subject:(glioblastoma)

Oregon State University

1. Lal, Sangeet Kumar. Calpain 2 proteolysis regulates glioblastoma cell invasion.

Degree: PhD, Biochemistry and Biophysics, 2011, Oregon State University

URL: http://hdl.handle.net/1957/19988

► Glioblastoma is the most malignant primary brain tumor with the average patients surviving only one year after diagnosis, even with aggressive therapy. The formation of… (more)

▼ Glioblastoma is the most malignant primary brain tumor with the average patients surviving only one year after diagnosis, even with aggressive therapy. The formation of numerous micro-tumors dispersed into the brain due to rapid invasion of tumor cells, presents the primary challenge to the surgical removal of tumors and limits the effectiveness of current treatments. This dissertation presents studies aimed at understanding the molecular mechanisms regulating invasion of human glioblastoma cells. Transplantation of human glioblastoma cells in the zebrafish brain showed that the knockdown of calpain 2, a calcium-activated protease, resulted in a three fold decrease in the tumor cell invasion. The result was further verified in the organotypic mouse brain slices where the knockdown cells demonstrated 2-fold decrease in the area of dispersal compared to control cells. Our data show that calpain 2 plays a role in the process of tumor cell angiogenesis. Glioblastoma cells were transplanted into the brain of zebrafish expressing GFP in the blood vessels and we observed that 23% of animals injected with control tumor cells demonstrated angiogenesis. In contrast, only 9% of fish that received calpain 2 knockdown cells showed the formation of new vessels. Consistent to the reports from human glioblastoma patients and rodent models, we did not observe metastasis of transplanted cells outside of the brain in the zebrafish, supporting for the use of zebrafish as an important model for glioblastoma cell invasion studies. These results provide evidence that calpain 2 protease activity is required for the dispersal of glioblastoma cells in the brain microenvironment. To determine the mechanism of calpain 2 regulation of tumor cell invasion, proteolysis of filamin by calpain 2 was studied. Filamin is an important actin cross-linking protein which develops orthogonal actin networks in the periphery of the cell. In this study, we show that the expression of filamin inhibits glioblastoma cell invasion. Hence, knocking down filamin expression by 80% resulted in 220% increase in the invasion of glioblastoma cells through Matrigel extracellular matrix. The regulated proteolysis of filamin is a potential mechanism to facilitate the cyclic turnover of actin orthogonal networks which is required for glioblastoma cell invasion. In this study, we identified a novel mechanism that the PI3 kinase activity regulates the cleavage of filamin by calpain 2 in glioblastoma cells. Binding of a membrane phospholipid phosphatidylinositol (3,4,5) triphosphate [PtdIns (3,4,5)-P₃] to filamin induces its proteolysis by calpain 2 after the amino acid lysine 268, removing the actin binding domain which in-turn abolishes the actin binding ability of filamin. Advisors/Committee Members: Greenwood, Jeffrey A. (advisor), Beckman, Joseph S. (committee member).

Subjects/Keywords: Glioblastoma

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APA (6^th Edition):

Lal, S. K. (2011). Calpain 2 proteolysis regulates glioblastoma cell invasion. (Doctoral Dissertation). Oregon State University. Retrieved from http://hdl.handle.net/1957/19988

Chicago Manual of Style (16^th Edition):

Lal, Sangeet Kumar. “Calpain 2 proteolysis regulates glioblastoma cell invasion.” 2011. Doctoral Dissertation, Oregon State University. Accessed February 24, 2021. http://hdl.handle.net/1957/19988.

MLA Handbook (7^th Edition):

Lal, Sangeet Kumar. “Calpain 2 proteolysis regulates glioblastoma cell invasion.” 2011. Web. 24 Feb 2021.

Vancouver:

Lal SK. Calpain 2 proteolysis regulates glioblastoma cell invasion. [Internet] [Doctoral dissertation]. Oregon State University; 2011. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/1957/19988.

Council of Science Editors:

Lal SK. Calpain 2 proteolysis regulates glioblastoma cell invasion. [Doctoral Dissertation]. Oregon State University; 2011. Available from: http://hdl.handle.net/1957/19988

Universidad de Cantabria

2. Fernández Fuente, Gonzalo. Contribución del microentorno a la quimiorresistencia de células iniciadoras de glioblastoma en modelos in vitro.

Degree: 2017, Universidad de Cantabria

URL: http://hdl.handle.net/10902/11393

► En este trabajo, hemos estudiado la biología de los Glioblastomas, el tumor cerebral primario más frecuente en adultos y que representa uno de los tipos… (more)

Subjects/Keywords: Glioblastoma

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fernández Fuente, G. (2017). Contribución del microentorno a la quimiorresistencia de células iniciadoras de glioblastoma en modelos in vitro. (Doctoral Dissertation). Universidad de Cantabria. Retrieved from http://hdl.handle.net/10902/11393

Chicago Manual of Style (16^th Edition):

Fernández Fuente, Gonzalo. “Contribución del microentorno a la quimiorresistencia de células iniciadoras de glioblastoma en modelos in vitro.” 2017. Doctoral Dissertation, Universidad de Cantabria. Accessed February 24, 2021. http://hdl.handle.net/10902/11393.

MLA Handbook (7^th Edition):

Fernández Fuente, Gonzalo. “Contribución del microentorno a la quimiorresistencia de células iniciadoras de glioblastoma en modelos in vitro.” 2017. Web. 24 Feb 2021.

Vancouver:

Fernández Fuente G. Contribución del microentorno a la quimiorresistencia de células iniciadoras de glioblastoma en modelos in vitro. [Internet] [Doctoral dissertation]. Universidad de Cantabria; 2017. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10902/11393.

Council of Science Editors:

Fernández Fuente G. Contribución del microentorno a la quimiorresistencia de células iniciadoras de glioblastoma en modelos in vitro. [Doctoral Dissertation]. Universidad de Cantabria; 2017. Available from: http://hdl.handle.net/10902/11393

University of Manitoba

3. Yuan, Haynes (Shek Hei). Counteracting temozolomide resistance in glioblastoma multiforme (GBM) through suppression of the base excision repair (BER) pathway.

Degree: Pharmacology and Therapeutics, 2019, University of Manitoba

URL: http://hdl.handle.net/1993/34166

► Background Glioblastoma Multiforme (GBM) is an aggressive cerebral cancer. Standard chemotherapeutic of GBM is Temozolomide; a DNA alkylating agent. Patients relapse mostly due to recurrence… (more)

▼ Background Glioblastoma Multiforme (GBM) is an aggressive cerebral cancer. Standard chemotherapeutic of GBM is Temozolomide; a DNA alkylating agent. Patients relapse mostly due to recurrence of resistant tumour. GBM resistance may involve DNA repair pathways that become hyperactivated, my project seeks to understand the molecular underpinnings of GBM resistance and recurrence in order to identify novel treatment paradigms that may serve to counteract drug-resistant GBM. Methods and Materials TMZ sensitive/resistant GBM models with nuclear fluorescent were generated, and resistance was validated with growth, DNA damage and death assays. Furthermore, RNA/protein expressions were compared to identify modifications in TMZ-resistant cells; significant changes were investigated via RNAi experiment. Data indicated that base excision repair featured prominently; showing enhanced DNA repair activity in TRR. As poly ADP-ribose polymerase (PARP) plays a pivotal role in BER signaling, PARP inhibitors (PARPi) were used in cell-based assays to evaluate the relative contribution of BER to TMZ resistance in GBM. Results TRR cells demonstrated robust performance toward TMZ in terms of growth, tolerance against DNA damage and resistance to TMZ-induced cell death. With RNA /protein analysis assays, XRCC1-mediated BER expression and activity was found enhanced, and further stimulated under subsequent treatment of TMZ indicating a plastic response to de novo DNA damage despite acquired resistance. Validation studies of XRCC1 knockdown in TRR and over-expression in SG suggested XRCC1 plays a critical role in TMZ-resistance. Furthermore, effects of 4 independent PARP inhibitors/trappers (PARPi/PARPt) were tested on this cell model to study the efficacy of chemical-mediated BER inhibition as a co-treatment strategy to re-sensitize TRR toward TMZ. PARPi/PARPt demonstrated cooperativity with TMZ, displaying growth suppression, enhanced DNA damage, and increased cell death in TRR. Conclusion In my study, base excision repair pathway was found to significantly contribute to TMZ resistance in rGBM. By inhibiting BER using PARPi/PARPt, re-sensitization to TMZ was restored in TRR, while the efficacy of TMZ was enhanced in SG. These data have potential implications on treating recurrence of rGBM. Furthermore, this novel cell-based model of pGBM/rGBM can be used in a variety of fluorescence-based high throughput small molecule drug screens to identify novel anti-GBM treatments. Advisors/Committee Members: Katyal, Sachin (Pharmacology and Therapeutics) (supervisor), Gibson, Spencer (Biochemistry and Medical Genetics).

Subjects/Keywords: Glioblastoma Multiforme; Glioblastoma Multiforme

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yuan, H. (. H. (2019). Counteracting temozolomide resistance in glioblastoma multiforme (GBM) through suppression of the base excision repair (BER) pathway. (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/34166

Chicago Manual of Style (16^th Edition):

Yuan, Haynes (Shek Hei). “Counteracting temozolomide resistance in glioblastoma multiforme (GBM) through suppression of the base excision repair (BER) pathway.” 2019. Masters Thesis, University of Manitoba. Accessed February 24, 2021. http://hdl.handle.net/1993/34166.

MLA Handbook (7^th Edition):

Yuan, Haynes (Shek Hei). “Counteracting temozolomide resistance in glioblastoma multiforme (GBM) through suppression of the base excision repair (BER) pathway.” 2019. Web. 24 Feb 2021.

Vancouver:

Yuan H(H. Counteracting temozolomide resistance in glioblastoma multiforme (GBM) through suppression of the base excision repair (BER) pathway. [Internet] [Masters thesis]. University of Manitoba; 2019. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/1993/34166.

Council of Science Editors:

Yuan H(H. Counteracting temozolomide resistance in glioblastoma multiforme (GBM) through suppression of the base excision repair (BER) pathway. [Masters Thesis]. University of Manitoba; 2019. Available from: http://hdl.handle.net/1993/34166

Universidade do Rio Grande do Sul

4. Chiela, Eduardo Cremonese Filippi. A autofagia e o ciclo celular desempenham papel central no mecanismo de ação do resveratrol e do co-tratamento com temozolomida em células de linhagens de glioblastoma humano.

