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NSYSU
1.
Hou, You-syuan.
Using proteomic approach to discover novel biomarkers involved in chemoresistance to B-RAF inhibitor in thyroid cancer.
Degree: Master, Institute of Biomedical Sciences, 2014, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0631114-003207 
► Thyroid carcinoma (TC) is the most common endocrine malignancy and is one of the most rapidly increasing human cancers worldwide. Anaplastic thyroid carcinoma (ATC) is…
(more)
▼ Thyroid carcinoma (TC) is the most common endocrine malignancy and is one of the most rapidly increasing human cancers worldwide. Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid gland malignancy. Patients with anaplastic thyroid cancer have a very poor prognosis, with a mean survival time of less than 6 months from the time of diagnosis.(Larkin et al.) Activating mutations of BRAF were reported recently in 60% of thyroid cancer, and BRAF mutation has been associated with poor prognosis, more cancer invasiveness, metastasis and recurrence in patients with thyroid cancer. In the present study, we sought to investigate the chemoresistance biomarkers for cisplatin, doxorubicin, PLX4032 (a specific BRAF
inhibitor) in thyroid cancer by using 2D-DIGE gel based proteomic approach. Anaplastic thyroid carcinoma cell lines were first cultured and long-term maintained in low concentration of cisplatin, doxorubicin, PLX4032 in order to establish chemoresistant stable clones, and further analyzed and characterized chemo-resistant associated proteins by using capillary LC/MS/MS proteomic method. Our results discovered that activated expression of GSTA1 after PLX4032 treatment in ARO cells. The identification of novel chemoresistant biomarker to PLX4032 may increase effectiveness of anaplastic thyroid cancer treatment, and improve the prognosis of thyroid cancer patients.
Advisors/Committee Members: Hung-Wen Huamg (chair), Kuang-hung Cheng (committee member), Chang-Chun Hsiao (chair).
Subjects/Keywords: thyroid cancer; BRAF inhibitor; proteomic; apoptosis; resistance
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APA (6th Edition):
Hou, Y. (2014). Using proteomic approach to discover novel biomarkers involved in chemoresistance to B-RAF inhibitor in thyroid cancer. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0631114-003207
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):
Hou, You-syuan. “Using proteomic approach to discover novel biomarkers involved in chemoresistance to B-RAF inhibitor in thyroid cancer.” 2014. Thesis, NSYSU. Accessed February 25, 2021.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0631114-003207.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Hou, You-syuan. “Using proteomic approach to discover novel biomarkers involved in chemoresistance to B-RAF inhibitor in thyroid cancer.” 2014. Web. 25 Feb 2021.
Vancouver:
Hou Y. Using proteomic approach to discover novel biomarkers involved in chemoresistance to B-RAF inhibitor in thyroid cancer. [Internet] [Thesis]. NSYSU; 2014. [cited 2021 Feb 25].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0631114-003207.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Hou Y. Using proteomic approach to discover novel biomarkers involved in chemoresistance to B-RAF inhibitor in thyroid cancer. [Thesis]. NSYSU; 2014. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0631114-003207
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Oxford
2.
Shan, Haidong.
Neuroprotection gene therapy in retinal degeneration.
Degree: PhD, 2013, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:30f9b5c3-b9a6-4ad0-a952-6840bd73bbc3
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581376
► Retinal degenerative disease, which includes age-related macular degeneration and retinitis pigmentosa, is the main cause of blindness in developed countries. Degeneration of the retinal pigment…
(more)
▼ Retinal degenerative disease, which includes age-related macular degeneration and retinitis pigmentosa, is the main cause of blindness in developed countries. Degeneration of the retinal pigment epithelium (RPE) and photoreceptor cells through apoptosis is believed to be the main mechanism of cell death. X-linked inhibitor of apoptosis (XIAP) is an endogenous anti-apoptotic protein that mediates its effects through the inhibition of caspases - the proteins regulating the final stages of apoptosis. The neuroprotection of XIAP has been demonstrated in various neurodegenerative models. Retinal gene therapy based on adeno-associated virus (AAV) has recently been proven safe and effective in clinical trials of Leber's congenital amaurosis. However, studies are very limited so far about AAV-mediated XIAP effect on degeneration of the RPE and photoreceptor cells. In this thesis, a comprehensive study of AAV-mediated XIAP was performed in the RPE and photoreceptor degenerative models. First, an oxidative stress model was investigated using H2O2 in a human RPE cell line. Second, AAV2-mediated XIAP conferred marked protection on the RPE cells against H2O2 induced apoptosis. Third, an in vivo analysis using confocal scanning laser ophthalmoscope was applied to the NaIO3 induced retinopathy in two transgenic mice (NRL-GFP and B6TGOPN1LW-EGFP). However, subretinal injection of AAV2-XIAP did not rescue photoreceptor cells in the NaIO3-treated animals. Finally, AAV8-XIAP was tested in a rhodopsin mutant mouse line with retinal degeneration (the Rho-/- B6TGOPN1LW-EGFP mouse) but did not reveal any protection on cone photoreceptors. Overall the work in this thesis indicates a limited protection of AAV-mediated XIAP on the RPE and photoreceptor cells in the degenerative models used. XIAP based gene therapy may be helpful for RPE preservation in atrophic AMD, but it needs further research.
Subjects/Keywords: 617.735; Ophthamology; X-linked inhibitor of apoptosis
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APA (6th Edition):
Shan, H. (2013). Neuroprotection gene therapy in retinal degeneration. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:30f9b5c3-b9a6-4ad0-a952-6840bd73bbc3 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581376
Chicago Manual of Style (16th Edition):
Shan, Haidong. “Neuroprotection gene therapy in retinal degeneration.” 2013. Doctoral Dissertation, University of Oxford. Accessed February 25, 2021.
http://ora.ox.ac.uk/objects/uuid:30f9b5c3-b9a6-4ad0-a952-6840bd73bbc3 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581376.
MLA Handbook (7th Edition):
Shan, Haidong. “Neuroprotection gene therapy in retinal degeneration.” 2013. Web. 25 Feb 2021.
Vancouver:
Shan H. Neuroprotection gene therapy in retinal degeneration. [Internet] [Doctoral dissertation]. University of Oxford; 2013. [cited 2021 Feb 25].
Available from: http://ora.ox.ac.uk/objects/uuid:30f9b5c3-b9a6-4ad0-a952-6840bd73bbc3 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581376.
Council of Science Editors:
Shan H. Neuroprotection gene therapy in retinal degeneration. [Doctoral Dissertation]. University of Oxford; 2013. Available from: http://ora.ox.ac.uk/objects/uuid:30f9b5c3-b9a6-4ad0-a952-6840bd73bbc3 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581376
University of Ottawa
3.
Enwere, Emeka K.
Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein
.
Degree: 2011, University of Ottawa
URL: http://hdl.handle.net/10393/20048
► The inhibitor of apoptosis (IAP) proteins traditionally regulate programmed cell death by binding to and inhibiting caspases. Recent studies have uncovered a variety of alternate…
(more)
▼ The inhibitor of apoptosis (IAP) proteins traditionally regulate programmed cell death by binding to and inhibiting caspases. Recent studies have uncovered a variety of alternate cellular roles for several IAP family members. The cellular inhibitor of apoptosis 1 (cIAP1) protein, for instance, regulates different axes of the NF-κB signalling pathway. Given the extensive functions of NF-κB signalling in muscle differentiation and regeneration, I asked if cIAP1 also plays critical roles in skeletal muscle myogenesis. In a primary myoblast cell-culture system, genetic and pharmacological approaches revealed that loss of cIAP1 dramatically increases the fusion of myoblasts into myotubes. NF-κB signalling occurs along a classical and an alternative pathway, both of which are highly active in cIAP1-/- myoblasts. Suppression of the alternative pathway attenuates myotube fusion in wildtype and cIAP1-/- myoblasts. Conversely, constitutive activation of the alternative pathway increases myoblast fusion in wildtype myoblasts. cIAP1-/- mice have greater muscle weight and size than wildtypes, as well as an increased number of muscle stem cells. These results identify cIAP1 as a regulator of myogenesis through its modulation of classical and alternative NF-κB signalling pathways.
Loss of the structural protein dystrophin in the mdx mouse model of Duchenne muscular dystrophy leads to chronic degeneration of skeletal muscle. The muscle pathology is strongly influenced by NF-κB signaling. Given the roles demonstrated for cIAP1 in cell culture and in vivo, I asked whether loss of cIAP1 would influence muscle pathology in the mdx mouse. To address this question, double-mutant mice were bred lacking both cIAP1 and dystrophin (cIAP1-/-;mdx). Histological analyses revealed that double-mutant mice exhibited reduced indications of damage on several measures, as compared to single-mutant (cIAP1+/+;mdx) controls. Unexpectedly, these reductions were seen in the “slow-twitch” soleus muscle but not in the “fast-twitch” extensor digitorum longus (EDL) muscle. The improvements in pathology of double-mutant solei were associated with reductions in muscle infiltration by CD68-expressing macrophages. Finally, the double-mutant mice exhibited improved endurance and resistance to damage during treadmill-running exercise. Taken together, these results suggest that loss of cIAP1, through its multiple regulatory functions, acts to improve myogenesis and increase muscle resistance to damage.
Subjects/Keywords: skeletal muscle;
myogenesis;
Transcription factor;
Apoptosis;
Inhibitor of apoptosis;
myoblast
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APA ·
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APA (6th Edition):
Enwere, E. K. (2011). Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/20048
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):
Enwere, Emeka K. “Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein
.” 2011. Thesis, University of Ottawa. Accessed February 25, 2021.
http://hdl.handle.net/10393/20048.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Enwere, Emeka K. “Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein
.” 2011. Web. 25 Feb 2021.
Vancouver:
Enwere EK. Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein
. [Internet] [Thesis]. University of Ottawa; 2011. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10393/20048.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Enwere EK. Regulation of Skeletal Muscle Formation and Regeneration by the Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein
. [Thesis]. University of Ottawa; 2011. Available from: http://hdl.handle.net/10393/20048
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Texas Medical Center
4.
Manton, Christa A.
Induction of caspase-dependent death by proteasome targeted therapy in glioblastoma.
