Phosphoregulation of the actin cytoskeleton during endocytosis in the yeast saccharomyces cerevisiae

Ph.DDOCTOR OF PHILOSOPH

Heterogeneity of Molecular Structure of Ag Photo-Diffused Ge\u3csub\u3e30\u3c/sub\u3eSe\u3csub\u3e70\u3c/sub\u3e Thin Films

Silver photodiffusion in thin Ge30Se70 films is investigated in order to understand the structure forming in the Ge-Se host after introduction of Ag in it. Optical micrographs point towards formation of homogeneous films after deposition of the Ge-Se material on glass substrate. This structure changes and occurrence of heterogeneous regions is imaged after Ag is introduced into the Ge-Se host. Raman spectroscopy provides data about the development of the structural organization in the host in depth. It confirms that while the initial non-doped films are organized in a structure corresponding to the bulk material with analogous composition, after Ag photodiffusion, the structure on the interface Ag/Ge30Se70 film is identified as being amorphous Ag8GeSe6 which continuously changes in depth to structure of Ge-rich material. Raman spectra testify that Ag distribution reaches the bottom of the hosting Ge30Se70 films

Metrical Analyses on Population and Economic Growth and Urban ‘Quality Of Life’ of Metropolitan Cities in China during the 00s

In the first decade of the 21st century, along with rapid economic growth, China also experienced rapid urbanization, more specifically, the concentration of large populations from rural areas into urban areas. In 2005, the Chinese Government, in its Eleventh Five-Year Plan, had an attitude of promoting the sound development of urbanization, while also promoting cooperative development in regions. However, there has emerging some mass media reports on the shadow side of the rapid growth and the rapid concentration such as environmental problems e.g. pollution affairs since early of the 2010’s. These are the same as Japan had already suffered from the 1960's to 70's, so it suggests that the new era has come when Chinese inquire their 'Quality Of Life (QOL)'. This paper analyses 51 metropolitan cities (prefecture-level cities with over one million population in 2000). Firstly, mainly based on Population Census Reports data in 2000 and 2010, we examine the economic growth and the urban in-flow migration, and the relationship between these two kinds of the indicators in detail. We show a classification of 51 cities through cluster analysis and their geographical distributions, and then we summarize the dynamics of all over China economy and population during this decade. Based on published statistical data in 2005 and 2010 such as China City Statistical Yearbooks, we propose an indicator-system on China urban QOL of the 51 metropolitan cities. This QOL system is consisted of five groups of indicators (Education/ Daily-Life Convenience/ Urban-Life Enivironment/ Consumer-Side Sustainability/ Indstry-Side Sustainability) of 23 elemental indicators. At one time-point, QOL value is defined as an average of the group indicators, each of which is an average of each standard scores of the elemental indicators. On the other hand, ‘Change of QOL’ value is defined as an average of each standard scores of the change ratios of the elemental indicators. Using these kinds of QOL indicators, we also show a classification of the metropolitan cities through cluster analysis and their geographical distributions in China. Furthermore, we analyse correlations between the five group indicators of the QOL system and the economic level and its growth through MRA. As the results, there can be observed the negative values of correlation between GRP per capita and Consumer-Side Sustainability and so on statistical significantly

Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype

Division of Translational and Clinical Oncolog

Low expression of γ-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype

金沢大学がん研究所分子標的がん医療研究開発センターThe CpG island methylator phenotype (CIMP+) in colorectal cancer (CRC) is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions. We previously demonstrated that CIMP+ was associated with elevated concentrations of folate intermediates in tumour tissues. In the present study, we investigated whether CIMP+ was associated with a specific mRNA expression pattern for folate- and nucleotide-metabolising enzymes. An exploratory study was conducted on 114 CRC samples from Australia. mRNA levels for 17 genes involved in folate and nucleotide metabolism were measured by real-time RT-PCR. CIMP+ was determined by real-time methylation-specific PCR and compared to mRNA expression. Candidate genes showing association with CIMP+ were further investigated in a replication cohort of 150 CRC samples from Japan. In the exploratory study, low expression of γ-glutamyl hydrolase (GGH) was strongly associated with CIMP+ and CIMP+-related clinicopathological and molecular features. Trends for inverse association between GGH expression and the concentration of folate intermediates were also observed. Analysis of the replication cohort confirmed that GGH expression was significantly lower in CIMP+ CRC. Promoter hypermethylation of GGH was observed in only 5.6% (1 out of 18) CIMP+ tumours and could not account for the low expression level of this gene. CIMP+ CRC is associated with low expression of GGH, suggesting involvement of the folate pathway in the development and/or progression of this phenotype. Further studies of folate metabolism in CIMP+ CRC may help to elucidate the aetiology of these tumours and to predict their response to anti-folates and 5-fluorouracil/leucovorin. © 2008 Cancer Research UK

Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase

金沢大学がん研究所分子標的がん医療研究開発センターPurpose: Glycogen synthase kinase-3β (GSK3β) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3β in gastrointestinal, pancreatic, and liver cancers. Experimental Design: Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3β expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3β activity by in vitro kinase assay. The effects of small-molecule GSK3β inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3β inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells. Results: Cancer cell lines and most cancer tissues showed increased GSK3β expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3β resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3β inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity. Conclusion: The results indicate that deregulated GSK3β sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase. © 2009 American Association for Cancer Research

Mechanism of decrease of oral bioavailability of cyclosporin a during immunotherapy upon coadministration of amphotericin B

金沢大学附属病院薬剤部The trough level of blood concentration of cyclosporin A (CyA) in a patient receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). This clinical observation was confirmed experimentally in Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after i.v. or p.o. administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67% or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in the duodenum to about three times the control, and expression of CYP3A2 mRNA in the liver was increased to about twice the control. The P-gp and CYP3A2 proteins were increased significantly. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased first-pass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. It is suggested that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA. Copyright © 2008 John Wiley & Sons, Ltd

Origin of giant photocontraction in obliquely deposited amorphous Ge_xSe_{1-x} thin- films and the intermediate phase

Obliquely deposited amorphous Ge_xSe{1-x} thin-films at several compositions in the 0.15 < x < 0.333 range, and at several obliqueness angles in the 0 < alpha < 80 range at each x were evaporated on Si and glass substrates. Here alpha designates the angle between film normal and direction of vapor transport. Raman scattering, ir reflectance and optical absorption measurements were undertaken to characterize the vibrational density of states and optical band gaps. Edge views of films in SEM confirm the columnar structure of obliquely (alpha = 80) deposited films. Films, mounted in a cold stage flushed with N2 gas, were irradiated to UV radiation from a Hg-Xe arc lamp, an

GSK3β阻害に基づく新しいがん治療法と抗がん剤,放射線感受性の修飾効果

金沢大学がん進展制御研究所glycogen synthase kinase(GSK)-3βは基幹的細胞機能を調節する多機能セリン・スレオニンキナーゼである.インスリン経路,神経細胞や造骨細胞に対する病的作用からGSK3βは糖尿病,神経変性疾患や骨粗鬆症の創薬標的として注目されている.我々は,正常細胞のWnt経路制御作用からがん抑制的に働く機能分子と認識されているGSK3βの消化器がんや呼吸器がんへの関与に着目した.そして,GSK3βの過剰発現やそのリン酸化による酵素活性調節の破綻が腫瘍細胞の生存や増殖を維持・推進するという,Wnt経路抑制機能とは異なる消化器がんに共通の病的作用を発見した.この発見に基づいて,GSK3β阻害による抗腫瘍効果を大腸がんや膵がん細胞とそれぞれの担がん動物モデルで実証し,本酵素が新しいがん治療標的であると提唱した.GSK3β阻害による制がん効果の分子メカニズムは細胞周期制御とがん抑制分子経路や細胞老化の誘導によることを明らかにした.また,GSK3β阻害により,消化器がん細胞に対する抗がん剤や放射線の効果が増強することを見出した.これらの結果は,消化器がんにおけるGSK3βの病的作用とGSK3β阻害による新しいがん治療法開発の理論根拠である.消化器がんとは異なり,肺がんではGSK3βの異常や病的作用は認められなかった.研究課題/領域番号:20890086, 研究期間(年度):2008 – 200