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Potential of new anti-cancer agents targeting the nuclear translocation signaling of HB-EGF C-terminal fragments during the development of colitis-associated cancer  [PDF]
Satoshi Tanida, Keiji Ozeki, Tsutomu Mizoshita, Hironobu Tsukamoto, Hiromi Kataoka, Takashi Joh
Advances in Bioscience and Biotechnology (ABB) , 2013, DOI: 10.4236/abb.2013.48A2004

In inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD), the duration and severity of inflammation are responsible for the development of colorectal cancer. Inflammatory cytokines such as interleukin (IL)-8 and tumor necrotic factor (TNF)-a, which are released by epithelial and immune cells, are involved in the pathogenesis of colitis-associated cancer. Current treatments for advanced colorectal cancers focus primarily on targeting epidermal growth factor receptor (EGFR) signaling. IL-8 (a G-protein coupled receptor (GPCR) agonist), which is involved in neutrophil recruitment and activation in persistent active colitis, also promotes cleavage of theproheparin-binding epidermal growth factor—like growth factor (proHB-EGF) through a disintegrin and metalloproteinase (ADAM), so that the resulting soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, where HB-EGF-CTF binds the nuclear promyelocytic leukemia zinc finger (PLZF) protein, resulting in the nuclear export of the PLZF transcriptional repressor and thereby affecting cell proliferation. Screening for potent chemical inhibitors of the interactions between HB-EGF-CTF and PLZF identified telmisartan (and related compounds in corporating a biphenyl tetrazole moiety) as inhibitors of cell proliferation. Here we focus on the inhibitory effects of these compounds on cell proliferation, demonstrating the potential for targeting the nuclear translocation of HB-EGF-CTF in the treatment of colitis-associated cancer.

Mechanisms of Cisplatin-Induced Apoptosis and of Cisplatin Sensitivity: Potential of BIN1 to Act as a Potent Predictor of Cisplatin Sensitivity in Gastric Cancer Treatment
Satoshi Tanida,Tsutomu Mizoshita,Keiji Ozeki,Hironobu Tsukamoto,Takeshi Kamiya,Hiromi Kataoka,Daitoku Sakamuro,Takashi Joh
International Journal of Surgical Oncology , 2012, DOI: 10.1155/2012/862879
Abstract: Cisplatin is the most important and efficacious chemotherapeutic agent for the treatment of advanced gastric cancer. Cisplatin forms inter- and intrastrand crosslinked DNA adducts and its cytotoxicity is mediated by propagation of DNA damage recognition signals to downstream pathways involving ATR, p53, p73, and mitogen-activated protein kinases, ultimately resulting in apoptosis. Cisplatin resistance arises through a multifactorial mechanism involving reduced drug uptake, increased drug inactivation, increased DNA damage repair, and inhibition of transmission of DNA damage recognition signals to the apoptotic pathway. In addition, a new mechanism has recently been revealed, in which the oncoprotein c-Myc suppresses bridging integrator 1 (BIN1), thereby releasing poly(ADP-ribose)polymerase 1, which results in increased DNA repair activity and allows cancer cells to acquire cisplatin resistance. The present paper focuses on the molecular mechanisms of cisplatin-induced apoptosis and of cisplatin resistance, in particular on the involvement of BIN1 in the maintenance of cisplatin sensitivity. 1. Introduction Gastric cancer is one of the most prevalent malignancies in Japan and East Asian countries [1], This cancer represents the major cause of mortality in these countries, despite great advances in diagnosis and multimodal treatments [2]. Cisplatin (cis-Diamminedichloroplatinum (II): CDDP) is an important chemotherapeutic agent in the treatment of advanced gastric cancer. Some trials of combination chemotherapy with S-1 and cisplatin as the first-line or second-line treatment for advanced and recurrent gastric cancer have yielded good responses and this treatment is well tolerated [3, 4]. However, there is diversity in the efficacy of cisplatin and in patient response to anti-cancer drugs including cisplatin, which can be of importance in terms of therapeutic outcome. Molecules and factors that are capable of predicting patient responses and resistance to anticancer agents are therefore of great interest and have been extensively studied. A recent study of the potent predictor of cisplatin sensitization Bridging integrator 1 (BIN1, also known as box-dependent MYC-interacting protein 1) demonstrated that BIN1 plays an important role in sensitization to cisplatin [5]. BIN1 is a nucleocytoplasmic adaptor protein that is involved in pleiotropic cellular functions such as suppression of oncogenic transformation. Here, we provide an overview of the molecular mechanism of cisplatin-induced apoptosis and of cisplatin resistance as well as of the mechanisms by