Degree: PhD, 2015, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/545
► New therapeutic options are needed for glioblastoma, a deadly disease with a median survival of only 14 months with current treatment. The proteasome inhibitor…
(more)
▼ New therapeutic options are needed for glioblastoma, a deadly disease with a median survival of only 14 months with current treatment. The proteasome
inhibitor bortezomib (BTZ) shows efficacy in cancers like myeloma, but its clinical utility in other cancer types has been more limited. Newer proteasome inhibitors such as marizomib (MRZ) have unique inhibitory and death inducing properties that have not been well examined in GBM. Additionally, targeting other components of the ubiquitin-proteasome system is possible, but has not been explored in GBM. Questions also still remain about the ability of BTZ and MRZ to be delivered to brain tumors in a relevant orthotopic system. The goal of this study was to determine the kinetics and mechanism of death induced by proteasome inhibitors in GBM and to compare the ability of BTZ and MRZ to cause proteasome inhibition in orthotopic brain tumors in order to establish a framework for the use of these drugs in the clinic by identifying potential biomarkers of efficacy and enabling design of a combination treatment strategy for potentiation of cell death in GBM. Using strategies that inhibited multiple proteasome components, I determined that inhibition of the standard proteasome by BTZ and MRZ was sufficient for optimal targeting of the ubiquitin-proteasome system in GBM. I then determined that both BTZ and MRZ induced caspase-dependent death in GBM cells that was dependent upon activation of caspase 9. Using an orthotopic xenograft model of GBM, I found that both BTZ and MRZ increased levels of the proteasome substrates p21 and p27 in intracranial tumors, with MRZ exerting slightly stronger effects, indicating that these drugs do affect brain tumors. Examination of cleaved caspase 3 and lamin A as markers of
apoptosis in brain tumors from mice showed increased cell death after treatment with BTZ or MRZ and the histone deacetylase
inhibitor vorinostat. Together, this data clarifies the optimal strategy for proteasome targeting in GBM, clarifies the hierarchy of caspase induction by proteasome inhibitors, and provides evidence that proteasome inhibitors can reach brain tumors where they exert functional effects and increase death in combination with vorinostat.
Advisors/Committee Members: Joya Chandra, Candelaria Gomez-Manzano, Terzah Horton.
Subjects/Keywords: bortezomib; marizomib; proteasome; proteasome inhibitor; glioblastoma; caspase; apoptosis; vorinostat; histone deacetylase inhibitor; Cancer Biology
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APA ·
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APA (6th Edition):
Manton, C. A. (2015). Induction of caspase-dependent death by proteasome targeted therapy in glioblastoma. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/545
Chicago Manual of Style (16th Edition):
Manton, Christa A. “Induction of caspase-dependent death by proteasome targeted therapy in glioblastoma.” 2015. Doctoral Dissertation, Texas Medical Center. Accessed February 25, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/545.
MLA Handbook (7th Edition):
Manton, Christa A. “Induction of caspase-dependent death by proteasome targeted therapy in glioblastoma.” 2015. Web. 25 Feb 2021.
Vancouver:
Manton CA. Induction of caspase-dependent death by proteasome targeted therapy in glioblastoma. [Internet] [Doctoral dissertation]. Texas Medical Center; 2015. [cited 2021 Feb 25].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/545.
Council of Science Editors:
Manton CA. Induction of caspase-dependent death by proteasome targeted therapy in glioblastoma. [Doctoral Dissertation]. Texas Medical Center; 2015. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/545
5.
Mehrotra, Swarna.
IAP Regulation of Tumor Metastasis: A Dissertation.
Degree: Cancer Biology, Department of Cancer Biology, 2009, U of Massachusetts : Med
URL: https://escholarship.umassmed.edu/gsbs_diss/437
► The dissemination of tumor cells to distant organs i.e. metastasis is an exceedingly complex process leading to 90% of all cancer deaths. Despite being…
(more)
▼ The dissemination of tumor cells to distant organs i.e. metastasis is an exceedingly complex process leading to 90% of all cancer deaths. Despite being so clinically important, little is known about this process that requires tumor cells to leave the primary tumor site, intravasate and transport through the blood stream, extravasate and colonize at secondary sites leading to distant metastases. Survivin, a member of the IAP (
Inhibitor of
Apoptosis) family with known functions in
apoptosis and mitosis, is highly expressed in aggressive tumors and is associated with poor prognosis and adverse clinical outcome. But the mechanistic role of survivin in metastatic dissemination has not been investigated. In this study, we demonstrate an important and novel role of survivin in activating a broad gene expression program in tumor cells. Of particular importance is the upregulation of a distinct class of cell adhesion molecules, particularly fibronectin. This IAP mediated gene regulation requires synergistic intermolecular cooperation between survivin and its related cofactor molecule, XIAP that results in activation of NF-κB dependent fibronectin gene expression. The binding of fibronectin with its cognate cell surface receptors initiates outside–in signaling leading to the autocrine and paracrine activation of cell motility kinases, FAK and Src, in turn leading to enhanced tumor invasion and metastasis. The importance of survivin and XIAP in the process of metastasis has also been demonstrated
in vivousing intrasplenic injections in mouse models.
Overall this study is the first to place survivin upstream of transcriptional activation of gene expression particularly fibronectin. In addition, it also demonstrates the importance of survivin-XIAP complex in mediating NF-κB activation which in turn switches on the expression of various target genes involved in tumor metastasis. Hence this study dissects the upstream and downstream requirements of survivin- XIAP complex mediated tumor dissemination and metastasis.
Significance of this Study
The hallmark of end-stage cancer is metastasis, an incurable condition almost invariably associated with death from disease. Despite a better understanding of the metastatic process, and the identification of key gene expression requirements of this pathway, the development of anti-metastatic therapies has lagged behind, with no viable options being currently offered in the clinical setting. Our findings that
Inhibitor of
Apoptosis (IAP) proteins functions as metastasis-promoting genes independently of cell survival, but through activation of cell motility could have important ramifications for the broader application of IAP antagonists currently in early clinical trials, as novel anti-metastatic therapies.
Advisors/Committee Members: Dario C. Altieri, M.D..
Subjects/Keywords: Neoplasm Metastasis; Inhibitor of Apoptosis Proteins; Fibronectins; Transcriptional Activation; X-Linked Inhibitor of Apoptosis Protein; Amino Acids, Peptides, and Proteins; Neoplasms
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APA ·
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APA (6th Edition):
Mehrotra, S. (2009). IAP Regulation of Tumor Metastasis: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/437
Chicago Manual of Style (16th Edition):
Mehrotra, Swarna. “IAP Regulation of Tumor Metastasis: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 25, 2021.
https://escholarship.umassmed.edu/gsbs_diss/437.
MLA Handbook (7th Edition):
Mehrotra, Swarna. “IAP Regulation of Tumor Metastasis: A Dissertation.” 2009. Web. 25 Feb 2021.
Vancouver:
Mehrotra S. IAP Regulation of Tumor Metastasis: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2021 Feb 25].
Available from: https://escholarship.umassmed.edu/gsbs_diss/437.
Council of Science Editors:
Mehrotra S. IAP Regulation of Tumor Metastasis: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/437
6.
甲斐, 健太郎.
Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis.
Degree: 博士(医学), 2016, Oita University / 大分大学
URL: http://hdl.handle.net/10559/15603
► PROBLEM: The purpose of this study is to evaluate the involvement of death receptor (DR) 6 in the pathogenesis of endometriosis.
METHODS OF STUDY: Endometriotic…
(more)
▼ PROBLEM: The purpose of this study is to evaluate the involvement of death receptor (DR) 6 in the pathogenesis of endometriosis.
METHODS OF STUDY: Endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were isolated from ovarian endometriotic tissues and the eutopic endometrial tissues, respectively. The effect of valproic acid (VPA) on the DR6 expression in ECSCs was examined. The roles of DR6 in NESC proliferation and apoptosis were investigated with DR6 siRNA transfection. The distribution of DR6 protein in ovarian endometriotic tissues and normal proliferative-phase endometrium was examined by immunohistochemistry. The expression of DR6 mRNA and protein in ECSCs and NESCs was also examined.
RESULTS: Death receptor 6 expression was attenuated in ECSCs and in endometriotic tissues, and its expression was upregulated by VPA stimulation. VPA treatment resulted in an accumulation of acetylated histone H4 in the promoter region of the DR6 gene. DR6 knockdown directed the stimulation of cell proliferation and the resistance to apoptosis in NESCs.
CONCLUSION: The present findings suggested that DR6 is involved in the pathogenesis of endometriosis by creating the proliferative and anti-apoptotic characteristics of endometriosis. The results also suggest that histone deacetylase inhibitors are promising agents for the treatment of endometriosis.
Subjects/Keywords: Apoptosis; death receptor 6; epigenetics; endometriosis; histone deacetylase inhibitor; proliferation
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APA ·
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APA (6th Edition):
甲斐, . (2016). Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis. (Thesis). Oita University / 大分大学. Retrieved from http://hdl.handle.net/10559/15603
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):
甲斐, 健太郎. “Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis.” 2016. Thesis, Oita University / 大分大学. Accessed February 25, 2021.
http://hdl.handle.net/10559/15603.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
甲斐, 健太郎. “Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis.” 2016. Web. 25 Feb 2021.
Vancouver:
甲斐 . Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis. [Internet] [Thesis]. Oita University / 大分大学; 2016. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10559/15603.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
甲斐 . Death Receptor 6 is Epigenetically Silenced by Histone Deacetylation in Endometriosis and Promotes the Pathogenesis of Endometriosis. [Thesis]. Oita University / 大分大学; 2016. Available from: http://hdl.handle.net/10559/15603
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Bradford
7.
Kamala, Ola.
A comparison of cultured human dermal fibroblasts derived from terminal and vellus hair bearing skin : differences in the expression of inhibitors of apoptosis proteins, oestrogen receptors, and responses to oestradiol under normal and wound induced conditions.
Degree: PhD, 2014, University of Bradford
URL: http://hdl.handle.net/10454/13841
► Wounds heal better in skin with terminal hair follicles (large and pigmented) as opposed to those with vellus hair follicles (small and unpigmented), while dermal…
(more)
▼ Wounds heal better in skin with terminal hair follicles (large and pigmented) as opposed to those with vellus hair follicles (small and unpigmented), while dermal fibroblasts from different anatomical regions also exhibit phenotypical differences. Tissue repair requires a tight control of cell proliferation, migration and apoptosis, and recent studies have shown the importance of inhibitors of apoptosis proteins (IAPs), which are proteins that prevent the process of apoptosis via their interaction with caspase molecules in wound healing. Oestrogens improve the rate and quality of wound healing, but their relationship with IAPs in human skin has not been studied. Therefore, terminal (scalp) and vellus (facial) hair bearing skin from the same donor was compared in situ and matching primary cultures of dermal fibroblasts were established from terminal (DF(T)) and vellus (DF(V)) hair bearing skin. Using immunofluorescent staining, the expression of IAPs and their antagonists was compared at different stages of the hair cycle following depilation using a murine model and then in terminal and vellus hair bearing human skin. The size and granularity of matching DF(T) and DF(V) cultures was compared by FACS analysis and mRNA and protein expression of Apollon, cIAP2, NAIP and XIAP and their antagonists DIABLO and Xaf1 analysed by qRT-PCR and immunocytochemistry in unwounded and mechanically wounded fibroblast cultures. Differences in proliferation, migration, viability and caspase 3 activity in the presence of 17β-oestradiol and changes in mRNA expression of the oestrogen receptors (GPR30, ERα and ERβ) were compared between the two cell types. IAP protein expression was generally found higher during mid anagen of the hair cycle in murine skin and hair follicles. Overall, expression was slightly higher in human terminal hair bearing skin compared to corresponding vellus hair bearing skin. IAP protein expression was similar in unwounded DF(T) and DF(V) cells with the exception of Apollon which was higher in DF(V) cells. With the exception of XIAP and its direct antagonist Xaf1, mRNA expression was higher in DF(V) cells compared to corresponding DF(T) cells. FACS analysis demonstrated that DF(V) cells were more granular than matching DF(T) cells and proliferated faster. 17β-oestradiol accelerated migration of DF(T) cells only. Mechanical wounding decreased XIAP mRNA in DF(T) and increased it in DF(V) cells, while simultaneously decreasing Xaf1 expression. In unwounded cells, 17β-oestradiol stimulated the expression of XIAP mRNA in both DF(T) and DF(V) cells, but in scratched monolayers, while it also increased expression in DF(T) cells it decreased it in DF(V) cells. A XIAP inhibitor reduced cell viability in both DF(T) and DF(V) cells, which was rescued by 17β-oestradiol in unwounded and mechanically wounded DF(T) cells, but only in unwounded DF(V) cells. 17β-oestradiol decreased caspase 3 activity in the presence of a XIAP inhibitor only in DF(T) cells. These results demonstrate significant differences between dermal…
Subjects/Keywords: 616.5; Wound Healing; Inhibitor of Apoptosis Proteins (IAPs); Oestrogen; Hair Follicle
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APA ·
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MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
Kamala, O. (2014). A comparison of cultured human dermal fibroblasts derived from terminal and vellus hair bearing skin : differences in the expression of inhibitors of apoptosis proteins, oestrogen receptors, and responses to oestradiol under normal and wound induced conditions. (Doctoral Dissertation). University of Bradford. Retrieved from http://hdl.handle.net/10454/13841
Chicago Manual of Style (16th Edition):
Kamala, Ola. “A comparison of cultured human dermal fibroblasts derived from terminal and vellus hair bearing skin : differences in the expression of inhibitors of apoptosis proteins, oestrogen receptors, and responses to oestradiol under normal and wound induced conditions.” 2014. Doctoral Dissertation, University of Bradford. Accessed February 25, 2021.
