Literatura académica sobre el tema "Gotō, Kenji"

İnsanların soyutlama ve kavram yaratma yetisi, onların günden güne yalnızca kendi yaratımları olan bu kavramlarla kuşatılmasını getirmiş, kendi bilinçlerinin sarsılmazlığına yönelik inancını pekiştirmiştir. Böylece, olasıdır ki, insanın doğayla arasındaki uzaklık daha da aşılmaz olmuştur. Peki, bilinç doğayı açıklama gücüne sahip midir ve daha da önemlisi, bilinçli bir varlık tasarımına sahip olmak, nasıl bir ahlâk anlayışı doğurur? Günlük yaşantımızda, dağarcığımızdaki kavramların dışsal dünyayı açıkladığına yönelik inancımız tamdır. Bu dünyayı kavrama ayrıcalığına sahip olduğumuz için, onun içerdiği zorunluluklardan bağışık olduğumuzu, eylemlerimizi özgür istencimiz uyarınca belirlediğimizi düşünürüz. Ancak Friedrich Nietzsche'ye göre, bu yöndeki sanılarımız yanılgıdan ibarettir; insanların bilinç sahibi varlıklar olmalarının ve kendi kavram dağarcıklarını oluşturmalarının ardında aslında, bedensel güçsüzlükten kaynaklanan bir zorunluluk bulunur. İnsanlar, güçsüz varlıklar olarak hayatta kalabilmek için, dünyayı kendi kavramlarıyla anlamlandırmaya mecburdur; ancak bu kavramlar, doğadaki zenginliği, “aynı olmayanı aynılaştırma” yoluyla budayan ortak eğretilemelerden ibarettir. İnsan, içselleştirdiği bu gönüllü yanılgıyı ahlâksal yaşantısına da yansıtır ve ortak kabuller uyarınca başkalarını sınıflandırabileceğine, onları yargılayabileceğine inanır. Çünkü bilinç, istenç özgürlüğünü, özgür istence ilişkin düşünce ise, kişileri eylemlerinden soyutlayabileceğimize yönelik bir önkabulü içerir. Ancak Nietzsche'ye göre bu varsayım tümüyle dayanaksızdır. Çünkü kişileri eylemlerinden sorumlu tutmak, güçlü olanın gücünü dışavurmasını engelleme amacı taşır ve hınç duygusundan kaynaklanır. İnsanlar ise, gerçekleştirdikleri eylemleri ortaya koymama özgürlüğüne sahip değildir, en bilinçli görünen eylemlerin ardında dahi içgüdüsel belirlenimler vardır ve dolayısıyla doğal zorunluluğa tabidir. Çalışmamızda, Nietzsche'nin gündelik bilinç kavrayışımız ve bu çerçevede gelişen ahlâksal varsayımlarımız arasında kurduğu bağlantıyı ve bu konudaki kabullerimize yönelttiği eleştirileri irdeleyeceğiz. Bu bağlamda, incelememizde yararlanacağımız film, Herkes Kendi İçin Yaşar ve Tanrı Herkese Karşıdır (Jeder für Sich und Gott gegen Alle, Werner Herzog, 1974) olacaktır. İlk gençlik yıllarına kadar bir mahzende tutularak toplumdan yalıtılmış, böylece ortak kavram evreni ve ahlâksal kabullerden bağışık kalmış bir başkarakterin yer aldığı bu film, incelememiz için uygun bir örnek oluşturmaktadır. Bu bakımdan, söz konusu film, ilerlediğimiz izlekteki sorgulamalarımızı derinleştirdiği yönleriyle irdelenmiştir.

This research discusses various issues experienced by four female characters, Masako, Yayoi, Kuniko, and Yoshie, in the novel Out by the Japanese novelist Natsuo Kirino. Furthermore, the positive and negative impacts on those characters resulting from these issues are also analyzed. The analysis method employed is feminist literary criticism. This research uses the descriptive analytical method, which involves collecting data and utilizing various techniques to achieve the research objectives. The findings indicate that female characters experiencing oppression in the novel Out can attain freedom by understanding the oppression they face, recognizing their abilities, adapting to society, and potentially working in the public sphere. Economic factors dominate the problems they face. Apart from that, there is also domestic violence and betrayal committed by husbands. Ultimately, they worked together to eliminate Kenji, Yayoi's husband. All of these problems have positive and negative impacts. With Kenji's death, Yayoi feels free, while Masako, Kuniko, and Yoshie feel happy with the money they got from Yayoi

