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Kuo C.-F.,Chang Gung University | Kuo C.-F.,Chang Gung Memorial Hospital | Luo S.-F.,Chang Gung Memorial Hospital | Luo S.-F.,Chang Gung University | And 11 more authors.
Scandinavian Journal of Rheumatology | Year: 2012

Objectives: Systemic sclerosis (SSc) has been associated with high cancer risk. We compared the cancer risk among SSc patients with that among the general Taiwanese population. Methods: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) was used to identify patients diagnosed with SSc and cancer in Taiwan during 19962008. The standardized incidence ratio (SIR) for cancer was calculated, and mortality was ascertained using the data from the National Death Registry. Results: Data analysis revealed that 2053 (472 men, 1581 women) Taiwanese individuals were diagnosed with SSc during the study period and 83 (30 men, 53 women) had cancer. The incidence of cancer was 6.9/1000 person-years. The most common cancer sites in male SSc patients were the lung (n = 10), oral cavity and pharynx (n = 8), and gastrointestinal tract (n = 4), and those in female patients were the breast (n = 11), lungs (n = 11), and blood (n = 6). Compared to the Taiwanese population of 1996, the all-cancer SIR for SSc was 1.63 [95% confidence interval (CI) 1.312.01]. Cancer risk was elevated for cancers of the lung (SIR 4.20), oral cavity and pharynx (SIR 3.67), and blood (SIR 3.50). A cancer diagnosis in SSc patients was associated with a hazard ratio (HR) of 2.15 (95% CI 1.303.53). Among cancer patients, a diagnosis of SSc was not associated with increased mortality. Conclusions: SSc patients are at high risk of developing cancer, especially of the lung, oral cavity and pharynx, and blood. © 2011 Informa Healthcare on behalf of The Scandinavian Rheumatology Research Foundation.


Liao C.-T.,Head and Neck Surgery | Chen S.-J.,Molecular Medicine Research Center | Yang L.-Y.,Clinical Trial Center | Tsao C.-K.,Chang Gung Memorial Hospital at Linkou | And 6 more authors.
Medicine (United States) | Year: 2016

An improved prognostic stratification of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically positive (pN) nodes is urgently needed. Here, we sought to examine whether an ultra-deep targeted sequencing (UDT-Seq) gene panel may improve the prognostic stratification in this patient group. A mutation-based signature affecting 10 genes (incluDing genetic mutations in 6 oncogenes and 4 tumor suppressor genes) was devised to predict disease-free survival (DFS) in 345 primary tumor specimens obtained from pN OSCC patients. Of the 345 patients, 144 were extracapsular spread (ECS)-negative and 201 were ECS-positive. The 5-year locoregional control, distant metastases, disease-free, diseasespecific, and overall survival (OS) rates served as outcome measures. The UDT-Seq panel was an independent risk factor (RF) for 5-year locoregional control (P=0.0067), distant metastases (P=0.0001), DFS (P<0.0001), disease-specific survival (DSS, P<0.0001), and OS (P=0.0003) in pN OSCC patients. The presence of ECS and pT3-4 disease were also independent RFs for DFS, DSS, and OS. A prognostic scoring system was formulated by summing up the significant covariates (UDT-Seq, ECS, pT3-4) separately for each survival endpoint. The presence of a positive UDT-Seq panel (n=77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P<0.0001). Among ECSnegative patients, those with a UDT-Seq-positive panel (n=31) had significantly worse DFS (P=0.0005) and DSS (P=0.0002). Among ECS-positive patients, those with a UDT-Seq-positive panel (n=46) also had significantly worse DFS (P=0.0032) and DSS (P=0.0098). Our UDT-Seq gene panel consisting of clinically actionable genes was significantly associated with patient outcomes and provided better prognostic stratification than traditional AJCC staging. It was also able to predict prognosis in OSCC patients regardless of ECS presence. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Chao M.,Chang Gung University | Wang H.-N.,Chang Gung University | Lu Y.J.,Chang Gung University | Chang Y.-S.,Chang Gung University | And 3 more authors.
Oncology Reports | Year: 2015

