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The Global ETD Search service is a free service for researchers
to find electronic theses and dissertations. This service is
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Networked Digital Library of Theses and Dissertations.
Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
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Showing 1 to 9 of 9 (0.015 seconds)| 1 |
La protéine de stress p8 permet l'adaptation des cellules cancéreuses pancréatiques aux conditions microenvironnementales extrêmes. : Etude de ses mécanismes d'action. / The stress protein p8 favors pancreatic cancer cell adaptation to hostile micro-environment : study of its mechanism of actionHamidi, Tewfik 18 December 2012 (has links)
La protéine de stress p8 fut découverte et caractérisée dans notre laboratoire. Cette protéine est surexprimée dans l'adénocarcinome pancréatique et possède un rôle dans la progression tumorale. Pendant ce travail de thèse, nous nous sommes focalisé sur le rôle de p8 dans les phases initiales de la tumorigénèse pancréatique et sur ses mécanismes d'action, impliqués dans la progression tumorale. Nous avons montré que p8 joue un rôle essentiel dans l'apparition des lésions PanINs suite à l'activation de l'oncogène Kras. Au niveau cellulaire, nous avons montré que la protéine p8 protège les cellules tumorales pancréatiques contre le stress de la privation en nutriments via la régulation de l'expression de RelB et IER3. La voie p8, RelB et IER3 est impliquée dans l'inhibition de l'apoptose suite au stress. De plus, nous avons observé que ces trois protéines sont co-exprimées dans les adénocarcinomes humains et leur expression corrèle avec l'évolution de la maladie. Dans un second lieu, nous avons démontré le rôle essentiel de la protéine p8 dans la résistance des cellules tumorales pancréatiques à l'hypoxie et à la privation en glucose. Nous avons identifié la voie p8/Aurora KinaseA, qui en réponse au stress métabolique, réduit l'apparition des dommages à l'ADN en contrôlant l'expression des gènes liés au cycle cellulaire et à la réparation de l'ADN. De plus, nos recherches ont montré que p8 protège les cellules tumorales du stress métabolique en inhibant la mort cellulaire dépendante de l'autophagie. Nous espérons que nos résultats aideront à mieux cibler les cellules tumorales pancréatiques et leur caractère résistant au stress micro-environnemental extrême. / The stress protein p8 was discovered and characterized in our laboratory. Over expressed in pancreatic adenocarcinoma, p8 is involved in tumor progression. During my PhD studies, we focused on the role of p8 in pancreatic cancer development and on its mechanisms of action. First, we demonstrated that p8 is essential for PanIN development following Kras oncogene activation. At the cellular level, we found that p8 protects pancreatic cancer cells upon nutrient starvation stress through the regulation of RelB and IER3 expression. p8, RelB and IER3-dependent cascade inhibits apoptosis after the starvation stress. Furthermore, we showed that these tree proteins are co expressed in human pancreatic adenocarcinoma. One the other hand, our study showed that p8 is involved in pancreatic cancer cells resistance to hypoxia and glucose starvation. We identified a p8/Aurora KinaseA pathway which, in response to such metabolic stress, reduces DNA damage by regulating cell cycle and DNA repair genes expression. Moreover, our studies demonstrated that p8/AURKA path protects cancer cells against metabolic stress by inhibiting autophagy-associated cell death. We expect that our data will help to get new therapeutics against pancreatic cancer.
