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Universidade do Rio Grande do Sul
1.
Lopez, Patrícia Luciana da Costa.
Influência das proteínas XIAP e Survivina na resistência de Gliomas.
Degree: 2012, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/142701 
► Glioblastomas (GBM) são tumores de difícil tratamento pela alta resistência a quimioterápicos. Entre os GBMs a presença de células tronco tumorais (CTT) foi associado a…
(more)
▼ Glioblastomas (GBM) são tumores de difícil tratamento pela alta resistência a quimioterápicos. Entre os GBMs a presença de células tronco tumorais (CTT) foi associado a um pior prognóstico para os pacientes, indicando que essas células podem contribuir para resistência aos tratamentos. Além disso, proteínas como XIAP e survivina (inibidoras de apoptose) estão altamente expressas em GBMs e, devido a sua capacidade de inibir caspases, podem participar de mecanismos de resistência a apoptose. Nesse trabalho foi estudado o silenciamento estável de XIAP ou survivina e seus efeitos na sensibilização de GBMs U87-MG a fármacos. Para isso, utilizou-se RNAs de interferência short hairpin e vetores lentivirais para o silenciamento estável de XIAP ou survivina combinados a diversos fármacos. Entre os fármacos testados, doxorrubicina (doxo 1 μM) e vincristina (vinc) (100 nM) apresentaram os melhores resultados na sensibilização dos GBMs silenciados através da indução de apoptose e senescência. Doxo elevou a expressão das proteínas p53 e H2Ax, indicando dano ao DNA de forma acentuada nas linhagens silenciadas. Vinc apresentou indução de vários tipos de morte, com taxas de apoptose, necrose e alterações no aspecto nuclear que indicaram catástrofe mitótica. O efeito crônico dos tratamentos em 48 horas com doxo, temozolamida e vinc foi avaliado em ensaio clonogênico sem que as diferenças de sensibilização fossem mantidas. Com isso, sugere-se que nas células silenciadas foram selecionados mecanismos de resistência após os tratamentos. A formação de tumor-esferas nas culturas de U87-MG, um indicativo da presença de CTTs, analisada após cinco dias de tratamento com doses reduzidas de doxo e tmz mostrou que doxo 1 nM selecionou as CTT e induziu senescência nas células diferenciadas, enquanto que doxo 10 nM e tmz 5 μM reduziram o número de CTTs. Esse estudo mostrou que a inibição de XIAP e survivina sensibiliza GBMs a determinados fármacos principalmente através da indução de apoptose e senescência pela sinalização de p53. A avaliação do efeito em longo prazo do tratamento agudo com os fármacos estudados deve ser considerada como indicativo de que células silenciadas para XIAP e survivina podem desenvolver mecanismos que revertem o efeito do silenciamento. Além disso, dependendo da dose, doxo pode interferir na participação de CTTs na resistência de GBMs.
Glioblastomas (GBM) are characterized by high resistance to chemotherapy and difficult treatment. The cancer steam cells in GBMs were associated to poor prognosis for patient, and may contribute to enhanced resistance. Moreover, inhibitors of apoptosis proteins as XIAP and survivin are high expressed in GBM and due to their ability to caspase inhibition can be involved in apoptosis resistance mechanisms. In this work we study the stable silencement of XIAP or survivin and its effects in U87-MG sensitization to chemotherapy drugs. For this, short hairpin RNA delivery through lentiviral vectors were used to stable knocking down XIAP or survivin combined with drugs. Among the drugs…
Advisors/Committee Members: Lenz, Guido.
Subjects/Keywords: Proteínas; Glioma
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APA (6th Edition):
Lopez, P. L. d. C. (2012). Influência das proteínas XIAP e Survivina na resistência de Gliomas. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/142701
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lopez, Patrícia Luciana da Costa. “Influência das proteínas XIAP e Survivina na resistência de Gliomas.” 2012. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/142701.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lopez, Patrícia Luciana da Costa. “Influência das proteínas XIAP e Survivina na resistência de Gliomas.” 2012. Web. 03 Mar 2021.
Vancouver:
Lopez PLdC. Influência das proteínas XIAP e Survivina na resistência de Gliomas. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2012. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/142701.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lopez PLdC. Influência das proteínas XIAP e Survivina na resistência de Gliomas. [Thesis]. Universidade do Rio Grande do Sul; 2012. Available from: http://hdl.handle.net/10183/142701
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
2.
Flores, Débora Gazzana.
Receptor do peptídeo liberador de gastrina (GRPR) em gliomas : expressão, influência na proliferação celular e mecanismos de sinalização.
Degree: 2009, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/17341
► Gliomas correspondem à grande maioria de tumores do sistema nervoso central (SNC), sendo que os glioblastomas multiformes são os mais comuns e mais malignos. O…
(more)
▼ Gliomas correspondem à grande maioria de tumores do sistema nervoso central (SNC), sendo que os glioblastomas multiformes são os mais comuns e mais malignos. O tratamento destes tumores ainda é ineficiente, pois a sobrevida média de pacientes com glioblastomas é de um ano após o diagnóstico. A ressecção cirúrgica, quando possível, acompanhada de radioterapia e quimioterapia são o tratamento padrão. A tendência é que a quimioterapia assuma um papel cada vez maior, devido ao desenvolvimento de quimioterápicos mais seletivos e com menores efeitos prejudiciais. Um peptídeo que vem sendo bastante estudado como fator de crescimento em vários tipos de câncer é o peptídeo liberador de gastrina (GRP), que atua no seu receptor (GRPR). O GRP pertence à família de peptídeos semelhantes à bombesina, e tem sido mostrado que o GRPR é super-expresso em muitos tipos tumorais. Os agonistas de GRPR, GRP e bombesina, estimulam o crescimento de diferentes tipos de células tumorais. Os objetivos para este estudo foram avaliar a expressão de GRPR em gliomas, avaliar a influência da ativação e inibição do GRPR sobre o crescimento de células de
glioma e avaliar o envolvimento de efetores atuantes na sinalização celular desencadeada por GRPR, como fosfatidilinositol-3-hidroxicinase, PI3K. Foi encontrada a expressão de RNA mensageiro de GRPR, pela reação da transcriptase reversa seguida da reação em cadeia da polimerase (RT-PCR, reverse transcription polymerase chain reaction) e a expressão ao nível protéico, por imuno-histoquímica, em linhagens de gliomas de rato (C6) e de humanos (U-87 e U373). O efeito sobre a proliferação celular do RC-3095, um antagonista de GRPR, foi analisado nestas linhagens. RC-3095 inibiu a proliferação celular 48 horas após o tratamento, nas linhagens U-87 e C6, mas não na linhagem U-373. A inibição sobre a proliferação foi de 45% em C6, na dose 0,1 µM, e de 24% e 26% em U-87 nas doses de 0,1 µM e 1,0 µM, respectivamente. Células quiescentes tratadas com bombesina proliferaram 50% a mais em relação ao controle. Esta indução na proliferação celular foi prevenida pelo antagonista de GRPR. Quando as células quiescentes foram pré-tratadas com inibidor de PI3K, LY294002, a bombesina não foi capaz de induzir proliferação, sendo, portanto, esta indução na proliferação dependente de PI3K. Depois da análise nas linhagens, foi avaliada a expressão de GRPR em material derivado de biópsias de 34 pacientes. GRPR esteve amplamente expresso em 100% destes tumores. Não foi encontrada expressão de GRPR em células gliais em amostras de necrópsias de cérebro de pacientes sem neoplasia, enquanto que a expressão de GRPR em neurônios humanos foi observada. A forte expressão de GRPR nestes 34 tumores não teve relação significativa com o grau tumoral ou com a sobrevida do paciente. Considerando a hipótese de que gliomas, assim como outros tumores, podem se originar de uma pequena população de células-tronco (CT) dentro do tumor, avaliamos o efeito da bombesina sobre esta população de células que em tumores do SNC, formam neuro-esferas.…
Advisors/Committee Members: Roesler, Rafael.
Subjects/Keywords: Glioma; Gastrinas
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APA (6th Edition):
Flores, D. G. (2009). Receptor do peptídeo liberador de gastrina (GRPR) em gliomas : expressão, influência na proliferação celular e mecanismos de sinalização. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/17341
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Flores, Débora Gazzana. “Receptor do peptídeo liberador de gastrina (GRPR) em gliomas : expressão, influência na proliferação celular e mecanismos de sinalização.” 2009. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/17341.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Flores, Débora Gazzana. “Receptor do peptídeo liberador de gastrina (GRPR) em gliomas : expressão, influência na proliferação celular e mecanismos de sinalização.” 2009. Web. 03 Mar 2021.
Vancouver:
Flores DG. Receptor do peptídeo liberador de gastrina (GRPR) em gliomas : expressão, influência na proliferação celular e mecanismos de sinalização. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2009. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/17341.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Flores DG. Receptor do peptídeo liberador de gastrina (GRPR) em gliomas : expressão, influência na proliferação celular e mecanismos de sinalização. [Thesis]. Universidade do Rio Grande do Sul; 2009. Available from: http://hdl.handle.net/10183/17341
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Southern California
3.
Pyrko, Peter.
Targeting ER stress for malignant glioma therapy.
Degree: PhD, Pathobiology, 2007, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/324413/rec/6326
► Poor chemosensitivity and the development of chemoresistance remain major obstacles to successful chemotherapy of malignant gliomas. Recently, a new goal has been set: changing malignant…
(more)
▼ Poor chemosensitivity and the development of
chemoresistance remain major obstacles to successful chemotherapy
of malignant gliomas. Recently, a new goal has been set: changing
malignant
glioma from a deadly to a chronic disease. To this end a
multidisciplinary approach to malignant
glioma treatment has been
proposed, in which surgery, radiotherapy and chemotherapy are
combined in order to most benefit the patients. We identified
endoplasmic reticulum (ER) as a novel target and outlined specific
pathways within the ER stress response (ESR) that lead to malignant
glioma cell death/apoptosis.; First, we report that ER chaperone
GRP78 is significantly elevated in malignant
glioma. Knockdown of
GRP78 using siRNA in glioblastoma cell lines significantly lowers
their resistance to temozolomide (TMZ), the chemotherapeutic agent
of choice for treatment of malignant gliomas, as established by
colony survival assays.; Second, we show that dimethyl celecoxib
(DMC), an analog of celecoxib (Cxb) lacking its anti
cox-2-inhibitory function, potently induces endoplasmic reticulum
stress response (ESR) and subsequent apoptotic cell death in vitro
and in vivo by modulating intracellular free calcium levels.;
Third, we demonstrate that human immunodeficiency virus type 1
(HIV-1) protease inhibitors (PIs) cause efficient cell death in
various malignant
glioma cell lines in vitro via the potent
stimulation of the ESR. Furthermore, we show that treatment of
cells with PIs leads to aggresome formation and accumulation of
polyubiquitinated proteins, implying proteasome inhibition. We also
show that nelfinavir inhibits the growth of xenografted human
malignant
glioma, with concomitant induction of the pro-apoptotic
ER stress marker CHOP.; In conclusion, we present a way to modify
existing
glioma therapy by modulating a protective ER chaperone,
which we show protects from TMZ treatment. In addition, we
demonstrate that Cxb and PIs are effective as single anti
glioma
agents in an in vitro setting through their potent induction of ESR
pathways. Since both Cxb and PIs have been shown to have chemo and
radiosensitizing potential, we propose that their ability to
increase chemo and radiosensitivity of
glioma cells should be
investigated in further detail.
Advisors/Committee Members: Chen, Thomas C. (Committee Chair), Lee, Amy S. (Committee Member), Hofman, Florence M. (Committee Member), Chuong, Cheng-Ming (Committee Member).
Subjects/Keywords: glioma
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APA (6th Edition):
Pyrko, P. (2007). Targeting ER stress for malignant glioma therapy. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/324413/rec/6326
Chicago Manual of Style (16th Edition):
Pyrko, Peter. “Targeting ER stress for malignant glioma therapy.” 2007. Doctoral Dissertation, University of Southern California. Accessed March 03, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/324413/rec/6326.
MLA Handbook (7th Edition):
Pyrko, Peter. “Targeting ER stress for malignant glioma therapy.” 2007. Web. 03 Mar 2021.
Vancouver:
Pyrko P. Targeting ER stress for malignant glioma therapy. [Internet] [Doctoral dissertation]. University of Southern California; 2007. [cited 2021 Mar 03].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/324413/rec/6326.
Council of Science Editors:
Pyrko P. Targeting ER stress for malignant glioma therapy. [Doctoral Dissertation]. University of Southern California; 2007. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll127/id/324413/rec/6326
Kaunas University of Medicine
4.
Kaselytė,
Agnė.
Assay of epigenetics changes in SFRP2 gene in
grade II and grade III gliomas able to infleunce drug
effects.