Colon Mucosa Exhibits Loss of Ectopic MUC5AC Expression in Patients with Ulcerative Colitis Treated with Oral Tacrolimus
Tsutomu Mizoshita,Satoshi Tanida,Hironobu Tsukamoto,Keiji Ozeki,Takahito Katano,Masahide Ebi,Yoshinori Mori,Hiromi Kataoka,Takeshi Kamiya,Takashi Joh
ISRN Gastroenterology , 2013, DOI: 10.1155/2013/304894
Abstract: Background. Tacrolimus (FK506) is effective for patients with ulcerative colitis (UC). However, there are few reports on tacrolimus therapy (TT) with respect to the relationship with endoscopic and clinicopathologic findings. Methods. Thirty patients with moderate/severe active UC refractory to or dependent on corticosteroid were treated with oral tacrolimus. The expression of ectopic MUC5AC in the colon was pathologically analyzed before and at 12 weeks after TT, evaluating the Mayo score and steroid-sparing effects. Results. Both mean disease and endoscopic activity index scores were reduced at levels of statistical significance in 26 UC patients receiving more than one month of TT ( ). The dose of prednisolone was reduced by a statistically significant amount ( ), and 14 of the 26 patients (53.8%) had steroid-free status 12 weeks after TT. The decrease in ectopic MUC5AC expression in the mucous cells of the colon was significantly associated with endoscopic improvement of inflammation in the UC patients with TT ( ). Loss of ectopic MUC5AC expression was detected in all patients who had complete response. Conclusions. Tacrolimus appears to be effective for the treatment of moderate/severe UC patients. Loss of ectopic MUC5AC expression may be important for pathologic remission in the colon of UC patients. 1. Introduction Ulcerative colitis (UC) is an idiopathic, chronic, and inflammatory disorder characterized by diarrhea, rectal bleeding, abdominal pain, fever, anemia, and body weight loss [1, 2]. Corticosteroid (CS) therapy is administered to patients with UC when flare-ups occur [1, 3]. Most patients with UC initially respond to CS therapy, but about 20% of patients become steroid dependent within 1 year after CS therapy starts [4]. Steroid-free status is important for patients with UC because CSs often induce undesirable side effects such as diabetes mellitus, osteoporosis, and opportunistic infections [2, 5]. Tacrolimus (FK506) is effective for patients with UC refractory to or dependent on CS and is usually used as a rescue and bridging therapy before initiating azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy [6–12]. Tacrolimus therapy is useful as an alternative therapy for steroid-refractory UC [13]. Tacrolimus induces inhibition of the transcription of the early activation genes encoding interleukin- (IL-) 2, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) that are responsible for the development of inflammation [6, 14]. A higher initial dose of tacrolimus has been observed to ensure achievement of target levels [15]. In a
The Effects of Trait Rumination and Reflection on Mental Health among Japanese University Athletes  [PDF]
Shohei Yamakoshi, Hironobu Tsuchiya
Psychology (PSYCH) , 2016, DOI: 10.4236/psych.2016.74054

The purpose of this study was to use structural equation modeling to examine the effects of trait rumination and reflection on stress response and subjective well-being among Japanese university athletes. One hundred and eighty-two Japanese university athletes (114 males, 68 females, mean age = 20.15 years) participated. Trait rumination was positively associated with stress response and negatively associated with subjective well-being. On the other hand, trait reflection showed a negative association with stress response and a positive association with subjective well-being. In order to develop effective interventions for athletes high in rumination and/or low in reflection, future research should examine the mechanism that explains the different effects of rumination and reflection on athlete mental health.