http://hdl.handle.net/10454/13841.
MLA Handbook (7th Edition):
Kamala, Ola. “A comparison of cultured human dermal fibroblasts derived from terminal and vellus hair bearing skin : differences in the expression of inhibitors of apoptosis proteins, oestrogen receptors, and responses to oestradiol under normal and wound induced conditions.” 2014. Web. 25 Feb 2021.
Vancouver:
Kamala O. A comparison of cultured human dermal fibroblasts derived from terminal and vellus hair bearing skin : differences in the expression of inhibitors of apoptosis proteins, oestrogen receptors, and responses to oestradiol under normal and wound induced conditions. [Internet] [Doctoral dissertation]. University of Bradford; 2014. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10454/13841.
Council of Science Editors:
Kamala O. A comparison of cultured human dermal fibroblasts derived from terminal and vellus hair bearing skin : differences in the expression of inhibitors of apoptosis proteins, oestrogen receptors, and responses to oestradiol under normal and wound induced conditions. [Doctoral Dissertation]. University of Bradford; 2014. Available from: http://hdl.handle.net/10454/13841
8.
COYLE, RACHEL.
Inhibitor of Apoptosis Proteins as Targets for the Treatment of Malignant Rhabdoid Tumours.
Degree: School of Biochemistry & Immunology. Discipline of Biochemistry, 2019, Trinity College Dublin
URL: http://hdl.handle.net/2262/86089
► Malignant rhabdoid tumor (MRT) is a rare paediatric cancer which unfortunately is highly refractive to treatment. Retrospective reviews commonly place the survival rate at approximately…
(more)
▼ Malignant rhabdoid tumor (MRT) is a rare paediatric cancer which unfortunately is highly refractive to treatment. Retrospective reviews commonly place the survival rate at approximately 30-35 %. Thus, there is an urgent need for the development of new targeted therapies which may improve patient outcomes. Several members of the
inhibitor of
apoptosis protein (IAP) family have been shown to inhibit
apoptosis namely; X-linked
inhibitor of
apoptosis (XIAP), cellular
inhibitor of
apoptosis proteins 1 and 2 (cIAP1, cIAP2), livin and survivin. These IAPs have been linked to chemotherapy resistance and their overexpression correlated with a poorer prognosis in several malignancies. Their role in MRT has not yet been established. In the present study, the expression of a number of these IAPs in a panel of MRT cell lines was detected. Also, treatment with the XIAP
inhibitor embelin, the SMAC mimetic BV6 and the survivin
inhibitor YM155 decreased the viability of these cell lines. Moreover, expression of XIAP, its target caspase 3 and its endogenous
inhibitor SMAC was demonstrated in patient samples.
In this study, the XIAP
inhibitor embelin was demonstrated to synergistically enhance cell death in combination with the front-line chemotherapeutic cisplatin in MRT cells. This was associated with complete depletion of the IAPs, alongside enhanced caspase activation following combination treatment. Likewise, treatment with BV6 was shown to decrease expression levels of a number of IAPs. As per the results seen with embelin, BV6 worked synergistically with cisplatin to enhance cell death in MRT cells. Preliminary results suggest possible ripoptosome involvement in cisplatin and BV6 mediated cell death.
Embelin was also found to sensitise MRT cell lines to TRAIL via the extrinsic apoptotic pathway with additional engagement of the intrinsic apoptotic pathway. This was supported by caspase 8/3 and Bid cleavage along with SMAC release into the cytosol. Also, addition of a general caspase
inhibitor, or a specific caspase 8
inhibitor prevented cell death. Western blot analysis over a wide range of timepoints suggested that this enhanced cell death likely occurred via a multifactorial mechanism encompassing decreased expression of a number of anti-apoptotic proteins including survivin, FLIPL and in particular Mcl-1, which had reduced levels from as early as 4 hours. The fact that embelin is an
inhibitor of XIAP and that siRNA mediated XIAP knockdown also significantly enhanced TRAIL mediated cell death suggests that XIAP inhibition is also partially responsible for the synergistic effects observed. Livin cleavage may also have been a contributing factor.
To conclude, this study provides pre-clinical evidence that IAP inhibition may be a therapeutic option in MRT either as a stand-alone or combinatorial treatment. Further studies are warranted and should include examination of IAP targeted therapeutics in an in vivo setting.
Advisors/Committee Members: Zisterer, Daniela.
Subjects/Keywords: Malignant rhabdoid tumour; XIAP; Cancer; Inhibitor of apoptosis proteins
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APA (6th Edition):
COYLE, R. (2019). Inhibitor of Apoptosis Proteins as Targets for the Treatment of Malignant Rhabdoid Tumours. (Thesis). Trinity College Dublin. Retrieved from http://hdl.handle.net/2262/86089
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):
COYLE, RACHEL. “Inhibitor of Apoptosis Proteins as Targets for the Treatment of Malignant Rhabdoid Tumours.” 2019. Thesis, Trinity College Dublin. Accessed February 25, 2021.
http://hdl.handle.net/2262/86089.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
COYLE, RACHEL. “Inhibitor of Apoptosis Proteins as Targets for the Treatment of Malignant Rhabdoid Tumours.” 2019. Web. 25 Feb 2021.
Vancouver:
COYLE R. Inhibitor of Apoptosis Proteins as Targets for the Treatment of Malignant Rhabdoid Tumours. [Internet] [Thesis]. Trinity College Dublin; 2019. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/2262/86089.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
COYLE R. Inhibitor of Apoptosis Proteins as Targets for the Treatment of Malignant Rhabdoid Tumours. [Thesis]. Trinity College Dublin; 2019. Available from: http://hdl.handle.net/2262/86089
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Bath
9.
Mafuva, Christopher.
Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells.
Degree: Thesis (D.Health), 2019, University of Bath
URL: https://researchportal.bath.ac.uk/en/studentthesis/effect-of-ethinylestradiol-and-levonorgestrel-on-nucleoside-reverse-transcriptase-inhibitorinduced-apoptosis-in-human-cervical-epithelial-cancer-cells(9d6b72a6-62d5-4608-bb3e-a0d2b6685f8d).html
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.817805
► Preliminary findings suggest an increase in cervical cancer among sub-Sahara African women on highly active antiretroviral treatment (HAART). There has been a sharp rise in…
(more)
▼ Preliminary findings suggest an increase in cervical cancer among sub-Sahara African women on highly active antiretroviral treatment (HAART). There has been a sharp rise in serious non-AIDS events among HAART recipients. This study explored the effect of co-administering combined contraceptive hormones with antiretroviral drugs on promoting human cervical epithelial cancer cell proliferation, DNA mutation and cell transformation. Combinations of abacavir (ABC), zidovudine (ZDV), lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) were co-administered with either ethinylestradiol or levonorgestrel. The combinations ZDV+3TC, ABC+ZDV+3TC, ZDV+3TC+NVP and d4T+3TC+NVP induced a time-dependent antiproliferative effect on HeLa cells. Co-treatment with levonorgestrel demonstrated antiproliferative effects on combination antiretroviral drug-treated cells while co-administering 0.5μg/ml ethinylestradiol increases HeLa cell proliferation (P≤ 0.5). Single drugs (ABC, ZDV, 3TC, d4T and NVP) showed a time-dependent DNA double strand breakage in both HeLa and Chinese hamster ovary cells. Both levonorgestrel and ethinylestradiol drastically increased apoptosis in ABC+3TC-, ZDV+3TC-, ABC+ZDV+3TC- and d4T+3TC+NVP-treated cells. Highly active antiretroviral treatment transformed pre-monocyte lymphoma (U937) cells to adherent cells with macrophage-like morphology and increased superoxide production. Increased HeLa cell death by apoptosis following co-administration of triple combination antiretroviral drugs with levonorgestrel suggests a protective effect against human cervical cancer cell proliferation among HAART users. Despite the drastic induction of apoptosis by 0.5μg/ml ethinylestradiol, ABC+3T-, ZDV+3TC-, ABC+ZDV+3TC- and ZDV+3TC+NVP-treated cells did not significantly differ from the untreated cells in their proliferation assayed by MTT (P≤0.05), thus suggesting a proliferative effect on the human cervical epithelial cancer cells. Transformation to macrophage-like morphology and increased superoxide anion production in U937 cells suggest precipitation of serious non-AIDs events among HAART users. The antiproliferative effect of HAART on cervical cancer cells suggests a protective role against cell proliferation. The antiproliferative effect of levonorgestrel suggests its potential as a progestogen-only contraceptive alternative for women on HAART treatment. The present results also suggest the downside effect of HAART through precipitation of serious non-AIDS events. Further in vivo clinical studies maybe of interest.
Subjects/Keywords: Nucleoside; reverse transcriptase inhibitor; apoptosis; cervical; cancer cells
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APA ·
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MLA ·
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CSE |
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Manager
APA (6th Edition):
Mafuva, C. (2019). Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells. (Doctoral Dissertation). University of Bath. Retrieved from https://researchportal.bath.ac.uk/en/studentthesis/effect-of-ethinylestradiol-and-levonorgestrel-on-nucleoside-reverse-transcriptase-inhibitorinduced-apoptosis-in-human-cervical-epithelial-cancer-cells(9d6b72a6-62d5-4608-bb3e-a0d2b6685f8d).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.817805
Chicago Manual of Style (16th Edition):
Mafuva, Christopher. “Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells.” 2019. Doctoral Dissertation, University of Bath. Accessed February 25, 2021.
https://researchportal.bath.ac.uk/en/studentthesis/effect-of-ethinylestradiol-and-levonorgestrel-on-nucleoside-reverse-transcriptase-inhibitorinduced-apoptosis-in-human-cervical-epithelial-cancer-cells(9d6b72a6-62d5-4608-bb3e-a0d2b6685f8d).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.817805.