Degree: Master, Pharmacy, 2010, Kaunas University of Medicine
URL: http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092807-14356
;
► Two different mechanisms participate in the loss of SFRPs expression in cancer cells: allelic loss and epigenetic silencing [1]. Methylation status in grade II and…
(more)
▼ Two different mechanisms participate in the
loss of SFRPs expression in cancer cells: allelic loss and
epigenetic silencing [1]. Methylation status in grade II and grade
III glioma differs. From previous studies which were performed in
Germany, 2010 by S. Gotze, M. Wolter, G. Reifenberger, O. Muller
and S. Sievers [2], it is known that in grade II glioma SFRP2 gene
supposed to be methylated (12.5% - 2 samples from 16 were
methylated) , while in grade III glioma commonly is unmethylated
(0% - from 14 samples no samples were methylated). SFRP2 gene mRNA
expression decreases during transformation of grade II to grade III
glioma, what’s why our researches were based on idea that SFRP2
expression level decreases because of methylation on this gene.
Secondly, another hypothesis we supported that SFRP2 gene could be
silenced due to loss of heterozygosity (LOH). IDH1 (isocitrate
dehydrogenase1) mutation occurs in tumor tissues while is absent in
normal tissue. Third hypothesis which we done, that IDH1 mutation
is a common event in malignant glioma tissues, and can be used for
glioma diagnostic as biomarker. Our object for this master thesis
was to find SFRP2 (Secreted frizzled related protein-2) gene
promoter methylation level in grade II and grade III gliomas. To
compare the results with the results publicated in previous
studies. The main goal of this thesis is to perform methylation
study of the promoter region of SFRP2 gene on 86 samples (42 WHO
grade II gliomas, 40 WHO grade III... [to full
text]
Centrinės nervų sistemos (CNS) gliomos yra
navikai, kilę iš paraminio nervinio audinio, esančio smegenyse. Yra
keletas skirtingų rūšių paraminio nervinio audinio ląstelių:
astrocitų, oligodendrocitų ir ependimocitų. Pirminiai centrinės
nervų sistemos navikai sudaro apie 2 % visų vėžių atveju. Tuo tarpu
gliomos sudaro 64-72% visų pirminių smegenų vėžių. Pirminiai CNS
navikai yra lyderiaujanti priežastis, sukelianti vaikų mirtis ir
ketvirtoje vietoje pagal svarbą įtakojanti suaugusiųjų (virš 54
metų) mirtis. Kasmet Jungtinėse Amerikos valstijose yra
registruojama apie 14 000 naujų gliomų atveju, t.y. 5 nauji
atvejai/ 100 000 gyventojų. Prancūzijoje šis skaičius yra 3000
naujų gliomų per metus, t.y. 8 nauji atvejai 100 000 gyventojų.
Pagal statistinius duomenis, Lietuvoje 2001 metais buvo
užregistruota 247 nauji pacientai sergantys gliomomis ( 7.1 nauji
atvejai / 100 000 gyventojų), o 2007 metais 211 naujų susirgimų
gliomomis ( 6.2 / 100 000 gyventojų). Pagal Pasaulinės Sveikatos
Organizacijos (PSO) priimtus kriterijus (pyktibiškumo laipsnį)
gliomos yra skirstomos į keturias stadijas : I- policitinė
astrocitoma ; II- astrocitoma, oligo-astrocytoma, oligodendroglioma
; III- anaplastinė astrocitoma, anaplastinė oligoastrocitoma,
anaplastinė oligodendrolglioma ; IV- glioblastoma. Daugumos atliktų
studijų metu nustatyta, jog gyvenimo prognozė labai priklauso nuo
piktybiškumo laipsnio. I stadijos gliomos nėra pavojingos, po
sėkmingo gydymo sergantieji išgyvena daug metų. II stadijos...
[toliau žr. visą tekstą]
Advisors/Committee Members: Gozé, Catherine (Master’s thesis supervisor), Briedis, Vitalis (Master’s thesis supervisor), Kežutytė, Toma (Master’s thesis reviewer), Rodovičius, Hiliaras (Master’s thesis reviewer), Borutaitė, Vilmantė (Master’s thesis reviewer), Ivanauskas, Liudas (Master’s degree committee chair), Savickas, Arūnas (Master’s degree committee member), Janulis, Valdimaras (Master’s degree committee member), Radžiūnas, Raimondas (Master’s degree committee member), Tarasevičius, Eduardas (Master’s degree committee member), Briedis, Vitalis (Master’s degree committee member), Pečiūra, Rimantas (Master’s degree committee member), Ramanauskienė, Kristina (Master’s degree committee member), Gumbrevičius, Gintautas (Master’s degree committee member), Ževžikovienė, Augusta (Master’s degree session secretary).
Subjects/Keywords: Glioma; Methylation; SFRP2 gene; Glioma; SFRP2; Methylation
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APA (6th Edition):
Kaselytė,
Agnė. (2010). Assay of epigenetics changes in SFRP2 gene in
grade II and grade III gliomas able to infleunce drug
effects. (Masters Thesis). Kaunas University of Medicine. Retrieved from http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092807-14356 ;
Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
Chicago Manual of Style (16th Edition):
Kaselytė,
Agnė. “Assay of epigenetics changes in SFRP2 gene in
grade II and grade III gliomas able to infleunce drug
effects.” 2010. Masters Thesis, Kaunas University of Medicine. Accessed March 03, 2021.
http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092807-14356 ;.
Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
MLA Handbook (7th Edition):
Kaselytė,
Agnė. “Assay of epigenetics changes in SFRP2 gene in
grade II and grade III gliomas able to infleunce drug
effects.” 2010. Web. 03 Mar 2021.
Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
Vancouver:
Kaselytė,
Agnė. Assay of epigenetics changes in SFRP2 gene in
grade II and grade III gliomas able to infleunce drug
effects. [Internet] [Masters thesis]. Kaunas University of Medicine; 2010. [cited 2021 Mar 03].
Available from: http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092807-14356 ;.
Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
Council of Science Editors:
Kaselytė,
Agnė. Assay of epigenetics changes in SFRP2 gene in
grade II and grade III gliomas able to infleunce drug
effects. [Masters Thesis]. Kaunas University of Medicine; 2010. Available from: http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092807-14356 ;
Note: this citation may be lacking information needed for this citation format:
Author name may be incomplete
Universidade do Rio Grande do Sul
5.
Ledur, Pítia Flores.
Prevalência de OPCS (células precursoras de oligodendrócitos) em gliomas é determinante para o estabelecimento de condições autênticas de cultivo e para a identificação de alvos terapêuticos.
Degree: 2015, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/141886
► Glioblastomas Multiformes (GBM) são tumores do Sistema Nervoso Central com altas taxas de invasibilidade e grande resistência a quimio e radioterapias, cuja origem foi inicialmente…
(more)
▼ Glioblastomas Multiformes (GBM) são tumores do Sistema Nervoso Central com altas taxas de invasibilidade e grande resistência a quimio e radioterapias, cuja origem foi inicialmente atribuída a células tronco neurais (NSCs). Mais recentemente, trabalhos de rastreamento de linhagem celular (lineage tracing) revelaram que a célula de origem em GBM, ao menos para certos subtipos, é na verdade a célula precursora de oligodendrócitos (OPC). A identificação da origem do tumor pode auxiliar na compreensão da doença e no desenvolvimento de terapias mais eficazes. OPCs são células com grande capacidade migratória e constituem a população de células cerebrais mais proliferativamente ativa, características compatíveis com a biologia de glioblastomas. Neste trabalho criamos uma meta-assinatura de OPCs que, quando aplicada a amostras populacionais e de céulas únicas de GBMs humanos, indica a presença de características de OPCs em virtualmente todos os tumores, principalmente dentre os do subtipo Proneural. Apesar disso, o cultivo de GBMs in vitro tem sido tradicionalmente realizado em meio próprio de NSCs, como forma de preservar as características originais do tumor. Entretanto, no caso de OPC ser a verdadeira célula de origem, o ideal seria a utilização de meio próprio para esta célula. Utilizamos meio padrão para NSCs e meio para OPCs em linhagens de camundongo bem como em biópsias humanas. Meio de NSCs provoca alterações morfológicas e em marcadores, enquanto meio de OPCs mantém as células mais similares ao tumor que lhes deu origem. Principalmente, meio de NSCs reduz o potencial tumorigênico das células in vivo, e faz com que alvos errôneos sejam identificados na resposta a drogas, devido à expressão de marcadores nãoautênticos pra célula de origem. A análise de gliomas humanos indica que a população proliferativamente ativa expressa marcadores de OPCs, independentemente do subtipo em que o tumor foi classificado. Assim, concluímos que o papel de OPCs no desenvolvimento de GBMs é mais importante do que se imaginava, e que a utilização de meio de cultivo baseado na célula de origem é fundamental para a correta identificação de alvos terapêuticos.
Glioblastoma Multiformes (GBM) are Central Nervous System tumors that present high invasibility rates and great resistance to chemo- and radiotherapies, whose origin was initially accredited to Neural Stem Cells (NSCs). More recently, papers employing lineage tracing revealed that the cell of origin in GBM, at least for certain subtypes, is in fact an Oligodendrocyte Precursor Cell (OPC). The elucidation about the origin of a tumor can help in the disease comprehension and in the development of more efficient therapies. OPCs are naturally migratory cells and constitute the most actively proliferating cell population in the brain, characteristics that are compatible with glioblastoma biology. In this work we created an OPC meta-signature that, once applied to populational and single-cell data in GBM, reveals the presence of OPC features in virtually every tumor, mainly from the…
Advisors/Committee Members: Lenz, Guido.
Subjects/Keywords: Glioma; Cérebro; Oligodendroglioma
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Manager
APA (6th Edition):
Ledur, P. F. (2015). Prevalência de OPCS (células precursoras de oligodendrócitos) em gliomas é determinante para o estabelecimento de condições autênticas de cultivo e para a identificação de alvos terapêuticos. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/141886
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ledur, Pítia Flores. “Prevalência de OPCS (células precursoras de oligodendrócitos) em gliomas é determinante para o estabelecimento de condições autênticas de cultivo e para a identificação de alvos terapêuticos.” 2015. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/141886.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ledur, Pítia Flores. “Prevalência de OPCS (células precursoras de oligodendrócitos) em gliomas é determinante para o estabelecimento de condições autênticas de cultivo e para a identificação de alvos terapêuticos.” 2015. Web. 03 Mar 2021.
Vancouver:
Ledur PF. Prevalência de OPCS (células precursoras de oligodendrócitos) em gliomas é determinante para o estabelecimento de condições autênticas de cultivo e para a identificação de alvos terapêuticos. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2015. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/141886.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ledur PF. Prevalência de OPCS (células precursoras de oligodendrócitos) em gliomas é determinante para o estabelecimento de condições autênticas de cultivo e para a identificação de alvos terapêuticos. [Thesis]. Universidade do Rio Grande do Sul; 2015. Available from: http://hdl.handle.net/10183/141886
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
6.
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
► 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)
▼ 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 (6th 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 (16th 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 March 03, 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 (7th Edition):
Tamajusuku, Alessandra Sayuri Kikuchi. “Expressão e funcionalidade do receptor P2X7 em linhagem de glioma de camundongo GL261.” 2010. Web. 03 Mar 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 Mar 03].
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
7.
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 ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th 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 (16th 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 March 03, 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 (7th Edition):
Kipper, Franciele Cristina. “Novas abordagens terapêuticas para glioblastoma baseadas no ensaio de resposta a terapias em culturas derivadas de pacientes.” 2017. Web. 03 Mar 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 Mar 03].
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
University of Toronto
8.
Mistry, Matthew.
BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma.
Degree: 2014, University of Toronto
URL: http://hdl.handle.net/1807/68561
► This thesis sought to uncover genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG) and to define transformation risk…
(more)
▼ This thesis sought to uncover genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG) and to define transformation risk using a population-based cohort (n=888) of PLGG with long clinical follow-up. We hypothesize early somatic exonic alterations, which are poorly understood, contribute to transformation. sHGG were observed in 3.2% of patients. BRAF and CDKN2A alterations were observed in 39% and 57% of sHGG respectively. All BRAF and 80% of CDKN2A alterations could be traced back to patient-matched PLGG counterparts. BRAF V600E distinguished secondary from primary HGG (p=0.0023), while BRAF and CDKN2A alterations were rarely observed in non-transformed PLGG (p
M.Sc.
Advisors/Committee Members: Tabori, Uri, Medical Science.
Subjects/Keywords: Glioma; Pediatric; 0306
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APA ·
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Export
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APA (6th Edition):
Mistry, M. (2014). BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/68561
Chicago Manual of Style (16th Edition):
Mistry, Matthew. “BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma.” 2014. Masters Thesis, University of Toronto. Accessed March 03, 2021.
http://hdl.handle.net/1807/68561.
MLA Handbook (7th Edition):
Mistry, Matthew. “BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma.” 2014. Web. 03 Mar 2021.