Degree: 2011, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/28430

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Glioblastomas (GBMs) são os tumores primários (gliomas) mais comuns e agressivos do Sistema Nervosos Central, classificados pelos oncologistas como um dos maiores desafios da oncoterapia.… (more)

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Glioblastomas (GBMs) são os tumores primários (gliomas) mais comuns e agressivos do Sistema Nervosos Central, classificados pelos oncologistas como um dos maiores desafios da oncoterapia. O prognóstico dos pacientes é ruim mesmo após terapia cirúrgica seguida de radio e quimioterapia com Temozolomida (TMZ). Células de GBM apresentam resistência intrínseca à apoptose, porém, se mostram mais sensíveis à indução de senescência, autofagia e catástrofe mitótica. Resveratrol (Rsv) é um polifenol com ação neuroprotetora ao tecido neural sadio e, por outro lado, ação citotóxica em células de GBM. Porém, o mecanismo de ação do Rsv nestas células ainda não está esclarecido. O objetivo do presente trabalho é avaliar o mecanismo de ação do Rsv, bem como o efeito do co-tratamento de Rsv e TMZ, em células de GBM. Rsv reduziu o número de células em 3 linhagens de GBM humano, induzindo autofagia e acúmulo de células nas fases S-G2/M do ciclo celular, com aumento de pCdc2(Y15), das ciclinas E, A e B e redução de ciclina D1. A inibição da autofagia induzida pelo Rsv aumentou a toxicidade do composto, ativou a apoptose (acompanhado do aumento de Bax e de clivagem de caspase 3) e inibiu a parada no ciclo celular induzida pelo Rsv, reduzindo os níveis das ciclinas e de pCdc2 (Y15). Estes dados sugerem um papel citoprotetor da autofagia no efeito do Rsv. Por outro lado, Rsv potencializou o efeito citotóxico da TMZ através da inibição da parada em G2/M induzido pela TMZ, sem reduzir o dano ao DNA induzido pela TMZ ou a ativação da proteína de reconhecimento de dano ATM. Núcleos das células expostas ao co-tratamento apresentaram características típicas de catástrofe mitótica, acompanhado pelo acúmulo de ciclina B e redução de pCdc2(Y15). Através de uma ferramenta de análise morfométrica nuclear desenvolvida por nós, mostramos que o cotratamento de Rsv e TMZ induziu um aumento no número de núcleos em catástrofe mitótica. Em conclusão, Rsv apresentou potencial aplicação em GBM a ser testada em modelos in vivo deste tumor, tanto como terapia primária (especialmente se combinado a inibidores de autofagia) ou como adjuvante à TMZ. Uma vez que as células cancerosas são resistentes à morte celular e sabendo que um único composto geralmente modula mais de um mecanismo celular, é importante considerar estas interações para o desenvolvimento de alternativas para sensibilizar as células cancerosas e aumentar a eficácia terapêutica.

Glioblastomas (GBM) are the most common and aggressive primary tumors (gliomas) of the Central Nervous System, classified by oncologists as one of the biggest challenges of oncotherapy. The prognosis for patients is poor, even after surgical therapy followed by radiotherapy and chemotherapy with Temozolomide (TMZ). GBM cells are intrinsically resistance to apoptosis, but more sensitive to the induction of senescence, autophagy and mitotic catastrophe. Resveratrol (Rsv) is a polyphenol with a neuroprotective effect on healthy neural tissue but it has a a cytotoxic activity in GBM cells. Unfortunately, the mechanism of…

Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Resveratrol

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chiela, E. C. F. (2011). A autofagia e o ciclo celular desempenham papel central no mecanismo de ação do resveratrol e do co-tratamento com temozolomida em células de linhagens de glioblastoma humano. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/28430

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Chiela, Eduardo Cremonese Filippi. “A autofagia e o ciclo celular desempenham papel central no mecanismo de ação do resveratrol e do co-tratamento com temozolomida em células de linhagens de glioblastoma humano.” 2011. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/28430.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Chiela, Eduardo Cremonese Filippi. “A autofagia e o ciclo celular desempenham papel central no mecanismo de ação do resveratrol e do co-tratamento com temozolomida em células de linhagens de glioblastoma humano.” 2011. Web. 24 Feb 2021.

Vancouver:

Chiela ECF. A autofagia e o ciclo celular desempenham papel central no mecanismo de ação do resveratrol e do co-tratamento com temozolomida em células de linhagens de glioblastoma humano. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2011. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/28430.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Chiela ECF. A autofagia e o ciclo celular desempenham papel central no mecanismo de ação do resveratrol e do co-tratamento com temozolomida em células de linhagens de glioblastoma humano. [Thesis]. Universidade do Rio Grande do Sul; 2011. Available from: http://hdl.handle.net/10183/28430

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

5. Silva, Mardja Mansur Bueno e. Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida.

Degree: 2016, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/150664

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Mitocôndrias desempenham funções celulares vitais. O funcionamento dessas organelas e seu papel no metabolismo celular, não surpreendentemente, têm sido implicados no desenvolvimento de diferentes cânceres.… (more)

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Mitocôndrias desempenham funções celulares vitais. O funcionamento dessas organelas e seu papel no metabolismo celular, não surpreendentemente, têm sido implicados no desenvolvimento de diferentes cânceres. Nos últimos anos, diversos estudos tem sugerido um papel importante para as mitocôndrias e o metabolismo celular na resposta à terapia e na resistência de células tumorais à essa terapia. Dado o papel central da mitocôndria na homeostase celular, avaliamos as alterações mitocondriais e metabólicas em células de glioblastoma em resposta ao tratamento com o quimioterápico Temozolomida (TMZ). O tratamento agudo com TMZ induziu um aumento transitório tanto na massa mitocondrial como no potencial de membrana mitocondrial (MMP) 5 dias após o tratamento, seguido de uma diminuição dos mesmos parâmetros no sétimo dia. O aumento desses parâmetros é acompanhado por uma diminuição nos níveis de expressão de PGC1a no dia 3 e um aumento progressivo nos níveis de autofagia, sugerindo que o aumento de massa mitocondrial é independente de PGC1a, podendo ser devido à um acúmulo de mitocôndrias. Além disso, o aumento de massa mitocondrial e potencial de membrana se correlacionam com os níveis mais elevados de estresse oxidativo e senescência no D5. Também foram avaliadas taxas de consumo de oxigênio tanto em células controle como tratadas com TMZ, observando-se no D5 células apresentam essas taxas elevadas e uma maior capacidade reserva. A fim de entender como alterações mitocondriais podem influenciar na resposta à quimioterapia, nós tratamos as células previamente tratadas com TMZ no dia 5 com inibidores de glicólise e/ou fosforilação oxidativa e acompanhamos o número de células. Os resultados sugerem que os inibidores diminuem a proliferação celular. Além disso, células tratadas com TMZ parecem ser mais sensíveis à inibição de fosforilação oxidativa do que glicólise, sugerindo que TMZ reprograma o metabolismo dessas células para um estado mais oxidativo.

Mitochondria play vital cellular functions. These organelles functions and roles in cellular metabolism not surprisingly have been implicated in a broad spectrum of diseases, including neurodegeneration and cancer. Lately, it has been given an important role for mitochondria and cellular metabolism in response and resistance of tumour cells to therapy. Given the central role of mitochondria in cellular homeostasis, we evaluated mitochondria network alterations in glioblastoma cells in response to treatment with the chemotherapeutic Temozolomide (TMZ). The acute treatment with TMZ induced an increase in both mitochondrial mass and mitochondrial membrane potential (MMP) 5 days after treatment, followed by a decrease in the same parameters on day 7. The increase in these parameters is accompanied by a decrease in PGC1a expression on day 3 and a progressive increase in autophagy levels, suggesting that the increase in mitochondrial mass is independent of PGC1a and may be due to an accumulation of mitochondria. Also, the increase in mitochondrial mass and MMP correlates with…

Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Temozolamida

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Silva, M. M. B. e. (2016). Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/150664

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Silva, Mardja Mansur Bueno e. “Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida.” 2016. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/150664.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Silva, Mardja Mansur Bueno e. “Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida.” 2016. Web. 24 Feb 2021.

Vancouver:

Silva MMBe. Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/150664.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Silva MMBe. Alterações mitocondriais e reprogramação metabólica em células de glioblastoma após tratamento com temozolomida. [Thesis]. Universidade do Rio Grande do Sul; 2016. Available from: http://hdl.handle.net/10183/150664

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

IUPUI

6. Folck, Anthony F. A Cell-Based Model to Study Factors that Drive Diffuse Astrocytoma Development.

Degree: 2016, IUPUI

URL: http://hdl.handle.net/1805/11053

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Indiana University-Purdue University Indianapolis (IUPUI)

Secondary gliomas are an incurable form of brain cancer that are diagnosed in people at a median age of 45… (more)

Subjects/Keywords: Astrocytoma; Glioblastoma

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Folck, A. F. (2016). A Cell-Based Model to Study Factors that Drive Diffuse Astrocytoma Development. (Thesis). IUPUI. Retrieved from http://hdl.handle.net/1805/11053

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Folck, Anthony F. “A Cell-Based Model to Study Factors that Drive Diffuse Astrocytoma Development.” 2016. Thesis, IUPUI. Accessed February 24, 2021. http://hdl.handle.net/1805/11053.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Folck, Anthony F. “A Cell-Based Model to Study Factors that Drive Diffuse Astrocytoma Development.” 2016. Web. 24 Feb 2021.

Vancouver:

Folck AF. A Cell-Based Model to Study Factors that Drive Diffuse Astrocytoma Development. [Internet] [Thesis]. IUPUI; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/1805/11053.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Folck AF. A Cell-Based Model to Study Factors that Drive Diffuse Astrocytoma Development. [Thesis]. IUPUI; 2016. Available from: http://hdl.handle.net/1805/11053

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidad de Cantabria

7. López López, Carlos. Factores pronósticos clínico-moleculares y modelos predictivos en glioblastoma multiforme a partir de una experiencia intramural : Servicio de Oncología Médica del Hospital Universitario Marqués de Valdecilla (2000-2010).

Degree: 2016, Universidad de Cantabria

URL: http://hdl.handle.net/10902/8433

► RESUMEN: El glioblastoma multiforme (GBM) es una neoplasia relativamente frecuente entre las del sistema nervioso central, que se caracteriza por su excepcional agresividad y por… (more)

Subjects/Keywords: Glioblastoma multiforme

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

López López, C. (2016). Factores pronósticos clínico-moleculares y modelos predictivos en glioblastoma multiforme a partir de una experiencia intramural : Servicio de Oncología Médica del Hospital Universitario Marqués de Valdecilla (2000-2010). (Doctoral Dissertation). Universidad de Cantabria. Retrieved from http://hdl.handle.net/10902/8433

Chicago Manual of Style (16^th Edition):

López López, Carlos. “Factores pronósticos clínico-moleculares y modelos predictivos en glioblastoma multiforme a partir de una experiencia intramural : Servicio de Oncología Médica del Hospital Universitario Marqués de Valdecilla (2000-2010).” 2016. Doctoral Dissertation, Universidad de Cantabria. Accessed February 24, 2021. http://hdl.handle.net/10902/8433.

MLA Handbook (7^th Edition):

López López, Carlos. “Factores pronósticos clínico-moleculares y modelos predictivos en glioblastoma multiforme a partir de una experiencia intramural : Servicio de Oncología Médica del Hospital Universitario Marqués de Valdecilla (2000-2010).” 2016. Web. 24 Feb 2021.

