Gotowa bibliografia na temat „Gliobastoma (GBM)”

Since the twentieth century, humanity has been experiencing a public health reality marked by numerous mosquito-borne diseases (belonging to the arthropod class), known as arboviruses. The Zika virus has become in recent years a risk to Brazilian and international public health due to its devastating effect due to its pathogenesis but also to fetal neurological development, causing serious health problems such as microcephaly and Guillain-Barré Syndrome, but also myelitis and meningoencephalitis. However, scientists studying the Zika virus have been trying to use the agent's ability to cause infections in healthy cells to attack and destroy cancer cells, such as the case of grade IV astrocytoma known as Gliobastoma Multiforme (GBM), which is a tumor of the very aggressive central nervous system and worse prognosis among primary cancers. As a result of effective therapy for GBM and the tropism of this etiological agent for brain cells, the hypothesis is that this virus would cause cell death in glioblastomas through metabolic alterations induced by the induced viral infection, but further studies must be carried out to demonstrate this therapeutic advantage in using the virus for the treatment of this malignant disease. Keywords: Zika virus; Gliobastoma Multiforme; Tumor of the Central Nervous System.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology.

Giant cell glioblastoma (GCG) is a rare subtype of glioblastoma multiforme (GBM) which represents 0.8% of all brain tumors and 5% of glioblastomas. This entity is all the more rarer in the pediatric age group. And, due to the limited number of case reports and case series in literature, its epidemiology, natural history and follow up are not well documented. We present this case for its rarity. A 14-year-old girl presented with history of recent onset headache and vomiting from last 10 days. Magnetic resonance imaging (MRI) brain revealed a mass lesion in the right temporo-parietal region, suggestive of a high-grade glioma. Histopathological examination revealed features typical of giant cell glioblastoma. Giant cell glioblastoma, is an extremely rare variant of gliobastoma multiforme, merits special mention because it has been hypothesized to be associated with a longer survival compared with GBM in both adults and children, possibly because of the younger age at presentation, certain histopathological and molecular characteristics of this entity.

Abstract INTRODUCTION The median survival of gliobastoma (GBM) patients remains less than two years despite aggressive treatments. Current targeted GBM therapies demonstrate initial therapeutic benefit; however, patients relapse due to therapeutic resistance and failure to eliminate GBM cells at the invasive margin. Therefore, we propose a two-prong approach: first, target pathologic disruption of the blood brain barrier (BBB) via exposure of neural ECM rather than disease markers to overcome therapy-resistant GBM; and second, designing therapeutic payloads that extracellularly spread throughout the tumor volume. METHODS Variable Lymphocyte Receptors (VLRs, a lamprey-derived antigen recognition system) were identified with high specificity for neural ECM. Candidate VLRs underwent further refinement using ex vivo tissue staining. Utilizing pathologic disruption of BBB as an approach for targeting GBM was confirmed in vivo with intracranial murine glioblastoma models. Finally, an immunogenic peptide was attached via a cleavable linker to the neural ECM binding VLRs for conditional release extracellularly to spread throughout the tumor. RESULTS The lead neural ECM-binding VLR candidate, named P1C10, demonstrates diffuse binding to parenchymal neural ECM, without detectable binding to other tissues. P1C10 demonstrates nanomolar affinity for neural ECM, and preferentially accumulates in intracranial GL261 and U87 murine GBM models. Finally, P1C10-targeted doxorubicin-loaded liposomes significant increased survival of mice with intracranial GBM. In additional studies, treating murine GBM models with a P1C10 VLR linked to an immunogenic peptide reduced GBM proliferation and increased infiltration of cytotoxic T cells. CONCLUSIONS We present proof-of-concept demonstration for targeting intracranial GBM via neural ECM exposed at pathological BBB disrupted sites. Additionally, P1C10 neural ECM-targeting VLR delivers chemotherapy-loaded nanoparticles and immunogenic peptides designed to spread extracellularly throughout the tumor. Thus, this novel strategy links a physiological ECM targeting scheme with extracellular-released therapeutics to treat primary GBM, and has potential for delivering therapies to other CNS diseases with pathological BBB.

