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Rationale and Study Protocol of the J-SAVER Study: A Phase II Study of S-1 on Alternate Days Combined with Bevacizumab in Patients Aged ≥75 Years with Metastatic Colorectal Cancer  [PDF]
Toshikazu Moriwaki, Tetsuya Eto, Akihito Tsuji, Nobushige Kakinoki, Mitsuo Shimada, Takashi Maeba, Hiroaki Hatano, Ikuo Takahashi, Hiroyasu Ishida, Kazuho Ikeda, Yoshiaki Bando, Ichinosuke Hyodo
Journal of Cancer Therapy (JCT) , 2017, DOI: 10.4236/jct.2017.811088
Abstract: Fluoropyrimidine combined with bevacizumab is commonly used in elderly patients with metastatic colorectal cancer worldwide. However, the proportion of elderly patients who discontinued treatment due to toxicities was higher than that of younger patients. The aim of this study is to develop a less toxic schedule of S-1, while maintaining the anti-tumor effect. This phase II study is aimed to evaluate an alternate-day administration of S-1 combined with bevacizumab in untreated elderly patients (aged ≥75 years) with metastatic colorectal cancer. The primary endpoint is progression-free survival, and the secondary endpoints are safety, response rate, and overall survival. The expected median progression-free survival is 8.5 months, and the minimum efficacy threshold is 5.0 months. The total required sample size is calculated as 50 patients, with a 2-sided type I error of 0.10 and a power of more than 80%. This study is ongoing, and fifty-four patients were enrolled until October 2016. We hope that S-1 on alternate days combined with bevacizumab for elderly patients with colorectal cancer is well tolerated and can maintain effectiveness. Trial registration: UMIN clinical trials UMIN000010402.
Myocardial insulin resistance does not always parallel skeletal muscle and whole body insulin resistance: A mini review
—Myocardial Insulin Resistance

Ikuo Yokoyama
Journal of Biomedical Science and Engineering (JBiSE) , 2013, DOI: 10.4236/jbise.2013.61005

Insulin resistance (IR) is recognized to be of critical importance in a variety of metabolic diseases and coronary artery disease (CAD). Impaired skeletal muscle glucose utilization (SMGU) plays an important role in the pathogenesis of IR, whereas it is controversial whether myocardial IR is similar in this respect. Methods: Twenty-two studies of myocardial IR and skeletal muscle IR using positron emission tomography (PET) and/or whole body IR were reviewed. Heart and skeletal muscle IR were measured with PET and18F-FDG under hyperinsulinemic euglycemic insulin clamp technique. Whole body IR was also determined at the time of PET under hyperinsulinemic euglycemic insulin clamp technique. Results: One study reported that heart and skeletal muscle IR is present in untreated type 2 diabetes mellitus (T2DM), hypertension and CAD (as reflected in a myocardial glucose utiliation rate (MGU) in T2DM vs control [p < 0.01], and an SMGU in T2DM vs control [p < 0.01]). A significant negative relationship between MGU and FFA (r = -0.665, p < 0.01) and a significant positive relationship between MGU and whole body IR (r = 0.855, p < 0.01) was also observed in T2DM. Significantly reduced MGU and SMGU and a positive correlation between them (r = 0.78, P < 0.0001) were noted in the normal myocardial segments of patients with CAD. Another study showed that heart and skeletal muscle IR was present in T2DM both with CAD (MGU):, p < 0.01; SMGU: p < 0.01) or without CAD (MGU: p < 0.01; SMGU: p = 0.06). A significant positive relationship between the whole body glucose disposal rate and MGU (r = 0.60, p < 0.01) as well as SMGU (r = 0.76, p < 0.01) was also reported. Much more severe myocardial IR in T2DM and hypertriglyceridemia (p < 0.05) due to increased plasma free fatty acids, FFA (r = -0.60, p < 0.01) and plasma triglycerides levels (r =-0.74, p < 0.001) was reported. A significant negative relationship between MGU and plasma triglycerides (r = -0.74, p < 0.001) was also noted. However, other studies reported that MGU was increased in essential hypertension despite the fact that SMGU and whole body IR were present. Furthermore, it has also been

Ezetimibe Completely Replaced LDL-Apheresis for the Treatment of Familial Hypercholesterolemia and Coronary Artery Disease after CABG—A Case Report  [PDF]
Ikuo Yokoyama
Journal of Biomedical Science and Engineering (JBiSE) , 2013, DOI: 10.4236/jbise.2013.62A028
Intensive treatment of hyperlipidemia is an important factor in the prevention of cardiovascular disease. Among several therapies, statins are well recognized as playing a central role, although low density lipoprotein bound cholesterol-apheresis can be used to treat very severe cases of familial hypercholesterolemia. However, statins are not always effective on their own and, recently, ezetimibe has emerged as a unique anti- hypercholesterolemic drug that acts as a cholesterol transporter inhibitor; its role is only partially understood. I experienced rare case that appeared to benefit from ezetimibe therapy, and report them as they help increase our knowledge of this novel drug.