Vancouver:

López López C. Factores pronósticos clínico-moleculares y modelos predictivos en glioblastoma multiforme a partir de una experiencia intramural : Servicio de Oncología Médica del Hospital Universitario Marqués de Valdecilla (2000-2010). [Internet] [Doctoral dissertation]. Universidad de Cantabria; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10902/8433.

Council of Science Editors:

López López C. Factores pronósticos clínico-moleculares y modelos predictivos en glioblastoma multiforme a partir de una experiencia intramural : Servicio de Oncología Médica del Hospital Universitario Marqués de Valdecilla (2000-2010). [Doctoral Dissertation]. Universidad de Cantabria; 2016. Available from: http://hdl.handle.net/10902/8433

Universidade do Rio Grande do Sul

8. Tamajusuku, Alessandra Sayuri Kikuchi. Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261.

Degree: 2010, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/30210

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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… (more)

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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…

Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioma; Glioblastoma; Camundongos

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tamajusuku, A. S. K. (2010). Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/30210

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tamajusuku, Alessandra Sayuri Kikuchi. “Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261.” 2010. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/30210.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tamajusuku, Alessandra Sayuri Kikuchi. “Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261.” 2010. Web. 24 Feb 2021.

Vancouver:

Tamajusuku ASK. Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2010. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/30210.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tamajusuku ASK. Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261. [Thesis]. Universidade do Rio Grande do Sul; 2010. Available from: http://hdl.handle.net/10183/30210

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

9. Kipper, Franciele Cristina. Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes.

Degree: 2017, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/170182

► Gliomas são tumores do sistema nervoso central caracterizados por alta invasibilidade e mortalidade. Inúmeros esforços foram feitos nas últimas décadas para melhorar a sobrevida dos… (more)

▼ Gliomas são tumores do sistema nervoso central caracterizados por alta invasibilidade e mortalidade. Inúmeros esforços foram feitos nas últimas décadas para melhorar a sobrevida dos pacientes, porém o último marco no tratamento se deu pela implementação da temozolomida (TMZ) combinada a ressecção cirúrgica e a radioterapia (RTX) em 2005. O projeto do atlas do genoma humano do câncer (TCGA) sequenciou tumores de mais de 500 pacientes com diagnóstico de glioblastoma (GBM) e categorizou os tumores em quatro subtipos moleculares, baseados na expressão, mutações e deleções de genes. Essas alterações genéticas já foram correlacionadas à melhora na sobrevida e à sensibilidade a terapia, porém, até o momento estudos prospectivos falham em direcionar o tratamento dos pacientes baseados nas características moleculares. Em busca de melhorar o entendimento sobre a correlação entre a sensibilidade a terapia in vitro e características genotípicas e fenotípicas, nós realizamos culturas primárias de células derivadas de tumores do sistema nervoso central de 23 pacientes (24 biopsias diferentes). As células foram crescidas em DMEM/F12 suplementado com soro fetal bovino e expostas aos tratamentos em doses e tempos semelhantes aos encontrados na clínica. Foram realizadas análises de viabilidade celular sete dias após o início do tratamento para 11 culturas primárias, ou as culturas foram tratadas por cinco dias em combinação, ou não, com RTX (sem RTX: 16 culturas; com RTX: 9 culturas) seguidos de sete dias em meio livre de droga, ao fim dos quais as células remanescentes foram contadas. A radioterapia e fármacos que agem sobre o citoesqueleto (vincristina, vimblastina, paclitaxel e mebendazole) sozinhos foram os tratamentos mais eficientes em reduzir a população celular. Uma segunda rodada de tratamento com TMZ, paclitaxel e a combinação de procarbazina, CCNU e vincristina (PCV) sugere que a resistência não é estável, e sucessivas exposições ao mesmo, ou a um fármaco diferente, podem ter seus efeitos somados na diminuição do crescimento populacional ou na massa tumoral final. Ao administrar PCV e paclitaxel nas células em cultura observamos um aumento nos níveis de autofagia que correlaciona com o declínio da população. Combinações desses fármacos com concentrações plasmáticas de um bloqueador da autofagia (cloroquina) não são capazes alterar o crescimento populacional. Resultados de análises do banco disponibilizado pelo TCGA mostram que alguns pacientes não apresentam aumento na sobrevida após tratamento com TMZ, e que essa falha no tratamento correlaciona com a baixa expressão de alguns genes nos seus tumores, por exemplo, aqueles com baixa expressão de FGFR3 e AKT2. As culturas primárias e linhagens celulares com menor expressão desses genes foram sensíveis in vitro a combinação de TMZ com dois fármacos que agem sobre o citoesqueleto: vimblastina e mebendazole (TVM). Essa associação retarda o crescimento de linhagens e culturas primárias resistentes a TMZ, além de induzir parada no ciclo celular, senescência e aumento da expressão… Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Glioma; Temozolomida

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kipper, F. C. (2017). Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/170182

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kipper, Franciele Cristina. “Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes.” 2017. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/170182.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kipper, Franciele Cristina. “Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes.” 2017. Web. 24 Feb 2021.

Vancouver:

Kipper FC. Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2017. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/170182.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kipper FC. Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes. [Thesis]. Universidade do Rio Grande do Sul; 2017. Available from: http://hdl.handle.net/10183/170182

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

10. Pereira, Mariana Brutschin. Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma.

Degree: 2017, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/170192

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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… (more)

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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…

Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Sistema imunológico

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pereira, M. B. (2017). Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/170192

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pereira, Mariana Brutschin. “Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma.” 2017. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/170192.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pereira, Mariana Brutschin. “Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma.” 2017. Web. 24 Feb 2021.

Vancouver:

Pereira MB. Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2017. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/170192.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pereira MB. Caracterização transcricional de infiltrados imunológicos e sua relação com a sobrevida de pacientes com glioblastoma. [Thesis]. Universidade do Rio Grande do Sul; 2017. Available from: http://hdl.handle.net/10183/170192

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

11. Silva, Andrew Oliveira. Avaliação dos efeitos antitumorais agudos e crônicos em resposta ao tratamento com temozolomida e sua combinação com vimblastia e mebendazole em células de glioblastoma.

Degree: 2016, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/150589

►

Apesar dos progressos na compreensão da biologia dos Glioblastomas (GBM), poucos avanços terapêuticos foram obtidos, desde que a Temozolomida (TMZ) foi implementada, em 2005, como… (more)

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Apesar dos progressos na compreensão da biologia dos Glioblastomas (GBM), poucos avanços terapêuticos foram obtidos, desde que a Temozolomida (TMZ) foi implementada, em 2005, como quimioterápico padrão no tratamento de GBMs. Uma das justificativas para o insucesso de novas terapias, pode estar relacionada com a condução equivocada dos experimentos in vitro, que utilizam doses exorbitantes dos fármacos e curtos períodos de tempo para avaliar sua eficácia terapêutica, não refletindo a realidade clínica da doença. Desta forma, o objetivo deste trabalho é caracterizar in vitro os efeitos da TMZ, mimetizando parâmetros clínicos, como dose plasmática e regime de tratamento em pacientes, e investigar possíveis fármacos de ação adjuvante à TMZ. Primeiramente, uma nova metodologia de análise de ensaios de proliferação celular a longo prazo foi proposta, a fim de quantificar os efeitos antitumorais crônicos de diferentes intervenções in vitro e in vivo. Em seguida, foram confirmados os principais mecanismos agudos desencadeados por TMZ e constatou-se a conservação do seu efeito antitumoral até uma semana após o fim do período de exposição ao fármaco. Apesar disso, em todas células de GBM testadas, houve a manutenção de subpopulações sobreviventes que readquiriram sua capacidade proliferativa, dentro do período de 28 dias. Aplicando a nova metodologia proposta, constatou-se que nenhum mecanismo ou ensaio utilizado neste trabalho foi capaz de predizer o comportamento proliferativo das células sobreviventes, mostrando a importância da análise crônica in vitro para avaliar a eficácia terapêutica de um tratamento. Então, o potencial adjuvante de Vimblastina (VBL) e Mebendazole (MBZ) foi testado e ambos causaram redução inicial na população, seguida de um recrescimento das células sobreviventes. Quando combinadas com TMZ, viu-se um completo bloqueio na proliferação durante todo o período analisado, menos em U138 e C6, que apresentaram efeitos semelhantes à utilização isolada de VBL ou MBZ. Já a combinação de MBZ, TMZ e VBL (MTV) reduziu consideravelmente a proliferação de C6 e U138, em 28 dias de análise. Portanto, a análise da proliferação celular in vitro a longo prazo, através desta nova abordagem proposta, parece ser uma forma mais adequada de investigar a eficácia terapêutica novos regimes de tratamento, e as combinações entre TMZ, VBL e MBZ parecem representar uma estratégia terapêutica promissora de ser testada em ensaios in vivo, como nova sugestão de tratamento para este tipo tumoral.

Despite the progress in understanding the biology of glioblastoma (GBM), little therapeutic improvements has been achieved, since the Temozolomide (TMZ) was implemented in 2005 as a standard chemotherapeutic agent in the treatment of GBMs. One of the reasons for the failure of new therapies may be related to the mistaken conduct of in vitro experiments, using exorbitant doses of drugs and short periods of time to evaluate their therapeutic efficacy, not matching the clinical reality of the disease. Thus, the objective of this study is to…

Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Temozolomida; Vimblastina

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Silva, A. O. (2016). Avaliação dos efeitos antitumorais agudos e crônicos em resposta ao tratamento com temozolomida e sua combinação com vimblastia e mebendazole em células de glioblastoma. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/150589

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Silva, Andrew Oliveira. “Avaliação dos efeitos antitumorais agudos e crônicos em resposta ao tratamento com temozolomida e sua combinação com vimblastia e mebendazole em células de glioblastoma.” 2016. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/150589.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Silva, Andrew Oliveira. “Avaliação dos efeitos antitumorais agudos e crônicos em resposta ao tratamento com temozolomida e sua combinação com vimblastia e mebendazole em células de glioblastoma.” 2016. Web. 24 Feb 2021.

Vancouver:

Silva AO. Avaliação dos efeitos antitumorais agudos e crônicos em resposta ao tratamento com temozolomida e sua combinação com vimblastia e mebendazole em células de glioblastoma. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/150589.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Silva AO. Avaliação dos efeitos antitumorais agudos e crônicos em resposta ao tratamento com temozolomida e sua combinação com vimblastia e mebendazole em células de glioblastoma. [Thesis]. Universidade do Rio Grande do Sul; 2016. Available from: http://hdl.handle.net/10183/150589

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Boston University

12. Finkelberg, Tomer. Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models.

Degree: MS, Medical Sciences, 2020, Boston University

URL: http://hdl.handle.net/2144/41237

► 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… (more)

Subjects/Keywords: Oncology; Cytomegalovirus; Glioblastoma

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Finkelberg, T. (2020). Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/41237

Chicago Manual of Style (16^th Edition):

Finkelberg, Tomer. “Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models.” 2020. Masters Thesis, Boston University. Accessed February 24, 2021. http://hdl.handle.net/2144/41237.