Epstein-Barr virus (EBV) can establish latent infection and has been associated with various human cancers. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein that is expressed in all EBV-associated malignant tissues. The N-and C-terminal domains of EBNA1, which are connected by internal glycine/alanine-rich short repeat sequences of various sizes, show sequence divergence across EBV strains isolated from around the world. At least five subtypes have been described, according to the amino acid at residue 487: P-ala, P-thr, V-val, V-pro, and V-leu. Whether the variations of EBNA-1 contribute to the pathogenesis of EBV or simply reflect the geographical distribution of EBV remain to be investigated. Furthermore, the cell effects conferred by EBNA1 subtypes that differ from that of the B95.8 prototype, which belongs to the P-ala subtype, remain to be elucidated. In this study, PCR was amplified with the full-length V-val EBNA1 gene from the CG3 cell line, an EBV-carrying lymphoblastoid cell line derived from a Taiwanese chronic myeloid leukemia patient. Plasmids expressing His-tagged EBNA1 fusion proteins in E. coli were constructed and used to raise antibodies in rabbit. The V-val EBNA1 gene was then cloned into a eukaryotic expression vector and successfully expressed in the transfected cultured cells. Expression of V-val EBNA1 rendered 293 cells able to undergo serum-independent cell proliferation, providing them with anti-apoptotic abilities, which are two characteristics of cancer cells. These data suggested that use of EBNA1 originally derived from tumor cells, rather than the more commonly utilized prototype, when investigating the potential role of EBNA1 in the oncogenesis of EBV-associated malignancies, is crucial.


Hassanshahi Dr. G.,Molecular Medicine Research Center | Khorramdelazad Dr. H.,Molecular Medicine Research Center | Hosseini Dr. S.M.H.,Rafsanjan University of Medical Sciences | Arababadi Dr. M.K.,Immunology of Infectious Diseases Research Center | Kennedy Dr. D.,Griffith University
Archives of Pathology and Laboratory Medicine | Year: 2013

Context.-Toll-like receptors (TLRs) play crucial roles in immune responses, especially innate immunity, against viral infections. Toll-like receptor 9 recognizes intracellular viral double-strand DNA, which leads to the activation of nuclear factor B (NF-κB) through the myeloid differentiation primary response 88 (MYD88) pathway. Defects in the expression of TLR9 and its signaling molecules may cause attenuated immune responses against hepatitis B virus. Objective.-To determine expression levels of TLR9 messenger RNA along with MYD88, interleukin 1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), and NF-κB in the peripheral blood mononuclear cells obtained from chronic hepatitis B virus (CHB)-infected patients. Design.-In this study, 60 CHB patients and 60 healthy controls were recruited and the expression of TLR9 and its downstream signaling molecules was examined by realtime polymerase chain reaction techniques using Β-actin asa housekeeping gene. Results.-Our results showed that expression of TLR9, MYD88, IRAK1, TRAF6, and NF-κB in peripheral blood mononuclear cells of CHB patients was significantly decreased in comparisonwithhealthy controls. Conclusions.-According to our results, it appears that CHB patients are unable to appropriately express genes in the TLR9 pathway, which may impede immune responses against hepatitis B virus infection. These results suggest a mechanism that may partially explain the fact that immune responses are disrupted in CHB patients.


Lin Y.-K.,Chang Gung Memorial Hospital | See L.-C.,Biostatistics Consultation Center | See L.-C.,Molecular Medicine Research Center | Chang Y.-C.,Chang Gung Memorial Hospital | And 6 more authors.
Dermatology | Year: 2011

Background: In the treatment of nail psoriasis, standardized therapeutic regimens are currently lacking. Objective: To evaluate the therapeutic efficacy of indigo naturalis oil extract in patients with nail psoriasis. Methods: Patients with nail psoriasis applied indigo naturalis oil extract on affected nails twice daily for 24 weeks. Efficacy was evaluated using the Nail Psoriasis Severity Index (NAPSI) and modified target NAPSI for the single most severely affected nail. Results: Twenty-eight out of 32 patients completed the study. The mean NAPSI was 36.1 ± 14.7 at baseline and decreased to 14.9 ± 11.1 at week 24 while the mean modified target NAPSI was 11.7 ± 3.9 at baseline and decreased to 3.6 ± 3.2 at week 24. Conclusions: Indigo naturalis oil extract appeared to improve nail psoriasis. Although preliminary, these results indicate that it could provide a novel therapeutic option for nail psoriasis, a disease notoriously difficult to treat. Copyright © 2011 S. Karger AG, Basel.


Wang P.-Y.,Kwei Shan | Wang P.-Y.,Molecular Medicine Research Center | Lin W.-C.,Molecular Medicine Research Center | Tsai Y.-C.,Graduate Institute of Biomedical science | And 9 more authors.
Genetics | Year: 2015