MLA Handbook (7th Edition):
Mafuva, Christopher. “Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells.” 2019. Web. 25 Feb 2021.
Vancouver:
Mafuva C. Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells. [Internet] [Doctoral dissertation]. University of Bath; 2019. [cited 2021 Feb 25].
Available from: https://researchportal.bath.ac.uk/en/studentthesis/effect-of-ethinylestradiol-and-levonorgestrel-on-nucleoside-reverse-transcriptase-inhibitorinduced-apoptosis-in-human-cervical-epithelial-cancer-cells(9d6b72a6-62d5-4608-bb3e-a0d2b6685f8d).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.817805.
Council of Science Editors:
Mafuva C. Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells. [Doctoral Dissertation]. University of Bath; 2019. Available from: https://researchportal.bath.ac.uk/en/studentthesis/effect-of-ethinylestradiol-and-levonorgestrel-on-nucleoside-reverse-transcriptase-inhibitorinduced-apoptosis-in-human-cervical-epithelial-cancer-cells(9d6b72a6-62d5-4608-bb3e-a0d2b6685f8d).html ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.817805
University of Southern California
10.
Fang, Hua.
Targeting BCL-2 family proteins and plasminogen activator
inhibitor-1 in turmor cell apoptosis.
Degree: Doctor of Medicine, Pathobiology, 2012, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/33557/rec/6323
► Resistance to cell death, especially to apoptosis, is an important feature of tumor cells, which is also described as one of the hallmarks in cancer.…
(more)
▼ Resistance to cell death, especially to
apoptosis, is
an important feature of tumor cells, which is also described as one
of the hallmarks in cancer. The
apoptosis machinery can be divided
into two major pathways based on the source of death signaling, the
Bcl-2-regulated (known as intrinsic or mitochondrial) apoptotic
pathway and death receptor-regulated (known as extrinsic) apoptotic
pathway. ❧ In Chapter 2 of this dissertation, I studied how tumor
cell
apoptosis could be a target for therapeutic intervention by
examining the synergistic activity of a novel drug combination-
ABT-737, a small molecule
inhibitor of Bcl-2 family proteins, and
Fenretinide (4-HPR), a cytotoxic retinoid - in preclinical models
of childhood cancer neuroblastoma. Multilog synergistic
cytotoxicity was observed for the drug combination in all of the
eleven neuroblastoma cell lines tested. ABT-737 + 4-HPR induced
greater mitochondrial membrane depolarization and mitochondrial
cytochrome c release, greater activation of caspases, Bax-α, t-Bid,
and Bak, and a higher level of
apoptosis than either drug alone. In
vivo, ABT-737 + 4-HPR increased the event-free survival (EFS) of
the multidrug-resistant human neuroblastoma line CHLA-119 implanted
subcutaneously in nu/nu mice. Thus, the combination of ABT-737 and
4-HPR warrants clinical trials in recurrent neuroblastoma. ❧ In
Chapter 3 of this dissertation, I have studied how tumor
apoptosis
could be regulated by plasminogen activator
inhibitor-1, which is
an
inhibitor of urokinase plasminogen activator, an extracellular
protease in tumor microenvironment. ❧ PAI-1 is a predictor of poor
outcome in cancer. An explanation for this paradoxical role has
been its pro-angiogenic activity. The effect of PAI-1 on tumor
cells has not been explored. Here we have examined the effect of
PAI-1 knockdown (KD) on the survival of human cancer cell lines in
vitro and in vivo. We demonstrated a decrease in survival and an
increase in
apoptosis in the four cell lines when PAI-1 was
genetically (siRNA) or pharmacologically (PAI-1
inhibitor, PAI-039)
suppressed.
Apoptosis was blocked by a caspase-8
inhibitor,
Fas/FasL neutralizing antibodies, and plasmin inhibitors. Stable
PAI-1 KD tumor cells were generated by the transduction of short
hairpin RNA lentivirus and examined for tumorigenicity in
immunodeficient PAI-1 wildtype and knockout (KO) mice. In vivo, we
observed a decrease in tumor growth, tumor take, cell proliferation
and angiogenesis and an increase in
apoptosis in PAI-1 KD HT-1080
in PAI-1 KO mice. A similar inhibition in tumor growth was observed
when PAI-1 KD HCT-116 or A549 cells were implanted in PAI-1 KO
mice. In conclusion, PAI-1 exerts a protective effect against
extrinsic
apoptosis in tumor cells. Downregulation of PAI-1 in both
tumor and host cells is necessary for a significant inhibitory
activity on tumorigenesis through a dual effect on tumor cell and
endothelial cell
apoptosis. The data suggest that PAI-1 may be
necessary for tumor growth and support further investigation of the
use of PAI-1…
Advisors/Committee Members: Dubeau, Louis (Committee Chair), DeClerck, Yves A. (Committee Member), Chuong, Cheng-ming (Committee Member), Erdreich-Epstein, Anat (Committee Member), Kalra, Vijay K. (Committee Member).
Subjects/Keywords: apoptosis; Bcl-2; ABT-737; plasminogen activator inhibitor-1; cancer
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Fang, H. (2012). Targeting BCL-2 family proteins and plasminogen activator
inhibitor-1 in turmor cell apoptosis. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/33557/rec/6323
Chicago Manual of Style (16th Edition):
Fang, Hua. “Targeting BCL-2 family proteins and plasminogen activator
inhibitor-1 in turmor cell apoptosis.” 2012. Doctoral Dissertation, University of Southern California. Accessed February 25, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/33557/rec/6323.
MLA Handbook (7th Edition):
Fang, Hua. “Targeting BCL-2 family proteins and plasminogen activator
inhibitor-1 in turmor cell apoptosis.” 2012. Web. 25 Feb 2021.
Vancouver:
Fang H. Targeting BCL-2 family proteins and plasminogen activator
inhibitor-1 in turmor cell apoptosis. [Internet] [Doctoral dissertation]. University of Southern California; 2012. [cited 2021 Feb 25].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/33557/rec/6323.
Council of Science Editors:
Fang H. Targeting BCL-2 family proteins and plasminogen activator
inhibitor-1 in turmor cell apoptosis. [Doctoral Dissertation]. University of Southern California; 2012. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/33557/rec/6323
11.
Wang, Jin.
Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors.
Degree: PhD, Pharmaceutical Sciences, 2015, University of Tennessee Health Science Center
URL: https://dc.uthsc.edu/dissertations/282
► The first part (Chapter 1 and 2) of this dissertation presents a novel combination study of melanoma therapy. Acquired clinical resistance to vemurafenib, a…
(more)
▼ The first part (Chapter 1 and 2) of this dissertation presents a novel combination study of melanoma therapy. Acquired clinical resistance to vemurafenib, a selective BRAFV600E
inhibitor, arises frequently after short term chemotherapy. Since the inhibitions of targets in the RAFMEK-ERK pathway result in G0/G1 cell cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin
inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in G1/G2/M phase, and significantly increased
apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the
apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of ERK phosphorylation. Finally, in vivo co-administration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current BRAF inhibition therapy.
The second part (Chapter 3 to 5) of this dissertation focuses on the discovery of a series of small molecule survivin inhibitors. Inhibitors of
apoptosis (IAP) proteins are widely considered as promising cancer drug targets, especially for drug-resistant tumors. Mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (Smac) is a rational strategy to design potential IAP inhibitors. In this report, we used the bioactive conformation of AVPI tetrapeptide in the N-terminus of Smac as a template and performed a shape-based virtual screening against a drug-like compound library to identify novel IAP inhibitors. Top hits were subsequently docked to available IAP crystal structures as a secondary screening followed by validation using in vitro biological assays. Four novel hit compounds were identified that potently inhibited cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines. The best compound, UC-112, has IC50 values ranging from 0.7 to 3.4 µM. UC-112 also potently inhibits the growth of P-glycoprotein (Pgp)…
Advisors/Committee Members: Wei Li, Ph.D..
Subjects/Keywords: BRAF inhibitor; combination therapy; inhibitor of apoptosis; melanoma; survivin inhibitor; tubulin inhibitor; Medicinal and Pharmaceutical Chemistry; Medicine and Health Sciences; Pharmaceutics and Drug Design; Pharmacy and Pharmaceutical Sciences
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Wang, J. (2015). Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/282
Chicago Manual of Style (16th Edition):
Wang, Jin. “Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors.” 2015. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed February 25, 2021.
https://dc.uthsc.edu/dissertations/282.
MLA Handbook (7th Edition):
Wang, Jin. “Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors.” 2015. Web. 25 Feb 2021.
Vancouver:
Wang J. Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2015. [cited 2021 Feb 25].
Available from: https://dc.uthsc.edu/dissertations/282.
Council of Science Editors:
Wang J. Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2015. Available from: https://dc.uthsc.edu/dissertations/282
Freie Universität Berlin
12.
Quast, Sandra-Annika.
Sensitization of melanoma cells for TRAIL-induced apoptosis by signaling
pathway inhibitors.
Degree: 2013, Freie Universität Berlin
URL: http://dx.doi.org/10.17169/refubium-8007
► The incidence of malignant melanoma, the most aggressive form of skin cancer, has grown dramatically worldwide in recent decades and is still growing faster than…
(more)
▼ The incidence of malignant melanoma, the most aggressive form of skin cancer,
has grown dramatically worldwide in recent decades and is still growing faster
than other malignancies. Despite increasing incidence, predictions and
survival rates have been improving since the 1960s, which can be attributed to
early diagnosis and early surgical removal of thin tumors. Nonetheless, the
metastatic melanoma is still characterized by an unbroken high mortality in
connection with therapy resistance. To date, there are no truly effective
therapies for malignant melanoma. The pronounced resistance to
chemotherapeutic agents as well as to an anti-tumor immune response is often
related to defects in proapoptotic signaling. Overcoming
apoptosis resistance
therefore appears to be a promising therapeutic goal for malignant melanoma.