MLA Handbook (7^th Edition):

Finkelberg, Tomer. “Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models.” 2020. Web. 24 Feb 2021.

Vancouver:

Finkelberg T. Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models. [Internet] [Masters thesis]. Boston University; 2020. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/2144/41237.

Council of Science Editors:

Finkelberg T. Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models. [Masters Thesis]. Boston University; 2020. Available from: http://hdl.handle.net/2144/41237

University of Ottawa

13. Gont, Alexander. Inactivation of Lgl1 in Glioblastoma .

Degree: 2016, University of Ottawa

URL: http://hdl.handle.net/10393/34965

► 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… (more)

▼ 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.

Subjects/Keywords: cancer; glioblastoma; Lgl

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Gont, A. (2016). Inactivation of Lgl1 in Glioblastoma . (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/34965

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Gont, Alexander. “Inactivation of Lgl1 in Glioblastoma .” 2016. Thesis, University of Ottawa. Accessed February 24, 2021. http://hdl.handle.net/10393/34965.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Gont, Alexander. “Inactivation of Lgl1 in Glioblastoma .” 2016. Web. 24 Feb 2021.

Vancouver:

Gont A. Inactivation of Lgl1 in Glioblastoma . [Internet] [Thesis]. University of Ottawa; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10393/34965.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Gont A. Inactivation of Lgl1 in Glioblastoma . [Thesis]. University of Ottawa; 2016. Available from: http://hdl.handle.net/10393/34965

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Toronto

14. Albert-Vartanian, Alenoush. Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma.

Degree: 2013, University of Toronto

URL: http://hdl.handle.net/1807/42661

►

Glioblastoma (GBM), similar to many other cancers, exhibits enhanced aerobic glycolysis with concomitant lactate production, a phenomenon known as the Warburg effect. We have demonstrated… (more)

Subjects/Keywords: Metabolism; Glioblastoma; 0992

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APA (6^th Edition):

Albert-Vartanian, A. (2013). Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/42661

Chicago Manual of Style (16^th Edition):

Albert-Vartanian, Alenoush. “Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma.” 2013. Masters Thesis, University of Toronto. Accessed February 24, 2021. http://hdl.handle.net/1807/42661.

MLA Handbook (7^th Edition):

Albert-Vartanian, Alenoush. “Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma.” 2013. Web. 24 Feb 2021.

Vancouver:

Albert-Vartanian A. Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma. [Internet] [Masters thesis]. University of Toronto; 2013. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/1807/42661.

Council of Science Editors:

Albert-Vartanian A. Role of Hexokinase 2 (HK2) in Modulating Tumor Metabolism and Response to Therapy in Glioblastoma. [Masters Thesis]. University of Toronto; 2013. Available from: http://hdl.handle.net/1807/42661

University of Houston

15. Avci, Naze Gul. The Influence of Human Umbilical Vein Endothelial Cells in the Formation of Glioblastoma Spheroids in Three-Dimensional Microwells.

Degree: PhD, Biomedical Engineering, 2015, University of Houston

URL: http://hdl.handle.net/10657/2005

► Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a high infiltrative capacity and increased vascularity. Despite current therapies overall patient survival rate… (more)

▼ Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a high infiltrative capacity and increased vascularity. Despite current therapies overall patient survival rate is still poor. Therefore, alternative therapies have been considered for GBM treatment such as oncolytic viruses (OVs). The studies with two-dimensional (2D) cell cultures have been used as physiological models for understanding the cellular and molecular behavior of the GBM tumors. They are also highly desirable for virus studies. However they may not provide threedimensional (3D) characteristics of the tumors. Therefore, there is an increasing need in 3D cell culture models to investigate cell growth and cell-cell interactions. In this thesis, we hypothesized that culturing GBM cells with endothelial cells in the hydrogel microwells would mimic the in vivo microenvironment of tumor cells. Thus, we could provide beneficial 3D in vitro co-culture models for GBM treatment with oncolytic adenovirus, Delta-24-RGD (Δ24RGD). Therefore, in the first part of this study, we used our recently designed 3D PEGDA hydrogel microwell platform to co-culture GBM and HUVEC. We investigated the gene expression differences to gain further insight into molecular mechanism of 3D in vitro co-culture. Our gene expression data suggested the relative up-regulation of tumor angiogenesis markers PECAM-1/CD31 and VEGFR2, in co-cultures. Finally, we treated GBM tumors using Δ24RGD. Our results showed a significant cell lysis in 3D spheroids. The cell viability was decreased approximately 37%, 54% and 65% with 10, 50 and 100 MOIs, respectively. The infection of the Δ24RGD was found more effective on 3D spheroids when compared to 2D monolayer cell culture. These results implicate that our hydrogel microwell platform could contribute to mimic in vivo microenvironment of the GBM tumors and provide a promising 3D model to investigate the oncolytic potential of the viruses in vitro. Advisors/Committee Members: Akay, Metin (advisor), Akay, Yasemin M. (committee member), Gorenstein, David G. (committee member), Omurtag, Ahmet (committee member), Chen, Ting Y. (committee member).

Subjects/Keywords: Glioblastoma; 3D spheroids

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APA (6^th Edition):

Avci, N. G. (2015). The Influence of Human Umbilical Vein Endothelial Cells in the Formation of Glioblastoma Spheroids in Three-Dimensional Microwells. (Doctoral Dissertation). University of Houston. Retrieved from http://hdl.handle.net/10657/2005

Chicago Manual of Style (16^th Edition):

Avci, Naze Gul. “The Influence of Human Umbilical Vein Endothelial Cells in the Formation of Glioblastoma Spheroids in Three-Dimensional Microwells.” 2015. Doctoral Dissertation, University of Houston. Accessed February 24, 2021. http://hdl.handle.net/10657/2005.

MLA Handbook (7^th Edition):

Avci, Naze Gul. “The Influence of Human Umbilical Vein Endothelial Cells in the Formation of Glioblastoma Spheroids in Three-Dimensional Microwells.” 2015. Web. 24 Feb 2021.

Vancouver:

Avci NG. The Influence of Human Umbilical Vein Endothelial Cells in the Formation of Glioblastoma Spheroids in Three-Dimensional Microwells. [Internet] [Doctoral dissertation]. University of Houston; 2015. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10657/2005.

Council of Science Editors:

Avci NG. The Influence of Human Umbilical Vein Endothelial Cells in the Formation of Glioblastoma Spheroids in Three-Dimensional Microwells. [Doctoral Dissertation]. University of Houston; 2015. Available from: http://hdl.handle.net/10657/2005

Boston University

16. Jindani, Rajika. Glioblastoma multiforme: etiology, progression, and treatment.

Degree: MS, Medical Sciences, 2017, Boston University

URL: http://hdl.handle.net/2144/26730

► Glioblastoma multiforme is the most common and malignant brain tumor, accounting for more than 52% of all primary brain tumors. The molecular heterogeneity of the… (more)

▼ Glioblastoma multiforme is the most common and malignant brain tumor, accounting for more than 52% of all primary brain tumors. The molecular heterogeneity of the tumor has made it difficult to treat, and even more difficult to cure. Due to the high mortality rate associated with the current treatments used, new innovative medical techniques are being explored. Prominent treatments that are currently being investigated are immune based therapies, focused on checkpoint inhibitors and biomarkers, the use of 2-deoxy-D-glucose to initiate tumor cell apoptosis, and the induction of alterations in DNA and miRNA to inhibit glioblastoma stem cell accelerated growth and tumorigenesis. Throughout the paper, various ongoing studies are summarized and discussed to compare the outcomes of different treatments. The goal of this paper is to present the different therapies and analyze which one of them is the most effective in treating and prolonging survival for patients with glioblastoma multiforme. This thesis reviewed the large collection of publications about glioblastoma multiforme and treatments for the disease. The use of immune based therapies, such as checkpoint inhibitors and biomarkers, are increasingly delivering promising results as an immunotherapy approach, but it is necessary to complete the phase III trials in order to truly know if these products are successful as anticancer agents or if further research into the matter is required. More research must be done to find the best route of treatment. In addition, the use of 2-deoxy-D-glucose has been successful in treating other types of cancer, such as breast cancer, and now studies look promising in GBM patients. This treatment is still in its initial stages of testing, so more work will need to be done to determine how efficacious this treatment is. By comparing the results of the different therapeutic agents, it was determined that genetic alterations seemed to be the most promising avenue of treatment with current information. The data showed that the greatest increase in survival time and least recurrence was achieved by MGMT promoter methylation and gene modifications of the tumor. Though these treatments have varying results in their efficacy and there are many different combinations of medications that have yet to be assessed, research in the area is greatly advancing and increasing the lives of GBM patients. By allocating resources in the best possible treatment, researchers can change the fatal prognosis of this illness.

Subjects/Keywords: Medicine; GBM; Glioblastoma

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APA (6^th Edition):

Jindani, R. (2017). Glioblastoma multiforme: etiology, progression, and treatment. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/26730

Chicago Manual of Style (16^th Edition):

Jindani, Rajika. “Glioblastoma multiforme: etiology, progression, and treatment.” 2017. Masters Thesis, Boston University. Accessed February 24, 2021. http://hdl.handle.net/2144/26730.

MLA Handbook (7^th Edition):

Jindani, Rajika. “Glioblastoma multiforme: etiology, progression, and treatment.” 2017. Web. 24 Feb 2021.

Vancouver:

Jindani R. Glioblastoma multiforme: etiology, progression, and treatment. [Internet] [Masters thesis]. Boston University; 2017. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/2144/26730.

Council of Science Editors:

Jindani R. Glioblastoma multiforme: etiology, progression, and treatment. [Masters Thesis]. Boston University; 2017. Available from: http://hdl.handle.net/2144/26730

Victoria University of Wellington

17. Brow, Susanna. Investigating the Potential Role of SIRT1 in Glioblastoma Multiforme: A Comparison Between Glioma and Normal Astrocyte Cells in Culture.