Statins Activate Human PPAR Promoter and Increase PPAR mRNA Expression and Activation in HepG2 Cells
Makoto Seo,Ikuo Inoue,Masaaki Ikeda,Takanari Nakano,Seiichiro Takahashi,Shigehiro Katayama,Tsugikazu Komoda
PPAR Research , 2008, DOI: 10.1155/2008/316306
Abstract: Statins increase peroxisome proliferator-activated receptor (PPAR) mRNA expression, but the mechanism of this increased PPAR production remains elusive. To examine the regulation of PPAR production, we examined the effect of 7 statins (atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) on human PPAR promoter activity, mRNA expression, nuclear protein levels, and transcriptional activity. The main results are as follows. (1) Majority of statins enhanced PPAR promoter activity in a dose-dependent manner in HepG2 cells transfected with the human PPAR promoter. This enhancement may be mediated by statin-induced HNF-4. (2) PPAR mRNA expression was increased by statin treatment. (3) The PPAR levels in nuclear fractions were increased by statin treatment. (4) Simvastatin, pravastatin, and cerivastatin markedly enhanced transcriptional activity in 293T cells cotransfected with acyl-coenzyme A oxidase promoter and PPAR/RXR expression vectors. In summary, these data demonstrate that PPAR production and activation are upregulated through the PPAR promoter activity by statin treatment.
A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2
Yasuhiro Takenaka, Ikuo Inoue, Takanari Nakano, Yuichi Shinoda, Masaaki Ikeda, Takuya Awata, Shigehiro Katayama
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065583
Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Pparγ (Pparγ1sv) that encodes PPARγ1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5′-UTR sequence, relative to those of Pparγ1 and Pparγ2 mRNAs, indicating the presence of a novel transcriptional initiation site and promoter for Pparγ expression. Pparγ1sv was highly expressed in the white and brown adipose tissues at levels comparable to Pparγ2. Pparγ1sv was synergistically up-regulated with Pparγ2 during adipocyte differentiation of 3T3-L1 cells and mouse primary cultured preadipocytes. Inhibition of Pparγ1sv by specific siRNAs completely abolished the induced adipogenesis in 3T3-L1 cells. C/EBPβ and C/EBPδ activated both the Pparγ1sv and Pparγ2 promoters in 3T3-L1 preadipocytes. These findings suggest that Pparγ1sv and Pparγ2 synergistically regulate the early stage of the adipocyte differentiation.
