreement between the NTCP parameter modeling based on SEF and QoL data, which gave a NPV of 100% with each dataset, and the QUANTEC guidelines, thus validating the cut-off values of 20 and 25 Gy. Based on these results, we believe that the QUANTEC 25/20-Gy spared-gland mean-dose guidelines are clinically useful for avoiding xerostomia in the HN cohort.
doi:10.1186/1471-2407-12-567
PMCID: PMC3536655  PMID: 23206972
NTCP; Xerostomia; Scintigraphy; Quality of Life (QoL); Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC)
5.  Significance of the TGF-β1/IL-6 axis in oral cancer 
Clinical Science (London, England : 1979)  2012;122(Pt 10):459-472.
The aim of the present study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments in oral cancer. The role of TGF-β1 (transforming growth factor-β1) and its predictive power in the prognosis of oral cancer has been identified. Human oral cancer cell lines, including SCC4 and SCC25, were selected for cellular experiments. Changes in tumour aggressiveness, responses to treatment and the signalling pathway responsible were investigated in vitro. Furthermore, 125 oral cancer tissue specimens were constructed into tissue microarray blocks for immunohistochemical analysis to correlate the expression of TGF-β1 with clinical outcome. Using in vitro experiments, our results revealed that activated TGF-β1 signalling resulted in more aggressive tumour growth, augmented the epithelial–mesenchymal transition and more resistance to treatment. Activated IL-6 (interleukin-6) signalling could be the mechanism underlying the effects of TGF-β1 on oral cancer. Regarding clinical data, the incidence of TGF-β1 immunoreactivity in oral cancer specimens was significantly higher than in non-malignant epithelium and positively linked to IL-6 staining. Furthermore, expression of TGF-β1 was significantly correlated with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III–IV oral cancer. In conclusion, the TGF-β1/IL-6 axis had predictive power in the prognosis of oral cancer, and targeting TGF-β1 could represent a promising treatment strategy.
doi:10.1042/CS20110434
PMCID: PMC3393047  PMID: 22103462
epithelial–mesenchymal transition; head and neck squamous cell carcinoma; interleukin-6 (IL-6); oral cancer; transforming growth factor-β1 (TGF-β1); ATM, ataxia telangiectasia mutated kinase; BrdU, bromodeoxyuridine; DAPI, 4′,6-diamidino-2-phenylindole; EMT, epithelial–mesenchymal transition; GFP, green fluorescent protein; HIF-1α, hypoxia-inducible factor-1α; HNSCC, head and neck squamous cell carcinoma; IL-6, interleukin-6; IRS, immunoreactive score; MMP-9, matrix metalloproteinase-9; OSCC, oral squamous cell carcinoma; 8-oxoG, 8-oxoguanine; PI3K, phosphoinositide 3-kinase; RFP, red fluorescent protein; RT, reverse transcription; STAT3, signal transducer and activator of transcription 3; TGF, transforming growth factor; TGF-βR, TGF-β receptor; TMA, tissue microarray; VEGF, vascular endothelial growth factor
6.  A Comparison of Epithelial Cells, Fibroblasts, and Osteoblasts in Dental Implant Titanium Topographies 
The major challenge for dental implants is achieving optimal esthetic appearance and a concept to fulfill this criterion is evaluated. The key to an esthetically pleasing appearance lies in the properly manage the soft tissue profile around dental implants. A novel implant restoration technique on the surface was proposed as a way to augment both soft- and hard-tissue profiles at potential implant sites. Different levels of roughness can be attained by sandblasting and acid etching, and a tetracalcium phosphate was used to supply the ions. In particular, the early stage attaching and repopulating abilities of bone cell osteoblasts (MC3T3-E1), fibroblasts (NIH 3T3), and epithelial cells (XB-2) were evaluated. The results showed that XB-2 cell adhesive qualities of a smooth surface were better than those of the roughened surfaces, the proliferative properties were reversed. The effects of roughness on the characteristics of 3T3 cells were opposite to the result for XB-2 cells. E1 proliferative ability did not differ with any statistical significance. These results suggest that a rougher surface which provided calcium and phosphate ions have the ability to enhance the proliferation of osteoblast and the inhibition of fibroblast growth that enhance implant success ratios.
doi:10.1155/2012/687291
PMCID: PMC3263600  PMID: 22287942
8.  Protein Profiling of Human Nonpigmented Ciliary Epithelium Cell Secretome: The Differentiation Factors Characterization for Retinal Ganglion Cell line 
The purpose of this paper was to characterize proteins secreted from the human nonpigmented ciliary epithelial (HNPE) cells, which have differentiated a rat retinal ganglion cell line, RGC-5. Undifferentiated RGC-5 cells have been shown to express several marker proteins characteristic of retinal ganglion cells. However, RGC-5 cells do not respond to N-methyl-D aspartate (NMDA), or glutamate. HNPE cells have been shown to secrete numbers of neuropeptides or neuroproteins also found in the aqueous humor, many of which have the ability to influence the activity of neuronal cells. This paper details the profile of HNPE cell-secreted proteins by proteomic approaches. The experimental results revealed the identification of 132 unique proteins from the HNPE cell-conditioned SF-medium. The biological functions of a portion of these identified proteins are involved in cell differentiation. We hypothesized that a differentiation system of HNPE cell-conditioned SF-medium with RGC-5 cells can induce a differentiated phenotype in RGC-5 cells, with functional characteristics that more closely resemble primary cultures of rat retinal ganglion cells. These proteins may replace harsh chemicals, which are currently used to induce cell differentiation.
doi:10.1155/2011/901329
PMCID: PMC3157028  PMID: 21860587
9.  Predictive factors of radiation-induced skin toxicity in breast cancer patients 
BMC Cancer  2010;10:508.