Degree: 2015, Victoria University of Wellington

URL: http://hdl.handle.net/10063/4879

► Objective Glioblastomas (GBMs) are the most prevalent primary brain tumours in adults and the outcome for this disease remains very poor. With treatment options limited,… (more)

▼ Objective Glioblastomas (GBMs) are the most prevalent primary brain tumours in adults and the outcome for this disease remains very poor. With treatment options limited, there is growing interest to find potential differences between normal and malignant molecular signaling pathways for this disease. SIRT1 is a histone deacetylase enzyme with key functions in cellular signaling responses including protecting DNA from damage and changing transcriptional events. SIRT1 can act as a switch to affect cellular senescence or anti-apoptotic responses, or alternatively affect autophagic and pro-apoptotic responses. The role of SIRT1 in GBM is unclear. This study aimed to investigate differences between glioma and normal astrocytes with respect to SIRT1. Research design and methods SIRT1 was analysed in murine normal and glioma astrocyte cell lines, and results compared to a normal human astrocyte cell line and a panel of human primary glioma cells taken from patients with GBM. Analysis of SIRT1 was assessed using Western blots and flow cytometry. Sub-cellular localisation was examined using Western blots and immunofluorescent microscopy. Activity for SIRT1 was assessed using acetylation of a key histone SIRT1 substrate, histone 4 lysine 16, and cell proliferation was measured using the MTT assay. Oxidative stress was induced using H₂O₂ and viability measured using propidium iodide exclusion and flow cytometry. To ascertain that activity was SIRT1 related, inhibition and activation of SIRT1 was done using nicotinamide and resveratrol, respectively. Results SIRT1 was mainly localised in the nucleus and to mitochondria of normal cells but was aberrantly distributed in the cytoplasm of glioma cells, which has not been reported before. This was consistent in both murine and human glioma models. Nicotinamide significantly inhibited cell proliferation more for glioma cells compared to normal, and resveratrol had the opposing effect. Nicotinamide rescued normal but not glioma cells from H₂0₂-induced oxidative stress, and resveratrol had the opposing effect. Western blots revealed secondary protein bands for SIRT1 indicating possible smaller species of SIRT1, and results for nuclear/cytoplasmic extractions suggested FL-SIRT1 and the smaller species of SIRT1 have a dynamic pattern of localisation under oxidative stress, nicotinamide and resveratrol treatments. Conclusions These results indicated SIRT1 is involved in both cell proliferation and oxidative stress responses, with a differential activity between glioma and normal astrocyte cells. Aberrant localisation of SIRT1 to the cytoplasm in glioma cells is a significant finding that needs further exploration. The need for further studies to elucidate changes in localisation for SIRT1 under different conditions is highlighted, as is the possible role of truncated variants of SIRT1. This study suggests there may be some potential for SIRT1 inhibition in patients suffering from glioblastoma. Advisors/Committee Members: McConnell, Melanie.

Subjects/Keywords: SIRT1; Sirtuin; Glioblastoma

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APA (6^th Edition):

Brow, S. (2015). Investigating the Potential Role of SIRT1 in Glioblastoma Multiforme: A Comparison Between Glioma and Normal Astrocyte Cells in Culture. (Masters Thesis). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/4879

Chicago Manual of Style (16^th Edition):

Brow, Susanna. “Investigating the Potential Role of SIRT1 in Glioblastoma Multiforme: A Comparison Between Glioma and Normal Astrocyte Cells in Culture.” 2015. Masters Thesis, Victoria University of Wellington. Accessed February 24, 2021. http://hdl.handle.net/10063/4879.

MLA Handbook (7^th Edition):

Brow, Susanna. “Investigating the Potential Role of SIRT1 in Glioblastoma Multiforme: A Comparison Between Glioma and Normal Astrocyte Cells in Culture.” 2015. Web. 24 Feb 2021.

Vancouver:

Brow S. Investigating the Potential Role of SIRT1 in Glioblastoma Multiforme: A Comparison Between Glioma and Normal Astrocyte Cells in Culture. [Internet] [Masters thesis]. Victoria University of Wellington; 2015. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10063/4879.

Council of Science Editors:

Brow S. Investigating the Potential Role of SIRT1 in Glioblastoma Multiforme: A Comparison Between Glioma and Normal Astrocyte Cells in Culture. [Masters Thesis]. Victoria University of Wellington; 2015. Available from: http://hdl.handle.net/10063/4879

University of Minnesota

18. Becker, Chani. Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma.

Degree: PhD, Neuroscience, 2016, University of Minnesota

URL: http://hdl.handle.net/11299/182319

► Glioblastoma multiforme (GBM) is a lethal cancer. Without treatment, patients diagnosed with this disease survive nine months. With the best therapeutics science has to offer,… (more)

▼ Glioblastoma multiforme (GBM) is a lethal cancer. Without treatment, patients diagnosed with this disease survive nine months. With the best therapeutics science has to offer, including surgical resection, radiation therapy, and temozolomide, patients survive only five more months. Despite numerous clinical trials, the vast majority of tested drugs fail to provide therapeutic benefit to patients. It was the intent of this thesis to characterize the molecular mechanisms that prevent or limit the efficacy of targeted agents against malignant glioma. This work specifically explores how the internal characteristics of the tumor including its invasiveness and genetic heterogeneity as well as external attributes of therapeutic agents including brain penetrance contributes to the chemotherapeutic failure in GBM. By clarifying the biological processes that constrain treatment of this disease, scientists can strategize the development of better therapeutics with greater likelihoods for clinical success. We compared the brain distribution, molecular targeting efficiency, and survival benefit of GDC-0980 and GNE-317, two PI3K/mTOR inhibitor analogues. We showed that GDC-0980 is liable for efflux by P-glycoprotein (Pgp) and Breast Cancer Resistance Protein (BCRP) at the blood-brain barrier (BBB) while GNE-317 remains relatively resistant to efflux. Because GNE-317 is more brain penetrant than GDC-0980, it showed greater accumulation in the brain and stronger ability to impede the activation of PI3K/mTOR pathways in the GL261 mouse glioma model. Unexpectedly, neither drug affected survival, an effect that underscores the challenges presented by the genetic heterogeneity associated with cancer and the consequences of inadequate target selection. We also sought to determine the influence of anti-angiogenic therapy (AAT) on the delivery and efficacy of concurrently administered targeted agents. Again, we used GDC-0980 and GNE-317 to determine whether susceptibility to efflux impacted these parameters. We demonstrated that the vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab (Avastin) could decrease the brain distribution of GDC-0980, although not significantly, but had no effect on the brain accumulation of GNE-317. We further showed that while bevacizumab alone provided a survival benefit in patient-derived glioma xenograft models, this therapeutic benefit could only be enhanced with co-treatment of a brain-penetrant drug like GNE-317. Collectively, these data suggest that AAT-induced BBB normalization is more likely to limit the delivery of targeted agents that are subject to active efflux. Finally, we examined the therapeutic potential of targeting cancer stem cells (CSCs) through experiments with parthenolide and LC-1 in the GL261 mouse glioma model. Effectively killing CSCs is an important goal in brain tumor research because this cell population is thought to responsible for tumor growth and recurrence, and is known to be particularly resistant to chemotherapies. In vitro studies of parthenolide and…

Subjects/Keywords: BBB; Glioblastoma; Glioma

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APA (6^th Edition):

Becker, C. (2016). Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/182319

Chicago Manual of Style (16^th Edition):

Becker, Chani. “Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma.” 2016. Doctoral Dissertation, University of Minnesota. Accessed February 24, 2021. http://hdl.handle.net/11299/182319.

MLA Handbook (7^th Edition):

Becker, Chani. “Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma.” 2016. Web. 24 Feb 2021.

Vancouver:

Becker C. Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma. [Internet] [Doctoral dissertation]. University of Minnesota; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/11299/182319.

Council of Science Editors:

Becker C. Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma. [Doctoral Dissertation]. University of Minnesota; 2016. Available from: http://hdl.handle.net/11299/182319

University of Melbourne

19. Daniel, Paul Marcel. Identification of CREB as a transcriptional regulator of glioblastoma biology.

Degree: 2015, University of Melbourne

URL: http://hdl.handle.net/11343/58851

► Glioblastoma (GBM) is both the most common and malignant type of brain tumour with a median survival of 7.4 months from the date of diagnosis;… (more)

▼ Glioblastoma (GBM) is both the most common and malignant type of brain tumour with a median survival of 7.4 months from the date of diagnosis; even following current treatment regimens of resection, radiation and chemotherapy, highlighting the need for a greater understanding of the molecular mechanisms driving tumour biology. The Cyclic-AMP Response Element Binding (CREB) protein is a kinase-inducible transcription factor which sits at a hub of pro-oncogenic signalling pathways. CREB is a critical regulator of normal brain development where it regulates proliferation, differentiation and survival. The phosphorylated form of CREB (pCREB) is overexpressed in several types of cancer where it regulates various aspects of tumour biology but little is known about the role of CREB in GBM. As such, this thesis hypothesises that pCREB is an oncogene in GBM where it is activated by multiple cancer signalling pathways and is essential for the maintenance of tumour biology. To investigate the pathways responsible for CREB activation in GBM and the potential of pCREB to serve as a prognostic biomarker, a combination of immunohistochemistry (IHC) and bioinformatics analysis were undertaken. pCREB was co-expressed in cells along with either pMAPK or pAKT in GBM specimens, implicating the PI3K/AKT and MEK/MAPK pathways in differentially activating CREB. Signalling through a MAPK-CREB axis was associated with cell proliferation whilst an AKT-CREB signalling axis was implicated in invasion. pCREB was not prognostic for survival in GBM however was associated with poor prognosis when analysed in the context of MEK/MAPK signalling. Investigation of the role of CREB in vitro confirmed the role of CREB in regulating proliferation. Knockdown of CREB resulted in slower cell cycle progression and this occurred through the transcriptional regulation of the cell cycle factor Cyclin D1. In addition, CREB was selectively regulated the activity of the PI3K/AKT pathway via a feedback mechanism which in turn regulated the expression of cell cycle factors Cyclin B1 and PCNA. In contrast to the PI3K/AKT and MEK/MAPK pathways, the cAMP/PKA pathway was not associated with CREB activation in GBM. Exogenous activation of the cAMP/PKA pathway resulted in BIM dependant apoptosis in selective GBM cell lines. CREB played a pro-survival role in this context where it inhibited BIM expression and apoptosis. To investigate the link between the PI3K/AKT pathway and CREB, hyperactivation of the PI3K/AKT pathway was induced in neural stem cells via an activating mutation of PIK3CA and loss of PTEN, leading to glioma initiation in vivo. Cells with these mutations expressed high levels of pAKT as well as CREB target genes Cyclin D1 and Cyclin B1 independently of exogenous growth factors. pCREB was expressed throughout PIK3CA/PTEN tumours and knockout of CREB in PIK3CA/PTEN tumours resulted in prolonged survival, demonstrating the key role of CREB in PI3K/AKT mediated tumour biology. Collectively this study establishes CREB as a pro-oncogenic factor in…

Subjects/Keywords: glioblastoma; CREB; transcription

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APA (6^th Edition):

Daniel, P. M. (2015). Identification of CREB as a transcriptional regulator of glioblastoma biology. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/58851

Chicago Manual of Style (16^th Edition):

Daniel, Paul Marcel. “Identification of CREB as a transcriptional regulator of glioblastoma biology.” 2015. Doctoral Dissertation, University of Melbourne. Accessed February 24, 2021. http://hdl.handle.net/11343/58851.

MLA Handbook (7^th Edition):

Daniel, Paul Marcel. “Identification of CREB as a transcriptional regulator of glioblastoma biology.” 2015. Web. 24 Feb 2021.

Vancouver:

Daniel PM. Identification of CREB as a transcriptional regulator of glioblastoma biology. [Internet] [Doctoral dissertation]. University of Melbourne; 2015. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/11343/58851.

