7,070 research outputs found
Increased Expression of 14-3-3 beta Promotes Tumor Progression and Predicts Extrahepatic Metastasis and Worse Survival in Hepatocellular Carcinoma (vol 179, pg 2698, 2011)
No full textStudies on the Roles of 14-3-3 Proteins and Focal Adhesion Kinases in Cancer Metastasis
No full text緒論：
肝癌是台灣地區的嚴重健康問題。雖然近年來在肝癌的早期診斷及積極治療方面有長足的進步，肝內復發以及肝外轉移依然還是許多病患治療失敗的原因。在我們先前的研究中發現，一種可以做為蛋白質co-factor的蛋白14-3-3，和大腸癌細胞的移動有密切的關係，而且其和細胞內一種和cytoskeleton關係密切的蛋白FAK (focal adhesion kinase)，的表現有相當高的一致性。由於在初步實驗中我們也發現14-3-3ε蛋白在部分肝癌細胞中有過度表現的情形，我們因此在本研究中假設14-3-3ε可以透過增加FAK蛋白的表現來增加肝癌的轉移，並嘗試加以證實；另外我們也將嘗試找尋可以抑制14-3-3ε-FAK途徑的標靶治療藥物，以期可以在臨床上應用本研究的成果。
病患及研究方法
在本研究中我們建立了兩個肝癌世代，收集了自西元1999年1月至西元2004年7月在台灣某醫學中心接受主要為手術切除治療的肝癌病患，兩個世代各有55人及114人，其中各有18人 (32.7%) 及34人 (29.8%) 後續發生肝外轉移。在本研究中，對病患檢體中14-3-3ε及FAK蛋白的表現量是以免疫組織染色 (immunohistochemical staining)檢驗，並以半定量的Quick score (Q-score) method方式判讀。其它的實驗方法則依照一般慣用的protocol及廠商提供的說明書加以進行。
結果
首先我們確認了在肝癌細胞株SK-Hep1中，14-3-3ε的過度表現會使其在two-chamber invasion assay中表現的細胞侵襲性明顯增加。而在病患世代研究中，14-3-3ε可以在61.3%病患的原發肝癌中發現其表現量增加，同時這些病患會有明顯較差的5年無疾病存活率 (54.9±7.7% vs. 28.6±5.4%，p=0.004)，明顯較差的5年整體存活率 (66.5±7.3% vs. 42.4±6.0%，p=0.007)，以及較高的5年累積肝外轉移發生率 (48.4±6.8% vs. 14.0±5.9%，p<0.001)。接著我們確認了在肝癌細胞株及病患檢體中14-3-3ε和FAK蛋白的表現有極高的一致性，同時在SK-Hep1細胞中14-3-3ε的過度表現會增加NF-κB 和FAK promoter的結合，因而增加FAK基因的轉錄及蛋白表現。另一方面，FAK蛋白也可以在61.8%的肝癌病患中過度表現，同時FAK的過度表現也和肝癌病患較差的5年無疾病存活率 (51.5±8.7% vs. 90.2±6.6%，p=0.041)，明顯較差的5年整體存活率 (51.5±8.7% vs. 90.2±6.6%，p=0.004) 以及較高的5年累積肝外轉移發生率 (36.1±9.2% vs. 20.9±8.4%，p=0.045) 明顯相關。在進一步的研究中，蛋白體抑制劑(proteasome inhibitors)如MG-132及PS-341 (bortezomib) 等，可以明顯在wound healing assay中抑制癌細胞的移動。而MG-132或PS-341均可以降低14-3-3ε和FAK promoter的活性，並進而抑制基因轉錄及蛋白表現。我們同時也證實MG-132或PS-341對FAK promoter的抑制是透過降低NF-κB和其promoter的結合而達成的。
結論及展望
在本研究中，我們確認14-3-3ε的過度表現可透過增加FAK的表現來促進肝癌的轉移，而且這個途徑具有重要的臨床意義；蛋白體抑制劑則具有抑制這個途徑的效果。根據這些結果，14-3-3ε及FAK蛋白的表現量可以做為肝癌病患的預後及發生肝癌轉移的重要預測因子，而蛋白體抑制劑也有可能可以做為肝癌病患接受根治性治療後預防再發或轉移的輔助治療 (adjuvant therapy) 之用；但這些概念的實際應用仍需待進一步的臨床試驗加以證實。Introduction:
Hepatocellular carcinoma (HCC) is a serious health problem in Taiwan. Despite the progress in early diagnosis and aggressive treatment for HCCs, intrahepatic recurrence and extrahepatic metastasis still result in a high proportion of treatment failure. In our previous study, we found that a co-factor protein, 14-3-3, is related to increased migration of colon cancer cells, and synchronized over-expression of a cytoskeleton protein, focal adhesion kinase (FAK), with 14-3-3 was identified also. Because our preliminary data revealed that 14-3-3ε is over-expressed in some HCCs, we hypothesized that 14-3-3ε can increase HCC metastasis through a FAK-mediated mechanism. Furthermore, we also want to explore if any targeted therapy could be used against this signaling pathway.
Patients and Methods:
Two patient cohorts were established in our study, enrolling 55 and 114 HCC patients, respectively, receiving mainly surgical resection from January of 1999 to July of 2004 in a medical center in Taiwan. Eighteen (32.7%) and 34 patients (29.8%) experienced extrahepatic metastasis in the two cohorts, respectively. The protein expression levels of 14-3-3ε and FAK in pathological specimens were evaluated by a semi-quantitative immunohistochemical staining method, i.e. the Quick score (Q-score) method. Other laboratory methods in this thesis were all complied with the usual protocols and the manufacturer’s instructions.
Results:
In the two-chamber invasion assay, SK-Hep1 cells with over-expressed 14-3-3ε showed increased invasiveness over control. In the 2nd cohort, 14-3-3ε over-expression was found in 61.3% of primary HCC, which predicted worse 5-year disease-free survival rate (54.9±7.7% vs. 28.6±5.4%, p=0.004), worse 5-year overall survival rate (66.5±7.3% vs. 42.4±6.0%, p=0.007) and higher 5-year cumulative incidence of extrahepatic metastasis (48.4±6.8% vs. 14.0±5.9%, p<0.001). Furthermore, we demonstrated the correlated protein expression of 14-3-3ε and FAK in cell lines and patient samples, and 14-3-3ε over-expression in SK-Hep1 cells resulted in increased NF-κB binding activities on FAK promoters and then increased FAK gene transcription. Next we found 61.8% of primary HCC over-expressed FAK, which was associated with worse 5-year disease-free survival rate (51.5±8.7% vs. 90.2±6.6%, p=0.041), worse 5-year overall survival rate (51.5±8.7% vs. 90.2±6.6%, p=0.004) and higher 5-year cumulative incidence of extrahepatic metastasis (36.1±9.2% vs. 20.9±8.4%, p=0.045). Proteasome inhibitors, MG-132 or PS-341 (bortezomib), significantly delayed the closure of wound by H1299 cells on a culture dish. In further experiments, the expression of 14-3-3ε was reduced by MG-132 or PS-341 treatment, and the effect is due to decreased 14-3-3ε promoter activities and transcription. FAK expression, similarly, can be suppressed by MG-132 or PS-341, and the effects were derived from suppression of FAK promoter activities in a NF-κB-dependent manner.
Conclusions and Perspectives:
We conclude that 14-3-3ε over-expression results in over-expressed FAK and increase in invasiveness of HCC. Proteasome inhibitors suppress the transcription of both 14-3-3ε and FAK. This study raises the potentials of 14-3-3ε and FAK as biomarkers for predicting prognosis and metastasis of HCC. Bortezomib may also serve as an adjuvant therapy to prevent metastasis after curative treatment for HCC. Further clinical and laboratory studies are required to confirm the concepts
Rotational Cropping and Irrigation Prevailed in Chinese Taipei
No full textUneven distribution of precipitation in space and time, together with lack of suitable storage dam sites due to weakness in geological land formation have caused the water utilization in Taiwan under unfavorable condition, regardless of its annual average precipitation being one of the highest in the World. Scarcity in water resources utilization still occurred so often that the rotational cropping pattern and rotational irrigation had to be developed to cope with that, the limited water resources could be shared equally by rotation with more water users; and the efficiency of water utilization could be enhanced by precisely arranging water distribution schedule also by rotation. In particular, during the period of 1950s tol98Os, these two practices had assisted the agriculture of Taiwan in fulfilling its designated contemporary goal of producing adequate food to meet the need of that era with comparatively small amount of water. This achievement might attribute to the technical renovation on water management and heavy investment in the improvement of irrigation facilities. Contemplatively, these practices had enabled water controllers to convince water users that, the scarcity of water is being distributed equitably to a maximum extent so that the use of water in the field could maintain orderly, of which might ascribe equally or even more than the technical amelioration and heavy investment to the success and sustainability of water management. Moreover, cropping rotated with paddy rice, upland crops and sugarcane has extended the paddy wet land covering area, which is deemed to be in favor of conserving ecosystem and enhancing biodiversity for the environment. Recognizing the fact that the profit of irrigation is no longer able to pay the strict rotational cropping and irrigation, these two practices have gradually relaxed and modified nowadays. The Government agency concerned is aware of this change and tries to preserve and apply the spirit of equity of these two practices to the allocation of agricultural resources in a more sustainable way
The Identification of System Modal Parameters of the Ship Hull Girder Vibrating in Its Vertical Plane by the Sea Trial Time Series
No full textOn the Application of the Time Series in Sturctural Failure Detection and Monitoring for Offshore Applications
No full textSynthesis diblock copolymer and it’s application
No full text在本篇論文中，我們將親水端聚乙二醇甲基醚(polyethylene glycol methyl ether)的末端以醯胺鍵結(amide link)的方式將三級碳溴2-溴-2-甲基丙醯溴(2-bromoisobutyryl bromide)連接上親水端做為巨始劑。利用ATRP(atom transfer radical polymerization)合成出疏水端為丙烯酸甲酯(methyl acrylate)的雙區塊聚合物。利用所合成的雙區塊聚合物在酸性水溶液下來進行孔洞性材料的合成，可以觀察到孔徑(pore size)隨疏水端的增加而增大。而在EO45-N-MA28和EO45-N-MA63、EO114-N-MA113為模板可以合成出立方結構(Im3m)和二維六角排列(p6mm)的特殊結構。
接下來在疏水端(MA)上做3-疊氮丙胺(3-azido-propylamine)官能基的修飾，以反應的時間控制修飾的數量，並且進一步修飾含鈀(Pd)與鎢(W)的金屬錯合物。由於金屬修飾在疏水端上，所以金屬氧化物的粒子會均勻的分散在孔洞裡面，而不是隨機的分佈在孔洞中或是孔壁內，使得金屬的表面是一個完完全全暴露在孔洞內的金屬氧化物。而含鈀和含鎢金屬的矽氧孔洞材料在Suzuki coupling與烯類的氧化反應上皆有不錯的催化效果，另外催化劑回收再利用上也得到不錯的成效。In this thesis, we prepared the amide link of polyethylene glycol methyl ether and 2-bromoisobutyryl bromide as the marcoinitiator. We used ATRP method to prepare amphiphilic diblock copolmers with narrow polydispersity. The hydrophilic end of these amphilic block copolymers is polyethylene glycol methyl ether, and the hydrophobic end of these amphilic block copolymers is methyl acrylate. We used EOm-MAn as templates to synthesize porous silica materials under acid aqueous condition. As the hydrophobic end (MA) increases, we can observe the pore size also increasing. When the templates were EO45-MA28, EO45-MA63,EO114-MA113, the cubic and 2-d hexagonal structures, were successfully made.
Moreover, we modified the organic function 3-azido-propylamine on the hydrophobic end, and using the different reaction time to control the modification amount. Using the organic function grafted the Palladium and Tungsten complex on the diblock polymers. Similarly sol-gel process to prepare mesoporous silicas with metal included, which were subjected for catalysis.Suzuki coupling and olefin oxidation by Pd and W respectively, show good activities. For recycle purpose, the catalyst remains activity after 5 run. The metal leach from the porous material was very less in the Tungsten material case.目錄
第一章 緒論……………………………………………………1
1-1孔洞性材料簡介……………………………………………..….1
1-2中孔洞性材料的修飾…………………………………….……..2
1-3中孔洞性材料在催化上的應用………………………………...6
1-4修飾高分子的應用…………………………………………….12
1-5本實驗室之前的研究工作…………………………………….16
1-6本實驗研究目的……………………………………………….17
第二章 兩性共聚物的合成………………………………….18
2-1聚乙二醇甲基醚(polyethylene glycol methyl ether)之末端修飾醯胺化反應………………………………………………………..18
2-2聚丙烯酸甲酯-聚乙二醇甲基醚雙區塊共聚合物(polymethyl acrylate -b-polyethylene glycol methyl ether)……………………..25
2-3聚丙烯酸甲酯-聚乙二醇甲基醚雙區塊共聚合物的修飾(modify on polymethyl acrylate -b-polyethylene glycol methyl ether)……………………………………………………………….30
第三章 以雙區塊共聚物(PEG-N-PMA)為模板進行矽氧孔洞材料的製備…………………………………………………...37
3-1以EO17-N-MAx作為模板…………………………………….37
3-2以EO45-N-MAx作為模板……………………………………..41
3-3以EO114-N-MAx作為模板…………………………………….50
3-4修飾EO45-N-MAx作為模板…………………………………..53
第四章 以雙區塊共聚物(PEG-N-PMA)為模板合成之矽氧孔洞材料在催化上的應用……………………………………...61
4-1矽氧中孔催化劑的鑑定………………………………………61
4-2含鈀金屬的矽氧孔洞材料在催化上的探討…………………63
4-3含鎢金屬的矽氧孔洞材料在催化上的探討…………………67
第五章 結論………………………………………………….74
第六章 實驗部份…………………………………………….75
6-1測試儀器………………………………………………………75
6-2溶劑與試劑的純化……………………………………………79
6-3實驗過程………………………………………………………80
參考文獻……………………………………………………...90
附圖…………………………………………………………...9
SEMIZLIGI BOR BOLALARDA PSIXOLOGIK HOLAT VA OVQATLANISH XULQ-ATVORIDAGI O`ZGARISHLAR
No full text53 children and adolescents with various degrees of obesity underwent clinical, laboratory and psychological examination. It has been established that obese children and adolescents have impaired ideas about food. A comprehensive assessment of the psychological state of children and adolescents with obesity showed that it depends on the level of body mass index.
In obese children and adolescents who have been examined, there is a violation of psychological adaptation, especially in severe cases. This fact requires the inclusion of psychotherapeutic methods in the complex treatment of children with obesity as a mandatory component of treatment in the treatment of children and adolescents with obesity. It also highlights the need for treatment programs for patients with eating disorders.53 ребенка и подростка с различной степенью ожирения прошли полное клинико-лабораторное и психологическое обследование. Установлено, что у детей и подростков, страдающих ожирением, нарушены представления о еде. Комплексная оценка психологического состояния детей и подростков с ожирением показала, что оно зависит от уровня индекса массы тела.
У детей и подростков с ожирением, прошедших обследование, отмечается нарушение психологической адаптации, особенно в тяжелых случаях. Этот факт требует включения психотерапевтических методов в комплексное лечение детей с ожирением как обязательный компонент при лечении детей и подростков с ожирением. Это также подчеркивает необходимость лечебных программ для пациентов с расстройствами пищевого поведения.Turli darajadagi semizlikga ega 53 nafar bola va o`smir klinik, labarator va psixologik tekshiruvdan o`tkazildi. Semizligi bor bolalar va o`smirda ovqatlanishdagi qarashlarida buzilishlar borligi aniqlandi. Semizligi bor bolalar va o`smirdaning psixologik holatini har tomonlama baholash esa uning tana massasi indeksi darajasiga bog'liqligini ko`rsatdi.
Tekshiruvdan o'tgan semizligi bor bolalar va o`smirlarda ayniqsa og`ir ko`rinishlarida psixologik moslashuvning bo`zilishi ko`zatilgan. Bu fakt semizligi bor bolalar va o`smirni davolashda majburiy davo komponenti sifatida semirib ketgan bolalarni kompleks davolashda psixoterapevtik usullarni ham kiritish zarurligini taqozo qiladi. Shuningdek ovqatlanishdagi qarashlarida buzilishi bo'lgan bemorlarda tuzatish dasturlari zarurligini taqozo etadi
Cordycepin Regulates GSK-3 beta/beta-Catenin Signaling in Human Leukemia Cells
No full textBackground: Leukemia stem cells (LSCs) are a limitless cell source for the initiation and maintenance of leukemia. Activation of the Wnt/beta-catenin pathway is required for the survival and development of LSCs. Therefore, targeting beta-catenin is considered a therapeutic strategy for the treatment of leukemia. The goal of this study was to explore whether cordycepin, an active component of the traditional medicine Cordyceps sinensis, regulates beta-catenin expression in leukemia cells.
Methodology and Principal Findings: In this study, we found that cordycepin significantly suppressed cell proliferation in all malignant cancer cells, including U937, K562, A549, HepG2, SK-Hep1 and MCF7 in a dose-dependent manner. However, cordycepin reduced beta-catenin levels in U937, K562 and THP1 leukemia cells and had no effect on other solid cancer cells. In addition, treatment with cordycepin significantly suppressed leukemia colony formation in soft agar assay. Cordycepin enhanced proteasome-dependent degradation and inhibited nuclear translocation of beta-catenin in leukemia cells. Cordycepin-reduced beta-catenin stability was restored by the addition of a pharmacological inhibitor of GSK-3 beta, indicating that cordycepin-suppressed beta-catenin stability is mediated by the activation of GSK-3 beta. Furthermore, cordycepin abolished the effect of Wnt3a-induced beta-catenin in leukemia cells. In addition, cordycepin-impaired beta-catenin is regulated by Akt activation but is not significantly influenced by AMPK or mTOR signal pathways.
Significance: Our findings show for the first time that codycepin selectively reduces beta-catenin stability in leukemia but not in other solid tumor cells. This suppressive effect is mediated by regulating GSK-3 beta. A synergistic combination of cordycepin with other treatments should be used as a novel strategy to eradicate leukemia via elimination of LSCs
Author Correction: IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling
No full textSheng X, Nenseth HZ, Qu S, et al. Author Correction: IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nature Communications . 2024;15(1): 6190
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