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Previous studies of human oligodendroglial neoplasms have demonstrated the diagnostic and prognostic values of histomorphologic features and immunocytochemical markers. Primary spontaneous canine intracranial tumors share many of the biologic behaviors and pathologic features of their human counterparts. The objectives of this study were to determine if associations existed between five histomorphologic features (mitoses, cellular atypia, necrosis, vascular hypertrophy, and vascular proliferation), and three immunocytochemical markers (GFAP, EGFR, and Ki-67 labeling index) and the degree of malignancy, as defined by WHO grading criteria, of 15 canine oligodendroglial tumors. Of the histomorphologic variables examined, mitoses and cellular atypia were significantly greater in Grade III oligodendrogliomas than in Grade II oligodendrogliomas (p = 0.002, and p = 0.004, respectively), but no differences were noted between these features and Grade II oligoastrocytomas and Grade II or Grade III oligodendrogliomas. No significant associations were found between GFAP or EGFR immunoreactivity and tumor type or grade. The median percentage of Ki-67 immunoreactivity was significantly different between all tumor types and grades (p < 0.05), and was significantly higher in Grade III oligodendrogliomas than in both oligoastrocytomas (p = 0.014) and Grade II oligodendrogliomas (p = 0.006). Results of this study indicate that although mitoses and cellular atypia are useful histomorphologic features for the differentiation of tumors with oligodendroglial phenotypes, none of the variables examined reliably distinguished mixed gliomas from oligodendrogliomas. The presence of GFAP immunoreactivity in all tumor types suggests that oligodendroglial tumors may arise from a common multipotential cellular lineage. Similar to what has been demonstrated in humans, the Ki-67 labeling index correlated well with the degree of malignancy in the tumors studied. / Master of Science

Mūsų darbo tikslas buvo ištirti naviko proliferacijos žymens Ki-67 prognozinę ir prediktyvinę reikšmę bei imunologinius pokyčius neišplitusia melanoma sergantiems pacientams Pacientai ir metodai: Tiriant Ki-67 žymens prognozinę ir prediktyvinę reikšmę, retrospektyviai buvo ištirti 80 pacientų, kuriems buvo nustatyta neišplitusi melanoma su naviko storiu ≥ 1,5 mm. Vykdant prospektyvinį tyrimą, buvo išanalizuoti imunologiniai duomenys 27 pacientų, kuriems buvo nustatyta neišplitusi melanoma (pTis-pT4N0M0). Melanoma sergančių pacientų imunologiniai rodikliai buvo palyginti su 39 kontrolinės grupės asmenų atitinkamais rodikliais. Rezultatai: Ki-67 žymuo neturėjo prognozinės reikšmės negydytiems IFN-α melanoma sergantiems pacientams, su naviko storių ≥ 1,5 mm. Tuo tarpu gydytų IFN-α pacientų su Ki-67<16% išgyvenimas buvo ilgesnis negu pacientų su Ki-67 ≥ 16% (p=0,016). Tiriant imunologinius parametrus buvo nustatyta, kad melanoma sergančių pacientų periferiniame kraujyje yra mažiau monocitų (p=0,0002) ir citotoksinių T limfocitų CD8highCD57- (p=0,009). Sergantys neišplitusia melanoma pacientai periferiniame kraujyje turi reikšmingai daugiau CD4+ (p=0,02) ir CD8low (p=0,04) limfocitų. Išvados: Ki-67 proliferacijos žymuo neturi prognozinės reikšmės neišplitusia melanoma sergantiems pacientams, ir įgyja prediktyvinę reikšmę gydytiems IFN-α pacientams. Neišplitusia melanoma sergantiems pacientams stebimi reikšmingi imunokompetentinių ląstelių pokyčiai periferiniame kraujyje. / The aim of the study was to explore the prognostic and predictive significance of proliferative index Ki-67 and changes of imunological parameters in non-metastatic melanoma patients MATERIALS AND METHODS: To explore the prognostic and predictive significance of the proliferative index Ki-67, a retrospective analysis was performed with 80 patients, in whom primary non-metastatic melanoma with tumour thickness of ≥ 1,5 mm was diagnosed. A prospective study was performed to explore the immunological parameters in 27 patients who had been diagnosed with non-metastatic melanoma (pTis-pT4N0M0). The immunologic parameter values of patients were compared with those of the control group (39 subjects). RESULTS: Proliferative index Ki-67 in primary tumours had no significant prognostic value in melanoma patients non-treated with IFN-α, tumour thickness≥ 1.5 mm. However, survival of IFN-α treated non-metastatic melanoma patients with Ki-67 expressed in <16% cells was longer than that of the patients with Ki-67 expressed in ≥ 16% cells (p=0,016). The investigation of immunological parameters showed that the peripheral blood of melanoma patients contained a smaller amount of monocytes (p=0.0002) as well as cytotoxic T lymphocytes CD8highCD57- (p=0,009) compared to healthy controls (p=0.009). Patients had significantly higher counts of CD4+ (p=0.02) and CD8low (p=0.04) lymphocytes compared to healthy controls. CONCLUSIONS: Ki-67 proliferative index has no prognostic significance and... [to full text]

