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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the 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.
21

Interação da crisotila com células de carcinoma de pulmão humano em cultura: interferência com a mitose utilizando genes repórteres e microscopia em tempo real e estudo do potencial genotóxico / Chrysotile interaction with human lung carcinoma cell culture: interference on mitosis using report genes and real time microscopy and the study of genotoxic potential

Cortez, Beatriz de Araujo 21 January 2010 (has links)
Asbesto é um nome geral dado a seis tipos de fibras minerais encontradas naturalmente na crosta terrestre. Estas fibras vêm sendo exploradas industrialmente desde 1970, porém diversos trabalhadores expostos às fibras apresentaram patologias no trato respiratório, como fibroses e carcinomas. Alguns tipos de fibra foram banidos do mercado, porém o tipo de asbesto crisotila ainda pode ser comercializado na maioria dos países. Estudos in vivo e in vitro tentam elucidar as alterações causadas pela exposição à asbesto nos tecidos e nas células que possam estar relacionadas ao aparecimento de doenças, e foi verificado que a exposição às fibras leva a quebras na dupla fita de DNA, estresse oxidativo, formação de células micronucleadas e células aneuploides. O presente estudo teve como objetivo verificar a presença de alterações causadas em células em cultura expostas à crisotila por 48 h e recuperadas em meio livre de fibras por 48 h, 4 dias e 8 dias, além de observar por microscopia em tempo real divisões aberrantes após a exposição as fibras por 24 e 48h. Foram verificadas alterações que permaneceram na cultura mesmo após 8 dias de recuperação, quando não foram mais observadas fibras na cultura, como formação de células aneuploides, diminuição de frequência de células em G0/G1, aumento de células em G2/M e aumento relativo de células em metáfase quanto à porcentagem de células em fases mais tardias da fase M do ciclo. Já aumento da frequência de células micronucleadas ocorreu apenas nos períodos quando foram observadas fibras na cultura. Para análise da formação de mitoses multipolares e destinos destas células foram construídos vetores para expressão de tubulinas fusionadas a proteínas fluorescentes RFP e GFP, padronizadas as condições de transfecção e de aquisição de imagens para que as células tratadas com crisotila fossem observadas por time-lapse. Alguns destinos de mitoses multipolares causadas pelo tratamento com crisotila foram observados, como morte em metáfase, divisão gerando duas ou três células filhas, fusão de células durante a telófase e retenção em metáfase. Os dados sugerem também a indução da amplificação centrossômica, que parece ocorrer inicialmente em células interfásicas, e também devido à fusão de células. / Asbestos is a general name given to six different fibrous silicate minerals found naturally in the earth\'s crust. These fibers are being exploited industrially since 1970, but several workers exposed to the fibers developed diseases in the respiratory tract, such as fibrosis and carcinomas. Some types of fiber were banished from the market, but the type of asbestos chrysotile can still be marketed in most countries. Studies in vivo and in vitro are trying to elucidate the asbestos effects in tissues and cells that could be related to the development of diseases, and these studies verified that asbestos exposure lead to DNA double strand breaks, oxidative stress, multinucleated and aneuploid cell formation. The present work aimed to verify the alterations in culture cells exposed to chrysotile for 48 h and recovered in fiber-free medium for 48 h, 4 days and 8 days, and also observe aberrant mitosis using time-lapse microscopy after 24 h and 48 h of chrysotile exposure. Some alterations were observed and remained in cell culture even after 8 days of recovery when chrysotile fibers were no longer observed - such as aneuploid cell formation, increased frequencies of G2/M cell, decreased frequencies of G1 cells, and increased frequencies of cells in early M phases as metaphase. The induction of micronuclei occurred only during the periods that fibers were observed in cell culture. For the analysis of multipolar mitosis formation and destinies of these cells after chrysotile treatment, DNA vectors for the expression of tubulins fused to fluorescent proteins (GFP and RFP) were constructed, and the conditions for cells transfection and image acquisition for time-lapse microscopy were established. The fate of some multipolar metaphases was observed: cell retention on metaphase, cell cycle progression generating two or three daughter cells, cell fusion during cytokinesis or during telophase after a multipolar anaphase, and cell death. The centrosome amplification was not observed during the M phase of cell cycle, and may occur in interphase, and also despite cell fusion.
22