Death ligands have demonstrated a certain potential for cancer therapy both in
vitro and in vivo. The death ligand TRAIL (TNF-related
apoptosis-inducing
ligand) appears to induce
apoptosis in a variety of cancer cell lines, while
normal cells remain largely unaffected. However, melanoma cells reveal both
preexisting and inducible TRAIL resistance. In the present work, mechanisms
for overcoming TRAIL-resistance were examined by various signaling pathway
inhibitors. These include the inhibitors of the PI3K-Akt/PKB-mTOR pathway
wortmannin and rapamycin. In addition to the death ligands and kinases,
potassium channels have also emerged as promising therapeutic targets because
they are heavily involved in tumor progression. The triarylmethane TRAM-34,
which inhibits the Ca2+-dependent potassium channel KCa3.1, was therefore also
examined. TRAM-34 is capable of enhancing death ligand-induced
apoptosis
synergistically and to overcome the resistance to TRAIL and the agonistic CD95
antibody (CH-11) in a variety of melanoma cell lines, although TRAM-34 itself
does not induce
apoptosis. In addition to the expression of KCa3.1 channels in
the plasma membrane, which had previously been described for melanoma, KCa3.1
expression was detected in the mitochondrial membrane. Inhibition of the
KCa3.1 channels by TRAM-34 resulted in a hyperpolarization of the
mitochondrial membrane and an early activation of Bax. Closer investigations
of the apoptotic signaling pathways revealed upregulation of both TRAIL
receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) and activation of the intrinsic
apoptosis pathway. The combination of TRAM-34 and TRAIL led to a strong
release of pro-apoptotic, mitochondrial factors cytochrome c, AIF and
SMAC/DIABLO. The knockout of Bax and Bcl-2 overexpression blocked the TRAM-34
/TRAIL-induced
apoptosis almost completely. In addition to Bax the balance
between the IAPs (
inhibitor of
apoptosis proteins) and SMAC/DIABLO has also
been shown to be important for the regulation of TRAIL sensitivity. The siRNA-
mediated Knockdown of SMAC resulted in blocking of the TRAM-34/TRAIL-induced
apoptosis, overexpression of XIAP to a partial blockage of
apoptosis. The
synergistic effects of TRAM-34/TRAIL resulted from the…
Advisors/Committee Members: [email protected] (contact), w (gender), Prof. F. Hucho (inspector), Prof. B. Wittig (inspector), PD Dr. Jürgen Eberle (firstReferee), Prof. Dr. Petra Knaus (furtherReferee).
Subjects/Keywords: melanoma; TRAIL; apoptosis; overcoming therapy resistance; PI3K inhibitor; mTOR inhibitor; Calcium-dependent potassium channel; 500 Naturwissenschaften und Mathematik
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Quast, S. (2013). Sensitization of melanoma cells for TRAIL-induced apoptosis by signaling
pathway inhibitors. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-8007
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):
Quast, Sandra-Annika. “Sensitization of melanoma cells for TRAIL-induced apoptosis by signaling
pathway inhibitors.” 2013. Thesis, Freie Universität Berlin. Accessed February 25, 2021.
http://dx.doi.org/10.17169/refubium-8007.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Quast, Sandra-Annika. “Sensitization of melanoma cells for TRAIL-induced apoptosis by signaling
pathway inhibitors.” 2013. Web. 25 Feb 2021.
Vancouver:
Quast S. Sensitization of melanoma cells for TRAIL-induced apoptosis by signaling
pathway inhibitors. [Internet] [Thesis]. Freie Universität Berlin; 2013. [cited 2021 Feb 25].
Available from: http://dx.doi.org/10.17169/refubium-8007.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Quast S. Sensitization of melanoma cells for TRAIL-induced apoptosis by signaling
pathway inhibitors. [Thesis]. Freie Universität Berlin; 2013. Available from: http://dx.doi.org/10.17169/refubium-8007
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
NSYSU
13.
Keng, Chun-Lan.
The apoptotic mechanism of angiogenesis inhibitor, vasostatin.
Degree: Master, Biological Sciences, 2003, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0624103-115653
► Abstract Vasostatin, the N-terminal 180 amino acids domain of calreticulin, induces apoptosis in endothelial cells and inhibits angiogenesis. However, the mechanism underlying the apoptosis induce…
(more)
▼ Abstract
Vasostatin, the N-terminal 180 amino acids domain of calreticulin, induces
apoptosis in endothelial cells and inhibits angiogenesis. However, the mechanism underlying the
apoptosis induce by vasostatin remains elusive. In the present study, we investigated the role of (1) Fas /FasL pathway, (2) oxidative stress, and (3) nitric oxide (NO) in the apoptotic mechanism of vasostatin in endothelial cells. Recombinant vasostatin was generated and shown to induce
apoptosis of bovine aortic endothelial cells (BAEC) as demonstrated by flow cytometry analysis, nucleus staining, and DNA fragmentation assay. Vasostatin elevated the levels of Fas and its adaptor, FADD, in BAEC. Furthermore, vasostatin treatment increased the activities as well as the expression of active form of caspase-8 and caspase-3 in BAEC. However, pretreatment with either caspase-3
inhibitor or caspase-8
inhibitor alone was not sufficient to blockade the vasostatin-mediated
apoptosis, suggesting the involvement of other pathways. Extensive screening using an array of caspase inhibitors further supported such notion. Oxidative stress is frequently involved in the
apoptosis of endothelial cells. Previous studies indicated that vasostatin enhanced WST-1-derived formazan formation despite its cytotoxic effect, suggesting vasostatin treatment might enhance the production of superoxide. By measuring the level of superoxide anion in cultured media by cytochrome c reducing test, it was found that vasostatin treatment increased the production of superoxide anion in endothelial cells. Antioxidants such as NAC, GSH, BHA partially attenuated the vasostatin-mediated cytotoxicity and cell death in endothelial cells. Noteworthingly, adding allopurinol,
inhibitor of xanthine oxidase, but not other oxidase inhibitors abrogated the cytotoxicity of vasostatin, indicating that xanthine oxidase could be the source of ROS produced by vasostatin relate with
apoptosis. The elecctrophoretic mobility shift assays (EMSA) suggested that vasostatin treatment increased the NFκB DNA binding activity. Western blot analysis indicated vasostatin increased the levels of NFκB but decreased IκB level, which seemed to coincide with the EMSA findings. NO plays an important role in endothelial function. To investigate the role of NO in the cytotoxicity by vasostatin, analyzed the levels of NO metabolites in cultured media of endothelial cells and found that vasostatin treatment increased NO release in time- dependent manners. The expression of eNOS, but not iNOS, in endothelial cells was upregulated by vasostatin. Besides, vasostatin treatment also increased the AP-1 binding activities. Moreover, NOS
inhibitor, L-NAME, or NO scavenger, carboxy-PTIO, slightly attenuated the cytotoxic effects of vasostatin in endothelial cells. In addition to direct cytotoxicity, NO may react with superoxide (O2-) to form peroxynitrite (ONOO-), which attacked the intracellular protein and caused the cell damage. Indeed, we also detected a dose-dependent increment in the nitrotyrosination of cellular…
Advisors/Committee Members: Ming-Hong Tai (committee member), Ching-Mei Hsu (chair), Jiin-Tsuey Cheng (chair).
Subjects/Keywords: BAEC; vasostatin; angiogenesis inhibitor; apoptosis; ROS
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APA (6th Edition):
Keng, C. (2003). The apoptotic mechanism of angiogenesis inhibitor, vasostatin. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0624103-115653
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):
Keng, Chun-Lan. “The apoptotic mechanism of angiogenesis inhibitor, vasostatin.” 2003. Thesis, NSYSU. Accessed February 25, 2021.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0624103-115653.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Keng, Chun-Lan. “The apoptotic mechanism of angiogenesis inhibitor, vasostatin.” 2003. Web. 25 Feb 2021.
Vancouver:
Keng C. The apoptotic mechanism of angiogenesis inhibitor, vasostatin. [Internet] [Thesis]. NSYSU; 2003. [cited 2021 Feb 25].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0624103-115653.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Keng C. The apoptotic mechanism of angiogenesis inhibitor, vasostatin. [Thesis]. NSYSU; 2003. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0624103-115653
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
NSYSU
14.
Lee, Li-ping.
Exploration of Therapeutic Effects of a Novel p21-activated protein kinase inhibitor, PF-3758309 in Urothelial Carcinoma.
Degree: Master, Biological Sciences, 2015, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0612115-111506
► Urothelial carcinoma of urinary bladder (UBUC) and upper tract (UTUC) are common cancer in Taiwan. Most of urothelial carcinoma, especially those of urinary bladder, are…
(more)
▼ Urothelial carcinoma of urinary bladder (UBUC) and upper tract (UTUC) are common cancer in Taiwan. Most of urothelial carcinoma, especially those of urinary bladder, are superficially invading and often cured by curettage. Some urinary bladder cancer developed unexpected local recurrence that followed by distal spreading. However, the molecular aberrations responsible for its tumor development and progression remain largely unclear. Therefore, it is beneficial to identify novel prognostic biomarkers and therapeutic targets for this malignancy.
P21-activated protein kinase1(PAK1) is a downstream effector of small Rho GTPase, Rac and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis and angiogenesis. Several studies report that PAK1 overexpressed in breast cancer and colon cancer, and it is correlate with metastasis. Other studies show that hyperphosphorylation of PAK1 promote cell migration . The aim of this study was to investigate the expression of PAK1 and phosphorylated PAK in cell lines of human urotheliel carcinoma and clarify whether PAK1 expression associated with phosphoryled PAK1. We also used PF-3758309, which is a ATP competitive
inhibitor of PAK to assess the therapeutic efficacy of PF-3758309 in RT9,BFTC909 and TSGH8301 cell lines and identify the biological and therapeutic relevance of PAK1 in urothelial carcinoma.
According our results, there is a positive correlation between PAK1 expression and phosphorylated PAK. Phosphorylated PAK may induce a cascade of cell signal resulting cell proliferation, migration and anti-
apoptosis; In opposition, PAK
inhibitor, PF-3758309 could cause cell
apoptosis by inhibiting phosphorylaton of PAK1.
Advisors/Committee Members: Wei-Ming Li (chair), Yow-Ling Shiue (committee member), Chien-Feng Li (chair).
Subjects/Keywords: P21-activated protein kinase1; apoptosis; PF-3758309; metastasis; PAK inhibitor; urothelial carcinoma
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lee, L. (2015). Exploration of Therapeutic Effects of a Novel p21-activated protein kinase inhibitor, PF-3758309 in Urothelial Carcinoma. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0612115-111506
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):
Lee, Li-ping. “Exploration of Therapeutic Effects of a Novel p21-activated protein kinase inhibitor, PF-3758309 in Urothelial Carcinoma.” 2015. Thesis, NSYSU. Accessed February 25, 2021.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0612115-111506.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lee, Li-ping. “Exploration of Therapeutic Effects of a Novel p21-activated protein kinase inhibitor, PF-3758309 in Urothelial Carcinoma.” 2015. Web. 25 Feb 2021.
Vancouver:
Lee L. Exploration of Therapeutic Effects of a Novel p21-activated protein kinase inhibitor, PF-3758309 in Urothelial Carcinoma. [Internet] [Thesis]. NSYSU; 2015. [cited 2021 Feb 25].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0612115-111506.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lee L. Exploration of Therapeutic Effects of a Novel p21-activated protein kinase inhibitor, PF-3758309 in Urothelial Carcinoma. [Thesis]. NSYSU; 2015. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0612115-111506
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
15.
Mezil M'Hidi, Lynda.
Repositionnement d'un inhibiteur de métalloprotéases dans le cancer du sein : Synthèse induite par rayonnement des polymères conducteurs et leurs nanocomposites métalliques.