Effects of Self-Presentation on One’s Self-Regulatory Resources When One Is Faced with the Multiple Audience Problem  [PDF]
Yu Kasagi, Ikuo Daibo
Psychology (PSYCH) , 2015, DOI: 10.4236/psych.2015.612141
Abstract: This study examined the effects of self-presentation on participants’ self-regulatory resources when the participants were faced with the multiple audience problem. In the experiment, participants (N = 38) were assigned to either the consistent condition or inconsistent condition, and were asked to make a speech in three sessions. The inconsistent condition was manipulated such that the participants would be confronted with the multiple audience problem in speech session 3. After the three speech sessions, the participants were told to work on 200 multiplication problems (3 digits × 3 digits) until they had finished solving all the problems or until they gave up or felt that they were unable to continue working on the problems. An experimenter timed the participants with a stopwatch as they worked on the problems. The results showed that the participants in the inconsistent condition gave up faster than the participants in the consistent condition. Moreover, the participants in the inconsistent condition solved less multiplication problems than the participants in the consistent condition. On the basis of these results, we concluded that when one was faced with the multiple audience problem, self-presentation was extremely difficult and entailed effortful forms of self-presentation that depleted one’s self-regulatory resources. Further research is necessary to examine the effects of compensatory self-enhancement, which has been found to be an effective coping strategy on self-regulatory resources when one is faced with the multiple audience problem.
Sentinel Lymph Node Biopsy as Guidance for Lateral Neck Dissection in Patients with Papillary Thyroid Carcinoma  [PDF]
Yoshifumi Ikeda
Surgical Science (SS) , 2011, DOI: 10.4236/ss.2011.22012
Abstract: Introduction: The surgical management of lateral lymph nodes in differentiated thyroid carcinoma is controversies. Therefore, we analyzed whether sentinel lymph nodes (SLN) biopsy of the first draining nodes in the jugulo-carotid chain is an accurate technique to select patients with true-positive but nonpalpable lymph nodes for selective lateral node dissection. Materials and Methods: From January 2009 to December 2009, 12 patients with solitary papillary carcinoma measuring 2 cm by ultrasonography were included in this study. After the thyroid gland was exposed to avoid injuring the lateral thyroid lymphatic connection, approximately 0.2 ml of 5mg/ml indocyanine green was injected into the parenchyma of upper and lower thyroid gland. Some stained lymph nodes in the jugulo-carotid chain could be identified following the stained lymphatic duct and dissected as the SLN. After that, thyroidectomy with modified neck dissection was performed. Results: The mean tumor size was 22.1 ± 4.6 mm. Identification and biopsy of stained SLN in the ipsilateral jugulo-carotid chain was successful in all 12 cases. In 6 cases, histopathological analysis of SLNs revealed metastases of the papillary thyroid carcinoma. Among them, 2 cases had additional metastatic lymph nodes in the ipsilateral compartment. Of the 6 patients who had negative lymph node metastasis (LNM) in SLNs, all patients had negative LNM in the ipsilateral compartment. Conclusions: The method may be helpful in the detection of true-positive but nonpalpable lymph nodes and may support a decision to perform a selective lateral node dissection in patients with papillary thyroid carcinoma.