Erforschung des Schicksals des Mittelkörpers anhand der ZF1-Methode / Investigating the Fate of the Midbody after Cytokinesis

Geisenhof [geb. Trinkwalder], Michaela January 2019 (has links) (PDF)
Bei der Teilung einer Zelle werden das Genom und die Zellbestandteile zwischen zwei Tochterzellen aufgeteilt. Dies erfordert verschiedene fein aufeinander abgestimmte Vorgänge. Unter anderem ist eine proteinreiche Struktur beteiligt, die 1891 entdeckt wurde: der Mittelkörper. In vorliegender Arbeit wurden gezielt gekennzeichnete Mittelkörperproteine analysiert und verschiedene Phasen des Transports unterschieden. Es erfolgten erstmals Messungen unter Nutzung der ZF1-Methode. Zudem wird anhand der ZF1-Technik nachgewiesen, dass im Rahmen der Zellteilung die Trennung der interzellulären Brücke zu beiden Seiten des Mittelkörpers stattfindet, woraufhin dieser nach extrazellulär abgegeben wird und über einen der Phagozytose ähnlichen und von Aktin abhängigen Mechanismus von einer Tochterzelle oder unverwandten Nachbarzelle aufgenommen wird. / In animals, the midbody coordinates the end of cytokinesis. Using the ZF1-mediated degradation technique it is shown that midbodies are released outside the cell in C. elegans embryos. Furthermore it is shown that midbodies are released after abscission cuts on both sides of the midbody and that released midbodies are internalized via actin-driven phagocytosis.
23

L'endothéline-1 module le calcium cytosolique et nucléaire ainsi que la prolifération cellulaire et l'apoptose des cellules du muscle lisse aortique humain

Choufani, Sanaa. January 2002 (has links)
Thèses (Ph.D.)--Université de Sherbrooke (Canada), 2002. / Titre de l'écran-titre (visionné le 20 juin 2006). Publié aussi en version papier.
24

Polyclonal B lymphocyte activation by bacteria

Banck, Göran. January 1982 (has links)
Thesis (doctoral)--Malmö, 1982.
25

Avaliação da citotoxicidade de derivados de sais de isotiourônio e tiazinodionas para estudo de leucemia in vitro