Degree: Docteur es, Pathologie humaine, 2013, Aix Marseille Université
URL: http://www.theses.fr/2013AIXM5000
► Dans cette étude, nous décrivons pour la première fois les propriétés anti-tumorales de composés de type thiomorpholine sulfonamide hydroxamate dans le cancer du sein. Nous…
(more)
▼ Dans cette étude, nous décrivons pour la première fois les propriétés anti-tumorales de composés de type thiomorpholine sulfonamide hydroxamate dans le cancer du sein. Nous avons montré que le TMI-1, un inhibiteur à spécificité double MMPs/ADAM-17, est un puissant inhibiteur de la croissance tumoral in vitro et in vivo. Cette activité anti-tumorale est indépendante de l’inhibition d’ADAM-17 et des MMPs. En effet, le TMI-1 inhibe la croissance tumorale in vitro de 89% des lignées tumorales mammaires à des IC50 de l’ordre du micromolaire, par sa double capacité d’induire l’arrêt du cycle cellulaire en G0/G1 et l’apoptose dépendante de la voie extrinsèque. TMI-1 n’a aucun effet sur les cellules normales. In vivo, le TMI-1 inhibe le développement tumoral et l’apparition de nouvelles tumeurs dans les souris transgéniques MMTV-ERBB2/neu. A la différence des drogues cytotoxiques conventionnelles, TMI-1 à une activité sélective sur les cellules tumorales en affectant le pool de cellules souches cancéreuses mammaires. De plus, le TMI-1 agit en synergie en association avec les drogues de chimiothérapie et de thérapies ciblées. TMI-1 a déjà été utilisé en clinique, est une molécule candidate au repositionnement clinique en cancérologie. D’une manière intéressante, une corrélation marquée a pu être mise en évidence entre TMI-1 et le statut mutationnel de P53. Finalement, TMI-1 représente une alternative thérapeutique prometteuse dans le traitement des cancers, d’autant que la sélectivité semble associée à un marqueur « compagnon » P53, muté dans environ 50% des cancers. Le lien existant entre ces composés et P53 passe par l’identification de la ou les cibles. Ce travail est actuellement en cours, utilisant des approches de protéomique inverse.
In this study, we focused on breast cancer and reported for the first time in vitro and in vivo antitumor properties of thiomorpholin sulfonamide hydroxamate compounds. We found that TMI-1, a dual ADAM-17 and MMP inhibitor is a strong anti-cancer agent. TMI-1 exerts its antitumor activity at micromolar range by induction of cell cycle arrest in G0/G1 and extrinsic apoptosis pathway. TMI-1 is not cytotoxic for normal cells. 89% of breast tumor cells are sensitive to TMI-1 in vitro. TMI-1 is also efficient in vivo, inhibits tumor growth and prevents the formation of additional tumors in MMTV-ERBB2/neu transgenic mice. Unlike conventional cytotoxic drugs, TMI-1 has a selective activity on tumor cells by affecting the pool of cancer stem cells. Interestingly TMI-1 is a potent synergistic drug for breast cancer therapy. TMI-1, already used to treat inflammatory disease, is a candidate for drug repositioning in oncology. Interestingly, a marked correlation was found between TMI-1 and the mutational status of P53. Finally, TMI-1 is of outstanding interest, as efficiency may be related to the surrogate marker P53 mutated in approximately 50% of cancers. The relationship between these compounds and P53 is currently in progress. This is done by a reverse proteomic approaches attempting to…
Advisors/Committee Members: Lopez, Marc (thesis director).
Subjects/Keywords: Cancer du sein; Apoptose; Inhibiteur de métalloprotéases; Repositionnement; Breast cancer; Apoptosis; Metalloprteases inhibitor; Repositioning
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mezil M'Hidi, L. (2013). Repositionnement d'un inhibiteur de métalloprotéases dans le cancer du sein : Synthèse induite par rayonnement des polymères conducteurs et leurs nanocomposites métalliques. (Doctoral Dissertation). Aix Marseille Université. Retrieved from http://www.theses.fr/2013AIXM5000
Chicago Manual of Style (16th Edition):
Mezil M'Hidi, Lynda. “Repositionnement d'un inhibiteur de métalloprotéases dans le cancer du sein : Synthèse induite par rayonnement des polymères conducteurs et leurs nanocomposites métalliques.” 2013. Doctoral Dissertation, Aix Marseille Université. Accessed February 25, 2021.
http://www.theses.fr/2013AIXM5000.
MLA Handbook (7th Edition):
Mezil M'Hidi, Lynda. “Repositionnement d'un inhibiteur de métalloprotéases dans le cancer du sein : Synthèse induite par rayonnement des polymères conducteurs et leurs nanocomposites métalliques.” 2013. Web. 25 Feb 2021.
Vancouver:
Mezil M'Hidi L. Repositionnement d'un inhibiteur de métalloprotéases dans le cancer du sein : Synthèse induite par rayonnement des polymères conducteurs et leurs nanocomposites métalliques. [Internet] [Doctoral dissertation]. Aix Marseille Université 2013. [cited 2021 Feb 25].
Available from: http://www.theses.fr/2013AIXM5000.
Council of Science Editors:
Mezil M'Hidi L. Repositionnement d'un inhibiteur de métalloprotéases dans le cancer du sein : Synthèse induite par rayonnement des polymères conducteurs et leurs nanocomposites métalliques. [Doctoral Dissertation]. Aix Marseille Université 2013. Available from: http://www.theses.fr/2013AIXM5000
16.
Oğlakçı İlhan, Ayşegül.
Ratlarda isoproterenol ile oluşturulan kalp krizi modelinde kronik alkol kullanımının miyokardiyal apoptoz üzerine etkisi ve kalpain inhibitörü 1’in (N-asetil-lösin-lösin-norlösinal) kardiyoprotektif rolünün araştırılması
.
Degree: ESOGÜ, Tıp Fakültesi, Tıbbi Biyokimya, 2016, Eskisehir Osmangazi University
URL: http://hdl.handle.net/11684/1057
► Alkol tüketimi ve alkolizm yüksek bir mortalite ve morbiditeye sahip sağlık sorunlarına yol açmaktadır. Aşırı dozda alkol tüketimi önemli bir kalp dokusu hasarı oluşturarak ani…
(more)
▼ Alkol tüketimi ve alkolizm yüksek bir mortalite ve morbiditeye
sahip sağlık sorunlarına yol açmaktadır. Aşırı dozda alkol tüketimi
önemli bir kalp dokusu hasarı oluşturarak ani ölümlere neden
olmaktadır. Alkolün oluşturduğu kalp dokusu hasarının mekanizması
tam olarak bilinmese de reaktif oksijen türlerinin oluşumu,
asetaldehidin protein adduktları oluşturması, mitokondri
fonksiyonlarının değişmesi gibi sebeplerin kalp dokusuna zarar
verdiği düşünülmektedir.
Kardiyovasküler hastalıklar gelişmiş ve gelişmekte olan
ülkelerde görülen ölümlerin başlıca sebeplerinden birisidir.
Kardiyovasküler hastalıklar içinde en sık görüleni de miyokart
infarktüsü (MI)’dür. MI, yetersiz doku perfüzyonundan kaynaklanan
uzamış iskemi sonucu meydana gelen geri dönüşümsüz miyokart
hücre hasarı ve nekrozudur.
Çalışmada MI’a bağlı apoptotik hücre ölümü üzerine kronik alkol
kullanımının etkisi ve kalpain inhibitörü-1 kullanımının rat kalp
dokusu üzerindeki koruyucu rolü biyokimyasal, histolojik ve
morfometrik olarak ortaya konulmaya çalışıldı. Çalışmamızda erkek
Wistar Albino cinsi ratlar kullanıldı. Ratlar kontrol, çözücü, alkol,
miyokart infarktüsü, alkol+miyokart infaktüsü ve alkol+miyokart
infarktüsü+inhibitör grubu olmak üzere 18’er rattan oluşan 6 gruba
ayrıldı. Rat kalplerinde miyokartiyal hasarın yol açtığı apoptozun
göstergesi olarak sitokrom c düzeylerinin kontrol grubu ile
karşılaştırıldığında alkol, MI ve alkol+MI gruplarında (p<0,001) ve
kaspaz 3 düzeylerinin alkol (p>0,05), MI (p<0,001) ve alkol+MI
(p<0,001) gruplarında istatiksel olarak artmış olduğu, sitokrom c
salınımında rol oynayan mitokondriyal kardiyolipin içeriğinin alkol,
MI ve alkol+MI gruplarında azalmış olduğu (p<0,001) ve apoptozun
tetiklenmesinde rol aldığı bilinen sistein proteazlardan kalpain
düzeylerinin arttığı ve bu artışın istatiksel olarak anlamlı olmadığı
(p>0,05) bulundu. Alkol+MI grubu ile karşılaştırıldığında inhibitör
grubunda kalpain düzeyleri (p<0,05), kaspaz düzeyleri (p<0,001) ve
sitokrom c düzeylerinin (p<0,001) azaldığı, kardiyolipin içeriğinin
(p<0,001) arttığı görülmüştür. MI göstergesi olarak EKG
(elektrokardiyogram) ölçümleri yapıldı ve kan serumlarında kreatin
kinaz MB (CK-MB) düzeyleri ölçüldü. Serum CK-MB enziminin kontrol
grubuna göre MI (p<0,001), alkol (p<0,001) ve alkol+MI
gruplarında (p<0,05) arttığı ve inhibitör grubunda MI grubuna göre
düşme (p<0,05) olduğu gözlendi. Histolojik özellikler ve doku
hasarının incelenmesi sonucu, alkolün tek başına sadece hemoraji ve ödem bulgularında arttırıcı etkisi gözlendi. MI ise tüm histopatolojik
kriterler açısından ciddi hasar yaratmıştı. Alkolün MI ile birlikte bu
hasarları biraz daha arttırdığı gözlendi. Alkol+MI grubuna kalpain
inhibitörü ile tedavi uygulandığında, kalpain inhibitörünün
istatistiksel olarak sadece miyokartiyal fragmentasyon ve çizgilenme
kaybında azalmaya yardımcı olduğu, diğer histopatolojik kriterler
açısından ise anlamlı olmayan, ancak iyileşmeye yardımcı olabilecek
bir ajan olduğu izlendi. Morfometrik inceleme sonucu, alkol ve…
Advisors/Committee Members: Kanbak, Güngör (advisor).
Subjects/Keywords: Alkol;
Miyokart İnfarktüsü (MI);
Kalpain İnhibitörü;
Apoptoz;
Alcohol;
Myocard Infarction (MI);
Calpain Inhibitor;
Apoptosis
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Oğlakçı İlhan, A. (2016). Ratlarda isoproterenol ile oluşturulan kalp krizi modelinde kronik alkol kullanımının miyokardiyal apoptoz üzerine etkisi ve kalpain inhibitörü 1’in (N-asetil-lösin-lösin-norlösinal) kardiyoprotektif rolünün araştırılması
. (Thesis). Eskisehir Osmangazi University. Retrieved from http://hdl.handle.net/11684/1057
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):
Oğlakçı İlhan, Ayşegül. “Ratlarda isoproterenol ile oluşturulan kalp krizi modelinde kronik alkol kullanımının miyokardiyal apoptoz üzerine etkisi ve kalpain inhibitörü 1’in (N-asetil-lösin-lösin-norlösinal) kardiyoprotektif rolünün araştırılması
.” 2016. Thesis, Eskisehir Osmangazi University. Accessed February 25, 2021.
http://hdl.handle.net/11684/1057.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Oğlakçı İlhan, Ayşegül. “Ratlarda isoproterenol ile oluşturulan kalp krizi modelinde kronik alkol kullanımının miyokardiyal apoptoz üzerine etkisi ve kalpain inhibitörü 1’in (N-asetil-lösin-lösin-norlösinal) kardiyoprotektif rolünün araştırılması
.” 2016. Web. 25 Feb 2021.