Aigai’daki arkeolojik çalışmaların önemli bir bölümü kentin yol ağı üzerine gerçekleştirilmektedir. Çalışmalar sonucunda Aigai’ın Antik Çağ’da güçlü bir ulaşım sisteminin parçası olduğu, özellikle Hellenistik Dönem ve Roma Dönemi’nde deniz ile iç kesimler ve kuzey ile güney arasında önemli bir kavşakta bulunduğu saptanmıştır. Kentin içindeki yol ağı üstüne yürütülen çalışmalar özellikle kentin gelişimini anlamak açısından önemli sonuçlar sunmaktadır. Aigai Arkaik ve Klasik Dönemler boyunca mütevazı bir kent olarak varlığını sürdürmüştür. Hellenistik Dönem’de ise yeniden imar edilmiş ve en parlak dönemini yaşamaya başlamış, kentin kapladığı alan neredeyse dört katına çıkmıştır. Kent, MS 3. yüzyılın ikinci yarısına kadar yoğun olarak yerleşim görmüş ve MS 3. yüzyılın üçüncü çeyreğinde gerçekleşen Got Akınları sırasında neredeyse tamamen terkedilmiştir. Kentteki son dönem yerleşimi, geç 12. yüzyıl ve erken 13. yüzyılda, Bizanslılar tarafından kurulmuştur. Yol ağındaki çalışmalar aynı zamanda Aigai’ın su altyapısına yönelik veriler de sunmaktadır. 2020 yılında yürütülen arkeolojik kazı çalışmaları sonucunda, Athena Caddesi olarak adlandırılan yolun bir bölümü açığa çıkarılmıştır. Alanda gerçekleştirilen kazı çalışmaları sonucunda kentin MS 5-6. yüzyıllarına ait bulgulara da erişmek mümkün olmuştur. Antik yolların açığa çıkarılması sayesinde arkeolojik bilgiye ulaşılmasını yanında ziyaretçilerin antik kenti çok daha iyi algılayabilmesi ve daha rahat gezmesi de sağlanmaktadır. Böylece arkeolojik bilginin halka ulaşması için de önemli bir kazanım elde edilmektedir.

Abstract Humanized mice with human hematopoietic and immune systems have been frequently used for examining in vivo anti-cancer effects of various drugs, including immune checkpoint inhibitors (ICIs) like anti-PD-1 or anti-CTLA-4 antibodies, yet the reliability of the mouse models to be improved. We have recently developed NOD-scid, IL-2Rγ KO (NOG) mice deficient for the mouse FcεRI and FcγIIb genes, thus lacking the expression of functional mouse FcγRs, (NOG-FcγR-/-) and the activity of endogenous antibody-dependent cellular cytotoxicity (ADCC). Reconstitution experiments with human hematopoietic stem cells (HSC) showed that NOG-FcγR-/- mice had higher engraftment capacity for human leucocytes than NOG mice, namely the numbers of HSC-derived human CD19+ B cells and CD33+ myeloid cells, but not CD3+ T cells, were higher in the various tissues in NOG-FcγR-/- mice than those in NOG mice. In tumor-bearing experiments using those reconstituted mice, it was of interest that humanized NOG-FcγR-/- mice (huNOG-FcγR-/-) could invoke strong tumor growth suppression or rejection in response to anti-PD-1 antibody (Nivolumab) treatment in several cancer cell lines, which was absent in conventional huNOG mice. Accordingly, Nivolumab treatment in huNOG-FcγR-/- mice induced a significant increase of human T cells in number in the spleen and infiltration of human T cells with Granzyme B and Perforin-expression into tumor. Furthermore, the composition of activated T cells was different between huNOG-FcγR-/- and huNOG mice. HuNOG-FcγR-/- mice had elevated numbers of activated T cells, both T central memory cells (TCM) and T effector memory cells (TEM), whereas huNOG mice showed an opposite trend, reduced TCM and TEM and increase of naïve T cells. Our results suggest that the novel NOG-FcγR-/- mice become a good model for elucidating the cellular and molecular mechanisms of human tumor rejection by human T cells, and that they will provide a superior in vivo platform for evaluation of anti-cancer drugs, especially, in combination with ICIs like Nivolumab. Citation Format: Ikumi Katano, Asami Hanazawa, Iyo Otsuka, Takuya Yamaguchi, Misa Mochiduki, Kenji Kawai, Ryoji Ito, Motohito Goto, Takahiro Kagawa, Takeshi Takahashi. A novel humanized mouse model based on NOG-FcgR-/-mice recapitulates anti-tumor immune reactions by human immune systems in response to anti-PD-1 antibody (Nivolumab) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6026.