Assunção, Laura Sartori January 2013 (has links)
Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2013. / Made available in DSpace on 2014-08-06T17:17:39Z (GMT). No. of bitstreams: 1 325597.pdf: 1891302 bytes, checksum: 73e6e93a7ecfb558a85d9aac97cd3495 (MD5) Previous issue date: 2013 / O câncer é caracterizado pelo crescimento desordenado de células anormais em tecidos e órgãos, podendo vir a espalhar-se por outras regiões do organismo. As células neoplásicas adquiriram a propriedade de proliferação além dos limites normais e de resistência à apoptose. O entendimento dos mecanismos moleculares de morte das células tumorais se faz necessário para o avanço em direção ao desenvolvimento de compostos antineoplásicos com maior citotoxicidade e maior seletividade para as células tumorais. A utilização de modelos celulares de leucemia na busca de novas terapias antitumorais torna-se interessante, uma vez que as linhagens celulares possibilitam a obtenção de resultados mais rápidos na prospecção de novos agentes antitumorais. Estudos anteriores demonstram que os sais de isotiourônio (SIs) apresentam atividade antibacteriana, antifúngica e antinflamatória, porém pouco ainda se sabe sobre uma possível atividade antitumoral. As tiazinodionas (TDs) são análogos das tiazolidinedionas, conhecidas pela atividade antihiperglicêmica já bem caracterizada e mais recentemente tem sido descrita a atividade antitumoral em diversos tipos de câncer como cólon, mama, pulmão. Diante deste cenário, o objetivo desse trabalho foi pesquisar novos potenciais agentes antileucêmicos a partir de sais de isotiourônio e tiazinodionas e investigar o mecanismo de morte celular induzida por estes compostos. Observou-se que os sais de isotiourônio MF 04, MF05, MF06, MF07 e MF08 apresentaram concentração citotóxica para 50% das células (CC50) na faixa de 3 a 12 µM com índice de seletividade = 2 para as células de leucemia. Além disso, esses compostos parecem induzir à morte celular através da indução do estresse metabólico com produção de espécies reativas de oxigênio (EROs) e perda do potencial de membrana mitocondrial. O composto MF08 que apresentou a menor CC50 e maior índice de seletividade em células de leucemia, além de causar alterações morfológicas que sugerem morte celular por mitose catastrófica. Por esse motivo, novos compostos derivados desse SI foram sintetizados, mas os mesmos apresentaram atividade inferior à molécula de origem. As tiazinodionas 1a e 1g apresentaram CC50 de 35 e 28 µM respectivamente e índice de seletividade em torno de 3. O mecanismo de morte envolvido na ação das tiazinodionas está relacionado a produção de EROs, perda de potencial de membrana mitocondrial e alteração nos níveis de cálcio intracelular sugerindo um estresse de retículo endoplasmático e ativação das caspases-12 e -3 culminando em apoptose. Considerando os compostos testados, ambas as classes mostram-se promissoras para estudos pré-clínicos.<br> / Abstract : Cancer is characterized by abnormal growth of normal cells in tissues and organs that can spread to other regions. Neoplastic cells acquired the property of proliferation beyond normal limits and apoptosis resistance. It is important to better understand the molecular mechanisms of tumoral cell death in order to promote the development of new antineoplastic compounds with higher toxicity and selectivity. Leukemia cell models in new antitumoral research are interesting due to their easy handling and feasibility. Previous studies showed that isothiouronium salts presented antibacterial, antifungal and anti-inflammatory activities, but the antitumoral activity is still unclear. The thiazinediones are thiazolidinediones analogs wich have its antihyperglycemic activity well characterized and recent studies presented their antitumoral activity in several types of cancer as colon, breast and lung. In this scenario, the aim of this work was to investigate new potential antileukemic agents by isothiouronium salts and thiazolidinediones derivatives and explore the cell death mechanism induced by them.. It was observed that isothiouronium salts MF 04, MF05, MF06, MF07 and MF08presented a range of 3 to 12µM of the cytotoxic concentration to reach 50% of cell death (CC50) and a selectivity index of = 2 to leukemia cells. Furthermore, these compounds seem to induce cell death by metabolic stress with reactive oxygen species production (ROS) and loss of mitochondrial membrane potential. Compound MF08 presented the lowest CC50 and higher selectivity index in leukemia cells and morphologic alterations suggest that it may induce mitotic catastrophe cell death pathway. Therefore novel compounds derived from MF08 where synthetized but it was observed inferior activity compared to original molecule. Thiazinediones 1a and 1g presented CC50 of 35 and 28µM respectively and selectivity index nearby 3. The mechanism of action of thiazinediones is related to ROS production, loss of mitochondrial membrane potential and calcium imbalance suggesting a endoplasmic reticulum stress and caspases -12 and 3 activation culminating in apoptosis cell death. Considering the tested compounds, both groups seem to be promising to further pre-clinical trials.
26

Interação da crisotila com células de carcinoma de pulmão humano em cultura: interferência com a mitose utilizando genes repórteres e microscopia em tempo real e estudo do potencial genotóxico / Chrysotile interaction with human lung carcinoma cell culture: interference on mitosis using report genes and real time microscopy and the study of genotoxic potential