The Relationship between the Motivation for Physical Activity and Life Skills among Chinese and Japanese College Students  [PDF]
Yulong Chen, Hironobu Tsuchiya
Advances in Physical Education (APE) , 2016, DOI: 10.4236/ape.2016.64029
Abstract: Participation in physical activity is beneficial for health and motivation is an important theme in sport psychology. The purpose of this study was to examine the difference of the relationship between the motivation for physical activity and daily life skills among Chinese and Japanese college students. A questionnaire survey was conducted for 1039 college students (Chinese, n = 526; Japanese, n = 513). Japanese and Chinese version of Physical Activity and Leisure Motivation Scale (PALMS, 1, 2) and a Daily Life Skills Scale for College Students (DLS, 3, 4) were completed by the participants. The PALMS includes eight sub scales which are Mastery, Physical Condition, Affiliation, Psychological Condition, Appearance, Others’ Expectations, Enjoyment and Competition/Ego. DLS includes 8 sub-scales, which are classified into 2 general skills: skills used mainly in personal situations (planning, knowledge summarization, self-esteem, and positive thinking), and skills used generally in interpersonal situations (intimacy, leadership, empathy, and interpersonal manner). The Chinese version of “Daily Life-Skills Scale” created in this study was confirmed, Significant differences between Chinese and Japanese University students were observed. Chinese college students had a higher mean score for the intimacy factor, leadership factor, planning factors, knowledge summarization factor and self-esteem factor. While Japanese college students had a higher mean scores for the aspects of empathy and interpersonal manner. This study found different relationships between the motivation for physical activity and daily life skills among Chinese and Japanese college students. It might be due to cultural differences between those countries. Future research should be focusing on gender and cultural differences of both countries regarding to the motivation for leisure.
Effects of Social Support on Athletes’ Psychological Well-Being: The Correlations among Received Support, Perceived Support, and Personality  [PDF]
Eriko Katagami, Hironobu Tsuchiya
Psychology (PSYCH) , 2016, DOI: 10.4236/psych.2016.713163
Abstract: The current study aimed to examine the impact of received support and perceived support on athletes’ psychological well-being. Furthermore, correlations between received support, perceived support, and personality were investigated. Two hundred and thirty-nine Japanese university student athletes (M age = 19.69 ± 1.01 years) completed the questionnaires regarding social support, psychological well-being, and personality. The results indicated that received support was positively correlated with athletes’ psychological well-being, while perceived support was not found to be a predictor of psychological well-being. Furthermore, it was demonstrated that received support and perceived support were positively correlated with each other. In addition, the results indicated that there was no relationship between received support and positive self-schema, whereas perceived support was positively correlated with positive self-schema. In conclusion, received support can be a salient predictor of athletes’ psychological well-being.
Focused Review: Efficacy of the Rector Spinae Plane Block  [PDF]
Hironobu Ueshima, Hiroshi Otake
Open Journal of Anesthesiology (OJAnes) , 2018, DOI: 10.4236/ojanes.2018.87022
Abstract: Since the original publication on the erector spinae plane (ESP) block in 2016, the technique of the ESP block has evolved significantly in the last few years. This review highlights recent developments in the technique for administering the ESP block and proposes directions for future research. Continuous efforts are being aimed at improving understanding regarding the administration of the ESP block. Current reports suggest that the ESP block provides effective analgesia in thoracic and abdominal sites in patients of all ages. However, no cohort studies or randomized controlled trials were performed in 2016 and 2017. The ESP block is an effective analgesic tool in a wide range of sites. However. We are uncertain how effective the ESP block is compared to other types of regional anesthesia. Therefore, more research on ESP blocks is required.