Abstract Despite recent advances in molecular profiling of bladder cancer, molecular mechanisms for urothelial carcinogenesis have not fully understood. It is partly because the lack of faithful disease models that accurately recapitulate human bladder cancer. In our previous study, we have analyzed mutation landscape of chemical-induced mouse bladder cancer and human bladder cancer by exome-sequence and found that some components of histone methyltransferase complex like Kmt2c, Kmt2d, Kdm6a were highly prevalent as common mutations and associated with Trp53. Additionally, the downregulation of tumor suppressor gene PTEN is known in human muscle invasive bladder cancer (MIBC). We also investigated cell of origin of chemical-induced mouse bladder cancer using lineage tracing method and found that Krt5 expressing cells with Trp53 alteration efficiently give a rise of high-grade MIBC with squamous differentiation. Based on these results, we have tried to make MIBC mouse model using genetically engineered mouse in which Cas9 and target gene mutation express specifically in Krt5 expressing cells by Cre-LoxP system, combined with CRISPR/Cas9 gene editing technique and 3D organoid culture system. Eight-week-old mice harboring Krt5CreERT2/+; LSL-Cas9; LSL-Trp53+/R172H were used in this study. After introducing gene recombination by administration of tamoxifen, we generated organoids from bladder epithelial cells. For further gene editing, we infected adeno-associated virus with sgPten and sgMll3 to the organoids, which successfully edited the target genes. There seemed to be no significant differences in growth of the organoids in culture between the wild-type and gene-edited organoids. However, gene-edited organoids showed tumorigenesis in vivo when inoculated in subcutaneous space, renal subcapsular space or bladder submucosa of athymic mice, whereas wild-type organoids did not show tumorigenesis in vivo. Histologically, the organoid-derived tumors showed morphological similarity to human urothelial carcinoma with squamous differentiation and intra-tumoral heterogeneity. Furthermore, tumor derived organoid has a potential of tumor development in immune-competent mice. These tumors also maintain squamous phenotype and tumor heterogeneity. These findings suggest that the technique is a promising approach toward the establishment of a useful model of human bladder cancer for the elucidation of bladder carcinogenesis including driver genes. In addition, we think our syngeneic mouse model may be useful tool for further research of tumor immunity and immune checkpoint inhibitor drugs. Citation Format: Akihiro Hamada, Yuki Kita, Hideaki Takada, Kenji Nakamura, Toru Sakatani, Takeshi Sano, Takayuki Goto, Atsuro Sawada, Shusuke Akamatsu, Takashi Kobayashi. Establishment of a bladder cancer model using organoids derived from bladder epithelium in genetically engineered mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6032.

