Publications by authors named "Naoko Seki"

29 Publications

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Dental Hygiene Learning Outcomes Obtained Through Computer-Assisted Simulation Modules.

J Dent Hyg 2020 Feb;94(1):32-38

: Education reflecting current knowledge is required for competent health care providers but the number of educators and/or lecture/clinical contact hours are often limited. The purpose of this study was to evaluate the learning outcomes and practicality of interactive simulation modules developed for a computerized learning system in dental hygiene education. Twenty-nine Japanese fourth-year dental hygiene undergraduates were given access to five interactive modules, delivered via a learning management system (LMS), for one month. The modules provided virtual clinical settings to take learners through decision-making processes for explaining procedures and treatments, and making appointments in English. Pre- and post-tests and a questionnaire were used to evaluate the knowledge gained and to receive learner's feedback. Participants were classified into two groups (study group and non-study group), based on their use/non-use of modules made available during the five-week period for statistical analysis. Post-test scores were significantly higher in the study group (n = 22) than in the non-study group (n = 6), ( = 0.024). Post-test scores were also significantly higher than the pre-test scores in the study group ( = 0.001). No significant differences in the post- versus pre-test scores were found in the non-study group. The questionnaire response rate of 100% (n = 29) indicated that participants considered the interactive modules, including the system operation, as convenient and beneficial. Modules made available via a LMS for self-study were beneficial for Japanese undergraduate dental hygiene students in the acquisition of knowledge and skills for clinical decision-making in English.
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February 2020

The combined effect of light-illuminating direction and enamel rod orientation on color adjustment at the enamel borders of composite restorations.

Clin Oral Investig 2020 Jul 24;24(7):2305-2313. Epub 2019 Oct 24.

Cariology and Operative Dentistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.

Objectives: To investigate the effect of light-illuminating direction (from composite or enamel side) on color adjustment at the coronal and cervical enamel borders in composite restorations.

Materials And Methods: Forty cylindrical holes (3.0-mm diameters) were prepared in bovine enamel disks (1.0-mm thickness). After application of a one-step self-etch adhesive, one of four resin composites (Estelite Asteria, EA; Estelite Pro, EP; Kalore, KA; Clearfil Majesty ES-2 Premium, MJ) was restored in the holes. After 24-h storage, the colors (L*, C*, or h* values) at the restored enamel disks over a black background were measured in a black box using a CIE XYZ camera, spotted with D65 standard illuminant either from coronal or cervical side at 45°/0° geometry. The color shifting rate was calculated at the coronal and cervical enamel borders of the composite restorations, and analyzed by three-way ANOVA with Dunnett's T3 and t test for post hoc analysis (p < 0.05).

Results: The light-illuminating directions significantly affected the L* shifting rate at the cervical enamel border in EP and MJ (p < 0.05), and the C* shifting rate at the coronal enamel border in EA, EP, and MJ (p < 0.05).

Conclusions: The color appearance at the border of the composite restoration was influenced by the light-illuminating direction in conjunction with the enamel rod orientation in the coronal or cervical enamel border.

Clinical Relevance: The line-of-vision angle would affect the perception of color adaptation at the enamel borders in the composite restorations.
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http://dx.doi.org/10.1007/s00784-019-03085-7DOI Listing
July 2020

Adenosquamous Carcinoma in the Midline Dorsum of the Tongue: A Rare Case Report.

J Oral Maxillofac Surg 2018 10 1;76(10):2131-2135. Epub 2018 May 1.

Department Head and Professor, Dental and Oral Medical Center, Kurume University School of Medicine, Fukuoka, Japan.

Adenosquamous carcinoma (ASC) is a rare malignant tumor of the oral and maxillofacial region that displays histologic features of both adenocarcinoma and squamous cell carcinoma. ASC in the midline dorsum of the tongue is exceedingly rare. We report the case of a 48-year-old man who presented with a painless mass in the midline dorsum of the tongue. Although the case was diagnosed as adenocarcinoma by biopsy, a final diagnosis of ASC was established after surgery. Ten months after the patient's initial visit, no recurrence or metastasis has been noted. ASC in the middle dorsum of the tongue is exceedingly rare, and no examples have been reported hitherto.
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http://dx.doi.org/10.1016/j.joms.2018.04.026DOI Listing
October 2018

Influence of enamel prism orientations on color shifting at the border of resin composite restorations.

Dent Mater J 2018 Mar 8;37(2):341-349. Epub 2017 Dec 8.

Cariology and Operative Dentistry, Oral Restitution Department, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

This study aimed to investigate the influence of enamel prism orientations on color adjustment of resin composite restoration. The color measurements (L*, C*, or h* values) at the restored bovine enamel disk (1.0 mm-thick) with resin composite (Estelite Asteria, Estelite Pro, Kalore, Clearfil Majesty) were performed using a CIE XYZ camera (RC500). The color shifting rate and range at the coronal and cervical border were calculated. The coronal border was significantly lower L* and C* color shifting rate than the cervical border (p<0.05). The L* color shifting range was significantly affected by regions in the 3-mm cavity group (p<0.05), but not in the 1-mm cavity group (p>0.05), while the C* color shifting range was not significantly affected by regions (p>0.05). The coronal enamel border with diagonal-cut of enamel prisms would have an advantage for color adjustment of resin composite restorations compared to the cervical border with longitudinal-cut of enamel prisms.
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http://dx.doi.org/10.4012/dmj.2017-094DOI Listing
March 2018

English education for healthcare professionals in Japan.

Jpn Dent Sci Rev 2017 Nov 3;53(4):111-116. Epub 2017 Mar 3.

Institute of Global Affairs, Tokyo Medical and Dental University, Japan 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8549, Japan.

