CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / O objetivo deste estudo, à avaliar a expressÃo das proteÃnas p53 e Ki-67 em adenomas colorretais, suas relaÃÃes com caracterÃsticas clinico-patolÃgicas e avaliar a relaÃÃo entre as duas proteÃnas. A amostra consistiu de 50 pÃlipos adenomatosos encontrados em pacientes submetidos a exames colonoscÃpicos. ApÃs a realizaÃÃo de polipectomia, os pÃlipos eram conservados em soluÃÃo tamponada de formalina a 10% e submetidos à rotina de preparo de cortes e lÃminas e coloraÃÃo pela hematoxilina-eosina para confirmaÃÃo da natureza adenomatosa. Realizou-se imunohistoquÃmica especÃfica para as proteÃnas p53 e Ki-67 pelo mÃtodo imunoenzimÃtico da streptoavidina-biotina-peroxidase para cada adenoma. A proteÃna p53 foi positiva em 18% dos adenomas e a proteÃna Ki-67, expresso como Ãndice (i.Ki-67), obteve mÃdia de 0,49. Houve diferenÃa estatisticamente significante na expressÃo de p53 (p=0,0003) e Ki-67(p=0,02) entre os adenomas com alto e baixo grau de displasia, sendo maior no primeiro grupo. Encontrou-se, ainda maior expressÃo da proteÃna Ki-67 nos adenomas retais em relaÃÃo aos de localizaÃÃo cÃlica (p= 0,02). NÃo houve relaÃÃo entre a expressÃo das duas proteÃnas, na amostra / Ki-67 (p=0,02) expression between adenomas with high and low grade dysplasia, greater in the first group. There was greater expression of Ki-67 protein in the rectal adenomas than colic adenomas (p=0,02). There was no relation between the expression of the two proteins in the sample.

Made available in DSpace on 2014-06-12T23:01:51Z (GMT). No. of bitstreams: 2 arquivo4255_1.pdf: 4065278 bytes, checksum: c0dabbd5dc05e703429eae598cc70d8d (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As displasias da laringe são lesões precursoras do carcinoma escamocelular invasivo e constituem lesões pouco comuns, pois, a maior parte dos casos é diagnosticada como carcinoma invasor. Freqüentemente, utilizam-se os critérios de cérvix uterina para graduação das displasias na prega vocal. Todavia, existem diferenças histopatológicas, patogênicas e epidemiológicas entre as lesões intraepiteliais cervicais e laríngeas. O epitélio de transição na prega vocal pode ocasionar problemas diagnósticos. Os autores procuram caracterizar as displasias acentuadas/carcinoma in situ da prega vocal quanto aos aspectos histopatológicos, morfométricos (área do epitélio e diâmetro dos núcleos) e índice proliferativo (Ki-67), comparando estes dados com os obtidos no epitélio escamoso normal e de transição. Dentre 1400 casos de carcinoma de laringe (1994 a 2006), 5 casos (0,35%) de displasia acentuada/carcinoma in situ foram estudados. O grupo controle constituiu-se de dois indivíduos masculinos, não tabagistas e não etilistas de 52 e 78 anos. Observaram-se nos pacientes com displasia predomínio do sexo masculino, na 6º década e associação com tabagismo e etilismo. Comparando-se o epitélio displásico com o epitélio normal e de transição verificou-se que foi maior a área ocupada pelo primeiro, bem como o diâmetro do núcleo das células displásicas. O diâmetro dos núcleos por camada mostrou diferenças significativas no epitélio escamoso normal, mas não no epitélio displásico e de transição. O índice proliferativo foi maior no epitélio displásico que no escamoso normal e de transição com núcleos corados na camada basal/parabasal no epitélio escamoso normal e de transição e em todos os níveis no epitélio displásico

Cell proliferation plays an important role in multistage chemical carcinogenesis. Again, several reports demonstrated that upregulation of metallothionein (MT) expression is associated with increased cell proliferation that may contribute to the pathogenesis of preneoplastic phenotype to frank malignancy. In this study, we evaluated the roles of early DNA damage, altered expressions of liver MT and Ki-67 nuclear antigen, and altered hepatic levels of zinc (Zn) and copper (Cu) on cell proliferation and the progression of hepatocarcinogenesis through premalignant, late premalignant and malignant transformation phases in male Sprague-Dawley rats. We have further studied the association between MT expression and cell proliferation in hepatocarcinogenesis. There was substantial induction of DNA single-strand breaks (SSBs) (P < 0.001) and development of hepatocellular premalignant lesions along with significant decrease in hepatic levels of Zn and increase