Council of Science Editors:

Daniel PM. Identification of CREB as a transcriptional regulator of glioblastoma biology. [Doctoral Dissertation]. University of Melbourne; 2015. Available from: http://hdl.handle.net/11343/58851

University of New South Wales

20. Mutyala, Naga. Evaluating a rodent model and treatments for glioblastoma using gene expression profiling.

Degree: Biotechnology & Biomolecular Sciences, 2019, University of New South Wales

URL: http://handle.unsw.edu.au/1959.4/66384

► Glioblastoma is the most lethal primary brain tumour in adults, with a poor prognosis and a median survival of less than 15 months. Clearly novel… (more)

▼ Glioblastoma is the most lethal primary brain tumour in adults, with a poor prognosis and a median survival of less than 15 months. Clearly novel therapies alternative to the standard temozolomide are urgently required. To evaluate the efficacy of novel treatments, in vivo experimental models resembling the human glioblastoma at the molecular level are essential. Molecular pathology identified four glioblastoma subtypes (classical, mesenchymal, neural and proneural), with differing treatment efficacy and prognosis. This indicates therapies that specifically target each subtype can improve outcomes. We have investigated the transcriptome in the F98 rat glioblastoma tumour model and mapped it onto published gene expression patterns of human glioblastoma subtypes.Meta-analysis studies indicate there is a reduced incidence of some cancers in patients which schizophrenia, which led to the hypothesis that drugs used in treatment of schizophrenia may inhibit tumour growth. Therefore, we also investigated the effect of an antipsychotic drug, olanzapine, alone and in combination with a chemotherapeutic temozolomide, in this tumour model.F98 rat glioblastoma cells transfected with a luciferase gene were intracranially implanted into Fisher rats and treatments with olanzapine, temozolomide and combination therapy were commenced following successful tumour implantation. Tumour growth and animal survival were recorded. Following drug treatments, changes in gene expression in the F98 tumour and control tissue (contralateral hemisphere with “normal” tissue) were measured using microarrays. Gene transcript changes associated with four glioblastoma subtypes were obtained from the literature and the overlap of F98 rat glioblastoma expression patterns with human glioblastoma subtypes were identified. Our study revealed that F98 rat glioblastoma tumours have a gene expression pattern like the human mesenchymal glioblastoma subtype, which has a poor prognosis, and indicates that the F98 rat glioblastoma tumour model is a good pre-clinical model for the development of therapies against this aggressive human glioblastoma subtype. While the survival of rats treated with the combination therapy was only marginally improved, gene expression analyses indicated this therapy down-regulates tumour promoting gene transcripts and pathways, indicating the treatment could be further optimized for treating human glioblastoma of the mesenchymal subtype. Advisors/Committee Members: Lutze-Mann, Louise, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW.

Subjects/Keywords: Glioblastoma; Gene expression

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APA (6^th Edition):

Mutyala, N. (2019). Evaluating a rodent model and treatments for glioblastoma using gene expression profiling. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/66384

Chicago Manual of Style (16^th Edition):

Mutyala, Naga. “Evaluating a rodent model and treatments for glioblastoma using gene expression profiling.” 2019. Doctoral Dissertation, University of New South Wales. Accessed February 24, 2021. http://handle.unsw.edu.au/1959.4/66384.

MLA Handbook (7^th Edition):

Mutyala, Naga. “Evaluating a rodent model and treatments for glioblastoma using gene expression profiling.” 2019. Web. 24 Feb 2021.

Vancouver:

Mutyala N. Evaluating a rodent model and treatments for glioblastoma using gene expression profiling. [Internet] [Doctoral dissertation]. University of New South Wales; 2019. [cited 2021 Feb 24]. Available from: http://handle.unsw.edu.au/1959.4/66384.

Council of Science Editors:

Mutyala N. Evaluating a rodent model and treatments for glioblastoma using gene expression profiling. [Doctoral Dissertation]. University of New South Wales; 2019. Available from: http://handle.unsw.edu.au/1959.4/66384

NSYSU

21. Lee, Ya-che. Hexane fraction of Pluchea indica (L.) Less. root extract induce autophagic cell death on glioblastoma multiforme U87 cells.

Degree: Master, Biological Sciences, 2016, NSYSU

URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0508116-175738

► Pluchea indica (L.) Less. is a perennial plant known for its versatile uses in traditional oriental medicine. In our previous study, we demonstrate the in… (more)

Subjects/Keywords: Glioblastoma Multiforme; Autophagy; Pluchea indica

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APA (6^th Edition):

Lee, Y. (2016). Hexane fraction of Pluchea indica (L.) Less. root extract induce autophagic cell death on glioblastoma multiforme U87 cells. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0508116-175738

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lee, Ya-che. “Hexane fraction of Pluchea indica (L.) Less. root extract induce autophagic cell death on glioblastoma multiforme U87 cells.” 2016. Thesis, NSYSU. Accessed February 24, 2021. http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0508116-175738.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lee, Ya-che. “Hexane fraction of Pluchea indica (L.) Less. root extract induce autophagic cell death on glioblastoma multiforme U87 cells.” 2016. Web. 24 Feb 2021.

Vancouver:

Lee Y. Hexane fraction of Pluchea indica (L.) Less. root extract induce autophagic cell death on glioblastoma multiforme U87 cells. [Internet] [Thesis]. NSYSU; 2016. [cited 2021 Feb 24]. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0508116-175738.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lee Y. Hexane fraction of Pluchea indica (L.) Less. root extract induce autophagic cell death on glioblastoma multiforme U87 cells. [Thesis]. NSYSU; 2016. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0508116-175738

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

22. Kagami, Luciano Porto. Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase.

Degree: 2017, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/170643

►

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… (more)

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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.

Advisors/Committee Members: Eifler-Lima, Vera Lucia.

Subjects/Keywords: Medicamentos; Glioblastoma; Modelagem molecular

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kagami, L. P. (2017). Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/170643

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kagami, Luciano Porto. “Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase.” 2017. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/170643.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kagami, Luciano Porto. “Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase.” 2017. Web. 24 Feb 2021.

Vancouver:

Kagami LP. Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2017. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/170643.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kagami LP. Estudo in silico de novas diidropirimidin-2-tionas com ação inibitória da enzima ecto-5'-nucleotidase. [Thesis]. Universidade do Rio Grande do Sul; 2017. Available from: http://hdl.handle.net/10183/170643

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

23. Silva, Andrew Oliveira. Silenciamento de XIAP potencializa os efeitos da superexpressão de TP53 na redução da proliferação e aumento da morte celular em gliomas.

Degree: 2012, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/150622

► Gliomas malignos compreendem o subtipo mais comum e devastador de tumores primários do sistema nervoso central (SNC), sendo o Glioblastoma Multiforme (GBM) a forma mais… (more)

▼ Gliomas malignos compreendem o subtipo mais comum e devastador de tumores primários do sistema nervoso central (SNC), sendo o Glioblastoma Multiforme (GBM) a forma mais agressiva e mortífera. Pacientes com este tipo de tumor apresentam um prognóstico de sobrevida que não ultrapassa os 18 meses, após o diagnóstico. Isso é decorrente do fato de que os GBMs possuem elevada resistência aos tratamentos de quimio e radioterapia, além de serem altamente infiltrativos e neurologicamente destrutivos. Um importante fator que contribui para essa resistência é a superexpressão da proteína XIAP (X-linked Inhibitor of Apoptosis), o mais potente inibidor de apoptose da família das IAPs. Este atua inibindo diretamente a ativação das Caspases 3, 7 e 9. P53 é considerada uma das mais potentes proteínas supressoras tumorais, uma vez que esta atua como reguladora central em diversas vias de sinalização de mecanismos celulares distintos, como a via de controle do ciclo celular, reparo ao DNA, apoptose, senescência, autofagia, entre outras. Isto justifica o fato de p53 estar frequentemente mutada, nos mais variados tipos de cânceres. Portanto, o objetivo do presente trabalho foi estudar os efeitos resultantes da interação entre a superexpressão da proteína supressora tumoral p53 e o silenciamento da proteína anti-apoptótica XIAP na proliferação, na sobrevivência de GBMs. Quando p53 foi superexpressa (P+) na linhagem de glioma U87 silenciada para XIAP (Xi), através de RNAi, a taxa de proliferação celular reduziu significativamente em relação às células com as intervenções isoladas (U87Xi e U87wtP+) ou em relação ao controle selvagem U87wt, ao longo de dez dias. O ensaio de citotoxicidade LDH revelou um aumento na desestabilização da membrana citoplasmática nas células com a manipulação gênica combinada (U87XiP+) em relação os controles U87Xi e U87wtP+. O ensaio com AnexinaV/PI demonstrou uma elevação na marcação de células U87XiP+ com os dois marcadores, indicando uma maior indução de morte celular em relação aos controles. Além disso, como consequência da modulação combinada de p53 e XIAP, os níveis das proteínas pró-apoptóticas Bax e PUMA aumentaram tanto na linhagem U87wt, quanto na linhagem U87Xi, ao superexpressar p53. Além disso, os níveis de p21 e da proteína anti-apoptótica Bcl-xL foram reduzidos na linhagem U87Xi em relação ao controle U87wt. Outra constatação importante foi o aumento dos níveis de caspase-3 na linhagem U87Xi em relação ao controle U87wt e um aumento ainda maior nas células com a intervenção combinada (U87XiP+). Todos estes dados convergem para o fato de que a combinação do silenciamento de XIAP e superexpressão de p53 é mais efetiva na redução da proliferação e indução de morte na linhagem de glioma U87, do que as manipulações gênicas realizadas de forma isoladas, além de sugerir uma possível via de integração entre XIAP e p53, tendo como ponto de conexão o controle dos níveis citoplasmáticos da proteína p21 tanto por p53, quanto por XIAP, mostrando que a modulação combinada de proteínas da via apoptótica é… Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Glioma; Apoptose; Autofagia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Silva, A. O. (2012). Silenciamento de XIAP potencializa os efeitos da superexpressão de TP53 na redução da proliferação e aumento da morte celular em gliomas. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/150622

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Silva, Andrew Oliveira. “Silenciamento de XIAP potencializa os efeitos da superexpressão de TP53 na redução da proliferação e aumento da morte celular em gliomas.” 2012. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/150622.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Silva, Andrew Oliveira. “Silenciamento de XIAP potencializa os efeitos da superexpressão de TP53 na redução da proliferação e aumento da morte celular em gliomas.” 2012. Web. 24 Feb 2021.

Vancouver:

Silva AO. Silenciamento de XIAP potencializa os efeitos da superexpressão de TP53 na redução da proliferação e aumento da morte celular em gliomas. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2012. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/150622.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Silva AO. Silenciamento de XIAP potencializa os efeitos da superexpressão de TP53 na redução da proliferação e aumento da morte celular em gliomas. [Thesis]. Universidade do Rio Grande do Sul; 2012. Available from: http://hdl.handle.net/10183/150622

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Rochester

24. Stripay, Jennifer L. Targeting a Network of Cancer Control Nodes through Rescue of c-Cbl; A Novel Therapeutic Approach for Glioblastoma Multiforme.