Vancouver:
Oğlakçı İlhan A. Ratlarda isoproterenol ile oluşturulan kalp krizi modelinde kronik alkol kullanımının miyokardiyal apoptoz üzerine etkisi ve kalpain inhibitörü 1’in (N-asetil-lösin-lösin-norlösinal) kardiyoprotektif rolünün araştırılması
. [Internet] [Thesis]. Eskisehir Osmangazi University; 2016. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/11684/1057.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Oğlakçı İlhan A. Ratlarda isoproterenol ile oluşturulan kalp krizi modelinde kronik alkol kullanımının miyokardiyal apoptoz üzerine etkisi ve kalpain inhibitörü 1’in (N-asetil-lösin-lösin-norlösinal) kardiyoprotektif rolünün araştırılması
. [Thesis]. Eskisehir Osmangazi University; 2016. Available from: http://hdl.handle.net/11684/1057
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Wayne State University
17.
Sosin, Angela.
Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma.
Degree: PhD, Cancer Biology, 2012, Wayne State University
URL: https://digitalcommons.wayne.edu/oa_dissertations/622
► Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, compromising p53 activity. Therefore, lymphoma is a suitable model for studying therapeutic value of…
(more)
▼ Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, compromising p53 activity. Therefore, lymphoma is a suitable model for studying therapeutic value of disrupting HDM2-p53 association by small-molecule inhibitors (SMIs). HDM2 SMIs have been developed and are currently under various stages of preclinical and clinical investigation. This study examined various molecular mechanisms associated and biological effects of two different classes of HDM2 SMIs: the spiro-oxindoles (MI-219) and cis-imidazoline (Nutlin-3) in lymphoma cell lines and patient-derived B-lymphoma cells. Surprisingly, results revealed significant quantitative and qualitative differences between these two agents. At the molecular level, effect of Nutlin-3 was generally more delayed (48h) and was notable for inducing cell cycle arrest. These findings indicate a response to a low level cellular stress and are supported by lower levels of p53 expression in Nutlin-3-treated cells. In contrast, MI-219 triggered an earlier response (12-24h), predominantly in the form of cell death associated with higher levels of p53 expression. Neither agent interfered with the E3 ligase function of HDM2, as confirmed in a cell-free autoubiquitination assay. Interestingly, these results report for the first time a novel mechanism of HDM2 antagonism by MI-219 in wt-p53 lymphoma cells that stimulates HDM2 autoubiquitination. Additionally, it corresponds with biological response of anti-lymphoma activity and may provide an explanation for the differences in efficacy between MI-219 and Nutlin-3. This study indicates that p53-HDM2 interaction and methods of its disruption are more complex than is currently realized and suggests that stimulation of HDM2 autoubiquitinating activity may be a novel treatment strategy for lymphoma.
Advisors/Committee Members: Ayad M. Al-Katib.
Subjects/Keywords: apoptosis; autoubiquitination; HDM2; lymphoma; p53; Small-molecule inhibitor; Cell Biology; Molecular Biology; Oncology
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APA ·
Chicago ·
MLA ·
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Export
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APA (6th Edition):
Sosin, A. (2012). Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/622
Chicago Manual of Style (16th Edition):
Sosin, Angela. “Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma.” 2012. Doctoral Dissertation, Wayne State University. Accessed February 25, 2021.
https://digitalcommons.wayne.edu/oa_dissertations/622.
MLA Handbook (7th Edition):
Sosin, Angela. “Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma.” 2012. Web. 25 Feb 2021.
Vancouver:
Sosin A. Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma. [Internet] [Doctoral dissertation]. Wayne State University; 2012. [cited 2021 Feb 25].
Available from: https://digitalcommons.wayne.edu/oa_dissertations/622.
Council of Science Editors:
Sosin A. Hdm2 Small-Molecule Inhibitors For Therapeutic Intervention In B-Cell Lymphoma. [Doctoral Dissertation]. Wayne State University; 2012. Available from: https://digitalcommons.wayne.edu/oa_dissertations/622
University of Ottawa
18.
Lejmi Mrad, Rim.
Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
.
Degree: 2016, University of Ottawa
URL: http://hdl.handle.net/10393/34260
► Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber…
(more)
▼ Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber size, fiber-type change and induction of markers of atrophy such as MuRF1 and Fn14. Recent studies have focused on understanding the fundamental role of signalling pathways and the proteolytic system in response to muscle atrophy. Unfortunately the exact mechanisms behind atrophy remain poorly understood. I recently demonstrated that cIAP1 and/or cIAP2 proteins are critical regulators of NF-kB activation, which has been shown to be involved in skeletal muscle atrophy. Here, I used genetic and pharmacological means to investigate the role of cIAP1 in a denervation-induced skeletal muscle atrophy model. Interestingly, I found that upon denervation loss of cIAP1 rescues muscle fiber size, prevents fiber-type changing and inhibits the expression of MuRF1 and Fn14. Moreover, treatment of mice with Smac mimetic compounds (SMC), a novel class of small molecule IAP antagonists, showed successful knockdown of cIAP1 in muscle and protects against denervation-induced muscle atrophy. Taken together, these data reveal that cIAP1 is both a novel mediator of skeletal muscle atrophy and an important therapeutic target.
Subjects/Keywords: Cellular inhibitor of apoptosis;
skeletal muscle atrophy;
NF-kB signaling pathway;
TWEAK/Fn14 system
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APA (6th Edition):
Lejmi Mrad, R. (2016). Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/34260
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):
Lejmi Mrad, Rim. “Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
.” 2016. Thesis, University of Ottawa. Accessed February 25, 2021.
http://hdl.handle.net/10393/34260.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lejmi Mrad, Rim. “Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
.” 2016. Web. 25 Feb 2021.
Vancouver:
Lejmi Mrad R. Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
. [Internet] [Thesis]. University of Ottawa; 2016. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10393/34260.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lejmi Mrad R. Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
. [Thesis]. University of Ottawa; 2016. Available from: http://hdl.handle.net/10393/34260
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Oxford
19.
Khan, Omar Ali.
HR23B, a biomarker for HDAC inhibitors.
Degree: PhD, 2013, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e
;
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618430
► As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has…
(more)
▼ As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has been strongly linked to tumourigenesis and the modulation of acetylation through targeting histone deacetylase (HDAC) has led to the introduction of many HDAC inhibitors. To date, two have had regulatory approval for the treatment of cutaneous T cell lymphoma (CTCL). Modifications in chromatin control underpin the mechanism of action of HDAC inhibitors. A genome wide loss-of-function screen identified HR23B as a gene that governs sensitivity to HDAC inhibitors. HR23B shuttles ubiquitinated cargo proteins to the proteasome and elevated levels may contribute to cell death mediated by this pathway. It also governs cell sensitivity to drugs that act directly on the proteasome. HDAC inhibitors influence proteasome activity and there may be a synergistic interaction with proteasome inhibitors. HR23B and HDAC6 interact and HDAC6 may be a negative regulator of apoptosis and a positive regulator of autophagy and through its ability to down-regulate HR23B, may impact on the cellular outcome of HDAC inhibitor treatment. Expression of HR23B has been correlated with clinical response to HDAC inhibitors in a retrospective analysis of CTCL patients. The tissue expression of HR23B and the autophagy marker LC3 has been investigated and there may be a reciprocal relationship in their expression in some tumours which may provide prognostic information and patients with low HR23B expression but high levels of autophagy appear to have a particularly poor prognosis. Well designed, biomarker-driven prospective clinical trials are needed to clarify the predictive and prognostic roles of HR23B.
Subjects/Keywords: 616.994; Medical Sciences; Clinical laboratory sciences; Oncology; Pharmacology; Tumours; HDAC inhibitor; biomarker; cancer; apoptosis; autophagy
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Manager
APA (6th Edition):
Khan, O. A. (2013). HR23B, a biomarker for HDAC inhibitors. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618430
Chicago Manual of Style (16th Edition):
Khan, Omar Ali. “HR23B, a biomarker for HDAC inhibitors.” 2013. Doctoral Dissertation, University of Oxford. Accessed February 25, 2021.
http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618430.
MLA Handbook (7th Edition):
Khan, Omar Ali. “HR23B, a biomarker for HDAC inhibitors.” 2013. Web. 25 Feb 2021.
Vancouver:
Khan OA. HR23B, a biomarker for HDAC inhibitors. [Internet] [Doctoral dissertation]. University of Oxford; 2013. [cited 2021 Feb 25].
Available from: http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618430.
Council of Science Editors:
Khan OA. HR23B, a biomarker for HDAC inhibitors. [Doctoral Dissertation]. University of Oxford; 2013. Available from: http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e ; http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618430
University of Melbourne
20.
Anderton, Holly.
Inhibitor of APoptosis proteins (IAPs) and SHARPIN regulate the immune response in the skin to limit inflammation and maintain homeostasis.
Degree: 2018, University of Melbourne
URL: http://hdl.handle.net/11343/221817
► The skin is a remarkable organ, a barricade between our vulnerable insides and a constantly changing environment full of physical, chemical, and biological aggressors. Maintenance…
(more)
▼ The skin is a remarkable organ, a barricade between our vulnerable insides and a constantly changing environment full of physical, chemical, and biological aggressors. Maintenance of barrier integrity, immune surveillance, and rapid response are fundamental, and this multifaceted protection is orchestrated by the epithelial barrier and immune cells. Acute and chronic inflammatory skin diseases can arise due to abnormal over-reactions to the changing environment. A number of these diseases have been associated with genetic aberrations of the TNF super family and innate receptors signalling. My PhD studies have focused on the role of particular E3 ligases in regulating inflammatory signalling in skin homeostasis and inflammation.
Inhibitor of APoptosis proteins (IAPs) and the Linear Ubiquitin-chain Assembly Complex (LUBAC) are E3 ubiquitin ligases that play crucial roles in innate immunity by regulating cell death and survival pathways from the TNF and pattern recognition receptor families. Genetic or pharmacological disruption of the IAPs or LUBAC member SHARPIN induce dermatological phenotypes with interesting parallels to a variety of human skin diseases.
To investigate the contribution of immune cells to the Sharpincpdm cutaneous phenotype I utilised the transgenic Diphtheria Toxin Receptor (DTR) system to specifically ablate particular immune cell subsets in-vivo. I have found that Langerhans cells play a pivotal role in the cell death mediated skin disease that arises in Sharpin mutant mice, placing them as a potential cellular source of pathogenic TNF in the Sharpincpdm skin, and highlighting a T-cell independent role for Langerhans cells in driving skin inflammation.