Telmisartan Inhibits Cell Proliferation by Blocking Nuclear Translocation of ProHB-EGF C-Terminal Fragment in Colon Cancer Cells
Keiji Ozeki, Satoshi Tanida, Chie Morimoto, Yoshimasa Inoue, Tsutomu Mizoshita, Hironobu Tsukamoto, Takaya Shimura, Hiromi Kataoka, Takeshi Kamiya, Eiji Nishiwaki, Hiroshi Ishiguro, Shigeki Higashiyama, Takashi Joh
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056770
Abstract: Background & Aims Current treatment target toward advanced colorectal cancers is mainly focused on the epidermal growth factor receptor (EGFR) signaling, but its additive effects with chemotherapy are still limited. A disintegrin and metalloproteinase (ADAM) cleaves the proheparin-binding epidermal growth factor like growth factor (proHB-EGF). And soluble HB-EGF activates EGFR. In parallel, the carboxy-terminal fragment of proHB-EGF (HB-EGF-CTF) translocates into the inner nuclear membrane, and subsequently exerts on the regulation of cell proliferation by binding nuclear promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor, thereby causing its nuclear export. We hypothesized that the inhibition of HB-EGF-CTF nuclear translocation may be a new strategy in preventing cell proliferation. Methods 12-O-tetradecanoylphorbor-13-acetate (TPA) was treated to activate ADAM. Nine-thousand chemical compounds were screened for their efficacies in blocking the binding of HB-EGF-CTF to promyelocytic leukemia zinc finger (PLZF) with Alphascreen system. The obtained candidates were then used to block the binding of HB-EGF-CTF to PLZF in colon cancer cells, HT29 and HCT116. Cell proliferation was investigated with a growth curve assay. The intracellular localization, and association between HB-EGF-CTF and PLZF, was assessed with immunofluorescent staining, and immunoprecipitation and Western blotting, respectively. The effects of obtained candidates on EGFR phosphorylation and on nuclear translocation of HB-EGF-CTF and export of PLZF during the angiotensin II type1 receptor (AT1R) knockdown were also investigated. Results Telmisartan and candesartan were found to be potential candidates. Telmisartan inhibited TPA-induced cell proliferation stronger than candesartan. Telmisartan, but not candesartan blocked the nuclear translocation of HB-EGF-CTF, and binding of HB-EGF-CTF to PLZF, during TPA stimulation. Both telmisartan and candesartan did not inhibit TPA-induced EGFR phosphorylation, and telmisartan, but not candesartan, inhibited TPA-induced nuclear translocation of HB-EGF-CTF after knockdown of AT1R. Conclusions The inhibition of HB-EGF-CTF nuclear translocation with telmisartan may be a novel strategy in preventing cell proliferation.
Questioning the Weber Thesis: Capitalist Ethics and the Hebrew Bible?  [PDF]
Sigmund Wagner-Tsukamoto
Sociology Mind (SM) , 2012, DOI: 10.4236/sm.2012.21001
Abstract: Weber’s thesis proposed that it was ascetic Protestantism which supported the emergence of modern capitalism in 17th and 18th century Europe, and that this was a completely new and unique phenomenon in the history of mankind up to that point in time. This paper casts doubt on the Weber thesis by examining findings from an economic reconstruction of the Hebrew Bible, and proposing that modern capitalism the way Weber understood it is already visible in the ancient religious text of the “Hebrew Bible”. By means of institutional economic reconstruction, I show that the Hebrew Bible and particularly the stories involving Jacob and Joseph reveal a conceptual structure that can be compared with ideas of modern constitutional and institutional economics. Through this reconstruction, I find myself in agreement with one of Weber’s early but largely forgotten adversaries, Werner Sombart, who suggested, in a behavioral tradition, that other religions, and more specifically Jewish thought, contributed to the emergence of modern capitalism long before the advent of Protestantism.
Complexity Reduced MIMO Interleaved SC-FDMA Receiver with Iterative Detection  [PDF]
Masaki Tsukamoto, Yasunori Iwanami
Int'l J. of Communications, Network and System Sciences (IJCNS) , 2014, DOI: 10.4236/ijcns.2014.712051
Abstract: In this paper, we propose the receiver structure for Multiple Input Multiple Output (MIMO) Interleaved Single Carrier-Frequency Division Multiple Access (SC-FDMA) where the Frequency Domain Equalization (FDE) is firstly done for obtaining the tentative decision results and secondly using them the Inter-Symbol Interference (ISI) is cancelled by ISI canceller and then the Maximum Likelihood Detection (MLD) is used for separating the spatially multiplexed signals. Furthermore the output from MLD is fed back to ISI canceller repeatedly. In order to reduce the complexity, we replace the MLD by QR Decomposition with M-Algorithm (QRD-M) or Sphere Decoding (SD). Moreover, we add the soft output function to SD using Repeated Tree Search (RTS) algorithm to generate soft replica for ISI cancellation. We also refer to the Single Tree Search (STS) algorithm to further reduce the complexity of RTS. By examining the BER characteristics and the complexity reduction through computer simulations, we have verified the effectiveness of proposed receiver structure.
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