Introduction. Elderly glioblastoma (GBM) patients often show limited response to treatment and poor outcome. Here, we provide a case series of elderly GBM patients from our Institution, in whom we assessed the clinical characteristics, feasibility of surgical resection, response to adjuvant treatments, and outcome, along with the impact of comorbidities and clinical status on survival. Patients and Methods. We included patients ≥ 65-year-old. We collected information about clinical and molecular features, extent of resection, adjuvant treatments, treatment-related complications, and outcome. Results. We included 135 patients. Median age was 71 years. In total, 127 patients (94.0%) had a Karnofsky Performance Status (KPS) ≥70 and 61/135 (45.2%) a Charlson Comorbidity Score (CCI) > 3. MGMTp methylation was found in 70/135 (51.9%). Subtotal resections (STRs), gross-total resections (GTRs), and biopsies were 102 (75.6%), 10 (7.4%) and 23 (17.0%), respectively. Median progression-free survival and overall survival (mOS) were 8.0 and 10.5 months for the whole cohort. Notably, GTR and radio-chemotherapy with temozolomide in patients with MGMTp methylation were associated with significantly longer mOS (32.8 and 44.8 months, respectively). In a multivariable analysis, risk of death was affected by STR vs. GTR (HR 2.8, p = 0.002), MGMTp methylation (HR 0.55, p = 0.007), and KPS at baseline ≥70 (HR 0.43, p = 0.031). Conversely, CCI and post-surgical complications were not significant. Conclusions. Elderly GBM patients often have a dismal prognosis. However, it is possible to identify a subgroup with favourable clinical and molecular features, who benefit from GTR and radio-chemotherapy with temozolomide. A comprehensive prognostic score is needed to guide treatment modality and predict the outcome

Abstract INTRODUCTION High grade brain cancers, like most solid tumors, often relapse and are resistant to current therapies. Limited efficacy to cell therapy may be related to intratumoral heterogeneity and the suppressive tumor microenvironment. Hence, we aimed to modify allogeneic natural killer (NK) cells, which can recognize expressed tumor stress ligands, to resist TGF-β and secrete IL15. METHODS Cord blood-derived NK cells were expanded and modified to express IL15 and a dominant negative receptor (DNR) against TGF-β. NK cell product activity against the GBM cell line U87MG were evaluated in vitro and in vivo. The behavior of these cells were also analyzed ex vivo, to evaluate the impact (including potential toxicity) of increasing the potency of this allogeneic NK cell product. RESULTS While animals injected with NK cells secreting IL15 and expressing DNR successfully cleared tumors 6 days after T cell infusion, we did not observe significant differences in survival between the groups (no treatment control mice vs treated with mock-transduced NK cell vs DNR-transduced NK cells vs IL-15/DNR-transduced NK cells). Therefore, we sought to determine whether cytokine-related toxicity was responsible for death in the setting of tumor clearance. We compared no treatment control mice vs mice treated with mock-transduced or IL-15/DNR-transduced NK cell products. Elevated levels of IL-15 were detected in the plasma of mice treated with IL-15/DNR-transduced NK cells. These elevated IL-15 levels corresponded with NK cell persistence in the brain measured by ddPCR. However, no other cytokines were upregulated. CONCLUSIONS We observed improved tumor clearance when NK cells were both protected against immune suppressive TGF-β and were capable of secreting the stimulatory cytokine IL15. We are currently performing additional experiments to determine whether toxicity from IL15 secretion occurs. To potentially mitigate this toxicity we plan to engineer a suicide gene into these constructs.

Abstract Background Epithelioid glioblastoma is a rare subtype of Glioblastoma. We examine two cases who presented acutely with symptoms of headache, neck stiffness and an eye squint. The purpose of this case review is to look at their management, the spread of the disease and propose the availability of BRAF inhibiting agents be made readily available for this subtype. Material and Methods The clinical records including pathology and surgical reports, multi-disciplinary team meeting documents, oncology plans and inpatient notes have all been reviewed alongside the literature on epithelioid GBM and BRAF V600e mutations and inhibitors. Results Patients were females aged 25 and 32 presenting with acute onset headache and neck stiffness to emergency Department. The 25 year old had developed a right eye squint within seven days of the other symptoms, her tumour was right frontal with midline shift. The 32 year old had symptoms for 10 days prior to presentation, the tumour was right temporal. They both underwent craniotomies. The frontal tumour was totally resected, while the temporal lobe tumour was haemorrhagic in nature and minimally de-bulked. Pre-operative stealth imaging showed that there had been an increase in the size of the temporal lesion in the fourteen days since presentation. Histology proved these to be epithelioid GBM’s with BRAF V600e mutations, IDH wild-type and TERT promoter mutant. Full pathology reports with molecular markers were available within ten days. The frontal lobe patient began chemo-radiation sixteen days from her surgical date. On day two she was admitted with severe headache and nausea. She became agitated, confused, and transferred back to the neurosurgery unit for management of hydrocephalus. She was diagnosed with PRES and simultaneously treated for this and hydrocephalus. Clinically she suffered storming, passing away exactly eight weeks from presentation. Seven days after surgery the temporal lobe tumour patient suffered a seizure and admitted for symptom management and expedite oncology treatment. She passed away six days later suffering continual neurological deterioration and the tumour progression with leptomeningeal spread. This was exactly four weeks from initial presentation. Conclusion The prognosis for epithelioid Glioblastoma is limited to weeks to short months. Extent of resection in these case studies demonstrates benefit in delaying progression though it is clear that time is of the essence from presentation, to surgery, to adjuvant treatment. Neither of these tumours were methylated meaning the standard treatment for glioblastoma is likely to lack efficacy. BRAF inhibitors should be made readily available for this rare sub-type to commence treatment expediently. Both patients suffered distressing neurological symptoms in their final days which require expert management and are best managed in a neurosurgical centre.