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The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis / BRG1/SOX9経路は膵腺房細胞由来の膵発癌において必須の役割を果たすTsuda, Motoyuki 25 March 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21645号 / 医博第4451号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 羽賀 博典, 教授 小西 靖彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation / 成熟膵および膵腫瘍形成においてHes1は状況依存性の役割を果たすMarui, Saiko 23 March 2023 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第24523号 / 医博第4965号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 藤田 恭之, 教授 波多野 悦朗 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Investigating the respective roles of SOX9 and PAR1 in pancreatic ductal adenocarcinoma initiation and immune evasionPatrick G Schweickert (8793230) 04 May 2020 (has links)
<div>
<p>Pancreatic ductal adenocarcinoma
(PDAC) is a poorly immune responsive, treatment refractory disease, representing
the fourth leading cause of cancer deaths in the United States. A lack of
significant improvements in patient prognoses over the last few decades
highlights the necessity for a more basic understanding of how PDAC develops
and progresses. To this end, the research outlined here investigates the
contributions of SOX9 and PAR1 in PDAC initiation and tumor immune evasion,
respectively. </p>
<p>SOX9 is a developmental
transcription factor important for proper pancreas development that is restricted
to only a small subset of cells in the adult organ. However, SOX9 is aberrantly
expressed in precancerous lesions of the pancreas and throughout PDAC
development. Using genetically engineered mouse models we demonstrated that
PDAC precursor lesions cannot form in the absence of SOX9 and conversely formed
at an accelerated rate when SOX9 was ectopically expressed. Surprisingly
deletion of SOX9 in primary mouse PDAC cell lines had no impact on tumor growth
in subcutaneous allograft experiments, indicating that although SOX9 expression
is necessary for PDAC initiation, it is dispensable in many cases for tumor
maintenance and growth. Research investigating the transcriptional changes
induced by SOX9 prior to lesion formation is ongoing to identify additional
downstream factors critical for disease initiation. </p>
<p>Previous research has shown that
PDAC tumors frequently display low levels of immune infiltration, which is a
major limitation for the use of immune-based therapeutics and is generally an
unfavorable prognostic factor. We show that in primary mouse tumor cells
ablation of the thrombin receptor PAR1 caused a significant increase in the
infiltration of tumor targeting CD8a<sup>+ </sup>T cells which in turn were found
to eliminate PAR1 knockout tumors. When PAR1<sup>KO</sup> and PAR1 expressing
PDAC tumor cells were co-injected into wild type mice, cells lacking PAR1 were preferentially
targeted and eliminated by the immune system, indicating that PAR1 provides
cell autonomous protection during an active anti-tumor adaptive immune
response. Furthermore, we identified a previously underappreciated association
between PAR1-mediated expression of <i>Csf2</i> and <i>Ptgs2</i>, and PDAC
tumor immune evasion. Together these findings provide novel insights into the
mechanisms and drivers of PDAC initiation and immune evasion.</p>
</div>
<br>
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Molekulargenetische Analysen zur Etablierung eines Progressionsmodells des PankreaskarzinomsGalehdari, Hamid 26 September 2000 (has links)
Recently the suspected precursor lesions of ductal adenocarcinoma of the pancreas have been called Pancreatic intraepithelial neoplasia (PanIN) and graded according to the degree of dysplasia. To correlate each grade of PanIN with molecular genetic alterations, we determined the frequency of allelic losses at chromosomal arms 9p (the location of the p16 gene), 17p (p53 gene) and 18q (DPC4/SMAD4 gene) in 81 microdissected PanINs, using a combination of whole genome amplification and microsatellite analysis. In addition, p53 and Dpc4 protein expression was determined by immunohistochemistry. Essentially no allelic losses were identified in the non-dysplastic PanIN-1 lesion. In PanIN-2 with low grade dysplasia the frequency of allelic losses at chromosomal region 9p, 17p and 18q was 20%, 33% and 17%, respectively, which increased to 46%, 77% and 58%, respectively, in PanIN-2 with moderate dysplasia, to 87%, 60% and 88% in PanIN-3 with high grade dysplasia, and to 100%, 91%, and 82% in the invasive carcinomas. The progressive occurrence of allelic losses at all three loci strongly supports the PanIN progression model for pancreatic carcinoma. Nuclear p53 and loss of Dpc4 protein expression was associated only with PanIN-3 and invasive carcinomas, consistent with the model that inactivation of p53 and DPC4 are late events in pancreatic carcinogenesis. Since the aberrant protein expression patterns, were preceded, however by a sharp increase in allelic losses from PanIN-2 with low grade dysplasia to PanIN-2 with moderate dysplasia it is suggested that the increasing grade of dysplasia in the PanIN lesions identify biologically relevant steps towards invasive carcinoma. The discrepancy between alleic loss frequencies and p53 and DPC4 expression also raises the possibility that additional tumor suppressor genes on chromosomes 17p and 18q promote early pancreatic carcinogenesis.