Background
To assess the factors affecting the incidence of radiation-induced dermatitis in breast cancer patients treated with adjuvant 3 D conformal radiotherapy by the analysis of dosimetry and topical treatments.
Methods
Between September 2002 and July 2009, 158 breast cancer patients were treated with adjuvant 3 D conformal radiotherapy after undergoing surgery. Before November 2006, 90 patients were subjected to therapeutic skin care group and topical corticosteroid therapy was used for acute radiation dermatitis. Thereafter, 68 patients received prophylactic topical therapy from the beginning of radiotherapy. The two groups did not differ significantly in respect of clinical and treatment factors. Furthermore, the possible mechanisms responsible for the effects of topical treatment on radiation-induced dermatitis were investigated in vivo.
Results
The incidence of radiation-induced moist desquamation was 23% across 158 patients. Higher volume receiving 107% of prescribed dose within PTV (PTV-V107%; >28.6%) and volume receiving 110% of prescribed dose within treated volume (TV-V110%; > 5.13%), and no prophylactic topical therapy for irradiated skin, were associated with higher incidence of acute radiation dermatitis. The protective effect of prophylactic topical treatment was more pronounced in patients with TV-V110% > 5.13%. Furthermore, using irradiated mice, we demonstrated that topical steroid cream significantly attenuated irradiation-induced inflammation, causing a decrease in expression of inflammatory cytokines and TGF-beta 1.
Conclusion
TV-V110% > 5.13% may be an important predictor for radiation induced dermatitis. Prophylactic topical treatment for irradiated skin can significantly improve the tolerance of skin to adjuvant radiotherapy, especially for patients with higher TV-V110%.
doi:10.1186/1471-2407-10-508
PMCID: PMC2955039  PMID: 20860847
10.  Androgen deprivation modulates the inflammatory response induced by irradiation 
BMC Cancer  2009;9:92.
Background
The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies.
Methods
The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis.
Results
We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis.
Conclusion
When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.
doi:10.1186/1471-2407-9-92
PMCID: PMC2667536  PMID: 19320990
11.  Gene expression in early and progression phases of autosomal dominant polycystic kidney disease 
BMC Research Notes  2008;1:131.
Background
Little is known about the genes involved in the initial cyst formation and disease progression in autosomal dominant polycystic kidney disease (ADPKD); however, such knowledge is necessary to explore therapeutic avenues for this common inherited kidney disease.
Findings
To uncover the genetic determinants and molecular mechanisms of ADPKD, we analyzed 4-point time-series DNA microarrays from Pkd1L3/L3 mice to generate high resolution gene expression profiles at different stages of disease progression. We found different characteristic gene expression signatures in the kidneys of Pkd1L3/L3 mice compared to age-matched controls during the initial phase of the disease. By postnatal week 1, the Pkd1L3/L3 kidney already had a distinctive gene expression pattern different from the corresponding normal controls.
Conclusion
The genes differentially expressed, either induced or repressed, in ADPKD are important in immune defense, cell structure and motility, cellular proliferation, apoptosis and metabolic processes, and include members of three pathways (Wnt, Notch, and BMP) involved in morphogenetic signaling. Further analysis of the gene expression profiles from the early stage of cystogenesis to end stage disease identified a possible gene network involved in the pathogenesis of ADPKD.
doi:10.1186/1756-0500-1-131
PMCID: PMC2632667  PMID: 19099603
12.  Caffeic acid phenethyl ester decreases acute pneumonitis after irradiation in vitro and in vivo 
BMC Cancer  2005;5:158.
Background
Lung cancer is relatively resistant to radiation treatment and radiation pneumonitis is a major obstacle to increasing the radiation dose. We previously showed that Caffeic acid phenethyl ester (CAPE) induces apoptosis and increases radiosensitivity in lung cancer. To determine whether CAPE, an antioxidant and an inhibitor of NF-kappa B, could be a useful adjuvant agent for lung cancer treatment, we examine the effects of CAPE on irradiated normal lung tissue in this study.
Methods
We compared the effects of CAPE on cytotoxicity and intracellular oxidative stress in normal lung fibroblast and a lung cancer cell line. For in vivo analysis, whole thorax radiation (single dose 10 Gy and 20 Gy) was delivered to BALB/c male mice with or without CAPE pretreatment. NF- kappaB activation and the expression levels of acute inflammatory cytokines were evaluated in mice after irradiation.
Results
The in vitro studies showed that CAPE cause no significant cytotoxicity in normal lung as compared to lung cancer cells. This is probably due to the differential effect on the expression of NF-kappa B between normal and malignant lung cells. The results from in vivo study showed that CAPE treatment decreased the expression of inflammatory cytokines including IL-1 alpha and beta, IL-6, TNF-alpha and TGF- beta, after irradiation. Moreover, histological and immunochemical data revealed that CAPE decreased radiation- induced interstitial pneumonitis and TGF-beta expression.
Conclusion
This study suggests that CAPE decreases the cascade of inflammatory responses induced by thoracic irradiation without causing toxicity in normal lung tissue. This provides a rationale for combining CAPE and thoracic radiotherapy for lung cancer treatment in further clinical studies.
doi:10.1186/1471-2407-5-158
PMCID: PMC1325253  PMID: 16336675

Results 1-12 (12)