Structured triacylglycerol containing behenic and oleic acids suppresses triacylglycerol absorption and prevents obesity in rats
Makiko Kojima, Nobuhiko Tachibana, Takashi Yamahira, Satoshi Seino, Ayako Izumisawa, Nobuo Sagi, Toshiharu Arishima, Mitsutaka Kohno, Kiyoharu Takamatsu, Motohiko Hirotsuka, Ikuo Ikeda
Lipids in Health and Disease , 2010, DOI: 10.1186/1476-511x-9-77
Abstract: In Experiment 1, rats were fed either BOO or soybean oil (SO) diet for 6 weeks. In the BOO diet, 20% of SO was replaced with an experimental oil rich in BOO. In Experiments 2 and 3, rats cannulated in the thoracic duct were administered an emulsions containing trioleoylglycerol (OOO) or an oil mixture (OOO:BOO, 9:1). Tri[1-14C]oleoylglycerol (14C-OOO) was added to the emulsions administered in Experiment 3.No observable differences were detected in food intake or body weight gain between the BOO and SO groups in Experiment 1. Plasma and liver TAG concentrations and visceral fat weights were significantly lower in the BOO group than in the SO group. The apparent absorption rate of fat was significantly lower in the BOO group than in the SO group. In Experiment 2, the lymphatic recovery of oleic and behenic acids was significantly lower at 5 and 6 h after BOO administration than after OOO administration. In Experiment 3, the lymphatic recovery of 14C-OOO was significantly lower at 5 and 6 h after BOO administration than after OOO administration.These results suggest that BOO prevents deposition of visceral fat and hepatic TAG by lowering and delaying intestinal absorption of TAG.Behenic acid is a long-chain saturated fatty acid consisting of 22 carbon atoms. The physiological functions of structured triacylglycerols (TAGs) containing behenic and medium-chain fatty acids have been examined in previous studies [1-3]. In these studies, structured TAGs were shown to reduce fat absorption in rats. This reduction has been attributed to the low absorbability of behenic acid. Therefore, behenic acid can be utilized as a functional component of low-calorie fats. Dietary fats containing behenic acid are expected to reduce visceral fat deposition. However, only few studies have examined the effects of TAG containing behenic acid on visceral fat deposition.1(3)-Behenoyl-2,3(1)-dioleoyl-rac-glycerol (BOO) is a structured TAG with behenic acid at the 1 or 3 position. In our previou
Multiple genome alignment for identifying the core structure among moderately related microbial genomes
Ikuo Uchiyama
BMC Genomics , 2008, DOI: 10.1186/1471-2164-9-515
Abstract: The method was applied to genome comparisons of two well-characterized families, Bacillaceae and Enterobacteriaceae, and identified their core structures comprising 1438 and 2125 OGs, respectively. The core sets contained most of the essential genes and their related genes, which were primarily included in the intersection of the two core sets comprising around 700 OGs. The definition of the genomic core based on gene order conservation was demonstrated to be more robust than the simpler approach based only on gene conservation. We also investigated the core structures in terms of G+C content homogeneity and phylogenetic congruence, and found that the core genes primarily exhibited the expected characteristic, i.e., being indigenous and sharing the same history, more than the non-core genes.The results demonstrate that our strategy of genome alignment based on gene order conservation can provide an effective approach to identify the genomic core among moderately related microbial genomes.A growing body of evidence is supporting the idea that horizontal gene transfers (HGT) have played a significant role in prokaryotic genome evolution [1-6]. Although these observations have stimulated researchers to develop a new paradigm of HGT-driven reticulate evolution that challenges the traditional tree-based phylogeny concept [7-9], it can be argued that prokaryotic phylogeny can still be inferred using a certain subset of genes ("core genes") that have mainly transferred vertically throughout evolution [10-12]. In fact, the genes constituting a prokaryotic genome appear to be divided into two classes: a "core gene pool" that comprises intrinsic genes encoding the proteins of basic cellular functions, and a "flexible gene pool" that comprises HGT-acquired genes encoding proteins which function under particular conditions, such as genomic islands [13]. Therefore, the identification of the genomic core conserved among each taxonomic group is crucial, not only for establishing t
Flat structure for the simple elliptic singularity of type $\widetilde {\bf E_6}$ and Jacobi form
Ikuo Satake
Physics , 1993,
Abstract: In order to construct the inverse mapping of the period mapping for the primitive form for the semi-universal deformation of a simple elliptic singularity, K.Saito introduced in [5] the ``flat structure'' for the extended affine root system. In section 3, we construct explicitly the flat theta invariants in the case of type $E_6$ using the Jacobi form introduced by Wirthm\"uller [7]. Combining the results of Kato [3], Noumi [4] (explicit description of the flat coordinates), this gives an answer to Jacobi's inversion problem (up to linear isomorphism) of this period mapping for a simple elliptic singularity of type $\tilde E_6$ (see also [6]). The details will be published elsewhere.
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