Beatriz de Araujo Cortez 21 January 2010 (has links)
Asbesto é um nome geral dado a seis tipos de fibras minerais encontradas naturalmente na crosta terrestre. Estas fibras vêm sendo exploradas industrialmente desde 1970, porém diversos trabalhadores expostos às fibras apresentaram patologias no trato respiratório, como fibroses e carcinomas. Alguns tipos de fibra foram banidos do mercado, porém o tipo de asbesto crisotila ainda pode ser comercializado na maioria dos países. Estudos in vivo e in vitro tentam elucidar as alterações causadas pela exposição à asbesto nos tecidos e nas células que possam estar relacionadas ao aparecimento de doenças, e foi verificado que a exposição às fibras leva a quebras na dupla fita de DNA, estresse oxidativo, formação de células micronucleadas e células aneuploides. O presente estudo teve como objetivo verificar a presença de alterações causadas em células em cultura expostas à crisotila por 48 h e recuperadas em meio livre de fibras por 48 h, 4 dias e 8 dias, além de observar por microscopia em tempo real divisões aberrantes após a exposição as fibras por 24 e 48h. Foram verificadas alterações que permaneceram na cultura mesmo após 8 dias de recuperação, quando não foram mais observadas fibras na cultura, como formação de células aneuploides, diminuição de frequência de células em G0/G1, aumento de células em G2/M e aumento relativo de células em metáfase quanto à porcentagem de células em fases mais tardias da fase M do ciclo. Já aumento da frequência de células micronucleadas ocorreu apenas nos períodos quando foram observadas fibras na cultura. Para análise da formação de mitoses multipolares e destinos destas células foram construídos vetores para expressão de tubulinas fusionadas a proteínas fluorescentes RFP e GFP, padronizadas as condições de transfecção e de aquisição de imagens para que as células tratadas com crisotila fossem observadas por time-lapse. Alguns destinos de mitoses multipolares causadas pelo tratamento com crisotila foram observados, como morte em metáfase, divisão gerando duas ou três células filhas, fusão de células durante a telófase e retenção em metáfase. Os dados sugerem também a indução da amplificação centrossômica, que parece ocorrer inicialmente em células interfásicas, e também devido à fusão de células. / Asbestos is a general name given to six different fibrous silicate minerals found naturally in the earth\'s crust. These fibers are being exploited industrially since 1970, but several workers exposed to the fibers developed diseases in the respiratory tract, such as fibrosis and carcinomas. Some types of fiber were banished from the market, but the type of asbestos chrysotile can still be marketed in most countries. Studies in vivo and in vitro are trying to elucidate the asbestos effects in tissues and cells that could be related to the development of diseases, and these studies verified that asbestos exposure lead to DNA double strand breaks, oxidative stress, multinucleated and aneuploid cell formation. The present work aimed to verify the alterations in culture cells exposed to chrysotile for 48 h and recovered in fiber-free medium for 48 h, 4 days and 8 days, and also observe aberrant mitosis using time-lapse microscopy after 24 h and 48 h of chrysotile exposure. Some alterations were observed and remained in cell culture even after 8 days of recovery when chrysotile fibers were no longer observed - such as aneuploid cell formation, increased frequencies of G2/M cell, decreased frequencies of G1 cells, and increased frequencies of cells in early M phases as metaphase. The induction of micronuclei occurred only during the periods that fibers were observed in cell culture. For the analysis of multipolar mitosis formation and destinies of these cells after chrysotile treatment, DNA vectors for the expression of tubulins fused to fluorescent proteins (GFP and RFP) were constructed, and the conditions for cells transfection and image acquisition for time-lapse microscopy were established. The fate of some multipolar metaphases was observed: cell retention on metaphase, cell cycle progression generating two or three daughter cells, cell fusion during cytokinesis or during telophase after a multipolar anaphase, and cell death. The centrosome amplification was not observed during the M phase of cell cycle, and may occur in interphase, and also despite cell fusion.
27