Uma das principais áreas de pesquisa em Biologia de Sistemas refere-se à descoberta de redes biológicas a partir de conjuntos de dados de microarrays. Estas redes consistem de um grande número de genes cujos níveis de expressão afetam os outros genes de vários modos. Nesta tese, apresenta-se uma nova maneira de analisar os conjuntos de dados de microarrays, com base nos diferentes tipos de ciclos encontrados entre os genes das redes de co-expressão construídas com dados quantificados obtidos a partir dos microarrays. A entrada do método de análise é formada pelos dados brutos, um conjunto de genes de interesse (por exemplo, genes de uma via conhecida) e uma função (ativador ou inibidor) destes genes. A saída do método é um conjunto de ciclos. Um ciclo é um caminho fechado com todos os vértices (exceto o primeiro e o último) distintos. Graças à nova forma de encontrar relações entre os genes, é possível uma interpretação mais robusta das correlações dos genes, porque os ciclos estão associados a mecanismos de feedback, que são muito comuns em redes biológicas. A hipótese é que feedbacks negativos permitem encontrar relações entre os genes que podem ajudar a explicar a estabilidade do processo regulatório dentro da célula. Ciclos de feedback positivo, por outro lado, podem mostrar a quantidade de desequilíbrio de uma determinada célula em um determinado momento. A análise baseada em ciclos permite identificar a relação estequiométrica entre os genes da rede. Esta metodologia proporciona uma melhor compreensão da biologia do tumor. Portanto, as principais contribuições desta tese são: (i) um novo método de análise baseada em ciclos; (ii) um novo método de classificação; (iii) e, finalmente, aplicação dos métodos e a obtenção de resultados práticos. A metodologia proposta foi utilizada para analisar os genes de quatro redes fortemente relacionadas com o câncer - apoptose, glicólise, ciclo celular e NF B - em tecidos do tipo mais agressivo de tumor cerebral (Gliobastoma multiforme - GBM) e em tecidos cerebrais saudáveis. A maioria dos pacientes com GBM morrem em menos de um ano, essencialmente nenhum paciente tem sobrevivência a longo prazo, por isso estes tumores têm atraído atenção significativa. Os principais resultados nesta tese mostram que a relação estequiométrica entre genes envolvidos na apoptose, glicólise, ciclo celular e NF B está desequilibrada em amostras de GBM em comparação as amostras de controle. Este desequilíbrio pode ser medido e explicado pela identificação de um percentual maior de ciclos positivos nas redes das primeiras amostras. Esta conclusão ajuda a entender mais sobre a biologia deste tipo de tumor. O método de classificação baseado no ciclo proposto obteve as mesmas métricas de desempenho como uma rede neural, um método clássico de classificação. No entanto, o método proposto tem uma vantagem significativa em relação às redes neurais. O método de classificação proposto não só classifica as amostras, fornecendo diagnóstico, mas também explica porque as amostras foram classificadas de uma certa maneira em termos dos mecanismos de feedback que estão presentes/ausentes. Desta forma, o método fornece dicas para bioquímicos sobre possíveis experiências laboratoriais, bem como sobre potenciais genes alvo de terapias.
One of the main research areas in Systems Biology concerns the discovery of biological networks from microarray datasets. These networks consist of a great number of genes whose expression levels affect each other in various ways. We present a new way of analyzing microarray datasets, based on the different kind of cycles found among genes of the co-expression networks constructed using quantized data obtained from the microarrays. The input of the analysis method is formed by raw data, a set of interest genes (for example, genes from a known pathway) and a function (activator or inhibitor) of these genes. The output of the method is a set of cycles. A cycle is a closed walk, in which all vertices (except the first and last) are distinct. Thanks to the new way of finding relations among genes, a more robust interpretation of gene correlations is possible, because cycles are associated with feedback mechanisms that are very common in biological networks. Our hypothesis is that negative feedbacks allow finding relations among genes that may help explaining the stability of the regulatory process within the cell. Positive feedback cycles, on the other hand, may show the amount of imbalance of a certain cell in a given time. The cycle-based analysis allows identifying the stoichiometric relationship between the genes of the network. This methodology provides a better understanding of the biology of tumors. As a consequence, it may enable the development of more effective treatment therapies. Furthermore, cycles help differentiate, measure and explain the phenomena identified in healthy and diseased tissues. Cycles may also be used as a new method for classification of samples of a microarray (cancer diagnosis). Compared to other classification methods, cycle-based classification provides a richer explanation of the proposed classification, that can give hints on the possible therapies. Therefore, the main contributions of this thesis are: (i) a new cycle-based analysis method; (ii) a new microarray samples classification method; (iii) and, finally, application and achievement of practical results. We use the proposed methodology to analyze the genes of four networks closely related with cancer - apoptosis, glucolysis, cell cycle and NF B - in tissues of the most aggressive type of brain tumor (Gliobastoma multiforme – GBM) and in healthy tissues. Because most patients with GBMs die in less than a year, and essentially no patient has long-term survival, these tumors have drawn significant attention. Our main results show that the stoichiometric relationship between genes involved in apoptosis, glucolysis, cell cycle and NF B pathways is unbalanced in GBM samples versus control samples. This dysregulation can be measured and explained by the identification of a higher percentage of positive cycles in these networks. This conclusion helps to understand more about the biology of this tumor type. The proposed cycle-based classification method achieved the same performance metrics as a neural network, a classical classification method. However, our method has a significant advantage with respect to neural networks. The proposed classification method not only classifies samples, providing diagnosis, but also explains why samples were classified in a certain way in terms of the feedback mechanisms that are present/absent. This way, the method provides hints to biochemists about possible laboratory experiments, as well as on potential drug target genes.