in Cu content following a single, necrogenic, intraperitoneal (i.p.) injection (200 mg/Kg body weight) of diethylnitrosamine (DEN) at week 4 of the experimental protocol. Moreover, DEN + phenobarbital (PB)-treatment significantly elevated MT-, Ki-67-, and BrdU-immunoexpressions along with their immunolabeling indices. Furthermore, positive correlations between MT- and Ki-67- labeling (P = 0.0006) at various time intervals, as well as, between MT immunoreactivity and 5'-bromo-2'-deoxyuridine-labeling index (BrdU-LI) (P = 0.0007) indicate that, MT expression might be associated with Ki-67 expression and cell proliferation thereby. The study suggests that DEN treatment may lead to alteration of Zn and Cu levels resulting in early DNA damage along with elevation of MT expression that may ultimately lead to hepatic cell proliferation. The results thus provide evidence in support of the role of MT as a potential positive regulator of cell growth during the early stages of hepatocellular transformation in rats.

A model's response for a given input pattern depends on the seen patterns in the training data. The larger the amount of training data, the more likely edge cases are covered during training. However, the more complex input patterns are, the larger the model has to be. For very simple use cases, a relatively small model can achieve very high test accuracy in a matter of minutes. On the other hand, a large model has to be trained for multiple days. The actual time to develop a model of that size can be considered to be even greater since often many different architecture types and hyper-parameter configurations have to be tried. An extreme case for a large model is the recently released GPT-3 model. This model consists of 175 billion parameters and was trained using 45 terabytes of text data. The model was trained to generate text and is able to write news articles and source code based only on a rough description. However, a model like this is only creatable for researchers with access to special hardware or immense amounts of data. Thus, it is desirable to find less resource-intensive training approaches to enable other researchers to create well performing models. This thesis investigates the use of pre-trained models. If a model has been trained on one dataset and is then trained on another similar data, it faster learns to adjust to similar patterns than a model that has not yet seen any of the task's pattern. Thus, the learned lessons from one training are transferred to another task. During pre-training, the model is trained to solve a specific task like predicting the next word in a sequence or first encoding an input image before decoding it. Such models contain an encoder and a decoder part. When transferring that model to another task, parts of the model's layers will be removed. As a result, having to discard fewer weights results in faster training since less time has to be spent on training parts of a model that are only needed to solve an auxiliary task. Throughout this thesis, the concept of siamese architectures will be discussed since when using that architecture, no parameters have to be discarded when transferring a model trained with that approach onto another task. Thus, the siamese pre-training approach positively impacts the need for resources like time and energy use and drives the development of new models in the direction of Green AI. The models trained with this approach will be evaluated by comparing them to models trained with other pre-training approaches as well as large existing models. It will be shown that the models trained for the tasks in this thesis perform as good as externally pre-trained models, given the right choice of data and training targets: It will be shown that the number and type of training targets during pre-training impacts a model's performance on transfer learning tasks. The use cases presented in this thesis cover different data from different domains to show that the siamese training approach is widely applicable. Consequently, researchers are motivated to create their own pre-trained models for data domains, for which there are no existing pre-trained models. / Die Vorhersage eines Models hängt davon ab, welche Muster in den während des Trainings benutzen Daten vorhanden sind. Je größer die Menge an Trainingsdaten ist, desto wahrscheinlicher ist es, dass Grenzfälle in den Daten