L'antigène de prolifération cellulaire Ki-67 est exprimé de manière constitutive dans les cellules de mammifères. Ki-67 est régulièrement utilisé en tant que marqueur de prolifération cellulaire pour classer les tumeurs. Cependant, malgré son utilisation fréquente en histopathologie, ses fonctions sont encore mal caractérisées. Mes travaux de thèse ont eu pour objectif d'améliorer la compréhension des fonctions biologiques de Ki-67 ainsi que d’étudier l’importance de son expression dans l’initiation et la progression des cancers. Nous avons montré que Ki-67 était dispensable à la prolifération cellulaire. Quant aux souris mutantes Ki-67, elles ne présentaient aucune anomalie de développement, étaient fertiles et vieillissaient normalement. Néanmoins, l’expression de Ki-67 s’est révélée être requise pour l’organisation de l'hétérochromatine dans les cellules prolifératives. En étudiant le contrôle de l'expression de Ki-67, nous avons pu mettre en évidence que les différents niveaux d’expression de Ki-67, souvent observés dans les lignées cellulaires transformées ou non, les tissus et les échantillons de tumeurs des patients, seraient expliqués par une régulation via la machinerie du cycle cellulaire.En utilisant nos souris mutantes Ki-67, nous avons également montré que l’absence de Ki-67 permettait de protéger les souris contre la carcinogenèse intestinale dans les deux différents modèles expérimentaux utilisés. De plus, l'analyse de la conséquence de l'ablation de Ki-67 dans la lignée tumorale murine, 4T1, a révélé que Ki-67 est requis pour le maintien des propriétés souches de ces cellules cancéreuses. En outre, la déplétion de Ki-67 a fortement affecté la croissance des tumeurs et la formation de métastases pulmonaires chez les souris. De façon similaire, l'absence de Ki-67 a fortement altéré le développement des xénogreffes de la lignée MDA-MB-231 dans des souris immuno-déficientes. De plus, le séquençage de l'ARN dans les cellules 4T1 a révélé l’existence d’altérations importantes au niveau transcriptomique, suite à la déplétion de Ki-67.L’ensemble de ces résultats suggère une implication spécifique de Ki-67 dans l'initiation et la progression tumorale et que Ki-67 serait une cible thérapeutique potentielle et intéressante dans le traitement du cancer. / The cell proliferation antigen Ki-67 is constitutively expressed in cycling mammalian cells and is widely used as a cell proliferation marker to grade tumours. Despite its use in cancer histo-pathology its functions are poorly understood. The aim of this project is to improve understanding of Ki-67 functions and its requirements in cancer initiation and progression. We found that Ki-67 is dispensable for cell proliferation and Ki-67 mutant mice did not exhibit any developmental abnormalities, and were fertile and aged well. Although Ki-67 was uncoupled from cell proliferation, Ki-67 was found to promote heterochromatin organization in proliferating cells. Studying Ki-67 expression control, we have found that cell cycle regulation accounts for Ki-67 variability levels in normal human cells, proliferating tissues in mice, human cancer cell lines and caner patients.Using our Ki-67 mutant mice, we found that Ki-67 depletion can protect mice from intestinal carcinogenesis in two different experimental models used. Moreover, analysis of the consequence of Ki-67 ablation in the mouse breast cancer cell line, 4T1 has revealed its requirements for the maintenance of the stem-like proprieties of these cancer cells. More importantly, Ki-67 depletion strongly affects 4T1 tumour growth and formation of lung metastases in vivo. Similarly, Ki-67 absence strongly impaired the development of the TNBC-derived MDA-MB-231 xenografts in vivo. Moreover, comparison of Ki-67 dependent alterations in gene expression in 4T1 cells by RNA sequencing revealed widespread transcriptome changes following Ki-67 depletion. Together, these results suggest a specific involvement of Ki-67 in cancer initiation and progression and may constitute a potential therapeutic target in cancer therapy.