Les glioblastomes (GBM) sont les tumeurs cérébrales humaines les plus agressives. Les personnes atteintes de cette maladie meurent généralement dans l'année suivant le diagnostic. La radiothérapie, qui est de plus en plus utilisée en présence d'un agent radiosensibilisant, est systématiquement appliquée afin de diminuer la progression tumorale. Néanmoins, elle se heurte au phénomène de radiorésistance. Afin de proposer dans un avenir proche une thérapie adaptée à chaque patient, une classification moléculaire des GBM est en train de naître. Celle-ci tient notamment compte d'un biomarqueur prédictif de chimiorésistance, mais non de radiorésistance. Dans ce contexte, nous avons cherché, dans un premier temps, à identifier in vitro de potentiels biomarqueurs de radiorésistance dans quatre lignées cellulaires humaines de GBM de radiosensibilité différente. Pour cela, nous avons eu recours à des méthodes analytiques holistiques et robustes telles que la RMN 1H métabolomique, la lipidomique et la transcriptomique. Une accumulation de composés à choline dans les deux lignées les plus radiorésistantes a ainsi été mise en évidence. Une méthode d'analyse du métabolisme des phosphatidylcholines par marquage deutéré et quantification par HILIC-ESI-MS/MS a été mise au point afin de confirmer ces résultats. Dans une seconde partie, nous avons cherché à identifier in vitro de potentiels biomarqueurs de mort radio-induite dans des lignées cellulaires humaines de GBM radiosensibilisées. La RMN 1H métabolomique a été privilégiée pour cette investigation et complétée par des études lipidomique et de mort cellulaire par cytométrie en flux pour l'un des projets. La taurine a ainsi été identifiée comme potentiel biomarqueur de mort cellulaire
Glioblastomas (GBM) are the most aggressive human brain tumors. Indeed, patients most often die within the year after the diagnostic. Radiotherapy generally associated to radiosensitizers is currently systematically used to reduce tumor progression. Nevertheless, a radioresistance phenomenon still occurs. An individual treatment is hoped for each patient. For this purpose, a molecular classification of GBM has been created, taking into account biomarkers such as a predictive chimioresistance factor, but not radioresistance one. In this context, we have searched for in vitro radioresistance biomarkers in four human GBM cell lines with different radiosensitivity profiles. This corresponds to the first part of the PhD manuscript. Comprehensive and robust analytical methods such as 1H NMR metabolomics, lipidomics and transcriptomics have been used. An accumulation of choline compounds has been observed in the two more radioresistant cell lines. An analytical method using deuterated labelling and HILIC-ESI-MS/MS has been developed to study the metabolism of phosphatidylcholines in the four cell lines. In the second part of the PhD project, we have focused on potential in vitro biomarkers of radio-induced cell death in radiosensitized human GBM cell lines. For this, NMR 1H metabolomics has been chosen. Taurine has been found as a good candidate in a cell line. Lipidomics and FACS analyses have then been used to confirm this result