A influência dos parâmetros de hipercelularidade, mitose e necrose em paliçada na vasculatura dos glioblastomas

Paula de Souza e Pinto, Ana 31 January 2011 (has links)
Made available in DSpace on 2014-06-12T22:58:23Z (GMT). No. of bitstreams: 2 arquivo2810_1.pdf: 2283343 bytes, checksum: ca8cbd5bb4e2ceac8a7c25a7641281a7 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2011 / O Glioblastoma multiforme é uma neoplasia astrocitária maligna e infiltrativa que se torna mais freqüente com a idade e tem uma incidência de 12% a 15% dentre as neoplasias intracranianas com uma sobrevida pós-operatória de 12 meses. Angiogênese é um dos principais pré-requisitos para o crescimento tumoral e para metástase. Em glioblastomas, a presença de vascularização atípica estabelece de forma marcante a malignidade de suas células que secretam fatores próangiogênicos alterando totalmente a estrutura do vaso, tornando-o similar a um glomérulo renal. O estudo dos indicadores de anaplasia (mitose, celularidade e necrose em paliçada) em região circunvizinha a angiogênese típica e atípica, em glioblastomas, esclarecerá a importância da estrutura vascular normal ou alterada para o desenvolvimento deste tipo de tumor. O presente estudo teve por objetivo avaliar a influência dos parâmetros histopatológicos de hipercelularidade, mitose e necrose em paliçada na vasculatura dos glioblastomas. Foram utilizados blocos de parafina com fragmentos teciduais cujos diagnósticos histopatológicos foram de glioblastomas. Foram preparadas lâminas e, após análise histológica, selecionados os casos que apresentaram vasculatura atípica. Em cada caso foram analisados os parâmetros de malignidade: hipercelularidade, mitose e presença de necrose em paliçada em áreas vasculares típicas para comparação com áreas vasculares atípicas. Após essa análise, a morfometria gerou as médias da contagem do número de células tumorais e número de mitoses que foram comparadas intra-grupo e esses achados foram correlacionados com a presença ou ausência de necrose em paliçada. O número de mitoses e células em regiões circunvizinhas a vasos atípicos foi estatisticamente superior, estando fortemente relacionados entre si. Constatou-se, que regiões onde há o aumento do número de células e mitoses predispõem a formação de vascularização atípica. A necrose em paliçada não teve correlação com o aumento do número de mitoses em áreas vasculares típicas ou atípicas, mas sua presença foi significativa quanto ao número de células, sendo encontrada uma maior celularidade nos casos em que estava presente esse tipo de necrose. Há interferência dos parâmetros histopatológicos relacionados a hipercelularidade e número de mitoses na áreas vasculares atípicas dos glioblastomas em relação às áreas vasculares típicas
28

Analyse et modélisation de la dynamique des chromosomes durant la mitose chez la levure à fission / Chromosome dynamics during mitosis in fission yeast

Mary, Hadrien 16 December 2015 (has links)
La mitose est une étape clé du cycle cellulaire, très préservée chez toutes les cellules eucaryotes, durant laquelle le matériel génétique de la cellule (les chromosomes) réparti de manière égale dans les deux cellules filles. Cette équipartition du matériel génétique est cruciale pour le maintien de la stabilité génétique. Durant ce processus, les chromosomes, composés des chromatides soeurs, établissent une plaque métaphasique au centre du fuseau mitotique. Chaque chromatide est attachée à un pôle du fuseau mitotique respectif (on parle d'attachement bipolaire) vers lequel elle se dirigera durant l'anaphase. Les chromatides sont l'unité indivisible du matériel génétique durant la mitose, à l'image des atomes dans une molécule. Initialement, une fois la chromatine condensée en chromosomes, chacun de ces " objets " est détaché et réparti suivant une position précise appellée territoires chromosomiques. Toute la complexité de la mitose est de capturer chacune des chromatides et de les positionner sur la plaque métaphasique avant leur séparation et migration vers leur pôle respectif durant l'anaphase. Cette étape de la division cellulaire requiert donc non seulement un réseau complexe d'interaction et de signalisation biochimique comme dans beaucoup d'autres processus biologiques mais aussi un fin contrôle spatio-temporel du mouvement et du positionnement de ces objets de grande taille à l'échelle de la cellule. Il semblerait que l'origine du mouvement des chromosomes provienne pour une grande part de la dynamique des microtubules. Ce qui est moins certain est la part relative accordée aux différents processus régulant cette dynamique; que ce soit la dynamique intrinsèque (appelée instabilité dynamique des microtubules) ou l'effet de différentes protéines sur les microtubules comme les MAPs (Microtubule Associated Proteins) et les kinésines (protéines motrices). On notera par ailleurs que le mécanisme de transfert d'énergie entre la dynamique des microtubules et le mouvement des chromosomes est encore très largement hypothétique. La dynamique des chromosomes durant la mitose est aussi largement contrôlée par un grand nombre d'acteurs autres que les microtubules. Certains d'entre eux étant responsables de l'attachement MTs-kinétochore comme les complexes NDC80 et DAM1, tandis que d'autres sont impliqués dans la régulation de la dynamique des microtubules comme la kinésine-8 et la kinésine-13. Durant mon travail de thèse, j'ai étudié la dynamique des chromosomes en mitose chez la levure à fission, modèle celulaire dont les mécanismes primordiaux qui contrôlent la mitose sont conservés avec les eucaryotes supérieurs. En effet, j'ai caractérisé deux de ces mécanismes conservés au cours de l'évolution: l'alignement des chromosomes durant la métaphase ainsi qu'un mouvement de va et vient plus ou moins régulier le long du fuseau aussi appelé oscillation des chromosomes. J'ai montré, en analysant les trajectoires des chromosomes que ces deux processus sont pour une large part indépendants [@Mary2015]. De plus, le processus d'alignement des chromosomes, encore mal compris, est en partie contrôlé par la kinésine-8 via une activité dépendante de la longueur des microtubules. Il semblerait donc que cette kinésine soit capable de fournir une information spatiale le long du fuseau mitotique afin de positionner correctement les chromosomes. Enfin, j'ai utilisé un modèle mathématique de la ségrégation des chromosomes précédemment développé dans l'équipe afin de tester de manière quantitative les hypothèses de mécanisme du centrage des chromosomes par la kinésine-8. L'ensemble de mon travail porte donc sur le contrôle du mouvement, de l'attachement et du positionnement des chromosomes durant la mitose afin de mieux comprendre les processus biophysiques associés à la mitose. / Mitosis is a highly preserved process in all eukaryotic cells during which the genetic material (chromosomes) is divided in two parts which spread in both daughter cells. This equipartition is crucial for maintaining genetic stability. During this process, chromosomes form a metaphasic plate at the center of the mitotic spindle. Each chromatid is attached to its respective spindle pole (called bipolar attachment) toward which it will move during anaphase. Chromatids are the indivisible units of genetic material during mitosis just like atoms in a molecule. Originally each of these "\ objects\ " are detached and organized in chromosomes territories. All the complexity of mitosis resides in the capture of each chromatid by the spindle pole to exert forces to position them on the metaphase plate before their separation and migration towards their respective poles in anaphase. This step of cell division not only requires complex interaction networks and metabolic signaling pathways just like many other biological processes but also a fine spatio-temporal control of movement and positioning of these big objects relative to cell size. It is usually accepted that the origin of chromosome movement arises from microtubule dynamics. However, what is less clear is the relative importance of each of these processes regulating chromosome movement: the intrinsic dynamic instability of microtubules or the effect of their associated proteins such as MAPs and kinesins. It is also important to note that the mechanism controlling the transfer of energy between microtubule dynamics and chromosome movement is still largely hypothetical. Moreover, chromosome dynamics during mitosis is regulated by a large number of actors apart from microtubules. Some of them being responsible for MT-kinetochore attachment such as NDC80 and DAM1 complex. While others are involved in the regulation of MT dynamics such as Kinesin-8 and Kinesin-13. During my PhD, I studied fission yest chromosome dynamic during mitosis. This cellular model has the advantage of sharing many fundamental mechanisms of symmetrically dividing higher eukaryotic cells. I characterized two of these conserved mechanisms: chromosome alignment during metaphase and back and forth movement along the spindle, called chromosome oscillation. By analyzing chromosome trajectories, I showed that both processes are performed through independent mechanisms [@Mary2015]. Moreover, chromosome alignment process, which is still poorly understood, is regulated by Kinesin-8 via a length dependent activity on microtubules. This suggests that Kinesin-8 is able to provide spatial information along the mitotic spindle to properly position chromosomes. Finally, I used a mathematical model of chromosome segregation in order to test quantitatively different hypotheses of chromosome centering process. This work is thus deciphering the control of movement, attachment and positioning of chromosomes during mitosis and seeks to better understand the biophysical processes controlling mitosis.
29

Verstärkung von Tumor Treating Fields durch Inhibition der MPS1 Kinase in Glioblastom-Zelllinien / Augmentation of Tumor-Treating-Field (TTField) effects on glioblastoma cells by MPS1 inhibition

Gross, Franziska January 2020 (has links) (PDF)
Tumor Treating Fields (TTFields) sind alternierende Wechselfelder mit einer intermediären Frequenz und niedrigen Intensität, die zu einer Destabilisierung des Spindelapparates während der Mitose führen. Sie sind als zusätzliche Behandlungsoption bei Glioblastoma multiforme zugelassen. Der mitotische Spindelkontrollpunkt überwacht eine fehlerhafte Anheftung der Spindelfasern von Schwesterchromatiden und leitet Reparaturprozesse ein. Monopolar spindle 1 (MPS1) ist eine Schlüsselkomponente dieses Kontrollpunktes und kann den durch TTFields physikalisch induzierten Spindelschäden entgegenwirken. Durch Zellzahlmessung, Zellzyklusuntersuchungen und durchflusszytometrische Analysen als auch Fluoreszenzfärbungen konnte gezeigt werden, dass eine Inhibition von MPS1 die antimitotischen Wirkungen von TTFields verstärken kann. / Tumor Treating Fields (TTFields) are alternating electric fields with low intensity and intermediate frequency approved for the therapy of glioblastoma multiforme. TTFields therapy interrupts the spindle formation through mitosis leading to misalignment of chromosomes. Spindle assembly checkpoint (SAC) and its key component monopolar spindle 1 (MPS1) regulate proper chromosomal arrangement and segregation. Here, we show that through the combination of physically interfering spindle formation by TTFields and chemical inhibition of MPS1, TTFields effects can be augmented promising a new target for multimodal treatment in glioblastoma therapy.
30

Expression der mitotischen Regulatorproteine Pds5A, Pds5B, Mad2A und Mad2B in astrozytären Tumoren im Kontext der chromosomalen Instabilität, Tumorprogression und Patientenprognose / Expression of the mitotic regulating proteins Pds5A, Pds5B, Mad2A and Mad2B in astrocytic tumors in the context of chromosomal instability, tumor progression and patient prognosis

Fett, Susanne January 2020 (has links) (PDF)
Die zunehmende Bedeutung der Molekularbiologie zeigt sich in der neuen WHO-Klassifikation von 2016 für ZNS-Tumoren und insbesondere astrozytäre Tumoren. Dabei gehört das Glioblastoma multiforme (GBM) mit einer äußerst ungünstigen Prognose zu den hoch-malignen Astrozytomen (WHO °IV) und ist durch eine ausgeprägte chromosomale Instabilität (CIN) gekennzeichnet. Der mitotische Spindelkontrollpunkt (SAC) und die zeitlich korrekte Auflösung der Schwesterchromatidkohäsion sorgen normalerweise für den fehlerfreien Ablauf der Mitose. Um der Ursache der CIN nachzugehen, wurden die Regulatorproteine des SAC Mad2A und Mad2B sowie der Schwesterchromatidkohäsion Pds5A und Pds5B in einem Patientenpanel immunhistochemisch untersucht. Alle vier Proteine wiesen eine hohe Expression in Proliferationszentren auf, die durch Ki67-Expression definiert wurden. Zusätzlich wurden Unterschiede in der Expressionsstärke bzw. der subzellulären Lokalisation detektiert. Pds5A könnte für die Ausbildung von Rezidiven niedriggradiger Astrozytome (low-grade astrozytoma, LGA) °II bzw. von sekundären GBM wichtig sein. Sein Ortholog war in allen Tumorentitäten gleichmäßig hoch exprimiert. Eine starke Mad2A-Expression war in allen GBM im Vergleich zu allen LGA °II signifikant vermindert und könnte durch den in GBM häufig vorkommenden Verlust von Chromosomenarm 4q bedingt sein, der das Mad2A-Gen enthält. Für sein Homolog Mad2B konnte ein signifikanter Anstieg in der Gesamt- bzw. Zytoplasmaexpression mit steigendem WHO-Grad ermittelt werden. Eine niedrige Gesamtexpression von Mad2A bzw. von Mad2B in Kern- und Zytoplasma könnte mit einem Überlebensvorteil für GBM-Patienten verbunden sein. Je nach Entität, Expressionsstärke und Expressionslokalisation gab es Korrelationen zwischen der Expression von Ki67, Pds5A, Pds5B, Mad2A und Mad2B. Die Expressionswerte dieser mitotischen Regulatorproteine könnten einerseits der Grund für, andererseits aber auch eine Konsequenz von CIN sein und eine Anpassung der Tumorzellen zur Ausbalancierung der Vor- und Nachteile genetischer Veränderungen darstellen, die ihr Überleben sichert (Rimkus et al., 2007). Damit könnten diese Regulatorproteine als neue Angriffspunkte einer noch spezifischeren Therapie in der Behandlung von astrozytären Tumoren und für die Prognose von Patienten Bedeutung erlangen. / The increasing relevance of molecular biology is shown in the latest 2016 WHO-Classification of Tumors of the Central Nervous System especially in regards to astrocytic tumors. Astrocytic tumors show aneuploidy. Pds5A, Pds5B, Mad2A and Mad2B have an important influence and impact on the correct segregation of chromosomes during mitosis. Precocious dissociation of sisters 5 A and B (Pds5A and B) bind to Cohesin and are part of the regulation of sister chromatid cohesion. Mitotic arrest deficient 2 A and B (Mad2A and B) are essential key-proteins for the spindle assembly checkpoint. Incorrect expression of these proteins leads to missegregation and aneuploidy. In this work I show the expression of the proteins Pds5A, Pds5B, Mad2A and Mad2B by immunohistochemistry in proliferating centers of tissue samples of 40 patients with astrocytic tumors (low-grade astroytoma (LGA °II) and glioblastoma multiforme (GBM)). Tissue samples comprise dormant LGA °II, recurrent LGA °II and their relapses, malignant progressing LGA °II developing to secondary GBM (IDH-mutant GBM), and primary GBM (IDH-wildtype GBM). All proteins showed high expression in the proliferating centers. The expressions of the different astrocytic grades have been statistically analysed (Comparison, Survival, Correlation). The results of the expression of the regulating proteins could be relevant for new therapies and the prognosis of patients.

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