CTP synthase (CTPsyn) plays an essential role in DNA, RNA, and lipid synthesis. Recent studies in bacteria, yeast, and Drosophila all reveal a polymeric CTPsyn structure, which dynamically regulates its enzymatic activity. However, the molecular mechanism underlying the formation of CTPsyn polymers is not completely understood. In this study, we found that reversible ubiquitination regulates the dynamic assembly of the filamentous structures of Drosophila CTPsyn. We further determined that the proto-oncogene Cbl, an E3 ubiquitin ligase, controls CTPsyn filament formation in endocycles. While the E3 ligase activity of Cbl is required for CTPsyn filament formation, Cbl does not affect the protein levels of CTPsyn. It remains unclear whether the regulation of CTPsyn filaments by Cbl is through direct ubiquitination of CTPsyn. In the absence of Cbl or with knockdown of CTPsyn, the progression of the endocycle-associated S phase was impaired. Furthermore, overexpression of wild-type, but not enzymatically inactive CTPsyn, rescued the endocycle defect in Cbl mutant cells. Together, these results suggest that Cbl influences the nucleotide pool balance and controls CTPsyn filament formation in endocycles. This study links Cbl-mediated ubiquitination to the polymerization of a metabolic enzyme and reveals a role for Cbl in endocycles during Drosophila development. © 2015 by the Genetics Society of America.


Wang L.-J.,Chang Gung University | Wu C.-C.,Molecular Medicine Research Center | Wu C.-C.,Chang Gung University | Lee S.-Y.,Kaohsiung Veterans General Hospital | Tsai Y.-F.,Chang Gung University
Journal of Child and Adolescent Psychopharmacology | Year: 2014

Objective: This prospective study aimed to investigate the relationships between salivary levels of neurosteroids, including dehydroepiandrosterone (DHEA), cortisol, and DHEA/cortisol ratios, and behavioral symptoms in patients with attention-deficit/hyperactivity disorder (ADHD) during treatment with methylphenidate (MPH). Methods: Fifty-eight ADHD patients (48 boys and 10 girls) were included in the study initially. Forty patients (mean age: 7.77±1.64 years; 32 boys and 8 girls) who completed the study received treatment with oral MPH with a dose range of 5-15 mg/day (mean dose: 12.47±7.74 mg/day.) for 6 months at the discretion of the psychiatrist. DHEA and cortisol levels were determined from saliva samples collected at 0800 h at baseline and 6 months from baseline. ADHD symptoms were evaluated with the Child Behavior Checklist (CBCL). Results: Salivary DHEA levels (mean difference=9.05 pg/mL, p=0.027) and DHEA/cortisol ratios (mean difference=32.42, p=0.007) in ADHD patients were significantly increased, but the cortisol levels did not change significantly. During a 6 month follow-up, all behavioral problems assessed using the CBCL improved significantly. Changes in salivary DHEA levels were positively correlated with changes in salivary cortisol levels (r=0.44, p=0.004); however, changes in salivary levels of DHEA, cortisol, and the DHEA/cortisol ratio were not significantly correlated with change in any subscales of the CBCL. Mean doses of MPH were not significantly correlated with changes in neurosteroid levels and behavioral symptoms. Conclusions: These findings provide evidence that MPH administration might affect DHEA levels and DHEA/cortisol ratios. Whether levels of neurosteroids are directly associated with brain function or behavioral problems in ADHD patients warrants further investigation. Copyright © 2014, Mary Ann Liebert, Inc.


Hassanshahi G.,Molecular Medicine Research Center | Arababadi M.K.,Molecular Medicine Research Center | Arababadi M.K.,Rafsanjan University of Medical Sciences | Khoramdelazad H.,Rafsanjan University of Medical Sciences | And 3 more authors.
Archives of Medical Research | Year: 2010

Background: Occult hepatitis B infection (OBI) is defined as a form of hepatitis in which, despite absence of detectable HBsAg, HBV-DNA is present in peripheral blood of patients. The main aim of this study was to determine an association between polymorphisms in +801 of CXCL12 (SDF-1α) and its serum level in OBI patients. Methods: In this experimental study, plasma samples of 3700 blood donors were tested for HBsAg and anti-HBc by ELISA. The HBsAg-/anti-HBc+ samples were selected and screened for HBV-DNA by PCR. HBV-DNA positive samples assigned as OBI cases and PCR-RFLP techniques were performed to examine the CXCL12 (SDF-1α) polymorphisms. The serum level of CXCL12 (SDF-1α) was also analyzed by ELISA. Results: Of 3700 blood samples, 352 (9.5%) were HBsAg/anti-HBc+ and HBV-DNA was detected in 57/352 (16.1%) of HBsAg-/anti-HBc+ samples. Our results showed a significant difference in genotypes and alleles of +801 region of CXCL12 (SDF-1α). However, the serum level of CXCL12 (SDF-1α) was decreased in OBI patients but was not significant. Our results also showed that the alleles of +801 region of CXCL12 (SDF-1α) were also not associated with serum level of the chemokine. Conclusions: The polymorphisms in +801 region of CXCL12 (SDF-1α) are possibly related to OBI. © 2010 IMSS.

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