Vancouver:
Mistry M. BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma. [Internet] [Masters thesis]. University of Toronto; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1807/68561.
Council of Science Editors:
Mistry M. BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma. [Masters Thesis]. University of Toronto; 2014. Available from: http://hdl.handle.net/1807/68561
Victoria University of Wellington
9.
Hunn, Martin Kent.
Improving immunotherapy for high grade glioma.
Degree: 2015, Victoria University of Wellington
URL: http://hdl.handle.net/10063/4869
► Glioblastoma multiforme (GBM) is a malignant primary brain tumour that is almost always fatal. Conventional treatment modalities are limited by toxicity. T cell-based immunotherapy is…
(more)
▼ Glioblastoma multiforme (GBM) is a malignant primary brain tumour that is almost always fatal. Conventional treatment modalities are limited by toxicity. T cell-based immunotherapy is a promising alternative that has the potential to specifically target tumour cells.
The author of this thesis was a principal investigator for a recently completed Phase I clinical trial in which patients with recurrent GBM were treated with surgery, dendritic cell-based immunotherapy and chemotherapy. In addition to conducting the trial in collaboration with others, the author used peripheral blood mononuclear cells from trial participants to assess anti-tumour immune responses before and after treatment. A broad correlation was observed between clinical outcome and anti-tumour immunity, with sustained progression-free survival occurring in two patients with baseline responses that persisted or increased after treatment. However, the overall clinical benefit was modest. For progress to be made, there is a need to develop a more potent vaccine.
With this in mind, a novel “
Glioma-Gal” vaccine was devised and tested in an orthotopic mouse model of
glioma, This simple vaccine consisted of irradiated autologous tumour cells pulsed with the glycolipid alpha-galactosylceramide, an immunoadjuvant that induces invariant Natural Killer T cells to licence endogenous dendritic cells. The vaccine was shown to be effective in a therapeutic setting when accompanied by depletion of regulatory T cells. Mechanistically, vaccine efficacy was dependent on CD4 T cells and the mediastinal lymph node was shown to be an important site of T cell priming. It was further shown that components of the immune system necessary for the vaccine to work were present and competent in a cohort of GBM patients.
The final chapters explore the idea of enhancing the therapeutic benefit of this vaccine by targeting certain tumour cell subsets or phenotypes. Cancer stem cells (CSC) are proposed to be a subset of tumour cells with a unique capacity for initiating and maintaining tumours. Eliminating these cells may therefore be both necessary and sufficient to achieve cure. Using the same mouse model, a variety of methods were assessed for their ability to isolate or enrich for a CSC subset. Of these, culture in serum-free medium in the presence of certain growth factors was shown to enrich for a more stem cell-like phenotype. However, a vaccine constructed from these stem cell-like cells was not more effective than the standard vaccine. Next, the author tested the hypothesis that a vaccine manipulated to target chemoresistant cells would be more effective than standard vaccine when used in combination with chemotherapy. However, the modified vaccine showed no advantage over standard vaccine in this model. In the course of these experiments, synergy was observed between the vaccine and the chemotherapy agent doxorubicin. The mechanism responsible for this supra-additive effect remains undetermined but is most likely due to an immunomodulatory effect of low dose doxorubicin.…
Advisors/Committee Members: Hermans, Ian.
Subjects/Keywords: Glioma; Immunotherapy; Vaccine
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APA ·
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Manager
APA (6th Edition):
Hunn, M. K. (2015). Improving immunotherapy for high grade glioma. (Doctoral Dissertation). Victoria University of Wellington. Retrieved from http://hdl.handle.net/10063/4869
Chicago Manual of Style (16th Edition):
Hunn, Martin Kent. “Improving immunotherapy for high grade glioma.” 2015. Doctoral Dissertation, Victoria University of Wellington. Accessed March 03, 2021.
http://hdl.handle.net/10063/4869.
MLA Handbook (7th Edition):
Hunn, Martin Kent. “Improving immunotherapy for high grade glioma.” 2015. Web. 03 Mar 2021.
Vancouver:
Hunn MK. Improving immunotherapy for high grade glioma. [Internet] [Doctoral dissertation]. Victoria University of Wellington; 2015. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10063/4869.
Council of Science Editors:
Hunn MK. Improving immunotherapy for high grade glioma. [Doctoral Dissertation]. Victoria University of Wellington; 2015. Available from: http://hdl.handle.net/10063/4869
University of Minnesota
10.
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 ·
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MLA ·
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CSE |
Export
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APA (6th 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 (16th Edition):
Becker, Chani. “Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma.” 2016. Doctoral Dissertation, University of Minnesota. Accessed March 03, 2021.
http://hdl.handle.net/11299/182319.
MLA Handbook (7th Edition):
Becker, Chani. “Molecular Mechanisms Underlying the Failures of Therapeutics in the Treatment of Malignant Glioma.” 2016. Web. 03 Mar 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 Mar 03].
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
Universidade do Rio Grande do Sul
11.
Villodre, Emilly Schlee.
Estratégias farmacológicas para a redução da população de células tronco tumorais em glioblastoma.
Degree: 2012, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/72311
► Glioblastomas são os tumores mais agressivos do Sistema Nervoso Central (SNC). Caracterizam-se por sua alta invasibilidade, proliferação, altos índices de recorrência e morte, assim como…
(more)
▼ Glioblastomas são os tumores mais agressivos do Sistema Nervoso Central (SNC). Caracterizam-se por sua alta invasibilidade, proliferação, altos índices de recorrência e morte, assim como quimio e radiorresistência. Tumores sólidos apresentam uma organização hierárquica, em que há uma pequena população de células tronco tumorais (CSCs) ou células iniciadoras de tumor (CICs). Essas células são capazes de repopular o tumor, que leva à recorrência. CSCs caracterizam-se por realizar também a mitose assimétrica, na qual parte das células continuam como CSCs e a outra parte sofre diferenciação. Essas células diferenciadas são incapazes de repopular o tumor, uma vez que perderam a sua capacidade tronco. CSCs mostraram ser relativamente resistentes as terapias anticâncer tradicionais como quimio e/ou radioterapia. Doxorrubicina (Doxo) é um agente anticâncer usado em diversos tipos de tumor e atua formando adutos no DNA e também inibindo a ação da topoisomerase II. Dependendo da concentração utilizada de Doxo, diferentes efeitos são observados; por exemplo, baixas doses (100 nM) levam à senescência celular, enquanto que altas doses (10 μM) levam à apoptose. Temozolomida (Tmz) é um anti-tumoral utilizado na terapia de diversos tumores, inclusive gliomas. Resveratrol (Rsv) é um polifenol encontrado em diversas plantas, como a uva, e possui efeitos como: neuroproteção, antiinflamatório, anti-oxidante, proteção cardíaca, entre outros. Nosso objetivo foi avaliar a influência do efeito dessas três drogas nas CSCs derivadas de glioblastoma humano. Realizou-se o ensaio de formação de esferas, um indicador da presença de CSCs, citometria de fluxo para Oct4 e Nanog e ensaio de senescência. Nossos ensaios utilizaram a linhagem U87 e dois tipos diferentes de meio de cultura. O primeiro continha DMEM Low Glucose com SFB e o segundo, um meio de cultura para células tronco (SCM), contendo DMEM F12 suplementado com FGF (fator de crescimento fibroblástico), EGF (fator de crescimento epidermal), LIF (fator inibidor de leucemia) e B27. Os tratamentos realizados utilizaram Doxo 1 e 10 nM; Tmz 5 μM e Rsv 1, 10 e 30 μM. O número de esferas formadas foi reduzido tanto em Doxo 1 quanto em 10 nM quando SFB foi utilizado. Doxo 1 não alterou o número de células Oct4 e Nanog positivas enquanto que Doxo 10 nM reduziu. Ambas as doses induziram senescência. Tmz reduziu o número de esferas formadas e também a porcentagem de células Oct4 e Nanog positivas. Usando SCM, observamos que Doxo e Tmz reduziram o número de esferas e a porcentagem de células Nanog e Oct4 positivas. Rsv 10 μM reduziu o número de esferas formadas enquanto que Rsv 30 μM reduziu o número de células positivas para CD133 e Oct4 com meio com SFB. Nossos resultados sugerem que Doxo 10 nM possui um melhor efeito nas CSCs do que Doxo 1 nM. Doxo 10 nM, além de reduzir o número de esferas, reduziu a porcentagem dos marcadores de CSCs e também induziu senescência celular na presença de SFB. Tmz e Rsv apresentaram resultados semelhantes à Doxo 10 nM.
Glioblastomas are the most aggressive tumors…
Advisors/Committee Members: Lenz, Guido.
Subjects/Keywords: Glioma; Temozolamida; Resveratrol; Doxorrubicina
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APA (6th Edition):
Villodre, E. S. (2012). Estratégias farmacológicas para a redução da população de células tronco tumorais em glioblastoma. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/72311
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Villodre, Emilly Schlee. “Estratégias farmacológicas para a redução da população de células tronco tumorais em glioblastoma.” 2012. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/72311.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Villodre, Emilly Schlee. “Estratégias farmacológicas para a redução da população de células tronco tumorais em glioblastoma.” 2012. Web. 03 Mar 2021.
Vancouver:
Villodre ES. Estratégias farmacológicas para a redução da população de células tronco tumorais em glioblastoma. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2012. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/72311.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Villodre ES. Estratégias farmacológicas para a redução da população de células tronco tumorais em glioblastoma. [Thesis]. Universidade do Rio Grande do Sul; 2012. Available from: http://hdl.handle.net/10183/72311
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
12.
Vargas, José Eduardo.
Estudos in vitro e in silico dos mecanismos moleculares da senescência celular em glioblastomas.
Degree: 2013, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/78129
► Os gliomas representam a maioria dos tumores do sistema nervoso central, sendo o glioblastoma o mais maligno entre eles. O tratamento destes tumores ainda é…
(more)
▼ Os gliomas representam a maioria dos tumores do sistema nervoso central, sendo o glioblastoma o mais maligno entre eles. O tratamento destes tumores ainda é ineficiente e a sobrevida média dos pacientes é de aproximadamente um ano após o diagnóstico. A remoção cirúrgica, quando possível, acompanhada de radioterapia e quimioterapia é o tratamento padrão. A tendência é que a quimioterapia assuma um papel mais importante, uma vez que possibilita a ativação de mecanismos endógenos antitumorais, como senescência celular. Este mecanismo possui potencial de induzir a perda irreversível da capacidade da divisão de células tumorais. O resveratrol e a quercetina, dois polifenóis naturais, induzem senescência em diferentes linhagens tumorais, incluindo os glioblastomas. Ambos têm efeitos pleiotrópicos e induzem a ativação de vários alvos moleculares, sendo SIRT1, um desses alvos. SIRT1 é uma histona desacetilase (HDAC) associada ao desenvolvimento de vários tipos de tumores. Por este motivo, foi avaliada a indução de senescência em células de glioblastomas pelo resveratrol e quercetina combinados com butirato de sódio, um inibidor de HDAC classe I e II. Os resultados mostram um efeito combinado do butirato de sódio e estes polifenóis para induzir a senescência nas linhagens celulares U87 e C6, mas não em astrócitos normais de ratos. Os co-tratamentos induzem perda de capacidade proliferativa e aumento do número de células positivas para β-galactosidase, um marcador de senescência. Estes resultados foram acompanhados de parada no ciclo celular na fase G2 na linhagem U87, mas nenhum efeito foi observado sobre o ciclo de células C6. A análise por Western Blot sugere o aumento do supressor tumoral p21 após co-tratamentos. Além disso, o co-tratamento com quercetina e butirato de sódio aumenta a produção de espécies reativas de oxigênio, mas não os níveis de gama-H2AX (um marcador de dano). Estes dados sugerem que o butirato de sódio em combinação com os polifenóis tem potencial terapêutico para a supressão de glioblastomas. Por outro lado, um dos problemas em biologia e medicina é entender como células pré-cancerosas e cancerosas entram em senescência ou conseguem evitá-la. A chave para a compreensão da indução da senescência e do seu bypass é a ativação da enzima telomerase (TERT), presente em 85 % dos tumores. Na segunda parte desta tese, ferramentas de biologia de sistemas foram utilizadas para projetar uma rede câncer e senescência humana com o objetivo de estudar a relação entre senescência e câncer (incluindo glioblastoma). Os resultados mostram uma interação direta entre TERT e oncogenes como MYC, E2F1, AKT1 e ABL1, que podem induzir a senescência. Além disso, uma associação metabólica forte entre estes oncogenes e sua capacidade de induzir senescência foi mostrada através de análise por ontologia gênica. Estes oncogenes também atuam como reguladores da transcrição e/ou pós-transcrição da subunidade catalítica de TERT. Resultados obtidos a partir da análise de centralidade da rede juntamente com dados de microarranjos…
Advisors/Committee Members: Lenz, Guido.
Subjects/Keywords: Glioma; Temozolamida; Resveratrol; Senescência
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APA ·
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APA (6th Edition):
Vargas, J. E. (2013). Estudos in vitro e in silico dos mecanismos moleculares da senescência celular em glioblastomas. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/78129
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Vargas, José Eduardo. “Estudos in vitro e in silico dos mecanismos moleculares da senescência celular em glioblastomas.” 2013. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/78129.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Vargas, José Eduardo. “Estudos in vitro e in silico dos mecanismos moleculares da senescência celular em glioblastomas.” 2013. Web. 03 Mar 2021.
Vancouver:
Vargas JE. Estudos in vitro e in silico dos mecanismos moleculares da senescência celular em glioblastomas. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2013. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/78129.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Vargas JE. Estudos in vitro e in silico dos mecanismos moleculares da senescência celular em glioblastomas. [Thesis]. Universidade do Rio Grande do Sul; 2013. Available from: http://hdl.handle.net/10183/78129
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
13.
Junior, Mário Luiz Conte da Frota.
A esponja marinha Polymastia janeirensis como fonte de novos fármacos contra o câncer.
Degree: 2008, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/13832
► Nos últimos anos, o ambiente marinho tem sido pesquisado para uma variedade de compostos com diferentes atividades biológicas. Entre todos os organismos marinhos, as esponjas…
(more)
▼ Nos últimos anos, o ambiente marinho tem sido pesquisado para uma variedade de compostos com diferentes atividades biológicas. Entre todos os organismos marinhos, as esponjas representam uma das fontes mais promissoras de novas drogas contra o câncer. Embora o litoral brasileiro seja o segundo mais extenso depois da Austrália, existem poucos estudos com esponjas marinhas coletadas no Brasil objetivando a descoberta de novos fármacos. Nesse trabalho, nós investigamos os efeitos de diferentes extratos da esponja marinha Polymastia janeirensis na viabilidade de uma linhagem de glioma humano (U138MG). Além disso, avaliamos a seletividade do efeito, caracterizamos os mecanismos envolvidos no processo de morte celular e isolamos as frações ativas responsáveis pelas atividades encontradas. De uma maneira geral, um efeito antiproliferativo foi observado quando as células forma expostas aos extratos (aquoso e orgânico) da esponja. Entretanto, as doses mais altas (50 e 100 μg/ml) foram extremamente citotóxicas, inibindo mais de 80% a proliferação e a viabilidade celular. Além disso, uma morte celular por necrose foi observada com essas doses, enquanto uma morte celular por apoptose foi observada com a dose mais baixa (10 μg/ml). Nós também demonstramos que a rota apoptótica ativada em resposta aos extratos era a via intrínseca, e que a produção de radicais livres estava, pelo menos em parte, relacionada ao efeito bifásico (apoptose ou necrose) encontrado. Os resultados aqui apresentados demonstram a existência de uma seletividade do efeito citotóxico, uma vez que os extratos não induziram morte em culturas de astrócitos na dose em que foi observada morte por apoptose nos gliomas. Ademais, uma potente atividade apoptótica foi observada com o composto ativo isolado da esponja marinha alvo desse estudo. Os nossos resultados sugerem que a esponja marinha alvo desse estudo pode ser considerada uma boa fonte para o desenvolvimento de novas drogas contra o câncer.
Over the last years, the marine environment has been screened for a variety of compounds with different biological activities. Among all marine organisms, sponges represent one of the most promising source of new drug leads for cancer. Although Brazil has the second most extensive coastline after Australia, there are just few reports in which the authors have screened Brazilian sponge extracts for biological activities. In this work, we examine the anti-proliferative effects of crude extracts of the marine sponge Polymastia janeirensis in the U138MG human glioma cell line. Moreover, we investigate the effects on selective cytotoxicity in the glioma cells in comparison with a normal, untransformed cell culture, as well as examine the apoptotic pathway activated in response to treatments with extracts of P. janeirensis. Yet, we performed a bioassayguided fractionation to found the active fractions in the extracts. Exposure of glioma cells to treatments resulted in cell number decrease with both aqueous and organic extracts. Moreover, sponge extracts reduced glioma cell…
Advisors/Committee Members: Moreira, Jose Claudio Fonseca.
Subjects/Keywords: Polymastia janeirensis; Farmacologia; Glioma; Câncer
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APA ·
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APA (6th Edition):
Junior, M. L. C. d. F. (2008). A esponja marinha Polymastia janeirensis como fonte de novos fármacos contra o câncer. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/13832
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Junior, Mário Luiz Conte da Frota. “A esponja marinha Polymastia janeirensis como fonte de novos fármacos contra o câncer.” 2008. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/13832.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Junior, Mário Luiz Conte da Frota. “A esponja marinha Polymastia janeirensis como fonte de novos fármacos contra o câncer.” 2008. Web. 03 Mar 2021.
Vancouver:
Junior MLCdF. A esponja marinha Polymastia janeirensis como fonte de novos fármacos contra o câncer. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2008. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/13832.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Junior MLCdF. A esponja marinha Polymastia janeirensis como fonte de novos fármacos contra o câncer. [Thesis]. Universidade do Rio Grande do Sul; 2008. Available from: http://hdl.handle.net/10183/13832
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
14.
Ledur, Pítia Flores.
Células tronco tumorais e o sistema purinérgico.
Degree: 2009, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/17066
► Gliomas são os tumores mais comuns no SNC, apresentando altas taxas de invasibilidade e proliferação, resistência à quimio e radioterapias, e elevados índices de recorrência…
(more)
▼ Gliomas são os tumores mais comuns no SNC, apresentando altas taxas de invasibilidade e proliferação, resistência à quimio e radioterapias, e elevados índices de recorrência e morte. As células-tronco tumorais constituem uma minoria dentre as células do tumor, apresentam características de células tronco neurais podendo sofrer diferenciação e auto-renovação. Linhagens celulares de gliomas, como U87, são capazes de produzir tumoresferas quando em alta confluência, que são similares às neuroesferas produzidas por células tronco neurais, e são ricas em células tronco tumorais (CSCs). Em gliomas, CSCs podem ser identificadas por expressarem o marcador de superfície CD133. Receptores purinérgicos estão envolvidos em diversos processos biológicos. O ATP induz respostas celulares como proliferação e diferenciação, e a degradação deste nucleotídeo por células de glioma é lenta, o que resulta no seu acúmulo no espaço extracelular. O objetivo deste trabalho é identificar a população de CSCs em U87 bem como o efeito do ATP na formação de esferas, expressão do marcador CD133, a expressão de genes de receptores purinérgicos e de genes marcadores de células diferenciadas (GLAST e CAMKII) e de células indiferenciadas (CD133 e OCT-4). U87 foram mantidas em condições padrão com 5% de SFB e esferas foram obtidas através de crescimento sobre ágar 1%. RNA total foi extraído de esferas e monocamada, e os genes de interesse foram amplificados em reação de RT-PCR com primers específicos. Esferas apresentam uma maior expressão de CD133, visto por citometria e imunodetecção. O mRNA de OCT-4 também foi mais expresso em esferas do que em monocamada, que expressa mais CAMKII e GLAST. ATP em uma concentração final de 100 µM reduz significativamente o número de esferas formadas (P<0.05) durante um período de 7 dias e também reduz a expressão de CD133. Dentre os receptores purinérgicos, a expressão de P2X4 foi maior em esferas, e P2X6 em monocamada. Estes resultados indicam que as esferas possuem componentes de células tronco e que a sinalização purinérgica pode estar envolvida em importantes aspectos da biologia de CSCs.
Glioblastoma multiformes are the most aggressive tumors in the CNS and are characterized by high invasion and proliferation rates, as well as for being resistant to chemo and radiotherapies. This leads to one of the worst prognosis among cancers. Cancer stem cells (CSCs) are scarce among the tumor cells, but can undergo differentiation and self-renewal, being fundamental for tumor maintenance. Tumorspheres, which resemble neurospheres, can grow in glioma cell cultures and are rich in CSC. Additionally, CSCs seem to be more resistant to radiotherapy and strategies aimed at differentiating these stem cells have potential to produce less aggressive and more efficient treatment regimes. CSCs have been identified in different tumor types as well as in established cell lines such as the human glioma cell line U87, and are characterized by the presence of the CD133 glycoprotein. Purinergic receptors are stimulated by nucleotides and…
Advisors/Committee Members: Lenz, Guido.
Subjects/Keywords: Glioma; Biologia molecular; Biologia celular
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APA ·
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MLA ·
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APA (6th Edition):
Ledur, P. F. (2009). Células tronco tumorais e o sistema purinérgico. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/17066
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ledur, Pítia Flores. “Células tronco tumorais e o sistema purinérgico.” 2009. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/17066.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ledur, Pítia Flores. “Células tronco tumorais e o sistema purinérgico.” 2009. Web. 03 Mar 2021.
Vancouver:
Ledur PF. Células tronco tumorais e o sistema purinérgico. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2009. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/17066.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ledur PF. Células tronco tumorais e o sistema purinérgico. [Thesis]. Universidade do Rio Grande do Sul; 2009. Available from: http://hdl.handle.net/10183/17066
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
15.
Zamin, Lauren Lúcia.
Resveratrol e quercetina : avaliação da atividade antitumoral e dos mecanismos de ação em linhagens de gliomas in vitro e em um modelo de implante de gliomas in vivo.
Degree: 2010, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/25145
► Dentre os tumores cerebrais primários, o glioblastoma (GBM) é o mais comum, apresentando alta taxa de mortalidade e morbidade. O tratamento convencional desses tumores tem…
(more)
▼ Dentre os tumores cerebrais primários, o glioblastoma (GBM) é o mais comum, apresentando alta taxa de mortalidade e morbidade. O tratamento convencional desses tumores tem surtido pouco efeito, com alta taxa de recorrência e progressão da doença. Neste trabalho, buscou-se aprimorar o conhecimento sobre a biologia destes tumores e, utilizando polifenóis amplamente distribuídos na natureza, procurar novas formas de terapia. Nesta tese demonstrou-se que o tratamento com resveratrol e quercetina diminuíram o número de células de maneira tempo e dose dependente em linhagens de GBM humano (U87 e U138), de camundongo (GL261) e de rato (C6), sendo a última a mais sensível e a utilizada neste trabalho. Esse efeito foi observado apenas em linhagens tumorais, não ocorrendo em cultura primária de astrócitos. Resveratrol em altas doses (50 M) induziu apoptose, necrose e parada no ciclo celular. Agudamente, o tratamento com doses baixas de resvetraol (10 M) mais quercetina (25 M) – 24 a 72 h - induziu apoptose, enquanto cronicamente – 12 dias – induziu senescência celular. Esses efeitos não ocorreram quando esses compostos foram utilizados isoladamente. Até então, a indução de senescência pela combinação destes compostos não tinha sido demonstrada. Como provável mecanismo de ação demonstrou-se que o tratamento combinado destes polifenóis induziu senescência através da indução de quebra dupla de DNA e ativação da via da p53. O tratamento com as drogas isoladas não induziu dano ao DNA. A partir de então, investigou-se o efeito destes compostos em um modelo in vivo de implante de gliomas em ratos. Inesperadamente, a quercetina (50 mg/kg/dia intraperitoneal (i.p.)) induziu aumento do volume tumoral, o que não foi observado com o resveratrol (30 mg/kg/dia i.p.) e com a combinação de resveratrol mais quercetina. Para explicar este efeito prevalente do resveratrol nós elaboramos as seguintes hipóteses: 1. necrose/angiogênese: por diminuir a necrose o resveratrol pode ter diminuido a angiogênese, que pode ter sido aumentada pela quercetina; 2. Modulação do sistema imunológico: a quercetina foi capaz de imunussuprimir os animais (por diminuir a proliferação das células T-periféricas após estimulação por fitohemaglutinina e concanavalina A) e a combinação de resveratrol mais quercetina aumentou a estimulação das células T periféricas. Hipoteticamente, atribuiu-se a divergência entre o efeito antitumoral in vitro e in vivo à ausência de senescência neste último, o que pode ser indicado pela ausência da diminuição do índice mitótico. Além disso, o estresse da cultura, um fator indutor de senescência celular, é perdido no modelo in vivo. Com base nos resultados aqui apresentados concluí-se que o resveratrol e a quercetina possuem um potencial antitumoral em gliomas in vitro que precisa de estudos mais aprofundados in vivo para melhorar o conhecimento dos efeitos exercidos por estes afim de se estabelecer uma dose segura para o tratamento dessa e de outras doenças para as quais essas moléculas possam vir a ser utilizadas.
Glioblastoma…
Advisors/Committee Members: Lenz, Guido.
Subjects/Keywords: Resveratrol; Quercetina; Atividade antitumoral; Glioma
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APA ·
Chicago ·
MLA ·
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CSE |
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APA (6th Edition):
Zamin, L. L. (2010). Resveratrol e quercetina : avaliação da atividade antitumoral e dos mecanismos de ação em linhagens de gliomas in vitro e em um modelo de implante de gliomas in vivo. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/25145
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Zamin, Lauren Lúcia. “Resveratrol e quercetina : avaliação da atividade antitumoral e dos mecanismos de ação em linhagens de gliomas in vitro e em um modelo de implante de gliomas in vivo.” 2010. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/25145.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Zamin, Lauren Lúcia. “Resveratrol e quercetina : avaliação da atividade antitumoral e dos mecanismos de ação em linhagens de gliomas in vitro e em um modelo de implante de gliomas in vivo.” 2010. Web. 03 Mar 2021.
Vancouver:
Zamin LL. Resveratrol e quercetina : avaliação da atividade antitumoral e dos mecanismos de ação em linhagens de gliomas in vitro e em um modelo de implante de gliomas in vivo. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2010. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/25145.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Zamin LL. Resveratrol e quercetina : avaliação da atividade antitumoral e dos mecanismos de ação em linhagens de gliomas in vitro e em um modelo de implante de gliomas in vivo. [Thesis]. Universidade do Rio Grande do Sul; 2010. Available from: http://hdl.handle.net/10183/25145
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
16.
Braganhol, Elizandra.
Sistema purinérgico e a progressão dos gliomas : avaliação de parâmetros proliferativos e inflamatórios.
Degree: 2010, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/26487
► Os nucleotídeos extracelulares modulam uma variedade de ações biológicas via ativação de receptores purinérgicos. Esses efeitos são controlados pela ação de ectonucleotidases, tais como as…
(more)
▼ Os nucleotídeos extracelulares modulam uma variedade de ações biológicas via ativação de receptores purinérgicos. Esses efeitos são controlados pela ação de ectonucleotidases, tais como as E-NTPDases e a ecto-5´-NT/CD73, as quais hidrolisam o ATP até adenosina no meio extracelular. Alterações no sistema purinérgico podem estar envolvidas na progressão dos gliomas. O ATP induz a proliferação celular dos gliomas e, ao contrário dos astrócitos, gliomas apresentam baixa expressão das E-NTPDases, particularmente da NTPDase2. Assim, a restauração da atividade ATPásica nesses tumores poderia ser uma estratégia para prevenir as ações mediadas pelo ATP. De acordo com essa idéia, a coinjeção de apirase/NTPDase1, uma enzima depletora de ATP, e gliomas diminuiu a progressão tumoral in vivo. O objetivo desse estudo foi aprofundar a participação dos receptores purinérgicos e das E-NTPDases na progressão dos gliomas. A análise das culturas de linhagem de glioma C6 e de C6 ex vivo revelou similaridade na expressão de receptores purinérgicos e das E-NTPDases, sugerindo que alterações nessa via estariam presentes em culturas primárias de gliomas. Ao contrário do esperado, o restabelecimento da expressão da NTPDase2 nos gliomas resultou em aumento da malignidade tumoral. A superexpressão da NTPDase2 aumentou a adesão das células C6 em cultura e em experimentos in vivo promoveu dramático aumento do crescimento tumoral e presença de alterações histológicas nos pulmões sugestivas de metástase. Esses eventos foram relacionados ao acúmulo de ADP extracelular, recrutamento de plaquetas para a área tumoral e pulmonar, aumento de angiogênese e da resposta inflamatória, denotado pela presença de infiltrado leucocitário nos gliomas e aumento sérico das citocinas IL-1 , TNF-a e IL-6. Além disso, os receptores purinérgicos modularam a secreção espontânea e estimulada por TLR de IL-8 e MCP-1, bem como a proliferação celular induzida por LPS em linhagem de glioma humano. Finalmente, a análise da expressão das ectonucleotidases em gliomas de ratos e de humanos revelou ausência das NTPDase1 e 2, baixa expressão da NTPDase3 e expressão elevada da ecto-5´-NT/CD73, indicando que a alteração no padrão de expressão das ectonucleotidases também é uma característica de tumores humanos. Os resultados dessa tese reforçam a hipótese do envolvimento do sistema purinérgico na progressão dos gliomas e sugerem esse sistema como um alvo interessante no combate dos tumores cerebrais.
Extracellular nucleotides modulate a variety of biological actions via purinergic receptor activation. These effects are modulated by ectonucleotidases, such as ENTPDases and ecto-5´-NT/CD73, which hydrolyze ATP to adenosine in the extracellular milieu. Disruption on purinergic signaling has been involved in glioma progression. ATP induces glioma cell proliferation and, in opposite to astrocytes, gliomas have low expression of all NTPDases, particularly NTPDase2. Therefore, the restoration of the ATPase activity to gliomas could be a strategy to overcome the ATP mediated effects.…
Advisors/Committee Members: Battastini, Ana Maria Oliveira.
Subjects/Keywords: Glioma; Receptores purinérgicos; Ectonucleotidases
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APA ·
Chicago ·
MLA ·
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APA (6th Edition):
Braganhol, E. (2010). Sistema purinérgico e a progressão dos gliomas : avaliação de parâmetros proliferativos e inflamatórios. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/26487
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Braganhol, Elizandra. “Sistema purinérgico e a progressão dos gliomas : avaliação de parâmetros proliferativos e inflamatórios.” 2010. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/26487.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Braganhol, Elizandra. “Sistema purinérgico e a progressão dos gliomas : avaliação de parâmetros proliferativos e inflamatórios.” 2010. Web. 03 Mar 2021.
Vancouver:
Braganhol E. Sistema purinérgico e a progressão dos gliomas : avaliação de parâmetros proliferativos e inflamatórios. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2010. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/26487.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Braganhol E. Sistema purinérgico e a progressão dos gliomas : avaliação de parâmetros proliferativos e inflamatórios. [Thesis]. Universidade do Rio Grande do Sul; 2010. Available from: http://hdl.handle.net/10183/26487
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
17.
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 ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th 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 (16th 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 March 03, 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 (7th 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. 03 Mar 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 Mar 03].
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 Alberta
18.
Mita, Raja.
Role of brain FABP and its ligands in malignant glioma cell
migration.
Degree: PhD, Department of Oncology, 2010, University of Alberta
URL: https://era.library.ualberta.ca/files/8w32r7236
► Patients diagnosed with malignant glioma tumours have median survivals of 1.6 yrs and 5 months, respectively, highlighting the deadly nature of this disease. Despite aggressive…
(more)
▼ Patients diagnosed with malignant glioma tumours have
median survivals of 1.6 yrs and 5 months, respectively,
highlighting the deadly nature of this disease. Despite aggressive
multimodal treatment, patients with malignant glioma often present
with secondary brain tumours at sites distal to the primary tumour
mass. These secondary tumours are a consequence of ‘renegade’
neoplastic cells that infiltrate the surrounding normal brain, a
hallmark feature of malignant glioma. Brain fatty acid-binding
protein (FABP7), which binds omega-3 docosahexaenoic acid (DHA) and
omega-6 arachidonic acid (AA), is overexpressed and associated with
a poor prognosis in patients with malignant glioma compared with
normal brain. These data suggest that FABP7 plays an important role
in gliomagenesis; however, the mechanism(s) underlying a role for
FABP7 in malignant glioma has, until now, been unexplored. Here, we
demonstrate that expression of FABP7 in malignant glioma cells is
accompanied by increased cell migration. Consistent with our in
vitro results, we show that expression of FABP7 in astrocytoma
tumours is associated with sites of tumour infiltration and tumour
recurrence. Furthermore, we demonstrate that the fatty-acid ligands
of FABP7 affect cell migration in an FABP7-dependent manner. More
specifically, DHA inhibits migration, whereas AA stimulates cell
migration. Finally, we reveal that uptake and incorporation of DHA
and AA in the phospholipids of malignant glioma cells is enhanced
by FABP7 expression, suggesting a mechanism by which DHA and AA may
affect cell migration by altering signal transduction at the cell
membrane. We propose that the inherent ability of malignant glioma
cells to express the radial glial marker FABP7 underlies their
infiltrative capacity, allowing tumour cells to migrate long
distances from the main tumour mass. We propose a model whereby
FABP7 expression and relative levels of DHA and AA determine tumour
infiltrative potential. Our findings provide insight into the role
of FABP7 and its fatty acid ligands in controlling the migration of
malignant glioma cells and point to the potential use of DHA as a
natural anti-infiltrative agent in the treatment of malignant
glioma. We believe that targeting FABP7-expressing cells may make a
significant impact on the treatment of high grade
astrocytomas.
Subjects/Keywords: fatty acids; glioma; fabp7
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APA ·
Chicago ·
MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Mita, R. (2010). Role of brain FABP and its ligands in malignant glioma cell
migration. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/8w32r7236
Chicago Manual of Style (16th Edition):
Mita, Raja. “Role of brain FABP and its ligands in malignant glioma cell
migration.” 2010. Doctoral Dissertation, University of Alberta. Accessed March 03, 2021.
https://era.library.ualberta.ca/files/8w32r7236.
MLA Handbook (7th Edition):
Mita, Raja. “Role of brain FABP and its ligands in malignant glioma cell
migration.” 2010. Web. 03 Mar 2021.
Vancouver:
Mita R. Role of brain FABP and its ligands in malignant glioma cell
migration. [Internet] [Doctoral dissertation]. University of Alberta; 2010. [cited 2021 Mar 03].
Available from: https://era.library.ualberta.ca/files/8w32r7236.
Council of Science Editors:
Mita R. Role of brain FABP and its ligands in malignant glioma cell
migration. [Doctoral Dissertation]. University of Alberta; 2010. Available from: https://era.library.ualberta.ca/files/8w32r7236
University of Alberta
19.
Swan, Amanda C.
An Anisotropic Diffusion Model for Brain Tumour
Spread.
Degree: PhD, Department of Mathematical and Statistical
Sciences, 2016, University of Alberta
URL: https://era.library.ualberta.ca/files/cpr76f371p
► Gliomas, tumours arising from the glial cells of the nervous system, are some of the most difficult tumours to treat. In particular, glioblastoma are a…
(more)
▼ Gliomas, tumours arising from the glial cells of the
nervous system, are some of the most difficult tumours to treat. In
particular, glioblastoma are a particularly aggressive glioma
subtype carrying a life expectancy of only 14 months. Typically,
treatment combines surgery, radiation and chemotherapy where a key
component of treatment planning is determining an appropriate
treatment region over which to administer radiation therapy.
Because gliomas are diffuse, only the main tumour mass shows up
using imaging, while many undetectable cancer cells infiltrate the
surrounding brain tissue. To account for this, treatment regions
typically extend the visible tumour mass by a uniform 2 \centi
\meter margin. We propose that a mathematical model for glioma
cell density could help by modelling the spread of cancer cells and
contribute to treatment plans that target the largest densities of
these undetectable cells. In this thesis, we focus on the
Painter-Hillen model for glioma spread, which uses anisotropic
diffusion, allowing the rate of spread of the cells to vary with
direction. This is meant to simulate the biological phenomenon
where cancer cells spread preferentially along the fibrous white
matter tracts within the brain, resulting in tumours having
irregular shapes and projections. We establish the utility of this
model by implementing it using data from ten patients, in both two
and three dimensions. For comparison, a previous isotropic glioma
model, the Swanson model, is used, as it has been applied
successfully in a clinical setting. The results of our simulations
indicate that the inclusion of anisotropy offers an advantage over
the previous model. Finally, we develop two extensions to the
Painter-Hillen model. In Chapter~6, we explore the derivation of a
``mass effect'' model, using a multiphase model framework. The mass
effect model includes the forces induced by the growing mass,
introducing a mechanical component to the model. This effect
becomes important where a tumour is growing in close proximity to
the skull, where the growth in this direction will be impeded by
the pressure generated by the increased density. In Chapter 7, we
discuss an extension of the Painter-Hillen model, using a transport
model framework. The generalization considered allows the turning
rate to vary with the direction that a cell is travelling in
relation to the underlying structure, since a cell travelling along
a fibre will turn less frequently than one travelling
perpendicularly. Both of these model extensions have potential for
further exploration.
Subjects/Keywords: Anisotropic Diffusion; Glioma; Mathematical Biology
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Swan, A. C. (2016). An Anisotropic Diffusion Model for Brain Tumour
Spread. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/cpr76f371p
Chicago Manual of Style (16th Edition):
Swan, Amanda C. “An Anisotropic Diffusion Model for Brain Tumour
Spread.” 2016. Doctoral Dissertation, University of Alberta. Accessed March 03, 2021.
https://era.library.ualberta.ca/files/cpr76f371p.
MLA Handbook (7th Edition):
Swan, Amanda C. “An Anisotropic Diffusion Model for Brain Tumour
Spread.” 2016. Web. 03 Mar 2021.
Vancouver:
Swan AC. An Anisotropic Diffusion Model for Brain Tumour
Spread. [Internet] [Doctoral dissertation]. University of Alberta; 2016. [cited 2021 Mar 03].
Available from: https://era.library.ualberta.ca/files/cpr76f371p.
Council of Science Editors:
Swan AC. An Anisotropic Diffusion Model for Brain Tumour
Spread. [Doctoral Dissertation]. University of Alberta; 2016. Available from: https://era.library.ualberta.ca/files/cpr76f371p
Texas A&M University
20.
Cherry, Evan Michael.
Noncanonical NF-κB Signaling in Glioma is Activated by TWEAK and Promotes Invasion.
Degree: PhD, Medical Sciences, 2017, Texas A&M University
URL: http://hdl.handle.net/1969.1/161267
► High-grade gliomas are an invasive and deadly brain cancer. We have shown that noncanonical NF-κB/RelB signaling can drive invasion in the aggressive mesenchymal subtype of…
(more)
▼ High-grade gliomas are an invasive and deadly brain cancer. We have shown that noncanonical NF-κB/RelB signaling can drive invasion in the aggressive mesenchymal subtype of
glioma. TNF-like weak inducer of apoptosis (TWEAK) can activate canonical/RelA and noncanonical/RelB NF-κB signaling, but its role in
glioma invasion is unclear. Moreover, the relevance of expression of TWEAK and NF-κB-inducing Kinase (NIK) in patient gliomas is unknown.
TWEAK-regulated NF-κB signaling and cell invasion were investigated in both established and primary high-grade
glioma tumor lines using a three-dimensional (3-D) collagen invasion assay. NF-κB proteins regulating both
glioma cell invasion and expression of Matrix Metalloproteinase 9 (MMP9) in response to TWEAK were evaluated using shRNA-mediated loss-of-function. NIK-promoted
glioma growth in vivo was investigated using an orthotopic xenograft mouse model. Expression of TWEAK, its receptor, NIK, and a negative regulator of NIK (altogether termed the TWEAK Axis) in
glioma tumors was evaluated using microarray data from the NCI-curated TCGA and REMBRANDT databases. TWEAK Axis expression was stratified by prognostic factor and
glioma subtype as well as correlated with expression of both NF-κB genes and
glioma subtype markers. Patient survival by TWEAK Axis gene expression was determined using Kaplan-Meier survival analysis.
Protein levels of RelB correlate positively with
glioma cell invasiveness. Loss of RelB attenuates invasion without altering RelA expression or phosphorylation. RelB promotes invasion independent of RelA. TWEAK selectively activates noncanonical NF-κB signaling through p100-p52 processing and nuclear accumulation of RelB and p52. TWEAK, but not TNFα, significantly increases NIK mRNA expression and sustains MMP9 mRNA expression. TWEAK-increased invasion is reversible by loss of NIK. NIK overexpression increases invasiveness in vitro and gliomagenesis in vivo. TWEAK, its receptor, and NIK are expressed primarily in mesenchymal gliomas and correlate negatively with survival.
Our data establish a key role for NIK and TWEAK in noncanonical NF-κB signaling and MMP9-dependent invasion in
glioma cells. Meta-analysis of patient
glioma tumors indicates poorer prognosis with increased TWEAK Axis expression in the aggressive mesenchymal subtype. Together, these studies reveal the importance of TWEAK and noncanonical NF-κB signaling in
glioma cell invasion and rationalize therapeutic targeting of TWEAK and NIK in
glioma.
Advisors/Committee Members: Sitcheran, Raquel (advisor), Bayless, Kayla J (committee member), Sohrabji, Farida (committee member), Wilson, Emily (committee member).
Subjects/Keywords: Glioma; TWEAK; Noncanonical NF-κB
Record Details
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APA ·
Chicago ·
MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Cherry, E. M. (2017). Noncanonical NF-κB Signaling in Glioma is Activated by TWEAK and Promotes Invasion. (Doctoral Dissertation). Texas A&M University. Retrieved from http://hdl.handle.net/1969.1/161267
Chicago Manual of Style (16th Edition):
Cherry, Evan Michael. “Noncanonical NF-κB Signaling in Glioma is Activated by TWEAK and Promotes Invasion.” 2017. Doctoral Dissertation, Texas A&M University. Accessed March 03, 2021.
http://hdl.handle.net/1969.1/161267.
MLA Handbook (7th Edition):
Cherry, Evan Michael. “Noncanonical NF-κB Signaling in Glioma is Activated by TWEAK and Promotes Invasion.” 2017. Web. 03 Mar 2021.
Vancouver:
Cherry EM. Noncanonical NF-κB Signaling in Glioma is Activated by TWEAK and Promotes Invasion. [Internet] [Doctoral dissertation]. Texas A&M University; 2017. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1969.1/161267.
Council of Science Editors:
Cherry EM. Noncanonical NF-κB Signaling in Glioma is Activated by TWEAK and Promotes Invasion. [Doctoral Dissertation]. Texas A&M University; 2017. Available from: http://hdl.handle.net/1969.1/161267
University of Newcastle
21.
Chan, Eric.
Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma.
Degree: PhD, 2014, University of Newcastle
URL: http://hdl.handle.net/1959.13/1050162
► Research Doctorate - Doctor of Philosophy (PhD)
Malignant gliomas (MGs) are the most common tumours of the central nervous system (CNS) and respond poorly to…
(more)
▼ Research Doctorate - Doctor of Philosophy (PhD)
Malignant gliomas (MGs) are the most common tumours of the central nervous system (CNS) and respond poorly to surgery, radiotherapy and chemotherapy. Despite conven- tional therapy, this disease is fatal within 1 to 2 years of the onset of symptoms. Preclinical studies have shown that low pathogenic human enteroviruses such as Coxsackievirus A21 (CVA21), CVA21-DAFv and Echovirus 1 (EV1) possess anti-cancer (oncolytic) potential against many different tumours, including melanoma, multiple myeloma, breast, prostate, gastric and ovarian cancer. The selective targeting of CVA21, CVA21-DAFv and EV1 is based on the overexpression of the cellular receptors intercellular adhesion molecule- 1 (ICAM-1), decay accelerating factor (DAF) and integrin α2β1 on the surface of many cancer cells compared to normal cells. The employment of CVA21 to control cancer progression is currently under Phase I/II clinical trials for the treatment of melanoma, breast, bladder, prostate and lung cancer. The bioselected variant of CVA21 (CVA21-DAFv) is an enhanced DAF-using phenotype, compared to the parental CVA21 strain which utilizes ICAM-1 and/or DAF. Moreover, EV1 infection requires the cell surface expression of integrin α2β1, enabling binding of the viral capsid, internalization, and subsequent lytic infection. Prior to the study of the potential use of these enteroviruses for the treatment of MG, screening for these such cellular receptors was performed by confirming mRNA gene expression profiles of ICAM-1, DAF and integrin α2β1 in cancerous brain tissues, in comparison to normal brain tissue biopsy material. The presence of these cellular receptors on the surface of glioma cells was also assessed using flow cytometry and immunohistochemical (IHC) staining. The in vitro screening to evaluate the oncolytic capacity of enteroviruses was subsequently performed in a range of established glioma cell lines (U87 MG, A172, T98G, U118 and GBM6) and normal brain cells (HCN-2). To further investigate the role of CVA21 or CVA21-DAFv in the treatment of MG, an orthotopic model of MG was established in athymic nude mice. To evaluate the efficacy of CVA21 or CVA21-DAFv as a single agent, mice bearing intracranial (i.c.) U87 MG-luc tumours were administered with either viruses. Mice were initially injected with a single administration into the tumour and subsequent intravenous (i.v.) doses of either viruses. In vivo, both CVA21 and CVA21-DAFv significantly reduced tumour growth early on in the study, but tumours eventually recurred. Given that oncolytic viruses may be used in the clinic together with existing treatment modalities such as chemotherapy, the combinatorial effects of human enteroviruses with a panel of standard of care chemotherapeutic agents [including temozolomide (TMZ), cyclophosphamide (CPA) and carboplatin (Cb)] were examined. The effects of these chemotherapeutic agents on human enterovirus oncolysis and viral replication were assessed in vitro to identify synergistic, additive or…
Advisors/Committee Members: University of Newcastle. Faculty of Health & Medicine, School of Biomedical Sciences and Pharmacy.
Subjects/Keywords: oncolytic virotherapy; malignant glioma; chemotherapy
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APA (6th Edition):
Chan, E. (2014). Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma. (Doctoral Dissertation). University of Newcastle. Retrieved from http://hdl.handle.net/1959.13/1050162
Chicago Manual of Style (16th Edition):
Chan, Eric. “Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma.” 2014. Doctoral Dissertation, University of Newcastle. Accessed March 03, 2021.
http://hdl.handle.net/1959.13/1050162.
MLA Handbook (7th Edition):
Chan, Eric. “Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma.” 2014. Web. 03 Mar 2021.
Vancouver:
Chan E. Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma. [Internet] [Doctoral dissertation]. University of Newcastle; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1959.13/1050162.
Council of Science Editors:
Chan E. Low pathogenic human enteroviruses as novel anti-cancer agents against malignant glioma. [Doctoral Dissertation]. University of Newcastle; 2014. Available from: http://hdl.handle.net/1959.13/1050162
NSYSU
22.
WU, HUI-CHUN.
Autophagy inducers modulated ATG4B expression in human brain tumor cells.
Degree: Master, Biological Sciences, 2018, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0605118-111049
► Autophagy is a self-eating mechanism in cells through which damaged proteins and organelles are recruited to autophagosomes and fused with lysosome for their bulk degradation…
(more)
▼ Autophagy is a self-eating mechanism in cells through which damaged proteins and organelles are recruited to autophagosomes and fused with lysosome for their bulk degradation and recycling during nutrient deprivation. Dysregulation of autophagy is associated with various diseases, including cancer. ATG4B is a cysteine protease required for autophagy machinery. Recent reports have shown that elevated ATG4B promoted tumorigenesis, malignancy and drug resistance, suggesting ATG4B might modulate autophagy to facilitate tumor progression. However, the role of autophagy on ATG4B in cancer cells remains unknown. In this study, we found ATG4B protein level was decreased in
glioma H4 and SHSY5Y cells during autophagy inducing conditions, including rapamycin and starvation. Moreover, autophagy inhibitors chloroquine or BafA1and proteosome inhibitor MG132 modestly recovered autophagy downregulated ATG4B in cells. Silencing ATG7 also partially recovered ATG4B protein level in cell treated with rapamycin, whereas it had no recovery effects in starved cells. Furthermore, mRNA level of ATG4B was decreased in rapamycin-treated H4 cells, but not starved cells. Luciferase fusion with 3âUTR of ATG4B as reporter assay was used to evaluate the effects of miRNA on ATG4B in cells during autophagy conditions. The luciferase activity was significantly decreased in H4 cells treated with rapamycin. However, the luciferase activity had little effects on recovery. The miR-34a was accordingly increased in the rapamycin-treated cells, while miR-34a was inhibited in BafA1 and CQ pretreated cells. Taken together, rapamycin may regulate autophagy and miR-34a to reduce ATG4B in
glioma cells. Our results may shed a light on potential mechanisms of rapamycin on tumor suppression.
Advisors/Committee Members: Ming-Hong Tai (chair), Pei-Feng Liu (chair), Chih-Wen Shu (committee member), Chen, Chun-Lin (committee member).
Subjects/Keywords: Rapamycin; Chloroquine; Glioma; Autophagy; ATG4B
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APA (6th Edition):
WU, H. (2018). Autophagy inducers modulated ATG4B expression in human brain tumor cells. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0605118-111049
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
WU, HUI-CHUN. “Autophagy inducers modulated ATG4B expression in human brain tumor cells.” 2018. Thesis, NSYSU. Accessed March 03, 2021.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0605118-111049.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
WU, HUI-CHUN. “Autophagy inducers modulated ATG4B expression in human brain tumor cells.” 2018. Web. 03 Mar 2021.
Vancouver:
WU H. Autophagy inducers modulated ATG4B expression in human brain tumor cells. [Internet] [Thesis]. NSYSU; 2018. [cited 2021 Mar 03].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0605118-111049.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
WU H. Autophagy inducers modulated ATG4B expression in human brain tumor cells. [Thesis]. NSYSU; 2018. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0605118-111049
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.
Gonçalves, Rosângela Mayer.
O papel da autofagia na resistência de gliomas ao tratamento com temozolomida e inibidor de histonas desacetilases.
Degree: 2017, Universidade do Rio Grande do Sul
URL: http://hdl.handle.net/10183/153333
► Glioblastoma multiforme é o tipo mais frequente de tumor cerebral primário, sendo caracterizado por uma alta agressividade e um prognóstico bastante limitado. O ácido hidroxâmico…
(more)
▼ Glioblastoma multiforme é o tipo mais frequente de tumor cerebral primário, sendo caracterizado por uma alta agressividade e um prognóstico bastante limitado. O ácido hidroxâmico suberoilanilida (SAHA) é um inibidor específico de histonas desacetilases aprovado para o tratamento de linfoma cutâneo de células T, e em fase de crescente investigação clínica e pré-clínica em tumores sólidos. Neste estudo, avaliamos a eficácia do ácido hidroxâmico suberoilanilida em tratamento combinado com temozolomida, o agente alquilante já utilizado em glioblastomas. Através de testes de viabilidade e analises por citometria de fluxo em células tumorais das linhagens U251MG e C6, observamos que não houve sinergismo de potenciação entre temozolomida e ácido hidroxâmico suberoilanilida, apenas efeito sinergismo de adição O tratamento combinado inicialmente promoveu parada do ciclo celular em fase G2/M (≥48 h) ao passo que a apoptose foi detectada apenas em exposição prolongada (≥96 h) aos fármacos em estudo. Ainda, as células tratadas com TMZ/SAHA apresentaram fenótipo autofágico, como determinado por citometria de fluxo e imunodetecção de proteínas marcadoras de autofagia como LC3 e o p62/SQSTM1. A autofagia temporalmente precedeu a apoptose e exerceu função citoprotetora, uma vez que o bloqueio da terminação autofágica com cloroquina promoveu uma significante redução na viabilidade celular, a qual foi associada a um aumento de apoptose em células de glioma tratadas com TMZ/SAHA. Portanto, os dados apresentados neste trabalho demonstram que a autofagia é um processo que diminui a eficácia antiglioma do temozolomida e do ácido hidroxâmico suberoilanilida, e a inibição deste fenômeno pode ser uma estratégia para aperfeiçoar a terapia com esses fármacos.
Glioblastoma multiforme (GBM) is the most frequent and aggressive type of primary brain tumor which has been associated with a dismal prognosis. In this study, we tested the efficacy of combining temozolomide (TMZ) with suberoylanilide hydroxamic acid (SAHA) - an inhibitor of HDACs 1, 2, 3, and 6 approved for the treatment of cutaneous T-cell lymphoma - in the viability of tumor cells. The data showed that potentiation synergism between TMZ e SAHA was not achieved due to activation of protective autophagy in vitro. The SAHA/TMZ treatment promoted arrest in the G2/M phase of the cell cycle as soon as 48 h after drug exposure whereas apoptosis was only detected after long-lasting exposure (≥96 h). In addition, SAHA and TMZ induced autophagy as detected by flow cytometry of acridine orange stained cells and immunodetection of the lipidated form of LC3 as well as decreases in p62/SQSTM1. Autophagy preceded apoptosis, and by blocking the termination step of autophagy with chloroquine promoted a significant reduction in the viability of glioma cells which was accompanied by increased apoptosis in SAHA/TMZ treatment. Overall, the herein presented data demonstrate that autophagy impairs the efficacy of combined TMZ/SAHA, and inhibiting this phenomenon could provide novel opportunities to…
Advisors/Committee Members: Zanotto Filho, Alfeu.
Subjects/Keywords: Autofagia; Glioma; Morte celular; Temozolamida
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APA (6th Edition):
Gonçalves, R. M. (2017). O papel da autofagia na resistência de gliomas ao tratamento com temozolomida e inibidor de histonas desacetilases. (Thesis). Universidade do Rio Grande do Sul. Retrieved from http://hdl.handle.net/10183/153333
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Gonçalves, Rosângela Mayer. “O papel da autofagia na resistência de gliomas ao tratamento com temozolomida e inibidor de histonas desacetilases.” 2017. Thesis, Universidade do Rio Grande do Sul. Accessed March 03, 2021.
http://hdl.handle.net/10183/153333.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Gonçalves, Rosângela Mayer. “O papel da autofagia na resistência de gliomas ao tratamento com temozolomida e inibidor de histonas desacetilases.” 2017. Web. 03 Mar 2021.
Vancouver:
Gonçalves RM. O papel da autofagia na resistência de gliomas ao tratamento com temozolomida e inibidor de histonas desacetilases. [Internet] [Thesis]. Universidade do Rio Grande do Sul; 2017. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10183/153333.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Gonçalves RM. O papel da autofagia na resistência de gliomas ao tratamento com temozolomida e inibidor de histonas desacetilases. [Thesis]. Universidade do Rio Grande do Sul; 2017. Available from: http://hdl.handle.net/10183/153333
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Boston University
24.
Gascon, Marc-Andre.
The prognostic value of biomarkers in the evaluation of glioblastoma multiforme.
Degree: MS, Physician Assistant Program, 2017, Boston University
URL: http://hdl.handle.net/2144/26587
► BACKGROUND: Glioblastoma multiforme (GBM) is a highly heterogeneous tumor of the central nervous system (CNS) that exhibits considerable variation in its clinical course. Recently, the…
(more)
▼ BACKGROUND: Glioblastoma multiforme (GBM) is a highly heterogeneous tumor of the central nervous system (CNS) that exhibits considerable variation in its clinical course. Recently, the World Health Organization (WHO) published a classification system for tumors of the CNS that combines histological features with molecular parameters to determine tumor grade. The incorporation of molecular biomarkers that carry both prognostic and predictive value adds another level of objectivity to the glioma grading system and will help guide clinical decision. As such, the assessment of biomarkers has become an integral part of tumor evaluation in neuro-oncology. This curriculum will discuss the clinical relevance of the most recently studied biomarkers with prognostic and predictive value in the evaluation of GBM. Biomarkers regularly used for the assessment of GBM include the IDH mutations, MGMT methylation status, and EGFRvIII. Furthermore, this review will offer a perspective on experimental approaches currently under investigation for treatment of GBM.
LITERATURE REVIEW FINDINGS: MGMT methylation of the promoter region is associated with better treatment response from temozolomide (TMZ), an alkylating therapeutic. Treatment benefit was most prominent in the elderly population and therapy should be individualized for that age group. Patients with GBM characterized by IDH1/IDH2 mutations carry a better overall prognosis primarily due to their higher sensitivity to chemo- and radiotherapy. The prognostic value of EGFRvIII remains controversial, although it may be associated with a worse prognosis. Nonetheless, EGFRvIII provides an ideal target for targeted molecular therapies as it is only found on tumor cells.
PROPOSED METHODS: A curriculum aimed at educating primary care providers (PCPs) about the most clinically significant biomarkers in GBM will be developed. The curriculum will be in a PowerPoint format, and the hour-long lecture will be presented at continuing medical education national conferences. A pre- and post-test consisting of the same 10 multiple- choice questions will be administered on a voluntary basis to help evaluate knowledge acquisition from the curriculum. Results will be evaluated with a paired t-test analysis. The tests will be will be administered through Poll Everywhere, a smartphone survey application.
CONCLUSION: There is increasing evidence to suggest that therapies should be individualized according to specific biomarkers with predictive value. PCPs are in a position where they are often the first providers to suspect the diagnosis of a brain tumor. Therefore, it is imperative for PCPs to be aware of the latest development in the field of neuro-oncology so that they may appropriately counsel patients.
Subjects/Keywords: Neurosciences; Biomarker; Glioblastoma; Glioma; Prognostic
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APA ·
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APA (6th Edition):
Gascon, M. (2017). The prognostic value of biomarkers in the evaluation of glioblastoma multiforme. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/26587
Chicago Manual of Style (16th Edition):
Gascon, Marc-Andre. “The prognostic value of biomarkers in the evaluation of glioblastoma multiforme.” 2017. Masters Thesis, Boston University. Accessed March 03, 2021.
http://hdl.handle.net/2144/26587.
MLA Handbook (7th Edition):
Gascon, Marc-Andre. “The prognostic value of biomarkers in the evaluation of glioblastoma multiforme.” 2017. Web. 03 Mar 2021.
Vancouver:
Gascon M. The prognostic value of biomarkers in the evaluation of glioblastoma multiforme. [Internet] [Masters thesis]. Boston University; 2017. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/2144/26587.
Council of Science Editors:
Gascon M. The prognostic value of biomarkers in the evaluation of glioblastoma multiforme. [Masters Thesis]. Boston University; 2017. Available from: http://hdl.handle.net/2144/26587
University of Edinburgh
25.
Brennan, Paul Martin.
Using novel models of glioma for cancer discovery science.
Degree: PhD, 2014, University of Edinburgh
URL: http://hdl.handle.net/1842/9613
► The prognosis for patients diagnosed with glioma has changed little over the past two decades. Many therapies that appeared promising in preclinical studies have been…
(more)
▼ The prognosis for patients diagnosed with glioma has changed little over the past two decades. Many therapies that appeared promising in preclinical studies have been unsuccessful in the clinic. In an attempt to address this problem I developed a method for the efficient derivation of glioma primary cultures from fresh human brain tumours. These cultures are enriched for putative cancer stem-like cells that are thought to be responsible for glioma initiation, therapy resistance and recurrence. This mechanism of tumour development is a departure from the traditional multistep model of cancer. It is hoped that preclinical models incorporating glioma stem-like cells will more effectively recapitulate the biology of human disease and so better predict the likely clinical efficacy of inhibitor compounds tested in vitro and in the preclinical setting. In contrast to the majority of the existing literature, I identified two distinct tumourderived glioma stem-like cell phenotypes in my primary cultures that I have called ‘branched’ and ‘flat.’ The branched cells had similarities to the radial glia-like cells previously described in glioma stem-like cultures. In contrast, the flat cells had mesenchymal-like features. I discuss the implications of these observations for understanding glioma cell biology. I describe the development of high content phenotypic assays that incorporate these putative glioma stem-like cells. I screened inhibitor compounds of the PI3 kinase pathway, which is important in glioma cell behaviour, and identified that PIK75, a drug that targets the p110α catalytic subunit of PI3 kinase, inhibited growth of all the primary cells tested. I examined PIK75 activity in some detail. In vivo models of glioma are used to validate the findings of in vitro compound screening, so I describe my attempt to develop a novel genetically engineered mouse model designed to initiate glioma formation from the glioma stem-like cell. Surprisingly, these mice actually developed malignant peripheral nerve sheath tumours and that gave me a novel insight into the pathogenesis of this rare disease. This also informed future work on my long-term goal of generating a genetic model of glioma that recapitulates human disease.
Subjects/Keywords: 616.99; glioma; stem cells
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APA (6th Edition):
Brennan, P. M. (2014). Using novel models of glioma for cancer discovery science. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/9613
Chicago Manual of Style (16th Edition):
Brennan, Paul Martin. “Using novel models of glioma for cancer discovery science.” 2014. Doctoral Dissertation, University of Edinburgh. Accessed March 03, 2021.
http://hdl.handle.net/1842/9613.
MLA Handbook (7th Edition):
Brennan, Paul Martin. “Using novel models of glioma for cancer discovery science.” 2014. Web. 03 Mar 2021.
Vancouver:
Brennan PM. Using novel models of glioma for cancer discovery science. [Internet] [Doctoral dissertation]. University of Edinburgh; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1842/9613.
Council of Science Editors:
Brennan PM. Using novel models of glioma for cancer discovery science. [Doctoral Dissertation]. University of Edinburgh; 2014. Available from: http://hdl.handle.net/1842/9613
University of Florida
26.
Brown, Alec C.
Pharmacokinetics of Molecular Transport across the Blood-Brain Barrier in Pontine Gliomas.
Degree: MS, Biochemistry and Molecular Biology, 2019, University of Florida
URL: https://ufdc.ufl.edu/UFE0055829
► Understanding the structure and function of the brain vasculature is vital to investigating neurodegenerative diseases such as Alzheimer's, or cancers such as pontine gliomas. Moreover,…
(more)
▼ Understanding the structure and function of the brain vasculature is vital to investigating neurodegenerative diseases such as Alzheimer's, or cancers such as pontine gliomas. Moreover, accurately assessing the prognosis of pontine gliomas is crucial for physicians to be able to assess treatment options. Tumors in the brain disrupt the blood-brain barrier and form immature, "leaky" blood vessels during tumor proliferation. This leakiness can be quantitatively assessed using the forward volumetric transfer constant (Ktrans) of contrast agent from blood vessels to brain parenchyma after acquiring images using dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). In this study, rats were injected with 9L gliosarcoma cells in vivo and then tumor structure was compared across DCE, T2-weighted, T1, and fractional anisotropy (FA) images acquired in vivo at three- and ten-days post-implantation on a 4.7T magnet. Ktrans was then estimated from the DCE images and compared to their respective tumor volumes. DCE estimated the largest tumor volume at days three and ten, and tumor growth factor was correlated to the day three Ktrans constant, which consistently fell off at day ten. These results suggest Ktrans is potentially a biomarker for tumor aggressiveness which can be assessed non-invasively and could be used to develop and optimize chemotherapeutic treatments to brain tumors. ( en )
Advisors/Committee Members: Mareci,Thomas H (committee chair), Merritt,Matthew E (committee member).
Subjects/Keywords: exchange – glioma – mri – pharmacokinetics
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APA (6th Edition):
Brown, A. C. (2019). Pharmacokinetics of Molecular Transport across the Blood-Brain Barrier in Pontine Gliomas. (Masters Thesis). University of Florida. Retrieved from https://ufdc.ufl.edu/UFE0055829
Chicago Manual of Style (16th Edition):
Brown, Alec C. “Pharmacokinetics of Molecular Transport across the Blood-Brain Barrier in Pontine Gliomas.” 2019. Masters Thesis, University of Florida. Accessed March 03, 2021.
https://ufdc.ufl.edu/UFE0055829.
MLA Handbook (7th Edition):
Brown, Alec C. “Pharmacokinetics of Molecular Transport across the Blood-Brain Barrier in Pontine Gliomas.” 2019. Web. 03 Mar 2021.
Vancouver:
Brown AC. Pharmacokinetics of Molecular Transport across the Blood-Brain Barrier in Pontine Gliomas. [Internet] [Masters thesis]. University of Florida; 2019. [cited 2021 Mar 03].
Available from: https://ufdc.ufl.edu/UFE0055829.
Council of Science Editors:
Brown AC. Pharmacokinetics of Molecular Transport across the Blood-Brain Barrier in Pontine Gliomas. [Masters Thesis]. University of Florida; 2019. Available from: https://ufdc.ufl.edu/UFE0055829
University of Minnesota
27.
Decker, Stacy Ann.
A spontaneous murine model for the study of CD44 In glioma progression.
Degree: PhD, Neuroscience, 2012, University of Minnesota
URL: http://purl.umn.edu/136786
► Mouse models of malignant glioma that accurately recapitulate the genetic and phenotypic heterogeneity are essential for advancing brain tumor therapeutics. We have developed a novel…
(more)
▼ Mouse models of malignant glioma that accurately recapitulate the genetic and phenotypic heterogeneity are essential for advancing brain tumor therapeutics. We have developed a novel model using the Sleeping Beauty transposable element to achieve chromosomal integration of human oncogenes into endogenous brain cells of any mouse strain. The phenotype of these genetically engineered brain tumors is influenced by the combination of oncogenes delivered, but many of the pathological features of malignant human glioma are present in the majority of cases. At least five different genes can be cotransfected simultaneously, including reporters that allow measurement of tumor progression. The flexibility of this model enabled studies on the role of the microenvironment in brain tumor development. The data presented here demonstrate that glioma cells make an abundance of CD44 and HA starting early in tumor development and continue to make both receptor and ligand as gliomas progress to highly invasive disease. We show that CD44-/- tumors progressed significantly slower than CD44+/+ tumors, but that expression of full length CD44 within tumors restores the CD44-/- tumor progression. In addition, we show that CD44 loss of function caused severe impairment in single cell motility. The data presented here suggest that HA-engaged CD44 mediates tumor progression by facilitating glioma cell invasion. These studies highlight the therapeutic potential for targeting the infiltrative glioma population through antagonists of the HA-CD44 complex.
Subjects/Keywords: CD44; Glioma; Invasion; Tumor development
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APA (6th Edition):
Decker, S. A. (2012). A spontaneous murine model for the study of CD44 In glioma progression. (Doctoral Dissertation). University of Minnesota. Retrieved from http://purl.umn.edu/136786
Chicago Manual of Style (16th Edition):
Decker, Stacy Ann. “A spontaneous murine model for the study of CD44 In glioma progression.” 2012. Doctoral Dissertation, University of Minnesota. Accessed March 03, 2021.
http://purl.umn.edu/136786.
MLA Handbook (7th Edition):
Decker, Stacy Ann. “A spontaneous murine model for the study of CD44 In glioma progression.” 2012. Web. 03 Mar 2021.
Vancouver:
Decker SA. A spontaneous murine model for the study of CD44 In glioma progression. [Internet] [Doctoral dissertation]. University of Minnesota; 2012. [cited 2021 Mar 03].
Available from: http://purl.umn.edu/136786.
Council of Science Editors:
Decker SA. A spontaneous murine model for the study of CD44 In glioma progression. [Doctoral Dissertation]. University of Minnesota; 2012. Available from: http://purl.umn.edu/136786
University of Minnesota
28.
Klank, Rebecca.
Physical Determinants of Glioma Cell Migration and Disease Progression.
Degree: PhD, Biomedical Engineering, 2015, University of Minnesota
URL: http://hdl.handle.net/11299/191324
► Glioblastoma (GBM) is a highly aggressive brain cancer (generally, “glioma”) with poor patient prognosis, even with current standard treatments. In order to rationally develop novel…
(more)
▼ Glioblastoma (GBM) is a highly aggressive brain cancer (generally, “glioma”) with poor patient prognosis, even with current standard treatments. In order to rationally develop novel treatments that can significantly extend patient survival, we must first understand at a basic scientific level how the disease progresses. GBM is thought to be fatal due to highly invasive cells that migrate beyond the visible bulk tumor and lead to tumor recurrence after therapeutic intervention. Therefore, we sought to investigate what makes GBM cells invasive at the single-cell level (Chapter 1). Using a genetically induced mouse glioma model and confocal imaging of intact tumor-containing brain slices, we found that, consistent with previous biophysical models, glioma cell migration is biphasic with respect to the concentration of the transmembrane cell adhesion molecule CD44. By contrast, cell proliferation is independent of CD44 level. Additionally, mouse model and human patient survival are also biphasic with respect to CD44 level, with poorest prognosis occurring at intermediate CD44 levels. Thus, migration and survival are both biphasic and are anti-correlated to each other, suggesting that CD44-dependent migration directly affects survival outcomes. We next investigated how these single-cell behaviors impact overall tumor growth and progression (Chapter 2). Noticing that previous models of GBM migration use parameter values for migration rate (defined by a diffusion coefficient, also known as a random motility coefficeint) that are much higher than our measurements of single-cell migration behavior in Chapter 1, a Brownian dynamics (BD) approach was used to simulate single-cell growth, proliferation, and migration, and compare model assumptions. These studies showed that employing the physically-based assumption that tumor cells occupy volume, an assumption not captured in current reaction-diffusion (RD) simulations, resulted in increased tumor spreading behavior with the same input parameters. Specifically, non-overlapping cells can enter a jammed regime where interior cells are subdiffusive, and peripheral cells become biased outward and superdiffusive in a quasi-ballistic expansion. Thus, we show that, when we account for volume conservation, the relatively low values of diffusion coefficient, such as what was measured in Chapter 1, can generate fast progressing tumors that are similar to RD simulations which use diffusion coefficients much greater than what is observed experimentally for single migrating cells. Therefore, we suggest that cellular jamming behavior contributes to the fast spreading of GBM tumors, and that subsequent simulations of GBM growth should incorporate this assumption so that models are physically grounded and achieve consistency between single-cell behavior and bulk tumor progression. Overall, these studies demonstrate the potential importance of fundamental physical effects in driving tumor progression generally, and glioblastoma specifically.
Subjects/Keywords: CD44; Glioblastoma; Glioma; Tumor Modeling
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APA (6th Edition):
Klank, R. (2015). Physical Determinants of Glioma Cell Migration and Disease Progression. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/191324
Chicago Manual of Style (16th Edition):
Klank, Rebecca. “Physical Determinants of Glioma Cell Migration and Disease Progression.” 2015. Doctoral Dissertation, University of Minnesota. Accessed March 03, 2021.
http://hdl.handle.net/11299/191324.
MLA Handbook (7th Edition):
Klank, Rebecca. “Physical Determinants of Glioma Cell Migration and Disease Progression.” 2015. Web. 03 Mar 2021.
Vancouver:
Klank R. Physical Determinants of Glioma Cell Migration and Disease Progression. [Internet] [Doctoral dissertation]. University of Minnesota; 2015. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/11299/191324.
Council of Science Editors:
Klank R. Physical Determinants of Glioma Cell Migration and Disease Progression. [Doctoral Dissertation]. University of Minnesota; 2015. Available from: http://hdl.handle.net/11299/191324
University of Melbourne
29.
Liubinas, Simon Vincent.
Radiological and molecular factors associated with seizures in patients with supratentorial gliomas.
Degree: 2013, University of Melbourne
URL: http://hdl.handle.net/11343/38036
► Tumour associated epilepsy (TAE) is a common and disabling symptom experienced by patients with supratentorial gliomas. The pathogenesis of TAE is likely to involve a…
(more)
▼ Tumour associated epilepsy (TAE) is a common and disabling symptom experienced by patients with supratentorial gliomas. The pathogenesis of TAE is likely to involve a complex interplay between macroscopic anatomical factors, molecular factors and individual patient factors. The overarching hypothesis of this thesis is that patients with TAE have tumours with different radiological, molecular and genetic features compared to those without TAE. Furthermore, identification of these features may allow the identification of patients who are at increased risk of the development of TAE, and provide tailored, individualized treatment of these patients. An improved understanding of the genetic and molecular features associated with TAE may also inform the development of novel therapeutic strategies for these patients.
There is an increasing body of evidence implicating glutamate, the most abundant neurotransmitter in the mammalian central nervous system, in the pathogenesis of TAE. Magnetic resonance spectroscopy (MRS) provides a non-invasive method to quantify brain metabolites in-vivo, but has not yet been validated for glutamate. In this thesis we firstly demonstrate that MRS quantification of glutamate has a modest, but statistically significant, correlation with concentrations of glutamate measured from tumour biopsy specimens. We then demonstrate that these MRS measurements of glutamate are useful in predicting not only glioma grade, but also the incidence of TAE. We also demonstrate that patients with low-grade gliomas and TAE are more likely to have larger tumours than patients without TAE. The opposite is found in patients with high-grade gliomas and TAE.
There is also evidence that common pathological processes, including glutamate excitotoxicity, may be involved in TAE and neurodegenerative conditions such as Alzheimer’s disease, the sequelae of traumatic head injury and idiopathic epilepsy. A number of molecular factors associated with neurodegeneration and excitotoxicity are therefore investigated for their association with TAE. Phosphorylation of tau was found to be lower in patients with TAE compared to those without TAE. Over-expression of glycogen synthase kinase (GSK3β) was found to correlate with TAE, as was loss of glutamic acid decarboxylase 67 (GAD67), potentially reflecting a selective loss of inhibitory interneurons. Finally, the expression of the IDH1-R132H mutation, the most common mutation in low-grade gliomas, is shown to correlate with TAE.
In conclusion, TAE results from a complex interaction of patient, environmental and tumour factors, including glutamate excitotoxicity, selective loss of inhibitory interneurons and IDH1-R132H expression. Not only do the results presented in this thesis suggest that TAE differs from other epileptic syndromes, but also that the mechanisms may differ between low and high-grade gliomas. Collaboration between neurosurgeons,…
Subjects/Keywords: glioma; seizures; epilepsy; IDH1
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APA ·
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MLA ·
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CSE |
Export
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APA (6th Edition):
Liubinas, S. V. (2013). Radiological and molecular factors associated with seizures in patients with supratentorial gliomas. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/38036
Chicago Manual of Style (16th Edition):
Liubinas, Simon Vincent. “Radiological and molecular factors associated with seizures in patients with supratentorial gliomas.” 2013. Doctoral Dissertation, University of Melbourne. Accessed March 03, 2021.
http://hdl.handle.net/11343/38036.
MLA Handbook (7th Edition):
Liubinas, Simon Vincent. “Radiological and molecular factors associated with seizures in patients with supratentorial gliomas.” 2013. Web. 03 Mar 2021.
Vancouver:
Liubinas SV. Radiological and molecular factors associated with seizures in patients with supratentorial gliomas. [Internet] [Doctoral dissertation]. University of Melbourne; 2013. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/11343/38036.
Council of Science Editors:
Liubinas SV. Radiological and molecular factors associated with seizures in patients with supratentorial gliomas. [Doctoral Dissertation]. University of Melbourne; 2013. Available from: http://hdl.handle.net/11343/38036
Duke University
30.
Killela, Patrick J.
Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas
.
Degree: 2014, Duke University
URL: http://hdl.handle.net/10161/9080
► Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years;…
(more)
▼ Gliomagenesis is driven by a complex network of genetic alterations and while the
glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving
glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie
glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of
glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (ATRX), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), and mutations in tumor protein 53 (TP53) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (TERT) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify TERT promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that TERT promoter mutations in combination with IDH1 and IDH2 mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi – gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.
Advisors/Committee Members: Yan, Hai (advisor).
Subjects/Keywords: Oncology;
Medicine;
Pathology;
Glioma;
Oncogenomics
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Record Details
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APA ·
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APA (6th Edition):
Killela, P. J. (2014). Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/9080
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Killela, Patrick J. “Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas
.” 2014. Thesis, Duke University. Accessed March 03, 2021.
http://hdl.handle.net/10161/9080.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Killela, Patrick J. “Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas
.” 2014. Web. 03 Mar 2021.
Vancouver:
Killela PJ. Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas
. [Internet] [Thesis]. Duke University; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/10161/9080.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Killela PJ. Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas
. [Thesis]. Duke University; 2014. Available from: http://hdl.handle.net/10161/9080
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