Degree: PhD, 2016, University of Rochester

URL: http://hdl.handle.net/1802/31636

► Glioblastoma multiforme is the most common primary brain tumor in adults, the most malignant of all intracranial tumors, and is associated with inevitable recurrence and… (more)

Subjects/Keywords: Cancer; cbl; Glioblastoma; Redox; Therapy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Stripay, J. L. (2016). Targeting a Network of Cancer Control Nodes through Rescue of c-Cbl; A Novel Therapeutic Approach for Glioblastoma Multiforme. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/31636

Chicago Manual of Style (16^th Edition):

Stripay, Jennifer L. “Targeting a Network of Cancer Control Nodes through Rescue of c-Cbl; A Novel Therapeutic Approach for Glioblastoma Multiforme.” 2016. Doctoral Dissertation, University of Rochester. Accessed February 24, 2021. http://hdl.handle.net/1802/31636.

MLA Handbook (7^th Edition):

Stripay, Jennifer L. “Targeting a Network of Cancer Control Nodes through Rescue of c-Cbl; A Novel Therapeutic Approach for Glioblastoma Multiforme.” 2016. Web. 24 Feb 2021.

Vancouver:

Stripay JL. Targeting a Network of Cancer Control Nodes through Rescue of c-Cbl; A Novel Therapeutic Approach for Glioblastoma Multiforme. [Internet] [Doctoral dissertation]. University of Rochester; 2016. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/1802/31636.

Council of Science Editors:

Stripay JL. Targeting a Network of Cancer Control Nodes through Rescue of c-Cbl; A Novel Therapeutic Approach for Glioblastoma Multiforme. [Doctoral Dissertation]. University of Rochester; 2016. Available from: http://hdl.handle.net/1802/31636

University of Utah

25. Sankaranarayanan, Preethi. Generalized singular value decomposition (GSVD) comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival.

Degree: MS, Bioengineering, 2013, University of Utah

URL: http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/2111/rec/1101

► Despite recent large-scale profiling efforts, the best prognostic predictor ofglioblastoma multiforme (GBM) remains the patient’s age at diagnosis. Wedescribe a global pattern of tumor-exclusive co-occurring… (more)

Subjects/Keywords: Copy number; Glioblastoma multiforme; GSVD

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Sankaranarayanan, P. (2013). Generalized singular value decomposition (GSVD) comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival. (Masters Thesis). University of Utah. Retrieved from http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/2111/rec/1101

Chicago Manual of Style (16^th Edition):

Sankaranarayanan, Preethi. “Generalized singular value decomposition (GSVD) comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival.” 2013. Masters Thesis, University of Utah. Accessed February 24, 2021. http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/2111/rec/1101.

MLA Handbook (7^th Edition):

Sankaranarayanan, Preethi. “Generalized singular value decomposition (GSVD) comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival.” 2013. Web. 24 Feb 2021.

Vancouver:

Sankaranarayanan P. Generalized singular value decomposition (GSVD) comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival. [Internet] [Masters thesis]. University of Utah; 2013. [cited 2021 Feb 24]. Available from: http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/2111/rec/1101.

Council of Science Editors:

Sankaranarayanan P. Generalized singular value decomposition (GSVD) comparison of patient-matched normal and tumor aCGH profiles reveals global copy-number alterations predicting glioblastoma multiforme survival. [Masters Thesis]. University of Utah; 2013. Available from: http://content.lib.utah.edu/cdm/singleitem/collection/etd3/id/2111/rec/1101

Boston University

26. Handley, Meghan Victoria. GSK-3 inhibitors in glioblastoma therapy: mechanisms of action.

Degree: MS, Medical Sciences, 2015, Boston University

URL: http://hdl.handle.net/2144/16063

► Glioblastoma multiforme (GBM) is the most malignant form of brain cancer. Therapies targeting glioblastoma have not consistently been able to give those diagnosed the best… (more)

▼ Glioblastoma multiforme (GBM) is the most malignant form of brain cancer. Therapies targeting glioblastoma have not consistently been able to give those diagnosed the best prognosis. Treatments that directly infiltrate into the tumor are highly sought after. Indirubins have been used to treat various types of cancers and are a promising avenue for future glioma research. In the current study, we further researched several key GSK-3 inhibitors, BIO (an indirubin) and CHIR99021, in addition to LiCl, to see their effects on the translocation of β-catenin to the nucleus, and the invasion and migration of cells in both a sphere assay and an aortic ring assay. Here we studied anti-invasive therapies that may have a future role in GBM treatment. It is thought that combining conventional treatments with anti-invasive therapies will create cytotoxicity in and reduce migration of the tumor. Three types of cells were used throughout the experiments: HBMEC, HUVEC, and U251 glioma cells. We reported that GSK-3 inhibitors might have a valuable role in the treatment of GBM. The selected inhibitors (BIO, CHIR99021, and LiCl) all were shown to lessen cell migration and invasion in vitro in a range of assays and in all cell lines tested. All inhibitors tested cause a dose-dependent, reversible inhibition of glioma cell invasion in spheroid assays. BIO was shown to cause a rapid upregulation of total and nuclear β-catenin. BIO, at higher concentrations, also created a toxic environment for cells, sometimes killing them. This shows that a more in-depth experiment involving different BIO concentrations is needed to test the optimal concentration for treatment. Each of the experimented GSK-3 inhibitors also showed a change in the junctions between cells. NaCl as a control showed normal, spikey, junctions, while CHIR99021 and BIO caused the junctions to become more smooth. This suggests that GSK-3 inhibition has a role in either maintaining the ECM and/or in communication between cells. Also in this assay, there was a heterogeneity between cells treated with the same inhibitor and in the same dish, indicating that not all cells respond to each drug the same way. The reasons for this are not known and further investigation is required. A new construct was also made to report β-catenin transcriptional coactivation using luciferase expression as the reporter in response to these selected GSK-3 inhibitors.With the combined results of these experiments, we concluded that GSK-3 inhibitors may be a promising approach to the treatment of GBM. Further investigation is required before any treatments can be administered to those diagnosed.

Subjects/Keywords: Medicine; Glioblastoma; GSK-3 inhibitors

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Handley, M. V. (2015). GSK-3 inhibitors in glioblastoma therapy: mechanisms of action. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16063

Chicago Manual of Style (16^th Edition):

Handley, Meghan Victoria. “GSK-3 inhibitors in glioblastoma therapy: mechanisms of action.” 2015. Masters Thesis, Boston University. Accessed February 24, 2021. http://hdl.handle.net/2144/16063.

MLA Handbook (7^th Edition):

Handley, Meghan Victoria. “GSK-3 inhibitors in glioblastoma therapy: mechanisms of action.” 2015. Web. 24 Feb 2021.

Vancouver:

Handley MV. GSK-3 inhibitors in glioblastoma therapy: mechanisms of action. [Internet] [Masters thesis]. Boston University; 2015. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/2144/16063.

Council of Science Editors:

Handley MV. GSK-3 inhibitors in glioblastoma therapy: mechanisms of action. [Masters Thesis]. Boston University; 2015. Available from: http://hdl.handle.net/2144/16063

Freie Universität Berlin

27. Onken, Julia Sophie. Experimental, translational and clinical aspects of individualized treatment of glioblastoma.

Degree: 2020, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-27455

► Die Zielsetzung der vorliegenden Arbeit ist es, neue Aspekte der experimentellen, translationalen und klinischen Forschung bei der individualisierten Behandlung des Glioblastoms darzustellen. Die Arbeiten befassen… (more)

▼ Die Zielsetzung der vorliegenden Arbeit ist es, neue Aspekte der experimentellen, translationalen und klinischen Forschung bei der individualisierten Behandlung des Glioblastoms darzustellen. Die Arbeiten befassen sich mit präklinischen und klinischen Ansatzpunkten der individualisierten Behandlung des Glioblastoms, der Definition geeigneter Einschlusskriterien für ein klinisches Studiendesign und der Interpretation von aktuellen Studienergebnissen sowie deren Übertragbarkeit auf die klinische Routineversorgung. Publikation eins befasst sich mit der experimentellen Forschung zur Effektivität eines kleinmolekularen Inhibitors der RTK AXL in vitro, ex vivo und in vivo. Zudem wird das Expressionsprofil der aktivierten RTK AXL (P-AXL) im humanen Glioblastom untersucht. Diese Arbeit soll die Grundlage bilden für die präklinische Weiterentwicklung von AXL Inhibitoren im Glioblastom und Translation der Ergebnisse in ein klinisches Studiendesign. Publikation zwei thematisiert die Ermittlung des prädiktiven Schwellenwertes der MGMT-Promotor-Methylierung. Aufgrund der unterschiedlichen Anforderungen und Voraussetzungen einzelner Methoden zur Bestimmung des MGMT-Promotor-Status besteht gegenwärtig kein internationaler Standard. Diese Arbeit zielt darauf ab, den prädiktiven Schwellenwert für die MGMT-Promotor-Methylierung anhand der Pyrosequenzierung zu definieren und somit MGMT-basierte Therapieentscheidungen zu erleichtern. Publikation drei beinhaltet klinische Daten zur individualisierten Bestrahlungsplanung von Glioblastompatienten. Untersucht wird die Effektivität einer dosiseskalierten Bestrahlung mit 66Gy im Vergleich zum Standardprotokoll mit 60Gy. Als primärer Endpunkt sind progressionsfreies und Gesamtüberleben definiert. Molekulare Marker wie der IDH-Status und der MGMT-Promotor-Status wurden bei der Auswertung berücksichtigt. Publikation vier und fünf beschäftigen sich mit der Akzeptanz, Compliance und Alltagsintegrität innovativer Therapiekonzepte am Beispiel von TTFields. Anhand eines detaillierten Fragebogens wurden zahlreiche Aspekte zur selbständigen Lebensführung und Lebensqualität unter TTFields erfasst und mit einer Kontrollpopulation verglichen. Die Daten aus Publikation vier und fünf liefern Einblicke zu Einflussfaktoren auf Akzeptanz und Compliance gegenüber TTFields in der klinischen Routineversorgung und alltagsrelevanten Einschränkungen aus Sicht der Patienten. Zudem geben sie Anstoß zur patientenorientierten Weiterentwicklung dieser aufwendigen Therapieform. Advisors/Committee Members: female (gender), Schroeder, Henry (firstReferee), Clusmann, Hans (furtherReferee).

Subjects/Keywords: glioblastoma; neuro-oncology; ddc:610

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Onken, J. S. (2020). Experimental, translational and clinical aspects of individualized treatment of glioblastoma. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-27455

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Onken, Julia Sophie. “Experimental, translational and clinical aspects of individualized treatment of glioblastoma.” 2020. Thesis, Freie Universität Berlin. Accessed February 24, 2021. http://dx.doi.org/10.17169/refubium-27455.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Onken, Julia Sophie. “Experimental, translational and clinical aspects of individualized treatment of glioblastoma.” 2020. Web. 24 Feb 2021.

