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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.
41

Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma

Pereira, Mariana Brutschin January 2017 (has links)
Introdução: A complexidade das populações de células do sistema imunológico infiltrando tumores humanos com seus efeitos sinérgicos ou antagônicos pode influenciar os tumores de forma diferente. Embora as células do sistema imunológico sejam encontradas dentro do sítio tumoral, a razão para incapacidade do sistema imunológico em eliminar o tumor foram pouco elucidadas. Objetivo: Avaliar a importância das diferentes populações de células no sistema imunológico presentes no microambiente tumoral de glioblastoma e seus efeitos sobre as demais células em relação ao prognóstico dos pacientes. Metodologia: Foram utilizados dados de transcriptoma e dados clínicos gerados pelo The Cancer Genome Atlas (TCGA) e meta-assinaturas representando diferentes células do sistema imunológico previamente descritas. A relação entre as meta-assinaturas foi avaliada através de análises de mapa de calor e correlação de Pearson. As análises de sobrevida foram realizadas através de gráficos de Kaplan-Meier das meta-assinaturas individualmente, com dois e três elementos. Resultados e Discussão: Assinaturas transcricionais de diversas populações do sistema imunológico com papel imunossupressor foram encontradas infiltrando tumores de pacientes com glioblastoma, tais como macrófagos, células NK e NK T, MDSCs e Tregs e correlacionaram com um pior prognóstico dos pacientes. As meta-assinaturas T CD8+ e CD4+ não foram capazes de predizer o prognóstico dos pacientes sozinhas. No entanto, na ausência de elementos de imunossupressão, os pacientes com alta expressão da meta-assinatura de células T CD8+ mostraram melhor sobrevida em relação aos demais. Observamos uma divisão das meta-assinaturas em 4 conjuntos distintos, sendo um deles formado por Macrófagos, MDSCs e Tregs demonstrando pior prognóstico e outro cluster contendo CD4 e CD8 conferindo um melhor prognóstico, ambos quando altamente expressos. Esses resultados não se repetiram para gliomas de grau II e III. Conclusão: Se considerarmos as assinaturas transcricionais dos diferentes aspectos da resposta imunológica de forma integrada, teremos um impacto preditivo sobre a sobrevivência com papel positivo para a meta-assinatura referente a linfócitos CD8 e negativos para as meta-assinaturas de macrófagos, MDSC, Tregs, NK e NK T em pacientes com glioblastoma pacientes. A compreensão acerca desses diversos fatores reguladores e estimuladores do sistema imunológico no paciente, bem como no microambiente tumoral, é essencial para delinear uma estratégia eficaz com o objetivo de aumentar a resposta imune antitumoral e gerar benefícios clínicos reais. / Introduction: The complexity of immune cell populations infiltrating human tumors with their synergistic or antagonistic effects may influence tumors differently. Although immune cells are found within the tumor site, the reason for the incapacity of the immune system in eliminating the tumor has hardly been elucidated. Objective: To evaluate the importance of different immune cell populations present in the glioblastoma tumor microenvironment and its effects on the other immune cells. Methodology: Transcriptome and clinical data were generated by The Cancer Genome Atlas (TCGA) and meta-signatures representing different cells of the immune system previously described were used. The relationship between meta-signatures was evaluated through heat-map analysis and Pearson's correlation. Survival analysis were performed through Kaplan-Meier plots of meta-signatures individually, with two and with three elements. Results and discussion: Infiltrating immune cells with immunosuppressive role were found in patients with glioblastoma, such as macrophages, NK and NK T cells, MDSCs and Tregs, and were correlated with poorer prognosis of patients. The CD8 + and CD4 + T meta-signatures were not able to predict patients’ prognosis alone. However, in the absence of immunosuppressive elements, patients with higher levels of CD8 + T-cell meta-signatures showed better survival than the opposite expression profile. We observed a division of meta-signatures into four clusters. The cluster consisting of macrophages, MDSCs and Tregs demonstrated the worst prognosis and the cluster containing CD4 and CD8 conferred the best prognosis, when both meta-signatures were highly expressed. These results were not reproduced for grade II and III gliomas. Conclusion: If we consider the transcriptional signatures of the different response immunological aspects in an integrated way, they will have a predictive impact on survival with positive role for CD8 and negative roles for macrophages, MDSC, Tregs, NK and NK T meta-signatures in glioblastoma patients. Understanding these regulatory factors and stimulators of the patients' immune system, as well as the tumor microenvironment, is essential to delineate an effective strategy to increase the anti-tumor immune response and generate real clinical benefits.
42

Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase

Kagami, Luciano Porto January 2017 (has links)
Os tumores cerebrais primários mais comuns são os gliomas. Os gliomas representam 31% de todos os tumores cerebrais diagnosticados nos Estados Unidos sendo 81% destes tumores malignos. O glioblastoma (GBM) é o tumor mais comum entre os gliomas, sua taxa de incidência varia de 0,59 a 3,69 a cada 100.000 pessoas, dependendo da idade e do país. A ecto-5’-nucleotidase regula os níveis extracelulares de AMP e adenosina, a qual tem sido amplamente descrita como fator indutor de proliferação celular. Estudos demonstraram que a atividade da enzima ecto-5’-nucleotidase foi aumentada em linhagens de células de glioma, quando comparada aos astrócitos. Também, o tratamento com 1 μM de APCP, um inibidor competitivo da ecto-5'-nucleotidase, causou uma redução significativa de 30% na proliferação das células de glioma. Através de estudos de modelagem molecular foi possível planejar três compostos com perfil farmacológico adaptado para o tratamento do glioblastoma. As moléculas LaSOM 281, LaSOM 282 e LaSOM 287, apresentaram um baixo risco toxicológico, capacidade de atravessar a barreira hematoencefálica e afinidade ao alvo pela predição realizada. Os compostos planejados foram sintetizados com bom rendimento e grau de pureza. No entanto os testes de atividade enzimática realizados para a enzima ecto-5’-nucleotidase das células de glioma, mostraram que os três compostos sintetizados não apresentaram ação inibitória, possivelmente por sua pouca solubilidade em meio aquoso. / The most common primary brain tumors are gliomas. Gliomas represent 31% of all brain tumors diagnosed in the United States and 81% of these tumors are malignant. Glioblastoma (GBM) is the most common tumor among gliomas, with an incidence rate ranging from 0.59 to 3.69 per 100,000 people, depending on the age and country. The ecto-5'-nucleotidase regulates the extracellular levels of AMP and adenosine, which has been widely described as a cell proliferation inducing factor. Studies have shown that the activity of the enzyme ecto-5'-nucleotidase was increased in glioma cell lines when compared to astrocytes. Also, treatment with 1 μM APCP, a competitive inhibitor of ecto-5'-nucleotidase, caused a significant 30% reduction in glioma cell proliferation. Through molecular modeling studies it was possible to plan three compounds with pharmacological profile adapted for the treatment of glioblastoma. The molecules LaSOM 281, LaSOM 282 and LaSOM 287 showed a low toxicological risk, ability to cross the blood brain barrier and affinity to the target by the prediction. The planned compounds were synthesized in good yield and purity. However, the enzymatic activity tests performed for the ecto-5'-nucleotidase enzyme of glioma cells showed that the three compounds did not present an inhibitory action, possibly due to their low solubility in aqueous medium.
43

Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261

Tamajusuku, Alessandra Sayuri Kikuchi January 2010 (has links)
O nucleotídeo de purina ATP, no meio extracelular, participa de diversos processos fisiológicos e patológicos como vasodilatação/constrição, proliferação, diferenciação, modulação sináptica, dor, inflamação e morte celular. Entre os receptores purinérgicos, o subtipo P2X7 é bem descrito como mediador de processos inflamatórios pela liberação de IL-1β e de morte celular com ativação de caspases. Evidências na literatura apontam para o envolvimento do sistema purinérgico no crescimento e na progressão de glioblastomas. Esses tumores são os mais comuns do SNC e seu alto grau de malignidade deve-se à capacidade de rápida proliferação e invasão no tecido sadio. Considerando a resistência que os glioblastomas apresentam à morte celular induzida por ATP, o objetivo desse trabalho foi investigar a expressão e funcionalidade do receptor citotóxico P2X7 em linhagens de gliomas e suas implicações na biologia tumoral. Entre as linhagens de glioblastomas estudadas, a linhagem de camundongo GL261 apresentou sensibilidade à morte induzida por ATP pela liberação de LDH, incorporação de iodeto de propídio e diminuição da viabilidade mitocondrial. O ATP foi tóxico em concentrações acima de 2 mM, o BzATP foi mais potente que o ATP e o antagonista oATP bloqueou completamente a morte celular. O silenciamento do receptor P2X7, na GL261, por RNA de interferência, também aboliu a morte celular induzida por ATP confirmando o envolvimento desse receptor, embora a formação de poro ainda tenha sido visível nestas células, ainda que diminuída. A morte celular apresentou características necróticas como a ruptura de membrana, a falta de ativação de caspases e a falta de externalização de fosfatidilserina, mas ao mesmo tempo houve encolhimento celular. Além dos efeitos mediados pela sua ativação, o silenciamento do receptor P2X7 na linhagem GL261 diminuiu a adesão e promoveu a migração celular, características de tumores mais invasivos. Em amostras de pacientes com gliomas, foi possível observar que a expressão de P2X7 correlaciona diretamente com a sobrevida dos pacientes. Juntamente com os dados da linhagem silenciada para o P2X7, é possível apontar o receptor P2X7 como uma possível molécula anti-tumoral, cuja redução na expressão diminui a adesão, aumenta a migração, torna a célula resistente à morte induzida por ATP, possivelmente diminuindo, desta forma, a sobrevida de pacientes acometidos por esta doença. / Purines nucleotides, particularly extracellular ATP, participate in diverse physiological and pathological processes such as vasodilatation/constriction, cell proliferation, differentiation, synaptic modulation, inflammation, pain sensation and cell death. Among purinergic receptors, the P2X7 subtype is well described as a mediator of inflammatory processes via IL-1β release and cellular death induced by caspases activation. Evidences in the literature point to the purinergic system involvement in growth and glioblastoma progression. These tumors are the most common in the central nervous system (CNS) and their high grade of malignance is the result of rapid proliferation and invasion abilities. Considering the resistance that glioblastomas show to ATP-induced cell death, the objective of this work was to investigate the expression and function of cytotoxic P2X7 receptor in glioma cell lines and their implications in tumor biology. Among the glioma cell lines, the mouse GL261 was sensitive to ATP-induced cell death with LDH release, iodide incorporation and a decrease in mitochondrial viability. ATP was toxic in concentrations above 2 mM, BzATP was more potent than ATP and the antagonist oATP blocked completely the cell death induced by ATP. P2X7 receptor silencing in GL261 by RNA interference, also abolished ATP-induced cell death, confirming this receptor involvement, although a diminished pore induction was observed. Cellular death had necrotic features like membrane rupture, lack of caspase activation and lack of phosphatidylserine exposure, but at the same time shrinking also occurs. Beyond its activation effects, P2X7 knockdown in GL261 decreased cell adhesion and promoted migration, features common to more invasive tumors. In human glioma samples, P2X7 receptor expression correlated directly with patients‟ survival. Together with data from P2X7-knocked down cell line, it is possible to suggest the P2X7 receptor as an anti-tumoral molecule, whose expression reduction leads to decreased adhesion, increased cell mobility, resistance to ATP-induced cell death, and therefore, decreased patients survival.
44

Inactivation of Lgl1 in Glioblastoma

Gont, Alexander January 2016 (has links)
Glioblastoma is the most aggressive and invasive adult brain cancer. In glioblastoma, the loss of the tumour suppressor PTEN is the most common genetic alteration resulting in aberrant activation of the PI3-kinase pathway. In Drosophila, the loss of tumour suppressor Lgl results in massive overgrowth of brain tissue that is highly invasive when transplanted into wildtype hosts. Subsequent study of Lgl protein function revealed that it is important for maintenance of cell polarity and neuroblast differentiation through asymmetric cell divisions. It is unclear if inactivation of Lgl occurs in human brain cancers and what role it plays in glioblastoma malignancy. Firstly, this study demonstrated that the loss of PTEN leads to inactivation of Lgl1 via phosphorylation by atypical protein kinase C iota (PKCι). In primary glioblastoma cultures, preventing Lgl1 inactivation by either PTEN expression, PKCι knockdown or expression of non-phosphorylatable Lgl (Lgl3SA) promoted differentiation. In a follow-up study, the effect of active Lgl1 in glioblastoma invasion was investigated. Lgl3SA expression inhibited invasion in vitro through decreased motility. In an orthotopic xenograft mouse model using primary glioblastoma cells, Lgl3SA expression promoted differentiation and decreased invasion. Therefore, PTEN loss, acting via PKCι and Lgl1, has a key role in maintaining glioblastoma in an undifferentiated, highly invasive state similar to what is observed following Lgl loss in Drosophila. PREX1 was investigated as a potential link between PTEN loss and activation of PKCι. PREX1, a Rac activator, is synergistically activated by the PI3-kinase product PIP3 and G protein-coupled receptor (GPCR) βγ subunits. PREX1 expression was detected in primary glioblastoma cell cultures as well as the majority of patient tumour samples. Both PI3-kinase and GPCR βγ subunit activity is required for PREX1 to promote invasion in glioblastoma. In primary glioblastoma cells, Rac1 preferentially associated with Par6a leading to activation of PKCι. Knockdown of PREX1 decreased activation of PKCι. Thus, PREX1 stimulates PKCι activity in glioblastoma likely by modulating the Rac1/Par6a/PKCι complex. The PI3-kinase pathway is activated by mutation in most glioblastomas and these results show this requires a context of GPCR signalling to promote invasion.
45

Stimulation of Glioblastoma Proliferation by Macrophages Through CD47/SIRPα

Badham, Katelyn January 2017 (has links)
Glioblastoma is the most common and aggressive type of adult brain tumour with a need for new treatments. CD47 has been shown to be overexpressed on some human cancers and to interact with macrophages but its role in glioblastoma has not yet been fully explored. Here, we identify a novel role for the CD47/SIRPα interaction between glioblastoma and macrophages in that it can stimulate glioblastoma proliferation in co-cultures. Blocking either CD47 or SIRPα resulted in decreased glioblastoma proliferation. Furthermore, we show that macrophage stimulated glioblastoma proliferation is not occurring through downstream signalling of SIRPα but likely through CD47 to the PI3Kβ pathway. Initial results of co-cultures using glioblastoma cells which express CD47 that is GPI linked to the membrane, and therefore cannot signal downstream, support these findings. The implication of this research is the possibility to develop new therapies targeted at CD47 to decrease glioblastoma proliferation.
46

Untangling Glioblastoma Invasion: Characterizing a Cell Culture Model of Glioblastoma Tumor Microtubes

Jomaa, Danny 26 July 2018 (has links)
Glioblastoma is the most common and most lethal primary brain tumor to affect adults. While current treatment options provide temporary recourse, the majority of patients experience tumor recurrence and few survive five years past their initial diagnosis. Recently, tumor microtubes (TMs) were identified in an in vivo model of glioblastoma. These membrane-bound structures formed physical connections between tumor cells, over short and long distances, and facilitated intratumoral communication, invasion, treatment resistance, and post-treatment tumor recovery. To date, this is the first instance of TMs being reported in glioblastoma. The lack of an in vitro model for these structures has delayed further characterization of how TMs form between cells, facilitate intercellular exchange, and how they can be therapeutically targeted to increase treatment susceptibility. The study presented here is the first instance of TMs characterized in an in vitro model of primary glioblastoma (PriGO) cells. These TMs recapitulated many of the structural and functional properties of those observed in vivo, making it a suitable model for further experimentation. Using this model, Rac1, a known orchestrator of cytoskeletal remodeling and motility, was shown to be integral to establishing a TM network between PriGO cells, as demonstrated by siRNA-mediated protein knockdowns. PREX1, a GEF necessary for Rac1 signaling activity, also played a role in PriGO TM formation as evidenced by CRISPR/Cas9-based knockouts. Re-introducing a PREX1 domain with Rac-GEF activity into cells lacking the protein led to a functional rescue of TM growth, thus confirming PREX1’s involvement. Characterizing a cell culture model of glioblastoma TMs is a necessary first step in the study of these structures, ultimately paving the way for future development of therapies that disrupt this network.
47

Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models

Finkelberg, Tomer 18 June 2020 (has links)
OBJECTIVES: To determine the effect of murine cytomegalovirus (MCMV) infection on the growth and proliferation of glioblastoma using murine models of differing genetic backgrounds, as well as to determine whether the observed effects are dependent on the mutational background of the glioblastoma models. METHODS: An experimental orthotopic murine glioblastoma model was established using latently MCMV infected C57BL/6 mice, with non-infected mice as controls. Mouse brains were harvested at the end-point and subject to histological analysis using immunostaining and visualization by confocal microscopy. Viral infectivity and protein expression levels were assayed using time-lapse microscopy and western blotting. RESULTS: Our results indicate that while the degree of viral infection may differ between experimental cell lines, MCMV-infected tumor-bearing mice consistently demonstrate accelerated tumor growth and worsened survival relative to the uninfected controls. Additionally, our results provide further evidence to support the previously reported findings implicating CMV as a driver of angiogenesis in vivo, as sections from MCMV-infected mice showed a greater density of blood vessels and more complete blood-brain barrier formation. Finally, our results show that the addition of antiviral agents as an adjunct therapy to first-line chemotherapeutics effectively reduced tumor sphere size and partially reversed viral infection by MCMV. CONCLUSIONS: Here we demonstrate the tumor-promoting effects of MCMV infection are consistently observed in different glioblastoma mouse models suggesting that these effects are independent of the tumor genetic background of our tested tumor models. Moreover, the success of preliminary in vitro studies using a combination treatment of antiviral and chemotherapy strengthen the case for targeting CMV therapeutically in the treatment of GBM.
48

The Role of Cytomegalovirus in Glioblastoma and Rhabdomyosarcoma

Price, Richard Lee, III 27 August 2012 (has links)
No description available.
49

Alteration of differentiation in glioblastoma: from spatial transcriptomics approaches to the identification of a suppressor event

Argento, Chiara Maria 11 April 2024 (has links)
Glioblastoma is one of the most devastating forms of primary brain tumor, with a survival of 14.6 months from the diagnosis. Despite the aggressive treatments used in the clinic, consisting of surgical resection followed by radiotherapy and concurrent chemotherapy using temozolomide, the absence of novel treatments and the development of resistance to standard-of-care therapies continue to position glioblastoma as the most challenging brain tumor in adults. The main factor contributing to the incurability of glioblastoma is the extensive heterogeneity. This heterogeneity, which is evident both at intratumoral and inter-patient levels, represents a substantial obstacle to the achievement of effective treatments. In this context, the use of single-cell resolution appears one of the most powerful means for understanding the intricacies and unravelling the heterogeneity of glioblastoma. Although single-cell RNA sequencing studies have provided and still provide valuable insights, they lack the essential spatial context that is critical for unravelling the heterogeneity of glioblastoma. This limitation impedes the understanding of interactions among distinct subpopulations and their intricate relationships with the neuronal microenvironment. To gain insights into the heterogeneity of glioblastoma, we used the spatially resolved RNA sequencing technology to analyse glioblastoma samples deriving from 3 different patients. For each patient, we focused on four distinct tumor regions, i. e. the proliferating tumor area, the necrotic core, the infiltrating area, and a distal healthy area. Cancer cells identified in the infiltrating regions exhibited a unique pattern of cell subpopulations, with the oligodendrocytes as the most represented in this area. In addition, we managed to generate patient-derived glioblastoma organoids from nearly all areas, with the tumor regions displaying the highest growth rates. These patient-derived organoids, which represent fundamental models useful to faithfully replicate the disease in vitro, may be employed in future analyses. Finally, we also derived glioblastoma stem cell cultures from the different tumor regions, with the proliferating tumor area showing the highest rate of success. In the second part, we aimed to gain a deeper understanding of the molecular mechanisms that underlie the development of glioblastoma, which is crucial for developing effective treatments, and characterise ELAVL2 role, highlighting its potential role as a potential tumor suppressor in glioblastoma. Collectively, our findings suggest that ELAVL2 promotes the exit of glioblastoma stem cells from quiescence, boosting their self-renewal capacity while also facilitating neuronal differentiation. The in vivo validation of our results using an orthotopic human glioblastoma stem cell xenograft model and a D. melanogaster genetic model strongly supports our findings and points to deletion of ELAVL2 as a factor that increases aggressiveness in glioblastoma stem cells and in vivo.
50

Vastatin, an endogenous anti-angiogenic agent, is of therapeutic benefit for glioblastoma multiforme through targeting the microvascular endothelial cells: 利用内源性血管生成抑制剂vastatin治疗胶质母细胞瘤的研究 / 利用内源性血管生成抑制剂vastatin治疗胶质母细胞瘤的研究 / Vastatin, an endogenous anti-angiogenic agent, is of therapeutic benefit for glioblastoma multiforme through targeting the microvascular endothelial cells: Li yong nei yuan xing xue guan sheng cheng yi zhi ji vastatin zhi liao jiao zhi mu xi bao liu de yan jiu / Li yong nei yuan xing xue guan sheng cheng yi zhi ji vastatin zhi liao jiao zhi mu xi bao liu de yan jiu

January 2014 (has links)
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour in adults. The employment of current standard of care management strategy, that is combining maximum but safe surgical resection, and concomitant chemoradiotherapy, only achieves very modest survival benefits. Antiangiogenesis is a widely studied therapeutic strategy, which restricts the tumour growth by cutting off blood supplement. Although several antiangiogenic agents are now under clinicaland preclinical trials, bevacizumab is still the only one that has been proven to be effective in the treatment of recurrent GBM. However, the clinical use of bevacizumab has encountered the emergence of drug resistance. Its therapeutic benefit is considered limited because of its single pathway targeting. Many researchers believe that the use of broad spectrum angiogenesis inhibitors may leadto better clinical outcomes by overcoming the shortcomings of bevacizumab. / Vastatin, the globular non-collagenous 1 (NC1) domain of collagen VIIIα1, was initially proved to inhibit the proliferation and migration of bovine aortic endothelial cells. Although vastatin is similar in origin to other collagen-derived antiangiogenic factors (CDAFs), its antiangiogenic capability in treatment of cancers has not been studied systematically. Our team members previously found that vastatin wasa safe and effective antiangiogenic therapeutic and a potential biomarker for liver cancer. In this thesis, I tried to explore the therapeutic potential of vastatin in treatment of GBM. / Using a recombinant adeno-associated virus mediated gene therapy, the antiangiogenic potential of vastatin was first confirmed in vitro that it inhibited proliferation, migration and tube formation of murine microvascular endothelial cells (MECs). These effects were further confirmed using another gene vector (H1) which was subsequently employed for the in vivo studies. H1 is a nanopolymer gene vector has high affinity with the folate receptors on tumour cells. Transfection ofH1/vastatin reduced MEC proliferation in a U87/MEC co-culture system, suggesting a paracrine inhibition. Mechanism studies showed that vastatin caused a wide range of changes in the global gene transcription level in MECs, indicating a broad spectrum of action. / Following the establishment of an orthotopic murine GBM model, the H1/DNA polyplexes were injected directly to the tumour area. Treatment induced a significant increase in intracranial mRNA level of the therapeutic gene. Both vastatin and endostatin, a positive control, prolonged the survivals of GBM bearing mice. Immunostaning showed that vastatin decreased microvessel density in the outer layer of the tumour, while decreased cell density and caused abnormal vessel structures inthe centre. No synergistic effect was observed when GBM was treated with the combination of H1/vastatin and temozolomide (TMZ) in this model. / Finally, the therapeutic effect of vastatin on a TMZ resistant model was studied. GBM cells with acquired TMZ resistance (ATR) were established by chronic exposure of U87 cells to TMZ. Animals grafted with the U87-ATR cells were proved to be tolerant of TMZ treatment. H1/vastatin injection significantly prolonged the survival in this model. More interestingly, H1/vastatin also resensitized these animals to TMZ treatment. Stem cell related drug resistance was supposed to be disturbed in this process. / In conclusion, the present study has demonstrated for the first time that vastatin, a broad spectrum endogenous angiogenesis inhibitor, is of therapeutic benefit in a murine orthotopic GBM model. Vastatin’s capability to reverse TMZ resistance highlights an important area for further research. / 胶质母细胞瘤(GBM)是成人最常见的恶性原发性脑肿瘤。目前的治疗手段包括了手术切除和放化疗,但是效果仍不能让人满意。与传统的化疗药不同,抗血管生成药物能通过抑制肿瘤内新血管的形成,切断血流供给,达到限制肿瘤生长的目标。贝伐单抗(Bevacizumab)是目前唯一获得批准用于临床GBM治疗的抗血管生成药物。然而Bevacizumab在临床应用中必须面对耐药性产生的问题, 而且因为Bevacizumab只单一性地阻断血管内皮生长因子相关的通路,所以它的治疗效果也受到了一定程度的限制,让肿瘤可以选择替代性的通路来获得新生血管。因此一些研究人员认为,改用多靶点或者广谱的抗血管生成药物,治疗效果应该会更好。 / Vastatin是VIII型胶原蛋白α1链上的球状非胶原裂解片断。人体内这一类的片段多被证明了具有抗血管生成的功能,它们统称为“源自胶原蛋白的抗血管生成因子”。Vastatin具有抑制牛主动脉内皮细胞增殖和迁移的作用,然而它在抗肿瘤血管生成方面的作用却没有被系统地研究过。我们之前的实验曾经发现Vastatin对肝癌模型中的血管生成具有明显的抑制效果,而本论文将对Vastatin是否同样具有治疗GBM的作用展开研究。 / 在体外,我们首先证明了重组腺相关病毒(rAAV)介导的Vastatin基因治疗能有效抑制MEC的增殖和迁移,并阻止其形成管状结构。我们同时也测试了另一种基因载体H1,以方便后续动物实验的开展。H1是一种纳米聚合物,对肿瘤细胞表面高表达的叶酸受体有高亲和力。H1 介导的Vastatin 基因治疗对肿瘤细胞和MEC都没有直接的作用,但在两种细胞的共培养体系中,Vastatin可以通过旁分泌的方式来抑制MEC的增殖。对机制的研究发现,Vastatin使MEC内基因转录的水平发生了大范围多通路的改变,说明了它的作用具有一定的广谱性。 / 实验进一步研究了Vastatin在小鼠原位GBM 模型中的作用。将H1/DNA 复合物直接注入瘤区可以明显提高颅内相应基因的转录水平。Vastatin和作为阳性对照的Endostatin都能有效地延长GBM小鼠的生存期。免疫组织化学的结果显示Vastatin 能降低肿瘤内部的微血管密度,并诱导组织坏死。这与之前报道过的Endostatin的作用相似。在同一模型上,我们还测试了Vastatin和Temozolomide(TMZ)结合给药的效果,但并没有了现明显的协同作用。 / 实验最后研究了Vastatin在TMZ耐药模型中的治疗效果。通过将U87细胞长期浸泡中含有TMZ的培养基中,我们成功地筛选出了具有TMZ耐药性的GBM细胞。用这些细胞建立的小鼠GBM模型对TMZ的作用不敏感。实验表明,H1/Vastatin基因疗法不仅能够明显延长模型小鼠的生存期,还可以逆转耐药性,使TMZ重新发挥作用。我们推测干细胞相关的耐药性的产生和维持可能在这个过程中受到了影响。 / 上述研究第一次阐明了Vastatin对GBM的治疗效果。Vastatin具有广谱的抗血管特性,能够通过作用于MEC抑制肿瘤内部新血管的生成。Vastatin不仅本身具有治疗作用,还能逆转动物模型对化疗药物的耐受性,因些具有很高的研究价值。相信对Vastatin更一步的探索不但可以拓宽我们对抗血管生成药物的理解,也可能意味着一个新的研究领域的出现。 / Li, Yi. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 102-110). / Abstracts also in Chinese. / Title from PDF title page (viewed on 05, January, 2017). / Li, Yi. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

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