vorkommen. Je größer jedoch die Anzahl der zu lernenden Mustern ist, desto größer muss jedoch das Modell sein. Für einfache Anwendungsfälle ist es möglich ein kleines Modell in wenigen Minuten zu trainieren um bereits gute Ergebnisse auf Testdaten zu erhalten. Für komplexe Anwendungsfälle kann ein dementsprechend großes Modell jedoch bis zu mehrere Tage benötigen um ausreichend gut zu sein. Ein Extremfall für ein großes Modell ist das kürzlich veröffentlichte Modell mit dem Namen GPT-3, welches aus 175 Milliarden Parametern besteht und mit Trainingsdaten in der Größenordnung von 45 Terabyte trainiert wurde. Das Modell wurde trainiert Text zu generieren und ist in der Lage Nachrichtenartikel zu generieren, basierend auf einer groben Ausgangsbeschreibung. Solch ein Modell können nur solche Forscher entwickeln, die Zugang zu entsprechender Hardware und Datenmengen haben. Es demnach von Interesse Trainingsvorgehen dahingehend zu verbessern, dass auch mit wenig vorhandenen Ressourcen Modelle für komplexe Anwendungsfälle trainiert werden können. Diese Arbeit beschäfigt sich mit dem Vortrainieren von neuronalen Netzen. Wenn ein neuronales Netz auf einem Datensatz trainiert wurde und dann auf einem zweiten Datensatz weiter trainiert wird, lernt es die Merkmale des zweiten Datensatzes schneller, da es nicht von Grund auf Muster lernen muss sondern auf bereits gelerntes zurückgreifen kann. Man spricht dann davon, dass das Wissen transferiert wird. Während des Vortrainierens bekommt ein Modell häufig eine Aufgabe wie zum Beispiel, im Fall von Bilddaten, die Trainingsdaten erst zu komprimieren und dann wieder herzustellen. Bei Textdaten könnte ein Modell vortrainiert werden, indem es einen Satz als Eingabe erhält und dann den nächsten Satz aus dem Quelldokument vorhersagen muss. Solche Modelle bestehen dementsprechend aus einem Encoder und einem Decoder. Der Nachteil bei diesem Vorgehen ist, dass der Decoder lediglich für das Vortrainieren benötigt wird und für den späteren Anwendungsfall nur der Encoder benötigt wird. Zentraler Bestandteil in dieser Arbeit ist deswegen das Untersuchen der Vorteile und Nachteile der siamesische Modellarchitektur. Diese Architektur besteht lediglich aus einem Encoder, was dazu führt, dass das Vortrainieren kostengünstiger ist, da weniger Gewichte trainiert werden müssen. Der wesentliche wissenschaftliche Beitrag liegt darin, dass die siamische Architektur ausführlich verglichen wird mit vergleichbaren Ansätzen. Dabei werden bestimmte Nachteile gefunden, wie zum Beispiel dass die Auswahl einer Ähnlichkeitsfunktion oder das Zusammenstellen der Trainingsdaten große Auswirkung auf das Modelltraining haben. Es wird erarbeitet, welche Ähnlichkeitsfunktion in welchen Kontexten empfohlen wird sowie wie andere Nachteile der siamischen Architektur durch die Anpassung der Trainingsziele ausgeglichen werden können. Die entsprechenden Experimente werden dabei auf Daten aus unterschiedlichen Domänen ausgeführt um zu zeigen, dass der entsprechende Ansatz universell anwendbar ist. Die Ergebnisse aus konkreten Anwendungsfällen zeigen außerdem, dass die innerhalb dieser Arbeit entwickelten Modelle ähnlich gut abschneiden wie extern verfügbare Modelle, welche mit großem Ressourcenaufwand trainiert worden sind. Dies zeigt, dass mit Bedacht erarbeitete Architekturen die benötigten Ressourcen verringern können.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20224号 / 医博第4183号 / 新制||医||1019(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 増永 慎一郎, 教授 武藤 学, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Im Rahmen des Projekts ESPEK wurden Häufigkeit und Relevanz bestimmter Schäden an verbreiteten Waggontypen analysiert und basierend darauf im Rahmen eines Konzepts „KI-gestützte Inspektion“ praxistaugliche, datenbasierte, durch künstliche Intelligenz unterstützte digitale Lösungen entwickelt, um Schäden an ausgewählten Personenwaggons automatisiert visuell zu erkennen. Ausgehend von den bisher maßgeblich manuellen Inspektionsabläufen und Checklisten können selbige durch die vorgeschlagenen Software- und Hardwareautomatisierungen effizienter gestaltet werden. Übergeordnet werden die Sicherheit der Fahrgäste erhöht, das Problem des Fachkräftemangel bekämpft sowie Ausfall- und Standzeiten reduziert, was letztlich zur besseren Auslastung des Systems Schiene insgesamt beiträgt und Zugfahren preiswerter und pünktlicher machen kann.

Der vorliegende Artikel befasst sich mit der Literatur zu Definition und Auswirkungen des Boreout- Syndroms, einer psychischen Erkrankung, die durch anhaltende Unterforderung, Langeweile und Desinteresse vorrangig im Arbeitsumfeld entsteht. Neben dem Burnout-Syndrom, welches als Krankheit offiziell anerkannt und seit den 1970er Jahren intensiv erforscht wird, ist das Boreout- Syndrom weitestgehend unerforscht, wird jedoch immer mehr als ernsthafte Herausforderung für Arbeitnehmer und Arbeitgeber erkannt. Es resultiert häufig aus zu wenig anspruchsvollen Aufgaben, schlechter Kommunikation, mangelnder Anerkennung und fehlender Identifikation mit der Arbeit. Dies kann zu körperlichen Stresssymptomen, Verlust der Motivation und psychischen Beschwerden führen. Besonders gefährdet sind Mitarbeitende in monotonen, wenig abwechslungsreichen Berufen, einschließlich hochautomatisierter, kollaborativen oder überwachenden Tätigkeiten in der Fertigung. Präventionsmaßnahmen umfassen eine abwechslungsreiche Arbeitsgestaltung, offene Kommunikation, Job-Rotation und Weiterbildungsmöglichkeiten. Es besteht weiterhin dringender Bedarf, dieses Thema im Kontext von Arbeitsgestaltung und Automatisierung bereits in der Ausbildung von Prozessgestaltenden und Programmierenden zu berücksichtigen, um negative Auswirkungen auf die Mitarbeitende und Unternehmen zu vermeiden.

A substância P (SP) é um neuropeptídeo da família das taquicininas que regula numerosas funções biológicas por meio da ligação ao seu receptor altamente específico neuroquinina-1 (NK-1R). Este complexo SP/NK-1R está envolvido em diversos processos relacionados à oncogênese, como a mitogênese, angiogênese, migração celular e metástase. O objetivo deste trabalho foi investigar a expressão de substância P e de seu receptor NK-1 e sua correlação com o índice de proliferação celular em 73 pacientes portadores de 90 carcinomas espinocelulares de boca, diagnosticados e tratados no Hospital General e Hospital de La Princesa, Jaen, Espanha, durante o período de 1995 a 2008. Todos os tumores foram corados pela técnica imunoistoquímica da estreptavidina-biotina-peroxidase com os anticorpos anti-SP, anti-NK-1R e anti-Ki-67. As alterações celulares epiteliais das margens cirúrgicas livres de doença também foram registradas. A expressão imunoistoquímica da substância P e do seu receptor neurokinina-1 foi avaliada na membrana, no citoplasma e no núcleo das células epiteliais malignas e do epitélio da mucosa bucal adjacente ao tumor, nos linfócitos e nos vasos sanguíneos dos tumores. O índice de proliferação celular tumoral foi determinado pela expressão imunoistoquímica de Ki-67 identificada no núcleo das células neoplásicas. As correlações entre as diversas localizações da SP, de seu receptor NK-1R e do índice de proliferação tumoral determinado pelo Ki-67 foram determinadas estatísticamente utilizando-se o Crosstab, Regress e Descript de SUDAAN. A expressão de SP foi identificada no estroma de 77% dos tumores, na membrana de 71% das células malignas e no citoplasma de 81,2% dos tumores. A maioria dos tumores apresentou altas taxas de proliferação das células neoplásicas com mais de 50% das células imunopositivas para o Ki-67. Ao analisar as margens cirúrgicas livres de doença, observou-se expressão da SP, sobretudo no terço inferior e médio, tanto no núcleo, como no citoplasma e na membrana celular. A expressão concomitante de substância P e do receptor neurokinina-1 no citoplasma das células neoplásicas ocorreu mais frequentemente nas células tumorais em proliferação. Verificou-se que expressão de SP no câncer bucal ocorre juntamente com o aumento da expressão de NK-1R, sugerindo que as células neoplásicas epiteliais bucais podem utilizar esta via para tornarem-se mais susceptíveis aos estímulos mediados pela SP. A expressão de substância P nos linfócitos do infiltrado inflamatório e vasos sanguíneos intratumorais e peritumorais se associaram a tumores de menor tamanho, menor estádio clínico e com menor frequência metástase ganglionar. Concluiu-se que as células neoplásicas epiteliais bucais podem utilizar a via substância P/NK-1R para tornarem-se mais susceptíveis aos estímulos mediados pela SP, particularmente aqueles associados à proliferação celular. Além disso, a expressão epitelial, citoplasmática e nuclear da substância P é um evento precoce na carcinogênese bucal podendo ser considerado um marcador da presença e intensidade de displasia epitelial. / The substance P (SP) is a neuropeptide of the tachykinin family that regulates multiple biological functions by binding to the highly specific receptor neurokinin-1. This complex SP/NK-1 is involved in several processes related to oncogenesis, such as mitogenesis, angiogenesis, cell migration and metastasis. This study investigated the expression of substance P and its receptor NK-1 and its correlation with the cell proliferation index in 73 patients with oral squamous cell carcinoma, diagnosed and treated at the General Hospital and Princess Hospital at Jaen, Spain, during the period 1995 to 2008. All tumors were stained immunohistochemically by the streptavidin-biotin-peroxidase technique using the antibodies anti-SP, anti-NK-1R and anti-Ki-67. The epithelial cell alterations on the disease-free surgical margins were registered. The immunohistochemical expression of SP and its receptor neurokinin-1 were evaluated on the membrane, cytoplasm and nucleus of malignant epithelial cells and cells of healthy oral mucosa adjacent to the tumor, as well as on the infiltrating lymphocytes and peritumoral or intratumoral blood vessels. The tumor cell proliferation index was determined by the immunohistochemical expression of Ki- 67 identified on the malignant cell nucleus. The correlations between the distinct localizations of SP, its receptor NK-1 and the proliferation index Ki-67 were statistically analyzed using the Sudaan Crosstab, Regress and Descript tests. The SP expression was identified on the stroma of 77% of tumors, on the membrane of 71% of malignant cells and cytoplasm of 81.2% of tumors. Most tumors presented high proliferation rates of neoplastic cells, with more than 50% of cells immunopositive for Ki-67. Analysis of the disease-free surgical margins revealed SP expression especially on the lower and medium third, both on the nucleus, cytoplasm and cell membrane. The simultaneous expression of substance P and its receptor NK-1 on the cytoplasm of neoplastic cells occurred more frequently in proliferating malignant cells. The expression of SP in oral cancer occurred simultaneously to an increased expression of NK-1R, suggesting that the oral malignant epithelial cells might use this pathway to become more susceptible to the stimuli mediated by the SP. The substance P expression on infiltrating lymphocytes and intratumoral or peritumoral blood vessels was associated with tumors of small size, lower clinical stage and less frequent node metastasis. It was concluded that the oral neoplastic epithelial cells may use the pathway SP/NK-1R to become more susceptible to the stimuli mediated by the SP, particularly those associated with cell proliferation. Additionally, the epithelial, cytoplasmic and nuclear expression of substance P is an early event in oral carcinogenesis and may be considered a marker of the presence and intensity of epithelial dysplasia.

Introduction et objectifs : Les méningiomes sont des tumeurs intracrâniennes pour la plupart de bas grade, dont les récidives sont cependant fréquentes. Le premier objectif de cette étude est d'évaluer la valeur pronostique de marqueurs de prolifération dans une série de 60 méningiomes. HuR (ELAV-like 1) est une protéine pro-oncogène pouvant stimuler la prolifération et la survie cellulaire. Dans la seconde partie de cette étude, nous analysons l'expression de HuR et les effets de l'inhibition de HuR sur la prolifération, l'apoptose et la résistance à l'hypoxie. Résultats : Il existe une corrélation significative entre le grade histologique et l'expression nucléaire de MCM6 (p<0,001), Ki-67 (p<0,001) et PHH3 (p<0,001), et une corrélation inverse entre ces marqueurs et la survie sans récidive (Cox ; MCM6 : p<0,001 ; Ki-67 : p=0,003 ; PHH3 : p=0,037). L'expression cytoplasmique de HuR est corrélée négativement avec la survie sans récidive (p=0,028), et positivement avec le grade (I vs II : p=0,0007), l'indice mitotique (p=0,0001), Ki-67 (p=0,0007) et MCM6 (p=0,0009). In vitro, l'inhibition de HuR (siRNA) entraîne une diminution de la croissance cellulaire (p=0,0004) et de la prolifération (Ki-67, p=0,0004), et une augmentation de l'apoptose (caspase 3 clivée, p=0,002), ces différents effets étant significativement augmentés en hypoxie. L'inhibition de HuR entraîne également une diminution de SIRT1 en normoxie (p=0,01) et en hypoxie (p=0,0006). Conclusion : MCM6 est un marqueur efficace pour identifier les méningiomes à haut risque de récidive. HuR est un marqueur de mauvais pronostic, dont l'inhibition permet de diminuer la prolifération cellulaire et d'augmenter l'apoptose / Introduction and objectives: Meningiomas are frequent and in most of cases low grade intracranial tumors, with frequent recurrences. The first objective of this study was to evaluate the prognostic value of proliferation and cell cycle markers in a series of 60 meningiomas. HuR (ELAV-like 1) is a pro-oncogenic protein that stimulates cell proliferation and survival. In the second part of this study, the objective was to evaluate HuR expression, and the effects of HuR inhibition on proliferation, apoptosis and resistance to hypoxia. Results: We found a significant correlation between histological grade and nuclear staining for MCM6 (p<0.001), Ki-67 (p<0.001) and PHH3 (p<0.001), and an inverse correlation between these markers and reccurence free survival (Cox; MCM6: p<0.001; Ki-67: p=0.003; PHH3: p=0.037). Cytoplasm staining for HuR was significantly stronger in atypical meningiomas (grades I vs II: p=0.0007), inversely correlated with progression free survival (p=0.028), and was positively correlated with mitotic index (p=0.0001), Ki-67 (p=0.0007) and MCM6 (p=0.0009). In vitro, HuR inhibition (siRNA) led to a significant decrease of cell growth (p=0.0004) and proliferation (Ki-67, p=0.0004), and an increase of apoptosis (cleaved caspase 3, p=0.002). These effects were significantly increased under hypoxia, comparing with normoxia. When HuR was inhibited, SIRT1 was decreased, both under normoxia (p=0.01) and hypoxia (p=0.0006). Conclusion: In conclusion, MCM6 is an efficient marker to identify meningiomas with high risk of recurrence. HuR is correlated with a poor prognosis. Its inhibition allows to decrease cell proliferation and to increase apoptosis