Vancouver:

Onken JS. Experimental, translational and clinical aspects of individualized treatment of glioblastoma. [Internet] [Thesis]. Freie Universität Berlin; 2020. [cited 2021 Feb 24]. Available from: http://dx.doi.org/10.17169/refubium-27455.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Onken JS. Experimental, translational and clinical aspects of individualized treatment of glioblastoma. [Thesis]. Freie Universität Berlin; 2020. Available from: http://dx.doi.org/10.17169/refubium-27455

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Vermont

28. Hermanowski, Henre Michael. Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors.

Degree: Biochemistry, 2019, University of Vermont

URL: https://scholarworks.uvm.edu/hcoltheses/321

► Abstract: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with a median survival of approximately 15 months. Standard care for GBM has… (more)

▼ Abstract: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with a median survival of approximately 15 months. Standard care for GBM has remained the same for more than 10 years and has yet to produce remission. Phosphatase and tensin homolog (PTEN) is a common biomarker of GBM, whose mutation is associated with defects in homologous recombination (HR), making it a candidate for targeted therapy by synthetic lethality (SL). PARylation is a transient, post-translational modification that modulates DNA repair fidelity and genomic stability. Inhibitors of PARylation (PARP inhibitors, PARPi; PARG inhibitors, PARGi) have been developed for therapeutic use in HR-defective cancers, and their efficacy has been demonstrated in HR-deficient breast and ovarian cancers based on the concept of SL. My main goal was to identify the DNA double-strand break repair pathways activated and/or inhibited by PARPi and PARGi in function of PTEN status, and to support the concept of SL in GBM cell lines. This was accomplished by various methods including flow cytometry and immunofluorescence. Subsequently, by western blot and immunohistochemistry, I aimed to uncover the expression and localization of PARP-1 and PARG in human tissue to validate the potential of PARPi and PARGi as therapeutic agents. I revealed that inhibitor treatment caused the accumulation of GBM cells in G2 phase without the initiation of apoptosis or necrosis. Importantly, PTEN-wildtype cells displayed higher levels of DNA damage after PARPi treatment compared to PTEN-mutant cells. However, there was no indication of efficient DNA repair by NHEJ. These findings strengthen the case for PARP and PARG inhibition as inducers of DNA damage, but do not support the concept of SL between PARP inhibition and PTEN mutations in GBM cells, despite PARP-1 and PARG over-expression in GBM tissues. Further research must be done to understand the complex relationship between PARylation and PTEN, and to propose PARPi and/or PARGi for personalized therapeutic use in GBM patients. Advisors/Committee Members: Delphine Quénet, Matthias Brewer.

Subjects/Keywords: glioblastoma; cancer; PARP; PARG; inhibition

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hermanowski, H. M. (2019). Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors. (Thesis). University of Vermont. Retrieved from https://scholarworks.uvm.edu/hcoltheses/321

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Hermanowski, Henre Michael. “Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors.” 2019. Thesis, University of Vermont. Accessed February 24, 2021. https://scholarworks.uvm.edu/hcoltheses/321.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Hermanowski, Henre Michael. “Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors.” 2019. Web. 24 Feb 2021.

Vancouver:

Hermanowski HM. Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors. [Internet] [Thesis]. University of Vermont; 2019. [cited 2021 Feb 24]. Available from: https://scholarworks.uvm.edu/hcoltheses/321.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hermanowski HM. Analysis of PARylation and PTEN Mutation Effects on PARP and PARG Inhibition Treatment in Primary Brain Tumors. [Thesis]. University of Vermont; 2019. Available from: https://scholarworks.uvm.edu/hcoltheses/321

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Texas Southwestern Medical Center

29. McEllin, Brian Matthew. Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems.

Degree: 2012, University of Texas Southwestern Medical Center

URL: http://hdl.handle.net/2152.5/1000

► Glioblastoma multiforme (GBM) are deadly brain tumors that are refractory to radiation and chemotherapy. Despite decades of work, little progress has been made in improving… (more)

▼ Glioblastoma multiforme (GBM) are deadly brain tumors that are refractory to radiation and chemotherapy. Despite decades of work, little progress has been made in improving patient outcomes. Recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these cancers commonly exhibit several signature mutations that promote gliomagenesis (e.g. EGFR amplification/activation, PTEN loss, p53 loss, Ink4a/Arf loss). How these genetic changes may modulate responses to radiation and chemotherapy is not well understood. To elucidate this relationship, genetically defined mouse models have been used for both in vitro and in vivo analysis. Work has uncovered novel links between oncogenic signaling and DNA repair pathways. First, activation of the Akt pathway by EGFRvIII, a constitutively active form of EGFR, promotes DNA double strand break repair by non-homologous end joining in astrocytes and glioma cell lines. This results in faster repair and increased radioresistance, both in vitro and in orthotopic GBM models. While activation of Akt by the loss of PTEN has similar results, data shows that PTEN loss reduces resistance to agents that induce replication-associated DSBs. This phenotype is due to reduced levels of homologous recombination, as astrocytes show increased radial chromosome aberrations and decreased sister chromatid exchanges after PTEN loss. These results have exciting implications, as it has identified two potential new therapeutic strategies for improving treatment in subsets of GBM patients. The cancer stem cell hypothesis postulates that cancers are organized similar to endogenous stem cell compartments, composed of a self-renewing cancer stem cell and other more “differentiated”, non-stem progeny. To determine how key GBM mutations affect the different cell types in GBM, I used the adult neural stem cell compartment as a reductionist model of a tumor. Surprisingly, data demonstrated that quiescent stem cells showed inherent resistance, even in a wild type mouse. In addition, stem cell-specific p53 loss increases radioresistance only in a subset of non-dividing progenitors, while proliferating progenitors remain sensitive to radiation. This model has offered novel insight into the effect of key pathways deregulated in GBM and how they impact different cell types. Advisors/Committee Members: Burma, Sandeep, Bachoo, Robert.

Subjects/Keywords: PTEN Phosphohydrolase; Brain Neoplasms; Glioblastoma

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

McEllin, B. M. (2012). Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/1000

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

McEllin, Brian Matthew. “Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems.” 2012. Thesis, University of Texas Southwestern Medical Center. Accessed February 24, 2021. http://hdl.handle.net/2152.5/1000.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

McEllin, Brian Matthew. “Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems.” 2012. Web. 24 Feb 2021.

Vancouver:

McEllin BM. Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2012. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/2152.5/1000.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

McEllin BM. Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems. [Thesis]. University of Texas Southwestern Medical Center; 2012. Available from: http://hdl.handle.net/2152.5/1000

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade do Rio Grande do Sul

30. Vigna, Alexandra Souza. Avaliação do papel da proteína ATR na indução de autofagia e senescência por temozolomida em células de glioblastoma.

Degree: 2017, Universidade do Rio Grande do Sul

URL: http://hdl.handle.net/10183/163683

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Autofagia é um processo de degradação fisiológico aumentado em diferentes condições de estresse, em que proteínas e organelas não funcionais são direcionadas ao lisossomo, onde… (more)

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Autofagia é um processo de degradação fisiológico aumentado em diferentes condições de estresse, em que proteínas e organelas não funcionais são direcionadas ao lisossomo, onde são degradadas e os produtos da degradação reutilizados pela célula. Senescência é o processo em que as células param de dividir e entram em um estado de parada celular irreversível. Os dois processos, autofagia e senescência, podem ser induzidos na presença de dano no DNA, porém a maquinaria molecular que realiza a intermediação neste processo ainda é incerta. Temozolomida (TMZ) é um agente alquilante, usado para tratar pacientes com Glioblastoma, que induz dano no DNA. Lesões produzidas por TMZ ativam a resposta ao dano no DNA (DDR), uma sinalização complexa que medeia as respostas celulares, tais como a dinâmica do ciclo celular, autofagia, senescência e morte celular, ao dano genotóxico. Dada a importância desses mecanismos, esse trabalho objetiva avaliar o impacto da inibição da cinase Ataxia Telangiectasia mutada dependente de Rad3 (ATR), reguladora chave da DDR, na proliferação, autofagia e senescência em células de glioblastoma tratadas com TMZ. Para tal, nós utilizamos um inibidor farmacológico para ATR (VE-821), bem como shRNA para ATR com vetor lentiviral em células U87. A inibição farmacológica da proteína ATR não alterou o estado autofágico e de senescência em comparação com as células tratadas somente com TMZ. Esses resultados foram obtidos usando o método Laranja de Acridina (AO) e a ferramenta de Análise Morfométrica Nuclear (NMA). Na ausência de uma sinalização dependente de ATR, obtida pelas células shATR tratadas com TMZ, também não observamos alteração significativa em relação a esses processos. No entanto, nós observamos um acúmulo da proteína SQSTM1/p62, substrato da autofagia, nas células silenciadas para ATR. Esta alteração não se refletiu em aumento de foci intracelulares da proteína SQSTM1/p62. Em conclusão, ATR não parece participar diretamente da ativação da Autofagia e da Senescência induzidas por TMZ.

Autophagy is a catabolic process, that shows increased levels in stressful situations, whereby dysfunctional proteins and organelles are engulfed and targeted to lysosomes for degradation and recycled back to the cell. Senescence is the process by which cells stop dividing and enter a state of growth arrest. Both processes, autophagy and senescence, can be induced by DNA damage, however, the molecular machinery that mediates this process is still uncertain. Temozolomide (TMZ) is an alkylating agent, used to treat patients with Glioblastoma, that drives DNA damage. Lesions produced by TMZ activate the DNA damage response (DDR), a complex signalling pathway, that mediates cellular outcomes such as cell cycle distribution, autophagy, senescence and cellular death, to genotoxic damage. Given the importance of such mechanisms, this work aims to evaluate the impact of inhibiting the Ataxia telangiectasia and Rad3 related (ATR) kinase, key regulator of the DDR, on cellular proliferation, autophagy and senescence, on…

Advisors/Committee Members: Lenz, Guido.

Subjects/Keywords: Glioblastoma; Temozolamida; Autofagia; Senescência

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Vigna, A. S. (2017). Avaliação do papel da proteína ATR na indução de autofagia e senescência por temozolomida em células de glioblastoma. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/163683

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Vigna, Alexandra Souza. “Avaliação do papel da proteína ATR na indução de autofagia e senescência por temozolomida em células de glioblastoma.” 2017. Thesis, Universidade do Rio Grande do Sul. Accessed February 24, 2021. http://hdl.handle.net/10183/163683.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vigna, Alexandra Souza. “Avaliação do papel da proteína ATR na indução de autofagia e senescência por temozolomida em células de glioblastoma.” 2017. Web. 24 Feb 2021.

Vancouver:

Vigna AS. Avaliação do papel da proteína ATR na indução de autofagia e senescência por temozolomida em células de glioblastoma. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2017. [cited 2021 Feb 24]. Available from: http://hdl.handle.net/10183/163683.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Vigna AS. Avaliação do papel da proteína ATR na indução de autofagia e senescência por temozolomida em células de glioblastoma. [Thesis]. Universidade do Rio Grande do Sul; 2017. Available from: http://hdl.handle.net/10183/163683

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations