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Background Since short bowel syndrome (SBS) patients face life-threatening conditions, the development of therapeutic strategies to induce intestinal adaptation has been investigated. Ghrelin, a ligand of growth hormone (GH) secretagogue-receptor that stimulates the release of GH and insulin like growth factor-1 (IGF-1), has several pleiotropic effects. We investigated whether ghrelin induces intestinal adaptation in parenterally fed rats with SBS. Methods Sprague-Dawley rats underwent venous catheterization and were divided into 3 groups: those receiving 90% small bowel resection while leaving the proximal jejunum and distal ileum (90% SBR) with TPN (SBS/TPN group), those receiving 90% SBR with TPN + ghrelin (SBS/TPN/ghrelin group), and those receiving sham operation and fed chow (sham group). Ghrelin was administered intravenously at 10 μg/kg/day. On Day 13, the rats were euthanized and the small intestine harvested, and the histology and crypt cell proliferation rates (CCPR), apoptosis, and nutrient transporter protein levels were analyzed and the plasma hormones were measured. Results The villus height and crypt depth of the ileum in the SBS/TPN/ghrelin group were significantly higher than in the SBS/TPN group. The CCPR of the jejunum and the ileum significantly increased by the administration of ghrelin; however, the apoptosis rates did not significantly differ between the SBS/TPN and SBS/TPN/ghrelin groups. Significant differences did not exist in the plasma IGF-1 and nutrient transporter protein levels among three groups. Conclusions The intravenous administration of ghrelin stimulated the morphological intestinal adaptation of the ileum to a greater degree than the jejunum due to the direct effect of ghrelin.

Aim We have recently established a novel swine model for studies of atherosclerosis using MicrominipigsTM (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries. Methods The µMPs were fed HcD supplemented with 0.7% CA (HcD＋CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated. Results The HcD＋CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD＋CA-fed µMPs. Conclusion To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.

Purpose: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. Experimental Design: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. Results: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. Conclusions: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

// Takuya Yoshimura 1 , Taiji Hamada 2 , Hiroshi Hijioka 1 , Masakazu Souda 2 , Kazuhito Hatanaka 2 , Takako Yoshioka 3 , Sohsuke Yamada 2 , Masato Tsutsui 4 , Yoshihisa Umekita 5 , Norifumi Nakamura 1 , Akihide Tanimoto 2 1 Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan 2 Department of Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan 3 Department of Pathology, Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan 4 Department of Pharmacology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan 5 Division of Organ Pathology, Faculty of Medicine, Tottori University, Yonago, Japan Correspondence to: Akihide Tanimoto, email: akit09@m3.kufm.kagoshima-u.ac.jp Keywords: PCP4/PEP19, breast cancer, EMT, migration, invasion Abbreviations: Purkinje cell protein 4/peptide 19, PCP4/PEP19; epithelial-mesenchymal transition, EMT Received: September 02, 2015 Accepted: January 22, 2016 Published: February 20, 2016 ABSTRACT Purkinje cell protein (PCP) 4/peptide (PEP) 19 is expressed in Purkinje cells where it has a calmodulin-binding, anti-apoptotic function. We recently demonstrated that PCP4/PEP19 is expressed and inhibit apoptosis in human breast cancer cell lines. In the present study we investigated the role of PCP4/PEP19 in cell morphology, adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cell lines. Knockdown of PCP4/PEP19 reduced the formation of filopodia-like cytoplasmic structures and vinculin expression, and enhanced E-cadherin expression. Activities of migration, invasion, and cell adhesion were also decreased after the knockdown of PCP4/PEP19 in MCF-7 and T47D cells. These results suggested that PCP4/PEP19 promotes cancer cell adhesion, migration, and invasion and that PCP4/PEP19 may be a potential target for therapeutic agents in breast cancer treatment which act by inhibiting epithelial-mesenchymal transition and enhancing apoptotic cell death.

Peroxiredoxin 4 (PRDX4) is a member of the peroxiredoxin family of antioxidant enzymes. Previously, we reported that PRDX4 can restrain the initiation and progression of nonalcoholic steatohepatitis by reducing local and systemic reactive oxygen species (ROS) levels. Oxidative stress is recognized as a key factor in hepatocarcinogenesis, and a high ROS level has also been found in hepatocellular carcinoma (HCC). Here, our aim is to investigate roles of PRDX4 in the initiation and progression of HCC.In this study, for hepatocarcinogenesis, wild-type (WT), PRDX4 knockout (PRDX4

// Taiji Hamada 1 , Masakazu Souda 1 , Takuya Yoshimura 2 , Shoko Sasaguri 1 , Kazuhito Hatanaka 1 , Takashi Tasaki 1 , Takako Yoshioka 1 , Yasuyo Ohi 3 , Sohsuke Yamada 4 , Masato Tsutsui 5 , Yoshihisa Umekita 6 and Akihide Tanimoto 1 1 Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 2 Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. 3 Department of Pathology, Sagara Hospital, Social Medical Corporation Hakuaikai, Kagoshima, Japan. 4 Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. 5 Department of Pharmacology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. 6 Division of Organ Pathology, Faculty of Medicine, Tottori University, Yonago, Japan. Correspondence to: Akihide Tanimoto, e-mail: akit09@m3.kufm.kagoshima-u.ac.jp Key words: PCP4/PEP19, breast cancer, apoptosis, CaMKK, Akt Received: April 23, 2014 Accepted: June 23, 2014 Published: July 08, 2014 ABSTRACT The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-Akt Thr308 , enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-Akt Thr308 and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.

