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Internal frontier: The pathophysiology of the small intestine
Haruhiko Sugimura,Satoshi Osawa
World Journal of Gastroenterology , 2013, DOI: 10.3748/wjg.v19.i2.161
Abstract: Even though the small intestine occupies a major portion of the abdominal space and is essential for life, in most pathology textbooks any chapter on small intestinal diseases, especially in human beings, is typically shorter than those for other gastrointestinal organs. Clinical and experimental investigations of the small intestine in various clinical situations, such as nutrition management, obesity interventions, and emergency care, have elucidated several important biological problems associated with the small intestine, the last frontier of gastroenterology. In this issue, a review by Professor Basson and his team at Michigan State University sheds light on the changes in the human small intestine under various conditions based on their clinical and surgical experience. With the advent of recent innovations in enteroscopy, a form of endoscopy used to examine deep within the small intestine, the issue that they highlighted, i.e., mucosal adaptation and atrophy of the human small intestine, has emerged as a major and manageable challenge for gastroenterologists in general, including the readers of the World Journal of Gastroenterology.
EPH-EPHRIN in human gastrointestinal cancers
Haruhiko Sugimura,Jian-Dong Wang,Hiroki Mori,Masaru Tsuboi
World Journal of Gastrointestinal Oncology , 2010,
Abstract: Ever since its discovery two decades ago, the erythropoietin-producing hepatoma (EPH)-EPHRIN system has been shown to play multifaceted roles in human gastroenterological cancer as well as neurodevelopment. Over-expression, amplification and point mutations have been found in many human cancers and many investigators have shown correlations between these up-regulations and tumor angiogenesis. Thus, the genes in this family are considered to be potential targets of cancer therapy. On the other hand, the down-regulation of some members as a result of epigenetic changes has also been reported in some cancers. Furthermore, the correlation between altered expressions and clinical prognosis seems to be inconclusive. A huge amount of protein-protein interaction studies on the EPH-EPHRIN system have provided a basic scheme for signal transductions, especially bi-directional signaling involving EPH-ERPHRIN molecules at the cell membrane. This information also provides a manipulative strategy for harnessing the actions of these molecules. In this review, we summarize the known alterations of EPH-EPHRIN genes in human tumors of the esophagus, stomach, colorectum, liver and pancreas and present the perspective that the EPH-EPHRIN system could be a potential target of cancer therapy.
癌变·畸变·突变 , 2009,
Abstract: ?背景与目的:初步探讨myh(mutyhomologue,myh)基因的变异与散发性大肠癌发病风险的关系。材料与方法:应用变性高效液相色谱(denaturinghighperformanceliquidchromatography,dhplc)和测序技术,对140例大肠癌患者及280名正常对照人群的myh基因16个外显子区域中的7个(外显子1、7、9、11、13、14和16)区域进行变异筛查,用spss统计软件进行数据分析。结果:exon1区域的变异位点为exon1-316g>a、exon1-292g>a和intron1+11c>t,3者同时出现在所有变异样本中,且病例组变异危险性均为对照组的8.16倍(p=0.04;or=8.16,95%ci为1.01~203.70);exon16区域的变异为nt1678-80delgtt,病例组中直肠癌患者的变异危险性为结肠癌患者的7.18倍(p=0.04;or=7.18,95%ci为1.102~165);exon11区域查出4例intron10-2a>g变异;exon13区域筛查出2例intron13+12c>t变异;exon14区域筛查出1种错义变异,即exon14+74t>a,p.v463e;exon7和exon9区域未筛查出任何变异。结论:myh变异可能会增加结直肠癌发病风险,应进行监测管理;未筛查到高加索人群中最常见的exon7区域的变异,提示人种之间变异存在差别。
Identification of 5 novel germline APC mutations and characterization of clinical phenotypes in Japanese patients with classical and attenuated familial adenomatous polyposis
Hong Tao, Kazuya Shinmura, Hidetaka Yamada, Masato Maekawa, Satoshi Osawa, Yasuhiro Takayanagi, Kazuya Okamoto, Tomohiro Terai, Hiroki Mori, Toshio Nakamura, Haruhiko Sugimura
BMC Research Notes , 2010, DOI: 10.1186/1756-0500-3-305