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Metabolic Profiling of Urine, Fecal, and Serum Samples and Pancreatic Tumors and Evaluation of HMGA1 Expression Levels in Pancreatic Intraepithelial Neoplasia Cells in the Ptf1a-Cre; LSL-KrasG12D Transgenic Mouse Model of Pancreatic CancerSchmahl, Michelle Jordan 18 April 2018 (has links)
No description available.
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Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCNDistler, Marius, Aust, Daniela E., Weitz, Jürgen, Pilarsky, Christian, Grützmann, Robert 11 July 2014 (has links) (PDF)
Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.
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Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCNDistler, Marius, Aust, Daniela E., Weitz, Jürgen, Pilarsky, Christian, Grützmann, Robert 11 July 2014 (has links)
Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.
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Polycomb group proteins Bmi1 and Ring1B are involved in cell plasticity and tumorigenesis of the pancreasMartínez Romero, Carles 21 December 2009 (has links)
L'adenocarcinoma ductal pancreàtic (PDAC) és un dels càncers més letals. Per tal de millorar el diagnòstic precoç, s'estan investigant les etapes inicials de la formació del càncer, com és el cas de les lesions preneoplàstiques, i es vol desxifrar l'origen cel·lular de la malaltia. Les proteïnes Polycomb constitueixen una família de silenciadors epigenètics que es troben en una varietat de tumors sòlids. La hipòtesi principal és que Polycomb pot estar participant en els processos preneoplàstics del pàncreas i en l'aparició i progressió del tumor. La expressió de Bmi1 i Ring1B fou analitzada durant el desenvolupament del pàncreas, en teixit pancreàtic de diferents models murins de la malaltia i en mostres humans de teixit pancreàtic. Es va dur a terme l'anàlisi del mecanisme de Bmi1 mitjançant models in vitro i induint la depleció de Bmi1. Bmi1 i Ring1B s'expressaren en precursors pancreàtics durant etapes primerenques del desenvolupament i en cèl·lules ductals i dels illots,però no en els acins, en el pàncrees adult. Bmi1 s'induí en cèl·lules acinars durant lesió aguda, en lesions metaplàstiques acinoductals, en neoplàsies intraepitelials pancreàtiques (PanIN) i en PDAC. Ring1B s'incrementà significativament en PanINs de grau alt i en PDAC. La disminució dels nivells de Bmi1 en la línia cel·lular acinar canvià l'expressió dels enzims digestius pancreàtics. Aquests resultats suggereixen que Bmi1 i Ring1B podrien estar contribuint de diferent manera en la progressió tumoral. / Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. To improve early diagnosis, research efforts are focused in characterising early events of cancer formation like preneoplastic lesions and deciphering the cell origin of the malignancy. Polycomb proteins constitute a family of epigenetic silencers found in a variety of solid tumours. The main hypothesis is that Polycomb might play a role in preneoplastic states in the pancreas and in tumour development and progression. The expression of Bmi1 and RingB was analysed during pancreatic development, in pancreatic tissue from mouse models of disease and in human pancreatic tissue samples. Mechanistic insights of Bmi1 were performed using in vitro models and with induced Bmi1 depletion. Bmi1 and Ring1B were expressed in pancreatic exocrine precursors during early development and in ductal and islet cells, but not in acinar cells, in the adult pancreas. Bmi1 was induced in acinar cells during acute injury, in acinar-ductal metaplastic lesions, in pancreatic intraepithelial neoplasia (PanIN) and PDAC. In contrast, Ring1B was significantly increased in high-grade PanINs and in PDAC. Bmi1 knockdown in acinar cell line changed the expression of pancreatic digestive enzymes. These results suggest that Bmi1 and Ring1B could contribute differently to tumour development.
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