Cette thèse porte sur les médiums (tâng-ki, « l’enfant de divination »), leurs différentes pratiques et évolution au cours de l’histoire dans la société taiwanaise. L’enjeu est d’étudier ce domaine médiumnique en employant des approches de sociologie historique et anthropologie religieuse mettant en œuvre une démarche comparative de l’image du médium et de celle perçue après une enquête de terrain. Afin de saisir « le vrai visage » du médium. D’un point de vue méthodologique, cette thèse s’appuie sur une démarche qualitative et l’usage des entretiens directs avec les médiums et médiums apprentis. Le corpus se compose de cinq chapitres. Au chapitre I il y a les travaux de recherche sur les médiums à Taïwan d’où l’exemple du professeur Lin Fu-shih. Les évènements après la libération de l’île de Taiwan ont été relatés ainsi qu’une étude sur l’histoire de la religion à Taiwan basée sur les faits historiques marquants. Pour le chapitre II, la thèse s’articule autour des éléments du terrain où il a été présenté le récit de l’enquête que l’auteur lui-même a mené ; il s’agit de la structuration des temples : exemples de temples publics et privés qui se terminent par l’entrée au temple Tshú-nai. Le chapitre III se consacre principalement à l’univers du médium aux quatre terrains enquêtés marqués par des commentaires et interprétation. Au chapitre IV l’intérêt est porté sur la présentation et description du temple Tshú-nai. Au dernier chapitre, il y a les étapes d’initiation des pratiquants de tsáo-lîng-san (se rendre sur la montagne des esprits) et les histoires annexes des médiums apprentis. / This thesis deals with mediums in taiwanese community (tâng-ki, « the child of divination »), their different practices and how they evolved with time. It aims at studying the medium field using some historical social facts and religious anthropology and a comparative approach to the general image of mediums and that obtained through a field survey to let people know the “real face” of a medium. Methodologically, this thesis relies on a qualitative approach and direct questioning of mediums and mediums to be. The corps of this paper is divided into five chapters. Chapter I is about researches on mediums in Taiwan with reference to Professor Lin Fu-shih. It also presents events which happen after the liberation of the Taiwan Island and a study on relevant historical religious facts in Taiwan. Chapter II deals with the results of a survey. The story of this survey lead by the author himself is reported in this chapter. It is mainly about how temples are structured. The study of some public and private temples will lead to the presentation of Tshú-nai temple. Chapter III specifically covers the medium’s universe discovered in the four areas of the survey followed by commentaries and interpretations. In chapter IV, the thesis focuses on the presentation and description of Tshú-nai temple. The last chapter reveals the different steps of the tsáo-lîng-san believers’ initiation (which includes going to the Spirits' Mountains) and a supplementary history of mediums to be.

O estudo das alterações neoplásicas do sistema nervoso (SN) de cães apresenta enorme desafio devido suas particularidades, entre as espécies de animais domésticos o cão Canis familiares é o que apresenta a maior ocorrência destes neoplasmas. O desenvolvimento deste trabalho visa estabelecer o estudo anátomopatológico, molecular e epidemiológico em neurooncologia veterinária, avaliando pela técnica de imuno-histoquímica marcadores da proliferação celular PCNA e Ki-67, expressão da proteína p53 e marcadores de diferenciação celular. Foram utilizados neste estudo 18 animais, da espécie canina, que deram entrada ao Serviço de Patologia vinculado ao Hospital veterinário (HOVET) e ao Departamento de Patologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, e que tiveram diagnóstico de neoplasia intracraniana primária confirmado, entre eles (8) meningiomas e (3) astrocitomas. Não houve predileção sexual e a idade média do aparecimento tumoral foi de 9 anos. O valor médio do índice proliferativo (IP) de meningiomas benignos para PCNA é 4,8% e Ki-67 é 2,8%, no astrocitoma fibrilar o valor do IP é para PCNA 1% e Ki-67 1%, no astrocitoma anaplásico o valor do IP é para PCNA 10% e Ki-67 5% e no xantoastrocitoma pleomórfico o valor do IP é para PCNA 20% e Ki-67 4%.Não foi detectada alterações em p53 e o IP foi útil para definir o comportamento tumoral benigno ou maligno e dois tipos tumorais que não haviam sido descritos em cães: xantoastrocitoma pleomórfico e tumor de parênquima pineal de diferenciação intermediária puderam ser diagnosticados graças ao conjunto de informações coletadas, morfologia celular, marcadores de diferenciação celular e índice proliferativo. / The study of neoplastic alterations of dogs nervous system (NS) presents huge challenges due their particularities, between domestic animals species the dog Canis familiars presents the highest of these neoplasms. The development of this research aims to establish the anatomical-pathological, molecular and epidemiology study in veterinary neuro-oncology, evaluating by Immunohistochemistry technique markers of cell proliferation PCNA and Ki-67, expression of p53 protein and markers of cell differentiation. In this study were used 18 animals, dogs, which had entry at the Pathology Service of the Veterinary Hospital (HOVET) and at the Department of pathology from Faculdade de Medicina Veterinária e Zootecnia of University of São Paulo, which had confirmed diagnose of primary intracranial neoplasia, among them (8) meningiomas and (3) astrocytomas. There wasn\'t sexual preference and the mean age of tumor manifestation was 9 years old. The mean value of labelling index (LI) of benign meningiomas for PCNA is 4,8% and Ki-67 is 2,8%, in fibrillary astrocytoma the mean value of LI is 1% for PCNA and 1% for Ki-67, in anaplastic astrocytoma the mean value of LI is 10% for PCNA and 5% for Ki-67 and in pleomorphic xanthoastrocytoma the mean value of LI is 20% for PCNA and 4% for Ki-67. The p53 alterations wasn\'t detected and the LI was useful to set the benign or malign tumor behavior and two tumor types which had not been described in dogs: pleomorphic xanthoastrocytoma and pineal parenchymal tumour of intermediate differentiation could be diagnosed through the set of information collected, cell morphology, markers of cell differentiation and labelling index.