Abstract: Nine germline APC mutations, but no large deletions, were identified in the APC locus of 8 (A)FAP patients, and 5 of the mutations, c.446A > T (p.Asp149Val), c.448A > T (p.Lys150X), c.454_457insAGAA (p.Glu152ArgfsX17), c.497insA (p.Thr166AsnfsX2), and c.1958G > C (p.Arg653Ser), were novel mutations. In one patient the p.Asp149Val mutation and p.Lys150X mutation were detected in the same APC allele. The c.1958G > C mutation was located in the last nucleotide of exon 14, and RT-PCR analysis revealed that the mutation resulted in abnormal splicing. The above findings meant that a nonsense mutation, a frameshift mutation, or an exonic mutation leading to abnormal splicing was found in every patient. The following phenotypes, especially extracolonic manifestations, were observed in our (A)FAP patients: (1) multiple gastroduodenal adenomas and early-onset gastric carcinoma in AFAP patients with an exon 4 mutation; (2) a desmoid tumor in two FAP patients with a germline APC mutation outside the region between codons 1403 and 1578, which was previously reported to be associated with the development of desmoid tumors in FAP patients; (3) multiple myeloma in an AFAP patient with an exon 4 mutation.Nine germline APC mutations, 5 of them were novel, were identified in 8 Japanese (A)FAP patients, and some associations between germline APC mutations and extracolonic manifestations were demonstrated. These findings should contribute to establishing relationships between germline APC mutations and the extracolonic manifestations of (A)FAP patients in the future.Familial adenomatous polyposis (FAP) is an autosomal dominant familial cancer syndrome characterized by the early onset of large numbers of adenomatous polyps throughout the entire colon and a nearly 100% lifetime risk of colorectal cancer (CRC) if the colon is not removed [1]. A small proportion of familial colorectal polyposis cases were recently found to be associated with biallelic germline mutations of the MutYH gene [2
The CRKL gene encoding an adaptor protein is amplified, overexpressed, and a possible therapeutic target in gastric cancer
Hiroko Natsume, Kazuya Shinmura, Hong Tao, Hisaki Igarashi, Masaya Suzuki, Kiyoko Nagura, Masanori Goto, Hidetaka Yamada, Matsuyoshi Maeda, Hiroyuki Konno, Satoki Nakamura, Haruhiko Sugimura
Journal of Translational Medicine , 2012, DOI: 10.1186/1479-5876-10-97
Abstract: A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH), and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360) of the primary gastric cancers that were analyzed. The CRKL copy number was also examined in 360 primary gastric cancers using a FISH analysis, and CRKL amplification was found to be associated with CRKL overexpression. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide.These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. Furthermore, our results suggested that CRKL protein has the ability to regulate gastric cell proliferation and has the potential to serve as a molecular therapy target for gastric cancer.Although the overall incidence of gastric cancer is decreasing in many countries, the high incidence of gastric cancer remains a serious health problem, and gastric cancer continues to be the second-leading cause of cancer-related death worldwide [1,2]. Gastric carcinogenesis is a multi-step process in which environmental and
Absence of germline mono-allelic promoter hypermethylation of the CDH1 gene in gastric cancer patients
Hidetaka Yamada, Kazuya Shinmura, Masanori Goto, Moriya Iwaizumi, Hiroyuki Konno, Hideki Kataoka, Masami Yamada, Takachika Ozawa, Toshihiro Tsuneyoshi, Fumihiko Tanioka, Haruhiko Sugimura
Molecular Cancer , 2009, DOI: 10.1186/1476-4598-8-63
Abstract: We prepared two groups of samples, a group of blood samples from 22 patients with familial gastric cancer or early-onset gastric cancer selected from among 39 patients, and a group of non-cancerous gastric tissue samples from 18 patients with sporadic gastric cancer showing loss of CDH1 expression selected from among 159 patients. We then investigated the allele-specific methylation status of the CDH1 promoter by bisulfite sequencing of multiple clones.Although there was a difference between the methylation level of the two alleles in some samples, there was no mono-allelic promoter hypermethylation in any of the samples.These results suggest that germline mono-allelic hypermethylation of the CDH1 promoter is not a major predisposing factor for gastric cancer.Gastric cancer is one of the most common cancers worldwide, including in Japan, and gastric carcinogenesis is a multistep process in which environmental and genetic factors interact [1-6]. Among the genetic factors, the CDH1 gene, alternatively referred to as the E-cadherin gene, is one of the most important tumor suppressor genes in gastric cancer [6], and mutations, chromosomal deletions, and epigenetic modifications have been reported as mechanisms that cause CDH1 inactivation [6-17]. Somatic CDH1 mutations have been found in about 50% of diffuse-type gastric cancers [7], and germline CDH1 mutations have been reported in familial gastric cancers in several ethnic groups [6,8-13]. Promoter region hypermethylation, histone deacetylation, and chromatin condensation have been reported as epigenetic events in the CDH1 gene [14-17]. Among these mechanisms that cause CDH1 inactivation, inactivating germline mutations are the only genetic mechanism which is inherited in gastric cancer. Furthermore, since the germline CDH1 mutations have been found in only a certain percentage of familial gastric cancers, it is reasonable to hypothesize that CDH1 inactivation due to a previously unknown mechanism or inactivation of a
“Demeurer vivant jusqu’à...”: La question de la vie et de la mort et le “religieux commun” chez le dernier Ric ur “Demeurer vivant jusqu’à...”: La question de la vie et de la mort et le “religieux commun” chez le dernier Ric ur
Yasuhiko Sugimura
études Ricoeuriennes / Ricoeur Studies , 2012, DOI: 10.5195/errs.2012.142
Abstract: In spite of his clear and deliberate distinction between philosophical and religious discourse, Ricoeur lets these two aspects of his thought interweave with respect to the deep "conviction" motiving it. The idea of “attestation”, considered as the "password" granting access to his last "hermeneutics of the self", testifies to this in particular. This term, while containing a religious connotation, refers to what Heidegger calls Fundamentalontologie, in which attestation (Bezeugung) is totally de-theologized to indicate how Dasein assumes its own death. But Ricoeur only incorporates this notion into his thought by making it undergo a profound modification. Ricoeur replaces “being–toward–death” with “remaining alive until…”, which allows him to recognize “the religious in common.” How can we develop a conception of the philosophy of religion from this winding process? This article marks a first step toward answering that question. Malgré sa distinction nette qu’il maintient délibérément entre le discours philosophique et le discours confessionnel, Ricoeur laisse s’entrecroiser ces deux niveaux de sa pensée lorsqu’il s’agit de la “conviction” profonde qui la motive. L’idée d’ “attestation ”, considérée comme le “mot de passe” à sa dernière “herméneutique du soi”, en témoigne particulièrement. Tout en renfermant une connotation religieuse, ce terme renvoie à l’ontologie fondamentale heideggérienne, où l’attestation (Bezeugung) est totalement dé-théologisée pour désigner la manière dont le Dasein assume sa propre mort. Mais Ricoeur ne reprend cette notion de Heidegger qu’en lui faisant subir une profonde modification. Il remplace “l’être-pour-la-mort” par le “ demeurer vivant jusqu’à...”, dans la profondeur de laquelle Ricoeur parvient à discerner “ le religieux en commun”. De cette démarche tortueuse, comment peut-on tirer une possible conception de la “philosophie de la religion”? Cet article constitue une première étape pour répondre à cette question.
Introduction Introduction
Yasuhiko Sugimura
études Ricoeuriennes / Ricoeur Studies , 2012, DOI: 10.5195/errs.2012.158
Abstract: The French Introduction to a special issue on Ricoeur and Theology. L'introduction francaise au numero special sur Ricoeur et theologie.
Introduction Introduction
Yasuhiko Sugimura
études Ricoeuriennes / Ricoeur Studies , 2012, DOI: 10.5195/errs.2012.157
Abstract: An introduction to Vol 3, no. 2 (2012), a special issue on Ricoeur and theology. L'introduction anglais au numero sur Ricoeur et la theologie.
In-in formalism on tunneling background: multi-dimensional quantum mechanics
Kazuyuki Sugimura
Physics , 2013, DOI: 10.1103/PhysRevD.88.025037
Abstract: We reformulate quantum tunneling in a multi-dimensional system where the tunneling sector is non-linearly coupled to oscillators. The WKB wave function is explicitly constructed under the assumption that the system was in the ground state before tunneling. We find that the quantum state after tunneling can be expressed in the language of the conventional in-in formalism. Some implications of the result to cosmology are discussed.
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