The purpose of this study was to evaluate a telemetry system for examining the cardiovascular system in the conscious common marmoset. Parameters obtained were blood pressure, heart rate, respiratory rate, ECG, body temperature and locomotor activity, and these were continuously recorded on a data recorder via the telemetry system and then processed by a computerized system. Diurnal rhythms of blood pressure, heart rate, body temperature and locomotor activity were observed in this system. We studied the effects of astemizole (antihistamine) and nicardipine (Ca2+ channel blocker) on cardiovascular parameters. Astemizole at 30 mg/kg (p.o.) and at 1 to 3 mg/kg (i.v.), prolonged QT interval and induced ventricular extrasystole. Torsades de pointes occurred in one of three cases at 3 mg/kg (i.v.) and 30 mg/kg (p.o.), while it did not affect the blood pressure, respiratory rate and body temperature. Nicardipine at 30 mg/kg (p.o.) caused sustained hypotension and tachycardia. These results demonstrate the usefulness of the telemetry system using the common marmoset for evaluating the cardiovascular effects of drugs under physiological conditions.

Many patients with invasive ductal carcinoma of the pancreas (IDC) have a poor outcome. MUC4 expression has been implicated as a marker for diagnosis and progression of IDC, but there are no studies of the relation between MUC4 expression and patient prognosis in IDC.To investigate the prognostic significance of MUC4 expression in IDC.The expression profiles of MUC4, ErbB2, p27, and MUC1 were investigated in IDC tissues from 135 patients by means of immunohistochemistry.MUC4 was expressed in 43 of the 135 patients with IDC (31.9%). The survival of 21 patients with high MUC4 expression (20% of neoplastic cells stained) was significantly worse than that of the 114 patients with low MUC4 expression (20% of neoplastic cells stained) (p = 0.0043). Univariate analysis showed that high MUC4 expression (p = 0.0061), large primary tumour status (T2) (p = 0.0436), distant metastasis (p = 0.0383), lymphatic invasion (p = 0.0243), and surgical margins (p = 0.0333) were significant risk factors affecting the outcome of patients with IDC. Backward stepwise multivariate analysis showed that MUC4 expression (p = 0.0121), lymph node metastasis (p = 0.0245), and lymphatic invasion (p = 0.0239) were significant independent risk factors. ErbB2, p27, and MUC1 were not independent risk factors.This study shows that MUC4 expression in IDC is a new independent factor for poor prognosis and predicts the outcome of patients with IDC.

Application of superconducting magnets to magnetic confinement fusion reactors is necessary to generate as strong magnetic field as possible since a huge amount of electrical power is consumed if normal conducting magnets are used. And the strong field from the superconducting magnets generates very large electromagnetic force into structural components. It is thus required to establish a design guideline for the superconducting magnet structures. Development of a computer code to calculate stress-strain state in the complex interior of the magnet could serve the requirements.In this paper mathematical formulations available for the finite element implementation are presented to solve detailed stress and strain in layered components of the magnets. The formulations are based on the composite theory of layered structures. Examples of numerical analysis are presented for electromagnetomechanical analysis of toroidal coils of the R-machine which has been discussed and promoted by Institute of Plasma Physics, Nagoya University. The numerical results are compared with those obtained from the beam-shell model. Significant differences are found at some portions between them indicating validity of the present code "MAGCOMP". Detailed stress distributions are shown for each component, which would be furthermore available to analysis and evaluation of quench phenomena.

The use of bellows in a magnetic fusion reactor gives, in many cases, more efficient penetration of the poloidal electric field and very efficient plasma heating in the first phase of operation. This is because bellows sections lead to higher electrical resistance of the vacuum vessel. There are many examples of its application to tokamak type experimental devices such as TFTR, JT-60 and so on. In addition to its higher electrical resistance, the bellows has an ability to absorb large deformation due to thermal expansion and radiation creep, and thus has been applied to the design of a first wall configuration in some conceptual designs of a commercial power reactor. Its application to a vacuum vessel of the Reacting Plasma machine, which was proposed by the Institute of Plasma Physics of Nagoya University, was examined for circular plasmas. When applying the numerical analysis to the bellows, a computational difficulty occurs. Too many unknows appear in a mesh division with a general shell element and these are not easily handled. Therefore in the present paper a finite element code is made to consider an axisymmetric structure loaded by nonsymmetric forces. In the code various types of electromagnetic forces are taken into account. These include the diamagnetic electromagnetic force, the toroidal-current-induced-electromagnetic forces, the electromagnetic forces due to toroidal coil current change and saddle shaped electromagnetic forces. Aluminum is selected as bellows material because of its low activation nature but there are large induced currents because of its higher electrical conductivity. Results of stress analysis show that a leak of the saddle shaped current into the thick aluminum vacuum vessel generates maximum bending stress near a joint between the bellows and the vessel. Stress due to other types of electromagnetic force are significantly smaller.