O estudo das alterações neoplásicas do sistema nervoso (SN) de cães apresenta enorme desafio devido suas particularidades, entre as espécies de animais domésticos o cão Canis familiares é o que apresenta a maior ocorrência destes neoplasmas. O desenvolvimento deste trabalho visa estabelecer o estudo anátomopatológico, molecular e epidemiológico em neurooncologia veterinária, avaliando pela técnica de imuno-histoquímica marcadores da proliferação celular PCNA e Ki-67, expressão da proteína p53 e marcadores de diferenciação celular. Foram utilizados neste estudo 18 animais, da espécie canina, que deram entrada ao Serviço de Patologia vinculado ao Hospital veterinário (HOVET) e ao Departamento de Patologia da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, e que tiveram diagnóstico de neoplasia intracraniana primária confirmado, entre eles (8) meningiomas e (3) astrocitomas. Não houve predileção sexual e a idade média do aparecimento tumoral foi de 9 anos. O valor médio do índice proliferativo (IP) de meningiomas benignos para PCNA é 4,8% e Ki-67 é 2,8%, no astrocitoma fibrilar o valor do IP é para PCNA 1% e Ki-67 1%, no astrocitoma anaplásico o valor do IP é para PCNA 10% e Ki-67 5% e no xantoastrocitoma pleomórfico o valor do IP é para PCNA 20% e Ki-67 4%.Não foi detectada alterações em p53 e o IP foi útil para definir o comportamento tumoral benigno ou maligno e dois tipos tumorais que não haviam sido descritos em cães: xantoastrocitoma pleomórfico e tumor de parênquima pineal de diferenciação intermediária puderam ser diagnosticados graças ao conjunto de informações coletadas, morfologia celular, marcadores de diferenciação celular e índice proliferativo. / The study of neoplastic alterations of dogs nervous system (NS) presents huge challenges due their particularities, between domestic animals species the dog Canis familiars presents the highest of these neoplasms. The development of this research aims to establish the anatomical-pathological, molecular and epidemiology study in veterinary neuro-oncology, evaluating by Immunohistochemistry technique markers of cell proliferation PCNA and Ki-67, expression of p53 protein and markers of cell differentiation. In this study were used 18 animals, dogs, which had entry at the Pathology Service of the Veterinary Hospital (HOVET) and at the Department of pathology from Faculdade de Medicina Veterinária e Zootecnia of University of São Paulo, which had confirmed diagnose of primary intracranial neoplasia, among them (8) meningiomas and (3) astrocytomas. There wasn\'t sexual preference and the mean age of tumor manifestation was 9 years old. The mean value of labelling index (LI) of benign meningiomas for PCNA is 4,8% and Ki-67 is 2,8%, in fibrillary astrocytoma the mean value of LI is 1% for PCNA and 1% for Ki-67, in anaplastic astrocytoma the mean value of LI is 10% for PCNA and 5% for Ki-67 and in pleomorphic xanthoastrocytoma the mean value of LI is 20% for PCNA and 4% for Ki-67. The p53 alterations wasn\'t detected and the LI was useful to set the benign or malign tumor behavior and two tumor types which had not been described in dogs: pleomorphic xanthoastrocytoma and pineal parenchymal tumour of intermediate differentiation could be diagnosed through the set of information collected, cell morphology, markers of cell differentiation and labelling index.

Passive loading of a specimen is a relatively cheap method to use in fracture mechanical testing compared to an actively loaded specimen. For stress corrosion cracking testing it is easier to use a passively loaded specimen since the specimen easily can be placed in a specific corrosive environment. The passive method lacks information about the crack growth over time and the load can not be regulated during the test to ensure crack growth. This thesis work was mainly about finding a specimen with a region of constant KI to ensure crack growth without the need of controlling the load and to find a way to estimate the crack growth over time. The work is based on Linear Elastic Fracture Mechanics and the Finite Element Method. The thesis work resulted in a specimen with constant KI in the region 23/50 ≤ a/W ≤ 33/50 of crack growth and an equation was found to describe the relation between the crack propagation and the strain measured on the specimens back face. / Passiv belastning av en provstav är en relativt billig metod att använda för brottmekanisk provning jämfört med en aktivt belastad provstav. En passivt belastad provstav är enklare att använda vid provning av spänningskorrosion då provstaven enkelt kan placeras i en specifik korrosiv miljö. Den passiva metoden är bristande i information om spricktillväxen över tid och belastningen på provstaven kan inte justeras för att upprätthålla fortsatt spricktillväxt under provningens gång. Detta examensarbete syftade till att ta fram en provstav med ett spricktillväxtomrade med konstant KI för fortsatt spricktillväxt vid konstant belastning samt att hitta en metod för att uppskatta spricktillväxten över tid. Arbetet är baserat på linjärelastisk brottmekanik och finita elementmetoden. Arbetet resulterade i en provstav med konstant KI i spricktillväxtområdet 23/50 ≤ a/W ≤ 33/50 och en relation mellan spricktillväxt och töjningen som mäts på provstavens baksida.

Die Hochschule Heilbronn hat ein virtuelles KI-Labor entwickelt, um kleinen und mittleren Unternehmen (KMU) einen niederschwelligen Zugang zu Künstlicher Intelligenz (KI) zu ermöglichen. Während große Unternehmen und Start-ups oft über Ressourcen und Fachwissen verfügen, um die Potenziale der KI auszuschöpfen, stehen KMU vor eigenen Herausforderungen: fehlende finanzielle Mittel, begrenztes technisches Know-how und mangelnde Zeit, um neue Technologien zu erforschen. Das virtuelle KI-Labor adressiert diese Barrieren, indem es praxisnahe Einblicke in KI-Anwendungen bietet und komplexe Themen durch virtuelle Realität (VR), interaktive Demonstratoren, Videos und 3D-Avatare verständlich aufbereitet. Ziel ist es, Hemmungen abzubauen, digitale Kompetenzen zu fördern und den Wissenstransfer zwischen Wissenschaft und Wirtschaft zu stärken. Die Plattform wird kontinuierlich durch neue Inhalte und Partnerschaften erweitert, um KMU effektiv bei der digitalen Transformation zu unterstützen.

Objectives: A decrease in Ki67 during neoadjuvant therapy predicts response to tamoxifen. Previous trials have shown a decreased Ki67 in breast tumors with as little as two or more weeks of preoperative tamoxifen. Shortening the preoperative treatment time in window of opportunity clinical trials makes these trials more attractive to women. POWERPIINC examined the effect of 7 days of preoperative tamoxifen on breast tumor proliferation and patient symptoms. Methods: Women with untreated stage I/II, ER-positive, invasive breast cancer with no contraindications to tamoxifen were enrolled. Women received 20 mg of tamoxifen for 7 days up to the day of surgery. Proliferation was assessed by Ki67 immunohistochemistry before and after 7 days of tamoxifen. Symptoms and QOL were assessed by the FACT-ES and MENQOL. Adherence was measured by pill counts. Results: 52 women were enrolled, and 44 were evaluable for Ki67. The median age was 58.5 years, and the median tumor diameter was 1.2 cm. Most women (73%) were post-menopausal. Most tumors were PR positive (88%) and HER2-negative (92%). The Ki67 decreased by a geometric mean of 40% (95% CI 29%-63%), and 73% (95% CI 57%-85%) of women had tumors with decreased proliferation (p = 0.0001 by paired t-test). Adherence to taking tamoxifen during the preoperative period was 100%. Women reported minimal bother from psychosocial or physical symptoms at baseline or on the day of surgery. Conclusion: Seven days of tamoxifen showed a similar relative decrease in Ki67 as that reported for longer courses, was acceptable to women, and could be considered for window of opportunity studies.