In a global environment, education for healthcare professionals should include cultivating human resources who have the necessary skills to work in an international arena. This article will review the current status of English education for dental healthcare professionals in Japan. After conducting a literature search using the keywords: English education, Japan, and dental, only a few studies were found that investigated and proposed suggestions for dental professional English education. Even so, these were still in the early stages with outcomes yet to be fully evaluated. Even though English is thought indispensable for global professionals, and that increasing chances for communication skills is necessary, little attention has been addressed to English education for dental professionals or the implementation of such education in the Japanese undergraduate dental curricula. With the current reality of field expansion in dentistry, the need for not only improved English communication skills for Japanese dentists, but also the acquisition of essential expertise, psychomotor, teambuilding, critical thinking, and creative thinking skills in English as well as Japanese, is a definite probability. In order to reach this level of knowledge, further efforts and research would be necessary for the advancement and development of dental professional English education in Japan.
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http://dx.doi.org/10.1016/j.jdsr.2017.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703692PMC
November 2017

Predictive factors of the tumor immunological microenvironment for long-term follow-up in early stage breast cancer.

Cancer Sci 2017 Jan 21;108(1):81-90. Epub 2017 Jan 21.

Department of Surgery, Kurume University School of Medicine, Kurume, Japan.

The aim of this research was to investigate the correlation of immunologic factors in the tumor environment of breast cancer, using immunohistological staining to evaluate the expression of programmed death 1/programmed death ligand 1 (PD-1/PD-L1), phosphatase and tensin homolog (PTEN), tumor infiltrating lymphocytes (TILs), and macrophages, and to analyze the association between the immunologic factors and clinical outcome for patients with early stage breast cancer (EBC). A total of 97 EBC patients who underwent standard surgery were investigated. Expression of PD-1/PD-L1 and PTEN and the density of CD3 TILs, CD8 TILs, and CD163 macrophages were evaluated by immunohistochemical analysis. The association between the immunologic factors and clinical outcome was statistically analyzed. The density of CD3 TILs, CD8 TILs, and CD163 macrophages and non-expression of PTEN was significantly higher in cases of triple negative breast cancer. CD8 TIL density and CD8 /PD-L1 expression were predictive factors for disease-free survival and overall survival (OS). Human epidermal growth factor 2 (HER2)-positive patients with PTEN expression and luminal/HER2-negative patients without PD-L1 expression had significantly longer OS compared to patients without PTEN expression (P = 0.049) and with PD-L1 expression (P = 0.036), respectively. Furthermore, patients with PD-L1 /CD8 expression had worse median progression-free survival (P = 0.022) and median OS (P = 0.037) compared with patients without PD-L1 /CD8 expression. The CD3 TILs, CD8 TILs, and CD163 macrophages were shown to infiltrate the tumor area of EBC. In particular, triple negative breast cancer had a higher rate of TIL infiltration within the tumor environment. Expression of PTEN and lack of PD-L1 expression were associated with favorable survival in HER2-positive and luminal/HER2-negative EBC patients, respectively. The PD-L1 expression combined with CD8 density was significantly associated with an aggressive clinical outcome.
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http://dx.doi.org/10.1111/cas.13114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5276839PMC
January 2017

Effect of enamel margin configuration on color change of resin composite restoration.

Dent Mater J 2016 ;35(4):675-83

Cariology and Operative Dentistry, Oral Restitution Department, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

This study aimed to investigate the effect of enamel margin configuration on color change of resin composite restoration. Enamel disks of 1.0 mm-thick were sliced from sixty bovine anterior teeth and divided into three groups by margin configuration (non-bevel, 45-degree bevel and 45-degree reverse-bevel). The color measurements (L*C*h* values) at the restored bovine enamel disk with resin composite (Estelite Asteria, Estelite Pro, Kalore, Clearfil Majesty) were performed using a digital camera with CIE XYZ color gamut (RC500). All the resin composite restorations with non-beveled and beveled cavities significantly increased L* values compared with the control composite disks (p<0.05). The bevel preparation increased L* values toward the enamel-composite border with gentle inclination, while the reverse-bevel preparation was significantly lower L* values at the enamel-composite border than the non-bevel preparation (p<0.05). Enamel margin configuration affected color shifting of resin composite restoration and color adjustment of the border.
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http://dx.doi.org/10.4012/dmj.2016-039DOI Listing
August 2017

The role of enamel thickness and refractive index on human tooth colour.

J Dent 2016 08 2;51:36-44. Epub 2016 Jun 2.

National Center for Geriatrics and Gerontology, Department for Advanced Dental Research, Center of Advanced Medicine for Dental and Oral Diseases, 36-3, Gengo, Morioka, Obu, Aichi, 474-8511, Japan.

Objectives: To investigate the role of enamel thickness and refractive index (n) on tooth colour.

Methods: The colour and enamel thickness of fifteen extracted human central incisors were determined according to CIELab colour scale using spectrophotometer (Crystaleye) and swept-source optical coherence tomography (SS-OCT), respectively. Subsequently, labial enamel was trimmed by approximately 100μm, and the colour and remaining enamel thickness were investigated again. This cycle was repeated until dentin appeared. Enamel blocks were prepared from the same teeth and their n were obtained using SS-OCT. Multiple regression analysis was performed to reveal any effects of enamel thickness and n on colour difference (ΔE00) and differences in colour parameters with CIELCh and CIELab colour scales.

Results: Multiple regression analysis revealed that enamel thickness (p=0.02) and n of enamel (p<0.001) were statistically significant predictors of ΔE00 after complete enamel trimming. The n was also a significant predictor of ΔH' (p=0.01). Enamel thickness and n were not statistically significant predictors of ΔL', ΔC', Δa* and Δb*.

Conclusions: Enamel affected tooth colour, in which n was a statistically significant predictor for tooth colour change.

Clinical Significance: Understanding the role of enamel in tooth colour could contribute to development of aesthetic restorative materials that mimic the colour of natural tooth with minimal reduction of the existing enamel.
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http://dx.doi.org/10.1016/j.jdent.2016.05.010DOI Listing
August 2016

Evaluation of simulation learning materials use to fill the gap in Japanese dental English education.

J Med Dent Sci 2016 ;63(1):1-8

Department of Dental Education Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

Even though English is most frequently the common language when the patient's native language differs from that of a dentist, the opportunities for Japanese undergraduate dental students to learn dental English are now quite limited. The purposes of our study were to investigate: the effectiveness and feasibility of the computer-assisted simulation materials as one solution strategy for dental English education in Japan, and the needs and demands for dental English from the learners' side. Interactive simulation materials for medical interviews in English and clinical cases which were translated to English, were delivered via Learning Management System (LMS) to nineteen trainee residents of dentistry (residents). Evaluation for the materials, learners' knowledge and interests in the contents, and ease of operation were obtained by post-questionnaire (response rates were 100% and 95%, respectively). Both questionnaire-surveys received positive feedback toward the materials, yet 47% answered that they lacked the level of knowledge about contents of the medical interview in English. Results were sufficient to suggest that the residents would like to have the opportunity to study or practice medical interview in English, or English related to dentistry, and that the simulation materials could be one of the solution strategies for opportunity provision.
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http://dx.doi.org/10.11480/jmds.630101DOI Listing
April 2017

CD44v3+/CD24- cells possess cancer stem cell-like properties in human oral squamous cell carcinoma.

Int J Oncol 2016 Jan 20;48(1):99-109. Epub 2015 Nov 20.

Department of Pathology, Kurume University School of Medicine, Kurume 830-0011, Japan.

Cancer stem cells (CSCs) or cancer stem cell-like cells (CSC-LCs) are a minority population of cells that relate to tumor progression, metastasis and drug resistance. To identify CSC-LCs in oral squamous cell carcinoma (OSCC), we used two OSCC cell lines, SAS and OSC20, and cell surface markers, CD44v3 and CD24. In addition, we examined CD44v3 and CD24 expression immunohistochemically and evaluated the relationship between the expression and clinicopathological parameters in 50 OSCC tissues. In SAS and OSC20, CD44v3+/CD24- cells showed a higher sphere forming ability than the other fractions, i.e., CD44v3+/CD24+, CD44v3-/CD24- and CD44v3-/CD24+ cells. The proportion of CD44v3+/CD24- cells in SAS and OSC20 was 10.7 and 24.1%, respectively. Regarding SAS, CD44v3+/CD24- cells also showed a higher drug resistance for CDDP, 5-FU and cetuximab and expressed higher mRNA levels of CSC property-related genes than the other cell fractions. The tumorigenicity of CD44v3+/CD24- cells was not significantly different from the other fractions in SAS. An immunohistochemical study revealed a significant correlation between CD44v3 expression in the invasive portion and lymph node metastasis. Kaplan Meier analysis revealed cases with CD44v3 expression in the invasive portion tended to show poor overall survival (OS) compared with those without CD44v3, and there was a significant difference in OS between CD44v3+/CD24- and CD44v3-/CD24- immunophenotypes in the invasive portion. In conclusion, the results suggest that the CD44v3+/CD24- cell population displays CSC-LC properties in a human OSCC cell line. Additionally, we present evidence that CD44v3 immunoexpression and CD44v3+/CD24- immunophenotypes could give prognostic information associated with unfavorable clinical outcomes.
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http://dx.doi.org/10.3892/ijo.2015.3261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734600PMC
January 2016

A proposed core curriculum for dental English education in Japan.

BMC Med Educ 2014 Nov 18;14:239. Epub 2014 Nov 18.

Institute of Health Biosciences Support Office of Frontier Oral Science, International Exchange and Collaboration, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima City 770-8504, Japan.

Background: Globalization of the professions has become a necessity among schools and universities across the world. It has affected the medical and dental professions in terms of curriculum design and student and patient needs. In Japan, where medicine and dentistry are taught mainly in the Japanese language, profession-based courses in English, known as Medical English and Dental English, have been integrated into the existing curriculum among its 83 medical and 29 dental schools. Unfortunately, there is neither a core curriculum nor a model syllabus for these courses.

Methods: This report is based on a survey, two discussion forums, a workshop, and finally, the drafting of a proposed core curriculum for dental English approved by consensus of the participants from each university.

Results: The core curriculum covers the theoretical aspects, including dental English terms and oral pathologies; and practical aspects, including blended learning and dentist-patient communication. It is divided into modules and is recommended to be offered for at least two semesters.

Conclusions: The core curriculum is expected to guide curriculum developers in schools where dental English courses are yet to be offered or are still in their early development. It may also serve as a model curriculum to medical and dental schools in countries in Asia, Europe, Africa, and Central and South America, where English is not the medium of instruction.
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http://dx.doi.org/10.1186/s12909-014-0239-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237740PMC
November 2014

Feasibility study of personalized peptide vaccination for metastatic recurrent triple-negative breast cancer patients.

Breast Cancer Res 2014 Jul 3;16(4):R70. Epub 2014 Jul 3.

Introduction: Since treatment modalities for metastatic recurrent triple-negative breast cancer (mrTNBC) are limited, a novel treatment approach including immunotherapy is required. We have developed a novel regimen of personalized peptide vaccination (PPV), in which vaccine antigens are individually selected from a pool of different peptide candidates based on the pre-existing host immunity. Herein we conducted a phase II study of PPV for metastatic recurrent breast cancer patients to investigate the feasibility of PPV for mrTNBC.

Methods: Seventy-nine patients with metastatic recurrent breast cancer who had metastases and had failed standard chemotherapy and/or hormonal therapy were enrolled. They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher peptide-specific immunoglobulin G (IgG) responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for the four HLA-IA phenotypes (HLA-A2, -A24, or -A26 types, or HLA-A3 supertypes), and were subcutaneously administered weekly for 6 weeks and bi-weekly thereafter. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses along with other laboratory analyses were conducted before and after vaccination.

Results: No severe adverse events associated with PPV were observed in any of the enrolled patients. Boosting of CTL and/or IgG responses was observed in most of the patients after vaccination, irrespective of the breast cancer subtypes. There were three complete response cases (1 mrTNBC and 2 luminal/HER2-negative types) and six partial response cases (1 mrTNBC and 5 luminal/HER2-negative types). The median progression-free survival time and median overall survival time of mrTNBC patients were 7.5 and 11.1 months, while those of luminal/HER2-negative patients were 12.2 and 26.5 months, and those of HER2-positive patients were 4.5 and 14.9 months, respectively.

Conclusions: PPV could be feasible for mrTNBC patients because of the safety, immune responses, and possible clinical benefits.

Clinical Trial Registration Number: UMIN000001844 (Registration Date: April 5, 2009).
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http://dx.doi.org/10.1186/bcr3685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227005PMC
July 2014

FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis.

Mol Clin Oncol 2013 Jul 26;1(4):625-632. Epub 2013 Apr 26.

Research Center for Innovative Cancer Therapy, School of Medicine, Kurume University, Kurume, Fukuoka 830-0011, Japan ; ; Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka 830-0011, Japan ;

The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in breast cancer patients. Of the 100 tumor specimens obtained from primary invasive breast carcinoma, 63 and 57% were evaluated as FOXP3 tumor cells and as being highly infiltrated by FOXP3 lymphocytes, respectively. Although FOXP3 expression in tumor cells was of no prognostic significance, FOXP3 lymphocytes were significantly associated with poor overall survival (OS) (n=98, log-rank test P=0.008). FOXP3 exhibited a heterogeneous subcellular localization in tumor cells (cytoplasm, 31%; nucleus, 26%; both, 6%) and, although cytoplasmic FOXP3 was associated with poor OS (P= 0.058), nuclear FOXP3 demonstrated a significant association with improved OS (P=0.016). Furthermore, when patients were grouped according to their expression of tumor cytoplasmic FOXP3 and lymphocyte FOXP3, there were notable differences in the Kaplan-Meier curves for OS (P<0.001), with a high infiltration of FOXP3 lymphocytes accompanied by a cytoplasmic FOXP3 tumor being the most detrimental phenotype. These findings indicated that FOXP3 expression in lymphocytes as well as in tumor cells may be a prognostic marker for breast cancer. FOXP3 in tumor cells may have distinct biological activities and prognostic values according to its localization, which may help establish appropriate cancer treatments.
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http://dx.doi.org/10.3892/mco.2013.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915667PMC
July 2013

Treatment outcome in patients with stage III breast cancer treated with neoadjuvant chemotherapy.

Exp Ther Med 2013 Nov 6;6(5):1089-1095. Epub 2013 Sep 6.

Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.

Despite the good responses of patients (pts) with stage III breast cancer to neoadjuvant chemotherapy (NAC), most eventually relapse and have a poor prognosis. We investigated the prognostic indicators in pts with stage III breast cancer treated with NAC, using epirubicin and/or docetaxel. A total of 22 women with stage III breast cancer underwent NAC between January 2005 and May 2011. The regimens of NAC comprised ED (epirubicin 60 mg/m and docetaxel 60 mg/m) in 10 cases, FEC (fluorouracil 500 mg/m, epirubicin 75-100 mg/m and cyclophosphamide 500 mg/m) in 10 cases and EC (epirubicin 60 mg/m and cyclophosphamide 600 mg/m) in two cases. Following four cycles of each regimen, a further four cycles of D (docetaxel 70 mg/m) were undertaken in nine cases. Subsequent to the completion of NAC and surgery, we assessed the clinicopathological results and performed prognostic analyses. Statistical analyses concerning disease-free survival (DFS) or overall survival (OS) were conducted by a Cox proportional hazard model. The median survival time was 66 months and there were 12 distant metastases and two local recurrences. Multivariate analyses showed the number of metastatic axillary lymph nodes (ALNs) [hazard ratio (HR), 1.079; P=0.023] was correlated with DFS, while the Ki-67 labeling index (HR, 1.109; P=0.042) and the number of meta-static ALNs (HR, 1.087; P=0.023) were correlated with OS. In conclusion, even if pts with stage III breast cancer show good responses to NAC using epirubicin and/or docetaxel, the majority eventually relapse and have a poor prognosis. The Ki-67 labeling index and the number of involved ALNs are suggested as prognostic indicators in stage III breast cancer.
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http://dx.doi.org/10.3892/etm.2013.1289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820806PMC
November 2013

Tricin inhibits proliferation of human hepatic stellate cells in vitro by blocking tyrosine phosphorylation of PDGF receptor and its signaling pathways.

J Cell Biochem 2012 Jul;113(7):2346-55

Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.

4',5,7-Trihydroxy-3',5'-dimethoxyflavone (Tricin), a naturally occurring flavone, has anti-inflammatory potential and exhibits diverse biological activities including antigrowth activity in several human cancer cell lines and cancer chemopreventive effects in the gastrointestinal tract of mice. The present study aimed to investigate the biological actions of tricin on hepatic stellate cells (HSCs) in vitro, exploring its potential as a treatment of liver fibrosis, since HSC proliferation is closely related to the progression of hepatic fibrogenesis in chronic liver diseases leading to irreversible liver cirrhosis and hepatocellular carcinoma. Tricin inhibited platelet-derived growth factor (PDGF)-BB-induced cell proliferation by blocking cell cycle progression and cell migration in the human HSC line LI90 and culture-activated HSCs. It also reduced the phosphorylation of PDGF receptor β and the downstream signaling molecules ERK1/2 and Akt, which might be due to its tyrosine kinase inhibitor properties rather than inhibition of the direct binding between PDGF-BB and its receptor. Our findings suggest that tricin might be beneficial in HSC-targeting therapeutic or chemopreventive applications for hepatic fibrosis.
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http://dx.doi.org/10.1002/jcb.24107DOI Listing
July 2012

The influence of light intensities irradiated directly and indirectly through resin composite to self-etch adhesives on dentin bonding.

Dent Mater J 2011 20;30(3):315-22. Epub 2011 May 20.

Department of Restorative Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

This study was designed to evaluate effects of light-irradiated intensities directly and indirectly through resin composites to one- and two-step self-etch adhesives on dentin bonding. One-step (Clearfil S(3) Bond; TS, Bond Force; BF) or two-step (Clearfil SE Bond; SE) self-etch adhesives was applied to dentin surface. The adhesive agent was light-cured with light-intensity of 350 or 600 mW/cm(2), and then resin composite with different colors (translucent or opaque shade) was filled and light-cured with the same light-intensity as the bonding procedure. After 24 h water storage, bond strengths to dentin were determined using µTBS test. For the 600 and 350 mW/cm(2) groups, translucent shade resin obtained higher µTBS than opaque shade resin. Using SE and BF, the 350 mW/cm(2) group in translucent shade resin was higher µTBS than the 600 mW/cm(2) group in opaque shade resin, while TS showed no different µTBS between them.
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http://dx.doi.org/10.4012/dmj.2010-156DOI Listing
November 2011

Dentin bond durability and water sorption/solubility of one-step self-etch adhesives.

Dent Mater J 2010 Oct 1;29(5):623-30. Epub 2010 Sep 1.

Cariology and Operative Dentistry, Department of Restorative Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.

The purpose of this study was to evaluate the dentin bonding durability of three HEMA-containing one-step self-etch adhesives after one-year water storage and to measure the amounts of their water sorption/solubility. OptiBond All-In-One (OP), Bond Force (BF) and Clearfil S³Bond (S³) were applied to the dentin surfaces according to manufacturers' instructions. Bond strengths to dentin were determined using µTBS test after water storage for 24 hours, six months, and one year. In addition, water sorption and solubility of the polymerized adhesives were measured. The µTBS of S³ and OP significantly decreased after one year. On the other hand, for BF there were no significant differences in µTBS between all storage periods. There were significant differences in water sorption and solubility among the adhesives (BF>S³>OP). The initial amounts of water sorption and solubility of the three adhesives did not affect their bonding durability to dentin.
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http://dx.doi.org/10.4012/dmj.2010-028DOI Listing
October 2010

Bortezomib sensitizes human esophageal squamous cell carcinoma cells to TRAIL-mediated apoptosis via activation of both extrinsic and intrinsic apoptosis pathways.

Mol Cancer Ther 2010 Jun 1;9(6):1842-51. Epub 2010 Jun 1.

Research Center for Innovative Cancer Therapy, Kurume University, Asahi-machi, Kurume, Japan.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive human cancers, and novel treatment modalities are required. We investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) in combination with the proteasome inhibitor bortezomib (Velcade) on human ESCC cell lines. Bortezomib enhanced the susceptibility to TRAIL in 12 of the 15 ESCC cell lines tested, although most showed low sensitivity to TRAIL as a single agent. The enhancement of TRAIL-induced apoptosis by bortezomib was caspase dependent. Increased processing of caspase-8 often accompanied enhancement of TRAIL-induced apoptosis by bortezomib. However, the increased cell surface expression of death receptors observed on bortezomib treatment did not seem to be crucial for this effect. For some ESCC, bortezomib treatment resulted in a more efficient recruitment of caspase-8 and the Fas-associated death domain to the death-inducing signaling complex. Additional downregulation of the cellular FLICE-inhibitory protein long isoform [c-FLIP(L)] could cooperate in the activation of the extrinsic pathway in some cases. For other ESCC, the crucial effect of bortezomib treatment seemed to be increased signaling via the intrinsic apoptotic pathway on subsequent exposure to TRAIL. Thus, bortezomib could sensitize ESCC to TRAIL apoptosis by multiple molecular mechanisms of action. Therefore, the combination of bortezomib and TRAIL might be a novel therapeutic strategy for ESCC patients who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway.
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http://dx.doi.org/10.1158/1535-7163.MCT-09-0918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884061PMC
June 2010

YB-1 prevents apoptosis via the mTOR/STAT3 pathway in HER-2-overexpressing breast cancer cells.

Future Oncol 2009 Mar;5(2):153-6

National Hospital Organization Kyushu Medical Cancer, Breast Care Center, Clinical Research Institute, Fukuoka, Japan.

Evaluation of: Lee C, Dhillon J, Wang MY et al.: Targeting YB-1 in HER-2 overexpressing breast cancer cells induces apoptosis via the mTOR/STAT3 pathway and suppresses tumor growth in mice. Cancer Res. 68 (21), 8661-8666 (2008). The transcription factor Y-box binding protein (YB)-1 is highly expressed in breast cancer cells and is strongly linked with breast cancer patient prognosis. In this paper, siRNA knockdown of YB-1 was used to investigate breast cancer cell proliferation. Six breast cancer cell lines that either overexpress HER-2 or were triple negative demonstrated growth inhibition following YB-1 knockdown. In particular, YB-1 knockdown induced apoptosis in BT-474-m1 and Au565 cells. Knockdown of YB-1 also decreased phosphorylation of STAT3S727, ERK1/2T202/Y204, mTORS2448 and total mTOR expression. When STAT3 was knocked down by siSTAT3, apoptosis was induced and constitutively active phosphorylated STAT3 was found to rescue YB-1-induced apoptosis. Furthermore, YB-1 knockdown remarkably suppressed colony formation in a soft agar assay, while delayed tumor formation was observed in mice. YB-1 knockdown inhibited cell growth and it is thought to involve induction of apoptosis via the mTOR/STAT3 intracellular signaling pathway. YB-1 is a promising molecular target for HER-2-overexpressing or triple-negative breast cancer cells.
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http://dx.doi.org/10.2217/14796694.5.2.153DOI Listing
March 2009

Characterization of IL-2-activated TILs and their use in intrapericardial immunotherapy in malignant pericardial effusion.

Cancer Immunol Immunother 2006 Oct 16;55(10):1219-27. Epub 2005 Dec 16.

Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, 830-0011, Kurume, Fukuoka, Japan.

Pericardial effusion (PE) and cardiac tamponade caused by malignant pericarditis are critical conditions in cancer patients, which still lack a recommended protocol for their long-term management. Percutaneous pericardiocentesis and simple drainage are commonly performed as the initial treatment. The aims of this study were to investigate the presence of cytotoxic T lymphocytes (CTLs) in malignant PE and to determine the clinical response to administering autologous tumor-infiltrating lymphocytes (TILs) into the pericardial cavity. Initially, we identified human lymphocyte antigen class-I-restricted and tumor-specific CTLs within the interleukin-2 (IL-2)-activated TILs in PEs from four patients, on the basis of interferon-gamma production and lactate dehydrogenase-release assays. Clinically we observed favorable responses to the pericardial transfer of IL-2-activated autologous TILs in four patients: one male with advanced esophageal cancer, one female with recurrent lung cancer and two females with recurrent breast cancer, respectively. Autologous TILs from PEs were expanded in vitro with IL-2, characterized for CD3, CD4 and CD8 markers, checked for contamination and then infused into the patient's pericardial space through a catheter. This was repeated biweekly. After treatment, there were no signs of recurrence of PE in either case, as determined by radiography, echocardiography and computed tomography. The only adverse effects seen were grade 1 fevers. These results suggested that intrapericardial cellular immunotherapy with autologous TILs could be a safe and effective treatment for controlling malignant pericarditis with associated cardiac tamponade, and that tumor-specific CTLs present in malignant PE might be important for tumor rejection.
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http://dx.doi.org/10.1007/s00262-005-0112-8DOI Listing
October 2006

[A case of asymmetric demyelinating neuropathy in a patient with chronic graft-versus-host disease].

Rinsho Shinkeigaku 2005 Oct;45(10):748-53

Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo.

A 47-year-old man, who suffered from acute lymphocytic leukemia at 45 years old and was treated with hematopoietic stem cell transplantation at 46 years old after the induction of complete remission by the standard chemotherapy, developed the symptoms of chronic graft-versus-host disease (cGVHD) such as dry eyes, dry mouth, skin thickening, skin scaling, skin pigmentation and impaired liver function. He was admitted to our hospital because of the acute development of diplopia and weakness of his left upper extremity accompanying with the exacerbation of other symptoms of cGVHD. Neurological examinations revealed the right abducens nerve palsy and asymmetric muscular weakness of the extremities; the proximal part of the left upper extremity and the distal part of the right upper extremity were markedly involved. Neurophysiological studies including magnetic motor root stimulation revealed demyelinating neuropathy specifically involving the motor nerves. On the basis of these findings, a diagnosis of peripheral neuropathy associated with cGVHD was made. Nighteen reports are available on peripheral neuropathy in cGVHD patients, but to date little is known about the pathophysiology of this condition. Most of those patients have been diagnosed as having symmetric demyelinating polyneuropathy, such as Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. In this study, contrary to previous reports, the asymmetric involvement of motor nerves is noteworthy. Accumulation and further analyses of the cases like the present case are necessary to elucidate the pathogenesis of peripheral neuropathy in cGVHD.
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October 2005

[The repetitive immune cell transfer therapy combining non-myelosuppressive chemotherapy for patients with advanced and refractory cancer].

Gan To Kagaku Ryoho 2004 Oct;31(11):1649-51

Dept of Surgery, Kurume University School of Medicine.

Autologous tumor cells stimulated with T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two-week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell lines and may have a potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on the conventional conditioning regimen in order to take advantage by both the anticancer effects and reconstruction of antitumor immunity. Nineteen patients were enrolled in a pilot clinical trial. The two administrations of AuTL were given prior to chemotherapy (ChT) for one treatment cycle. The treatment was repeated at least for three cycles over a one-week interval. The conventional ChT regimen was based on the standard dosage. The pts consisted of 3 of gastric cancer, colon cancer, lung adenocarcinoma, respectively, 6 of esophageal cancer, and 2 of breast and pancreas carcinoma, respectively. AuTLs were administered 1x/2 weeks using direct injection or intraarterial infusion. The median duration of the treatment was over 11.5 months, and the median survival time was 14.8 months. Adverse events related to both the ChT and AuTL transfers at all dosages were minimal. Four of the 13 pts achieved major tumor responses (2 CR: complete regression and 2 PR: partial regression) in this study. Three pts showed progressive disease, and 6 pts had stable disease for over 90 days. PBMC were evaluated for cytokine production prior to the treatment and after 3 treatments. Two and one of 4 CR/PR pts had increased IFN-gamma and TNF-alpha production with no TGF-beta1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after the treatment had high IFN-gamma and TNF-alpha responses and no TGF-beta1 or IL-4 response. TGF-beta1 and IL-4 secretion increased in parallel in 3 out of 3 pts that experienced progressive disease after the treatment. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without serious adverse events and without reducing Th1 cytokine responses in peripheral blood for most of the pts that responded to the treatment. According to each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with non-myeloablative ChT for various kinds of cancers should be performed to manage the immunodeficiency in the pts with advanced cancer and to improve the effect of antitumor AuTLs.
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October 2004

Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves' ophthalmopathy.

Hum Immunol 2004 Jun;65(6):632-9

Department of Endocrinology, Medical Research Center in Warsaw, Poland.

Tumor necrosis factor (TNF)-alpha plays a central role in the development of ophthalmopathy in patients with Graves' disease (GD). The aim of this study was to investigate the association of TNF promoter polymorphisms at positions -1031 (T-1031C), -863 (C-863A), -857 (C-857T), -308 (G-308A), and -238 (G-238A) with Graves' ophthalmopathy (GO). We studied the distribution of TNF and human leukocyte antigen (HLA) DRB1 alleles in 228 Polish white patients with GD, 106 of whom had ophthalmopathy (NOSPECS class > or = III) and 248 healthy subjects. TNF -308A and HLA-DRB1*03 alleles were significantly increased in patients with GD compared with healthy subjects. Stratification analysis revealed no independent association of -308A with GD when the DRB1*03 status was considered. Subdividing GD according to eye involvement revealed that the distribution of TNF promoter haplotypes differed significantly in patients with or without ophthalmopathy. The haplotype containing the -238A allele was absent in GO. The association of G-238A with GO was independent of DRB1 alleles. These results indicate that TNF G-308A is associated with susceptibility to GD (however, this association is not independent of HLA-DRB1*03) and that TNF G-238A is associated with the development of ophthalmopathy, suggesting that G-238A or a gene in linkage disequilibrium may be disease modifying in GD.
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http://dx.doi.org/10.1016/j.humimm.2004.02.033DOI Listing
June 2004

Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy.

J Exp Med 2004 Feb 9;199(4):437-48. Epub 2004 Feb 9.

Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan.

Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.
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http://dx.doi.org/10.1084/jem.20031457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211825PMC
February 2004

The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP.

Blood 2003 Jul 13;102(1):303-10. Epub 2003 Mar 13.

Basic Sciences Program, SAIC-Frederick, Center for Cancer Research, National Cancer Institute/NIH, Bldg 560, Rm 31-30, Frederick, MD 21702-1201, USA.

Because of the pivotal role the proteasome plays in apoptosis, inhibitors of this enzyme, such as PS-341, provide a great opportunity for exploring synergy between proteasome inhibition and other apoptosis-inducing agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. In overnight assays, combinations of PS-341 and TRAIL were much more effective than either agent alone in promoting apoptosis of a murine myeloid leukemia, C1498, and a murine renal cancer, Renca. For C1498 cells, apoptosis sensitization by PS-341 affected neither the activity of nuclear factor kappaB (NF-kappaB) nor the levels of most antiapoptotic proteins. However, reductions in the antiapoptotic protein c-FLIP in response to PS-341 were observed in both C1498 and Renca cells. Treatment of normal bone marrow mixed with C1498 tumor cells for 18 hours with a combination of PS-341 and TRAIL resulted in a specific depletion of the tumor cells. Upon transfer to irradiated syngeneic recipient mice, mixtures treated with the PS-341 plus TRAIL combination resulted in enhanced long-term tumor-free survival of mice. These data therefore support the targeting of apoptotic pathways in tumor cells, using combinations of agents such as PS-341 and TRAIL that interact synergistically to preferentially promote tumor cell apoptosis.
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http://dx.doi.org/10.1182/blood-2002-09-2975DOI Listing
July 2003

Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses.

J Immunol 2003 Mar;170(5):2727-33

Department of Microbiology, University of Nevada School of Medicine, Reno, NV 89557, USA.

In cancer, the coordinate engagement of professional APC and Ag-specific cell-mediated effector cells may be vital for the induction of effective antitumor responses. We speculated that the enhanced differentiation and function of dendritic cells through CD40 engagement combined with IL-2 administration to stimulate T cell expansion would act coordinately to enhance the adaptive immune response against cancer. In mice bearing orthotopic metastatic renal cell carcinoma, only the combination of an agonist Ab to CD40 and IL-2, but neither agent administered alone, induced complete regression of metastatic tumor and specific immunity to subsequent rechallenge in the majority of treated mice. The combination of anti-CD40 and IL-2 resulted in significant increases in dendritic cell and CD8(+) T cell number in advanced tumor-bearing mice compared with either agent administered singly. The antitumor effects of anti-CD40 and IL-2 were found to be dependent on CD8(+) T cells, IFN-gamma, IL-12 p40, and Fas ligand. CD40 stimulation and IL-2 may therefore be of use to promote antitumor responses in advanced metastatic cancer.
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http://dx.doi.org/10.4049/jimmunol.170.5.2727DOI Listing
March 2003

Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis is an important endogenous mechanism for resistance to liver metastases in murine renal cancer.

Cancer Res 2003 Jan;63(1):207-13

Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201, USA.

Recent reports have suggested that the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) may partially limit the formation of hepatic metastases of a variety of mouse tumors, and the major source of TRAIL in the liver was shown to be local natural killer cells. We isolated a clone (R331) of the murine renal cancer cell line Renca that was strikingly more sensitive to both Fas and TRAIL death receptor-mediated apoptosis in vitro. R331 grew in tissue culture in vitro at a rate similar to that of the parental Renca cell line but formed larger and more numerous colonies than parental Renca in soft agar. After s.c. implantation, R331 tumors progressed more rapidly than parental Renca tumors. However, R331 formed far fewer lung and liver metastases in wild-type (WT) BALB/c mice. Administration of antibodies that neutralized TRAIL dramatically increased the number of R331 liver metastases. Furthermore, numbers of R331 liver metastases were much greater in TRAIL(-/-) than in WT BALB/c mice. In contrast, no difference was seen in numbers of lung metastases when comparing TRAIL(-/-) and WT mice, suggesting that the antitumor effects of TRAIL in vivo were compartment specific. Transfection of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein into R331 increased the numbers of liver metastases in BALB/c mice by up to 10-fold, indicating that local TRAIL in the liver was directly mediating tumor cell apoptosis. These organ-specific differences in the endogenous levels of death ligands may apply different selective pressures on the development of liver or lung metastases. Consequently, the efficacy of TRAIL therapy may vary depending on the location of the tumor metastases.
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January 2003

Tumor-specific CTL kill murine renal cancer cells using both perforin and Fas ligand-mediated lysis in vitro, but cause tumor regression in vivo in the absence of perforin.

J Immunol 2002 Apr;168(7):3484-92

Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.

Kidney cancer is a devastating disease; however, biological therapies have achieved some limited success. The murine renal cancer Renca has been used as a model for developing new preclinical approaches to the treatment of renal cell carcinoma. Successful cytokine-based approaches require CD8(+) T cells, but the exact mechanisms by which T cells mediate therapeutic benefit have not been completely identified. After successful biological therapy of Renca in BALB/c mice, we generated CTLs in vitro using mixed lymphocyte tumor cultures. These CTL mediated tumor-specific H-2K(d)-restricted lysis and production of IFN-gamma, TNF-alpha, and Fas ligand (FasL) in response to Renca. CTL used both granule- and FasL-mediated mechanisms to lyse Renca, although granule-mediated killing was the predominant lytic mechanism in vitro. The cytokines IFN-gamma and TNF-alpha increased the sensitivity of Renca cells to CTL lysis by both granule- and FasL-mediated death pathways. Adoptive transfer of these anti-Renca CTL into tumor-bearing mice cured most mice of established experimental pulmonary metastases, and successfully treated mice were immune to tumor rechallenge. Interestingly, we were able to establish Renca-specific CTL from mice gene targeted for perforin (pfp(-/-)) mice. Although these pfp(-/-) CTL showed reduced cytotoxic activity against Renca, their IFN-gamma production in the presence of Renca targets was equivalent to that of wild-type CTL, and adoptive transfer of pfp(-/-) CTL was as efficient as wild-type CTL in causing regression of established Renca pulmonary metastases. Therefore, although granule-mediated killing is of paramount importance for CTL-mediated lysis in vitro, some major in vivo effector mechanisms clearly are independent of perforin.
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http://dx.doi.org/10.4049/jimmunol.168.7.3484DOI Listing
April 2002

A polymorphism of the 5' flanking region of tumour necrosis factor α gene is associated with thyroid-associated ophthalmopathy in Japanese.

Clin Endocrinol (Oxf) 2000 Jun;52(6):759-764

Departments of Immunology,Paediatrics,,Endocrinology and Metabolism, Kurume University School of Medicine, Kurume,Department of Tissue Physiology, Division of Adult Diseases, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Objective: We have studied the polymorphism of the 5' flanking region of the tumour necrosis factor (TNF)-α gene in order to better understand the genetic background of autoimmune thyroid disorders and thyroid-associated ophthalmopathy.

Patients And Methods: We studied the polymorphism of the 5' flanking region of the TNF-α gene at positions - 1031 (T to C change, termed as - 1031C), - 863 (C to A, - 863 A), - 857 (C to T, - 857T), - 308 (G to A, - 308 A) and - 238 (G to A, - 238 A) in Japanese patients with Graves' disease [n = 173, 62 of whom had associated ophthalmopathy (American Thyroid Association (ATA) class III or greater)] and healthy control subjects (n = 575), using a polymerase chain reaction sequence-specific oligonucleotide probe method.

Results: The allele frequency of - 857T in the Graves' disease patients (22.5% vs. 17.7%, OR  = 1.35, P  = 0.045, corrected P  = 0.23) was slightly greater than in the Japanese healthy subjects, respectively. However, the difference was not statistically significant. In Graves' disease patients with evident ophthalmopathy (ATA class III or greater), the allele frequencies of - 1031C and - 863 A were significantly greater than those with no or mild ophthalmopathy (ATA class 0-II) (31.5% vs. 13.5%, OR =2.94, P < 0.0001, corrected P < 0.0005; 23.4% vs. 11.7%, OR =2.30, P  = 0.0044, corrected P  = 0.022, respectively) and in control subjects. The strength of the association of the polymorphism - 1031C increased with the severity of ophthalmopathy, with odds ratios of 2.36 for ATA class III, and 5.43 for ATA class IV-VI, respectively, compared with Graves' disease with no or mild ophthalmopathy (ATA class 0-II). Although the phenotype frequency of DRB1*0901 was not different among Graves' disease patients with or without ophthalmopathy and control subjects, the phenotype frequency of DRB1*0901(-)/-1031C(+) was significantly increased in Graves' disease patients with ophthalmopathy compared to those with no or mild ophthalmopathy (OR = 4.91, P  = 0.0005) or control subjects (OR = 4.59, P < 0.0001).

Conclusions: These results suggest that the - 1031C or - 863 A alleles, or a gene in linkage disequilibrium with the TNF-α gene, predispose to the development of ophthalmopathy in Japanese patients with Graves' disease.
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http://dx.doi.org/10.1046/j.1365-2265.2000.01011.xDOI Listing
June 2000