BioMed CentralActa Medica Okayama1471-24071712017Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study314322ENT.YokotaDivision of Gastrointestinal Oncology, Shizuoka Cancer CenterT.OgawaDepartment of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of MedicineS.TakahashiDepartment of Medical Oncology, The Cancer Institute Hospital of JFCRK.OkamiDepartment of Otolaryngology, Center of Head and Neck Surgery, Tokai UniversityT.FujiiDepartment of Otolaryngology, Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular DiseasesK.TanakaDepartment of Medical Oncology, Kindai University Faculty of MedicineS.IwaeDepartment of Head and Neck Cancer, Hyogo Cancer CenterI.OtaDepartment of Otolaryngology-Head and Neck Surgery, Nara Medical UniversityT.UedaDepartment of Otorhinolaryngology-Head and Neck Surgery, Hiroshima University HospitalN.MondenDepartment of Head and Neck Surgery, Shikoku Cancer CenterK.MatsuuraDepartment of Head and Neck Surgery, Miyagi Cancer CenterH.KojimaDepartment of Otorhinolaryngology, Jikei University School of MedicineS.Ueda Medical Oncology, Nara Hospital, Kindai University School of MedicineK.SasakiHead and Neck, Chiba Cancer CenterY.FujimotoDepartment of Otorhinolaryngology, Nagoya University, Graduate School of MedicineY.HasegawaDepartment of Head and Neck Surgery, Aichi Cancer Center Hospital and Research InstituteT.BeppuDivision of Head and Neck Surgery, Saitama Cancer CenterHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalS.HiranoDepartment of Otolaryngology-Head and Neck Surgery, Kyoto University HospitalY.Naka Headquarters of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd.Y.Matsushima Headquarters of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd.M.FujiiDepartment of Otolaryngology, Eiju General HospitalM.TaharaDepartment of Head and Neck Medical Oncology, National Cancer Center Hospital EastBACKGROUND:
Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC).
METHODS:
Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee.
RESULTS:
From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups.
CONCLUSIONS:
The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide.
TRIAL REGISTRATION:
ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama17574749512013Inflammatory diarrhea due to enteroaggregative Escherichia coli: evidence from clinical and mice model studies36ENDhira Rani SahaDivision of Histology & Electron microscopy, National Institute of Cholera and Enteric DiseasesSucharitaGuinNatl Inst Cholera & Enter Dis, Div BacteriolRajendranKrishnanNatl Inst Cholera & Enter Dis, Div Data ManagementDhrubajyotiNagNatl Inst Cholera & Enter Dis, Div BacteriolHemantaKoleyNatl Inst Cholera & Enter Dis, Div BacteriolSumioShinodaOkayama Univ Infect Dis India, Collaborat Res CtrThandavarayanRamamurthyNatl Inst Cholera & Enter Dis, Div BacteriolBackground@
This study was conducted to determine the role of enteroaggregative Escherichia coli (EAEC) in inflammatory diarrhea among hospitalized patients in Kolkata. The inflammatory pathogenesis of EAEC was established in mice model and histopathological studies. Presence of fecal leucocytes (FLCs) can be suspected for EAEC infection solely or as a mixed with other enteric pathogens.@
Methods@
Active surveillance was conducted for 2 years on 2 random days per week with every 5th patient admitted to the Infectious Diseases Hospital (IDH). Diarrheal samples were processed by conventional culture, microscopy, ELISA and molecular methods. Two EAEC isolated as sole pathogens were examined in mice after induced intestinal infection. The intestinal tissue samples were processed to analyze the histological changes.@
Results@
Of the 2519 samples screened, fecal leucocytes, erythrocytes and occult blood were detected in 1629 samples. Most of the patients had acute watery diarrhea (75%) and vomiting (78%). Vibrio cholerae O1 was the main pathogen in patients of 5–10 years age group (33%). Shigellosis was more in children from 2–5 years of age (19%), whereas children <2 years appeared to be susceptible for infection caused by EAEC (16%). When tested for the pathogenicity, the EAEC strains colonized well and caused inflammatory infection in the gut mucosa of BALB/C mice.@
Conclusion@
This hospital-based surveillance revealed prevalence of large number of inflammatory diarrhea. EAEC was the suspected pathogen and <2 years children appeared to be the most susceptible age group. BALB/C mice may be a suitable animal model to study the EAEC-mediated pathogenesis.No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama1746-159682013De novo CD5-positive diffuse large B-cell lymphomas show high specificity for cyclin D2 expression81ENTakuroIgawaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYasuharuSatoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesKatsuyoshiTakataDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNorikoIwakiDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTakehiroTanakaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaokoAsanoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYoshinobuMaedaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesYorihisaOritaDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesNaoyaNakamuraDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesShigeoNakamuraDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesTadashiYoshinoDepartment of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences@D cyclins positively regulate the cell cycle and mediate the pathogenesis of some lymphomas. Cyclin D1 overexpression is the hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 are reportedly not as specific to certain lymphomas as cyclin D1. In this study, cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive diffuse large B-cell lymphomas (DLBCLs) (50/51) and in 28% of CD5-negative DLBCLs (14/51). A statistically significant difference was observed between these two groups (p<0.0001). In contrast, no statistical difference was found in the cyclin D3 expression between CD5-positive (18/51) and CD5-negative (24/51) DLBCLs (p=0.23). Based on these findings, cyclin D2 is therefore considered to be closely associated with de novo CD5-positive DLBCLs. This insight may be useful for overcoming the inferior survival of this aggressive lymphoma.No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama72006Simultaneous gene transfer of bone morphogenetic protein (BMP)-2 and BMP-7 by in vivo electroporation induces rapid bone formation and BMP-4 expressionENMarikoKawaiKazuhisaBesshoHirokiMaruyamaJun-ichiMiyazakiToshioYamamoto<p><b>Background:</b> Transcutaneous in vivo electroporation is expected to be an effective gene-transfer method for promoting bone regeneration using the BMP-2 plasmid vector. To promote enhanced osteoinduction using this method, we simultaneously transferred cDNAs for BMP-2 and BMP-7, as inserts in the non-viral vector pCAGGS.<br />
<b>Methods:</b> First, an in vitro study was carried out to confirm the expression of BMP-2 and BMP-7 following the double-gene transfer. Next, the individual BMP-2 and BMP-7 plasmids or both
together were injected into rat calf muscles, and transcutaneous electroporation was applied 8 times at 100 V, 50 msec.<br />
<b>Results:</b> In the culture system, the simultaneous transfer of the BMP-2 and BMP-7 genes led to a much higher ALP activity in C2C12 cells than did the transfer of either gene alone. In vivo, ten days after the treatment, soft X-ray analysis showed that muscles that received both pCAGGS-BMP-2 and pCAGGS-BMP-7 had better-defined opacities than those receiving a single gene. Histological examination showed advanced ossification in calf muscles that received the double-gene transfer.
BMP-4 mRNA was also expressed, and RT-PCR showed that its level increased for 3 days in a timedependent manner in the double-gene transfer group. Immunohistochemistry confirmed that BMP-
4-expressing cells resided in the matrix between muscle fibers.<br />
<b>Conclusion:</b> The simultaneous transfer of BMP-2 and BMP-7 genes using in vivo electroporation induces more rapid bone formation than the transfer of either gene alone, and the increased
expression of endogenous BMP-4 suggests that the rapid ossification is related to the induction of
BMP-4.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama52005Evaluation of the Total Design Method in a survey of Japanese dentistsENYukieNakaiPeterMilgromToshikoYoshidaChikakoIshiharaTsutomuShimono<p>Background: This study assessed the application of the Total Design Method (TDM) in a mail survey of Japanese dentists. The TDM was chosen because survey response rates in Japan are
unacceptably low and the TDM had previously been used in a general population survey.<br />
Methods: Four hundred and seventy eight dentist members of the Okayama Medical and Dental Practitioner's Association were surveyed. The nine-page, 27-item questionnaire covered dentist
job satisfaction, physical practice, and dentist and patient characteristics. Respondents to the first mailing or the one-week follow-up postcard were defined as early responders; others who responded were late responders. Responder bias was assessed by examining age, gender and training.<br />
Results: The overall response rate was 46.7% (223/478). The response rates by follow-up mailing were, 18% after the first mailing, 35.4% after the follow-up postcard, 42.3% after the second mailing, and 46.7% after the third mailing. Respondents did not differ from non-respondents in age or gender, nor were there differences between early and late responders.<br />
Conclusion: The application of TDM in this survey of Japanese dentists produced lower rates of response than expected from previous Japanese and US studies.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama312005Effect of connective tissue growth factor (CCN2/CTGF) on proliferation and differentiation of mouse periodontal ligament-derived cellsENMasahiroAsanoSatoshiKubotaTohruNakanishiTakashiNishidaTomoichiroYamaaiGenYosimichiKazumiOhyamaTomosadaSugimotoYojiMurayamaMasaharuTakigawa<p><b>Background:</b> CCN2/CTGF is known to be involved in tooth germ development and periodontal tissue remodeling, as well as in mesenchymal tissue development and regeneration. In this present study, we investigated the roles of CCN2/CTGF in the proliferation and differentiation of periodontal ligament cells (murine periodontal ligament-derived cell line: MPL) in vitro.<br />
<b>Results:</b> In cell cultures of MPL, the mRNA expression of the CCN2/CTGF gene was stronger in sparse cultures than in confluent ones and was significantly enhanced by TGF-. The addition of Recombinant CCN2/CTGF (rCCN2) to MPL cultures stimulated DNA synthesis and cell growth in a dose-dependent manner. Moreover, rCCN2 addition also enhanced the mRNA expression of alkaline phosphatase (ALPase), type I collagen, and periostin, the latter of which is considered to be a specific marker of the periosteum and periodontium; whereas it showed little effect on the mRNA expression of typical osteoblastic markers, e.g., osteopontin and osteocalcin. Finally, rCCN2/CTGF also stimulated ALPase activity and collagen synthesis.<br />
<b>Conclusion:</b> These results taken together suggest important roles of CCN2/CTGF in the development and regeneration of periodontal tissue including the periodontal ligament.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama312005Comparable response of ccn1 with ccn2 genes upon arthritis: An in vitro evaluation with a human chondrocytic cell line stimulated by a set of cytokinesENNorifumi HMoritaniSatoshiKubotaToshioSugaharaMasaharuTakigawa<p><b>Background:</b> The chondrosarcoma-derived HCS-2/8 has been known to be an excellent model of human articular chondrocytes. By mimicking the arthritic conditions through the treatment of HCS-2/8 cells with cytokines, we estimated the gene expression response of ccn1 and ccn2 during the course of joint inflammation in vitro.<br />
<b>Results:</b> In order to mimic the initiation of inflammation, HCS-2/8 cells were treated with tumor necrosis factor (TNF)-. To induce pro-inflammatory or reparative responses, TGF- was employed. Effects of an anti-inflammatory glucocorticoid were also evaluated. After stimulation, expression levels of ccn1 and ccn2 were quantitatively analyzed. Surprisingly, not only ccn2, but also ccn1 expression was repressed upon TNF- stimulation, whereas both mRNAs were uniformly induced by transforming growth factor (TGF)- and a glucocorticoid.<br />
<b>Conclusion:</b> These results describing the same response during the course of inflammation suggest similar and co-operative roles of these 2 ccn family members in the course of arthritis.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama1471-240752005Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylationENTadashiHanafusaToshiyukiShinjiHidenoriShirahaKazuhiroNousoYoshiakiIwasakiEichiroYumotoToshiroOnoNorioKoide<p><b>Background:</b> Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulinlike
growth factors (IGF<sub>s</sub>) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in
human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.<br />
<b>Methods:</b> In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation
constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.<br />
Results: Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus
sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility
shift assay that p53 binding to the promoter region was diminished when methylated.<br />
<b>Conclusion:</b> From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of
IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama1465-5411642004Addition of granulocyte-colony stimulating factor (G-CSF) may further increase chemosensitive state in premenopausal node-positive breast cancer patients with induced angiogenesis after surgeryENKadriAltundagOzdenAltundagMehmetGunduzNo potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama1465-5411642004Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of actionR291R299ENMikiTsujita-KyutokuTakashiYuriNaoyukiDanbaraHidetoSenzakiYasuhikoKiyozukaNorihisaUeharaHidehoTakadaTakahikoHadaTeruoMiyazawaYutakaOgawaAiroTsubura<p><b>Introduction</b> The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA).<br />
Methods KPL-1 cell growth was assessed by colorimetric 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21<sup>Cip1/Waf1</sup>, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet.<br />
<b>Results</b> CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 mol/l and 270 mol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G<sub>1</sub> fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G<sub>0</sub>/G<sub>1</sub> arrest, which involved increased expression of p53 and p21<sup>Cip1/Waf1</sup>, and decreased expression of cyclin D<sub>1</sub>. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner.<br />
<b>Conclusion</b> CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama32004Elevated levels of tissue inhibitor of metalloproteinases (TIMPS) in human hepatocellular carcinomasENEijiMatsumotoHarushigeNakatsukaKazuhioNousoShin-ichiroNakamuraMayumiSuzukiYoshiyukiKobayashiMasayukiUemuraSyuichiroSatoEi-ichiroSatoJunkoYokoyamaSouTsuboiHironoriTanakaYoshitakeTakumaTatsuyaFujikawaYasushiShiratoriNo potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama32003No association between the sigma receptor type 1 gene and schizophrenia: results of analysis and meta-analysis of case-control studiesENNaohikoUchidaHiroshiUjikeKenjiNakataManabuTakakiAkiraNomuraTakeshiKatsuYujiTanakaTakakiImamuraAyumuSakaiShigetoshiKuroda<p><b>Background:</b> Several lines of evidence have supported possible roles of the sigma receptors in the etiology of schizophrenia and mechanisms of antipsychotic efficacy. An association study provided genetic evidence that the sigma receptor type 1 gene (SIGMAR1) was a possible susceptibility factor for schizophrenia, however, it was not replicated by a subsequent study. It is necessary to evaluate further the possibility that the SIGMAR1 gene is associated with susceptibility to schizophrenia.
Methods: A case-control association study between two polymorphisms of the SIGMAR1 gene, G-241T/C-240T and Gln2Pro, and schizophrenia in Japanese population, and meta-analysis including present and previous studies.<br />
<b>Results:</b>There was no significant association of any allele or genotype of the polymorphisms with schizophrenia. Neither significant association was observed with hebephrenic or paranoid subtype of schizophrenia. Furthermore, a meta-analysis including the present and previous studies comprising 779 controls and 636 schizophrenics also revealed no significant association between the SIGMAR1 gene and schizophrenia.<br />
<b>Conclusion:</b> In view of this evidence, it is likely that the SIGMAR1 gene does not confersusceptibility to schizophrenia.</p>No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama22002High-susceptibility of photosynthesis to photoinhibition in the tropical plant Ficus microcarpa L. f. cv. Golden LeavesENShunichiTakahashiAyumuTamashiroYasukoSakihamaYasusiYamamotoYoshinobuKawamitsuHideoYamasaki<p><b>Background:</b> The tropical plant Ficus microcarpa L. f. cv. Golden Leaves (GL) is a high-light sensitive tropical fig tree in which sun-leaves are yellow and shade-leaves are green. We compared the response of photosynthetic activities to strong light between GL and its wild-type (WT, Ficus microcarpa L. f.).<br /></p>
<p><b>Results:</b> Field measurements of maximum photosystem II (PSII) efficiency (F<sub>v</sub>/F<sub>m</sub>) of intact sunleaves in GL showed that photo synthetic activity was severely photoinhibited during the daytime (F<sub>v</sub>/F<sub>m </sub>= 0.46) and subsequently recovered in the evening (F<sub>v</sub>/F<sub>m</sub> = 0.76). In contrast, WT did not show any substantial changes of F<sub>v</sub>/F<sub>m</sub> values throughout the day (between 0.82 and 0.78). Light dependency of the CO2 assimilation rate in detached shade-leaves of GL showed a response similar
to that in WT, suggesting no substantial difference in photosynthetic performance between them.Several indicators of photoinhibition, including declines in PSII reaction center protein (D1)content, F<sub>v</sub>/Fm value, and O2 evolution and CO2 assimilation rates, all indicated that GL is much
more susceptible to photoinhibition than WT. Kinetics of PAM chlorophyll a fluorescence revealed
that nonphotochemical quenching (NPQ) capacity of GL was lower than that of WT.<br /></p>
<p><b>Conclusion:</b> We conclude that the photosynthetic apparatus of GL is more highly susceptible to
photoinhibition than that of WT.</p>No potential conflict of interest relevant to this article was reported.