Abstract In recent years, immuno-checkpoint inhibitors have expanded the range of treatment options in advanced bladder cancer, but there are still many issues to be overcome, such as drug resistance, effect of combination therapy and prediction of adverse events. To address these issues, there is an urgent need for useful animal models with normal immune system. About half of the human muscle invasive bladder cancers (MIBCs) show p53 mutations in which over 60% are missense mutations. Additionally, the downregulation of tumor suppressor gene PTEN is known in human MIBC. We also investigated cell of origin of chemical-induced mouse bladder cancer using lineage tracing method and found that Krt5 expressing cells with Trp53 alteration efficiently give a rise of high-grade MIBC with squamous differentiation. Based on these results, we have been working on establishing MIBC mouse model using genetically engineered mouse (GEM) in which Cas9 and target gene mutation express specifically in Krt5 expressing cells by Cre-LoxP system. We have also used CRISPR/Cas9 gene editing technique and 3D organoid culture system. We generated organoids from the GEM bladder urothelium with Krt5CreERT2/+; LSL-Cas9; LSL-Trp53R172H/+. For further gene editing, we infected adeno-associated virus with sgRNA to the organoids. The organoid with Trp53R172H/+ and Pten knock-out showed tumorigenicity in immunodeficient mice. The organoid-derived tumors are histologically similar with the basal-squamous subtype of human bladder cancer. Moreover, these tumors exhibited wild type (WT) Trp53 loss of heterozygosity in genomic level. Similarly, we confirmed tumorigenicity in immunodeficient mice with organoids from Trp53flox/flox; Ptenflox/flox and Trp53R172H/flox; Ptenflox/flox mice, but not from Trp53R172H/flox;Pten+/+ mice or Trp53R172H/+; Ptenflox/flox mice, suggesting that both loss of WT Trp53 and Pten loss are required for tumor formation in this setting. RNA sequencing showed Pten loss is associated with up-regulation of metabolism related gene sets and loss of WT Trp53 is associated with up-regulation of proliferation related gene sets. Furthermore, Trp53R172H/flox; Ptenflox/flox organoids showed higher engraftment rate in immunocompetent mice with less infiltration of CD8+ cells compared with Trp53flox/flox; Ptenflox/flox organoids, suggesting that gain of function of mutant Trp53 may affect immune microenvironment. Our data illustrates the usefulness of clinically relevant syngeneic bladder cancer mouse model from GEM-derived organoids for the research of tumor immunity. Citation Format: Akihiro Hamada, Yuki Kita, Takeshi Sano, Ryosuke Ikeuchi, Hideaki Takada, Kenji Nakamura, Toru Sakatani, Takayuki Goto, Atsuro Sawada, Shusuke Akamatsu, Takashi Kobayashi. A novel bladder cancer syngeneic mouse model using gene-edited organoids derived from bladder urothelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 21.

Abstract Purpose: Genomic profiling in urothelial carcinoma (UC) conventionally uses tissue DNA. However, tissue biopsy is so invasive that it can be difficult in some cases. Cell-free DNA (cfDNA) assay is a minimally invasive tool obtaining a comprehensive genomic information reflecting a tumor heterogeneity. Recently, the investigation of cfDNA assay in UC is widely conducted, but its clinical utility remains largely unknown. We aimed to establish plasma cfDNA assay and clarify its clinical role in UC. Method: Blood and matched tissue were obtained from 48 cases with advanced UC before 1st line systemic therapy or radical surgery. For genomic profiling of all samples, we applied a customed targeted DNA-sequencing strategy capturing 54 UC-relevant genes. Somatic mutations were required to be supported by a minimum variant allele frequency (VAF) of 0.5% in plasma cfDNA and 5% in tissue DNA. All mutation calls were filtered against matched leukocyte DNA. The result of mutational analysis was validated with digital PCR. The proportion of tumor-derived cfDNA (circulating tumor DNA (ctDNA) fraction) was estimated. We investigated the association between genomic profile and molecular subtyping with RNA sequencing and immunohistochemistry (IHC). Result: Fifty-five somatic mutations were detected in 22 cfDNA samples (22/48, 45.8%). Twenty-six of all somatic mutations identified in cfDNA (26/55, 47.3%) were concurrently present in tumor tissues. In 14 mutations randomly selected from all of those detected in cfDNA, VAF of digital PCR was statistically consisted with the result of NGS (p<0.001, R2=0.95). Furthermore, digital PCR showed that mutations detected in cfDNA alone were cleared via radical surgery. And those were found in another tissue sample from the same patient. Of the 22 cases, 6 had a ctDNA fraction greater than 2% of total cfDNA. High ctDNA fraction was associated with advanced clinical tumor stage, high PD-L1 expression in tumor tissue by IHC and basal molecular subtype (p = 0.04, 0.02, <0.01, respectively). Conclusions: We established cfDNA assay for genome profiling in advanced UC. The result of validation using digital PCR suggested that cfDNA assay can identify the mutation which cannot be detected in tissue sample as a tumor heterogeneity. Additionally, cfDNA assay generate the information for classifying UC cases by molecular subtypes and predicting the expression of immune checkpoint molecules. Further investigation is needed as a promising minimally invasive assay to predict an immunotherapy responsiveness against metastatic UC. Citation Format: Yuki Kita, Takayuki Sumiyoshi, Takeshi Sano, Akihiro Hamada, Toru Sakatani, Kenji Nakamura, Hideaki Takada, Ryousuke Ikeuchi, Takayuki Goto, Atsuro Sawada, Shusuke Akamatsu, Takashi Kobayashi. Establishing clinical utility for genomic profiling with plasma cell free DNA in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 235.