Epidermal specific genetic deletion of the cellular IAPs (cIAPs) resulted in early post-natal lethality due to widespread dermatoses. Pharmacological loss of cIAP1, cIAP2 and XIAP by subcutaneous injection of an IAP antagonist drug (smac-mimetic; SM) into mice induced a Toxic Epidermal Necrolysis (TEN) like local inflammatory lesion characterised by keratinocyte cell death, immune cell infiltration, and increased production of pro-inflammatory cytokines. Both the genetic and pharmacological phenotypes can be ameliorated by the loss of a single allele of RIPK1. I have conducted a screen injecting SM into a panel of knock-out and mutant mouse strains in order dissect the complex set of interactions initiated by injection of SM and leading to the TEN like lesional response. I found that disruption of IAPs leads to a breakdown in immune tolerance to commensal microorganisms, which can then initiate inflammatory responses in the skin. A full response to SM depends on interactions between innate immune signalling pathways, immune cells, and the microbiota, nicely highlighting the multifaceted processes involved in skin inflammation and cell death.
Subjects/Keywords: inhibitor of Apoptosis proteins; Sharpin; cell death; inflammation; skin disease; dermatology; Langerhans cells; microbiome
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APA (6th Edition):
Anderton, H. (2018). Inhibitor of APoptosis proteins (IAPs) and SHARPIN regulate the immune response in the skin to limit inflammation and maintain homeostasis. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/221817
Chicago Manual of Style (16th Edition):
Anderton, Holly. “Inhibitor of APoptosis proteins (IAPs) and SHARPIN regulate the immune response in the skin to limit inflammation and maintain homeostasis.” 2018. Doctoral Dissertation, University of Melbourne. Accessed February 25, 2021.
http://hdl.handle.net/11343/221817.
MLA Handbook (7th Edition):
Anderton, Holly. “Inhibitor of APoptosis proteins (IAPs) and SHARPIN regulate the immune response in the skin to limit inflammation and maintain homeostasis.” 2018. Web. 25 Feb 2021.
Vancouver:
Anderton H. Inhibitor of APoptosis proteins (IAPs) and SHARPIN regulate the immune response in the skin to limit inflammation and maintain homeostasis. [Internet] [Doctoral dissertation]. University of Melbourne; 2018. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/11343/221817.
Council of Science Editors:
Anderton H. Inhibitor of APoptosis proteins (IAPs) and SHARPIN regulate the immune response in the skin to limit inflammation and maintain homeostasis. [Doctoral Dissertation]. University of Melbourne; 2018. Available from: http://hdl.handle.net/11343/221817
University of Melbourne
21.
Pollock, Georgina Lauren.
Investigating the molecular mechanisms of enteropathogenic Escherichia coli pathogenesis.
Degree: 2019, University of Melbourne
URL: http://hdl.handle.net/11343/227758
► During infection the gastrointestinal pathogen enteropathogenic Escherichia coli (EPEC) forms a characteristic lesion on the surface of infected enterocytes known as an attaching effacing lesion.…
(more)
▼ During infection the gastrointestinal pathogen enteropathogenic Escherichia coli (EPEC) forms a characteristic lesion on the surface of infected enterocytes known as an attaching effacing lesion. Defining features of this lesion include intimate attachment of the bacteria to the host surface, manipulation of the host cytoskeleton beneath the site of bacterial attachment, and effacement of the surrounding microvilli. EPEC utilises a type III secretion system (T3SS) to translocate effector proteins directly into the cytosol of infected cells. Once inside the host cell, these effector proteins modulate normal host cell processes, such as cytoskeletal dynamics and cell autonomous defenses, to aid in bacterial pathogenesis.
One such effector protein is the Non-LEE encoded effector NleB1, which inhibits extrinsic apoptotic signaling via the FAS death receptor. NleB1 transfers a single GlcNAc residue to Arg117 in the death domain of FADD and inhibits FAS ligand (FasL) stimulated caspase-8 cleavage. Another effector secreted by the T3SS is NleF. Previous studies have shown that NleF binds to and inhibits the activity of caspase-4, -8 and -9 in vitro. Here we investigated a role for NleF in the inhibition of FAS signaling and apoptosis during EPEC infection. We show NleF prevents the cleavage of caspase-8, caspase-3 and RIPK1 in response to FasL stimulation. When translocated into host cells by the T3SS or expressed ectopically, NleF also blocked FasL-induced cell death. Using the EPEC-like mouse pathogen C. rodentium we found that NleB but not NleF contributed to colonization of mice in the intestine. Hence, despite their shared ability to block FasL/FAS signaling, NleB and NleF appear to have distinct roles during infection.
Another two translocated effectors are NleH1 and NleH2, which together form a new family of bacterial kinases. The phosphorylated targets of these kinases within the host cell have not been previously described. To identify putative host targets of NleH1 and NleH2 kinase activity, we conducted a phospho-proteomic comparison of intestinal epithelial cells infected with wild type EPEC or an EPEC double mutant lacking nleH1 and nleH2. We identified previously undescribed serine phosphorylation of the host proteins Eps8, Eps8L1 and Eps8L2 during wild type infection, that was absent during infection with EPEC ΔnleH1 ΔnleH2. Phosphorylation of Eps8 by NleH1 and NleH2 kinases was confirmed in vitro, in addition we used co-immunoprecipitation and yeast-2-hybrid protein interaction analysis to demonstrate an interaction between Eps8 and the bacterial kinases. Eps8 is a dual function actin capping and bundling protein that specifically localises to the distal tips of microvilli. Loss of Eps8 results in microvilli shortening in mouse intestinal models and polarized epithelial cells. We examined the impact of phosphorylation on Eps8 function and investigating a role for NleH1 and NleH2 in the microvilli effacement observed during EPEC infection. This work extends our understanding of defensive mechanisms in…
Subjects/Keywords: pathogenic E. coli; EPEC; apoptosis; caspase inhibitor; FAS signalling; bacterial kinase; AE lesion; microvilli effacement
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APA ·
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APA (6th Edition):
Pollock, G. L. (2019). Investigating the molecular mechanisms of enteropathogenic Escherichia coli pathogenesis. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/227758
Chicago Manual of Style (16th Edition):
Pollock, Georgina Lauren. “Investigating the molecular mechanisms of enteropathogenic Escherichia coli pathogenesis.” 2019. Doctoral Dissertation, University of Melbourne. Accessed February 25, 2021.
http://hdl.handle.net/11343/227758.
MLA Handbook (7th Edition):
Pollock, Georgina Lauren. “Investigating the molecular mechanisms of enteropathogenic Escherichia coli pathogenesis.” 2019. Web. 25 Feb 2021.
Vancouver:
Pollock GL. Investigating the molecular mechanisms of enteropathogenic Escherichia coli pathogenesis. [Internet] [Doctoral dissertation]. University of Melbourne; 2019. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/11343/227758.
Council of Science Editors:
Pollock GL. Investigating the molecular mechanisms of enteropathogenic Escherichia coli pathogenesis. [Doctoral Dissertation]. University of Melbourne; 2019. Available from: http://hdl.handle.net/11343/227758
22.
Cheema, Tasbir.
Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line
.
Degree: 2012, University of Ottawa
URL: http://hdl.handle.net/10393/20737
► Programmed cell death (apoptosis) is the most common mechanism of cell death in eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has…
(more)
▼ Programmed cell death (apoptosis) is the most common mechanism of cell death in eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has become a hallmark feature of cancer. This is accomplished through a family of proteins known as the inhibitor of apoptosis proteins (IAPs). X-Linked inhibitor of apoptosis protein (XIAP) is one of the best characterized IAPs. XIAP suppresses apoptosis by forming complexes with cysteine-aspartic proteases (caspase), through one of its baculovirus IAP repeat (BIR) domains. Its activity is endogenously antagonized by a second mitochondria derived activator of caspase (Smac). The anti-apoptotic behaviour of XIAP and the critical role it plays in the apoptotic program makes the Smac-XIAP interaction an important drug target. To this end, our laboratory is interested in synthesizing biologically related Smac mimetics which can induce apoptosis in a MDA-MB-231 cell line.
Efforts have focused on (1) understanding BIR domain binding sites which allow for this interaction, and (2) the design and synthesis of molecules which are much more effective at inducing apoptosis compared to other well known analogues.
Through the synthesis and evaluation of various divalent Smac mimetics we have been able to support the hypothesis that the likely binding site on XIAP is the BIR3 domain. As well, through the synthesis of a library of novel compounds, as described in the thesis, we have been able to assess the nature of the linker which joins the two tetrapeptide units. In our effort to understand which domains Smac binds with, various divalent analogues were synthesized containing MeAVPI-linker-IPVMeA (forward-reverse) and MeAVPI-linker-MeAVPI (forward-forward) sequence, which incorporated linkers with varying degrees of flexibility. We hypothesized that the forward-forward divalent mimetics would have decreased activity compared to the peptides synthesized in a forward-reverse fashion.
Lastly, information gathered from structure activity relationship (SAR) studies have shown that substituting the lysine (P2) and isoleucine residues (P4) in the AVPI protein can create more potent inducers of apoptosis than its native AVPI sequence. As one of the most potent Smac mimetic that has been previously made known contains an alkyne bridge at P2 and a large hydrophobic moiety at P4, we hypothesized that similar Smac mimetics containing a propargyl glycine residue at P2 and a bulky hydrophobic moiety at P4 will be much more potent in inducing apoptosis.
Subjects/Keywords: Apoptosis;
Smac;
XIAP;
X-Linked inhibitor of apoptosis protein;
Caspase;
Inhibitor of apoptosis proteins;
BIR domain
…apoptosis proteins (IAPs). X-Linked inhibitor of apoptosis protein (XIAP) is… …Figure 3.14
Triglycine linked divalent Smac mimetics show no ability to induce
apoptosis at… …Programmed cell death (apoptosis) is the most common mechanism of cell death in… …eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has become a
hallmark… …feature of cancer. This is accomplished through a family of proteins known as the
inhibitor of…
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APA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Cheema, T. (2012). Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/20737
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):
Cheema, Tasbir. “Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line
.” 2012. Thesis, University of Ottawa. Accessed February 25, 2021.
http://hdl.handle.net/10393/20737.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Cheema, Tasbir. “Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line
.” 2012. Web. 25 Feb 2021.
Vancouver:
Cheema T. Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line
. [Internet] [Thesis]. University of Ottawa; 2012. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10393/20737.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Cheema T. Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line
. [Thesis]. University of Ottawa; 2012. Available from: http://hdl.handle.net/10393/20737
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
23.
Francisco Washington AraÃjo Barros.
Estudo do potencial anticÃncer de novos derivados acridÃnicos sintÃticos em modelos experimentais in vitro.
Degree: Master, 2010, Universidade Federal do Ceará
URL: http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4750
;
► Acridinas sÃo molÃculas policÃclicas aromÃticas planares que possuem a capacidade de intercalar no DNA nuclear. Muitos dos seus representantes apresentam propriedades antibacterianas, antiparasitÃrias e antitumorais.…
(more)
▼ Acridinas sÃo molÃculas policÃclicas aromÃticas planares que possuem a capacidade de intercalar no DNA nuclear. Muitos dos seus representantes apresentam propriedades antibacterianas, antiparasitÃrias e antitumorais. O presente estudo avaliou o potencial citotÃxico de 22 novos compostos acridÃnicos em linhagens de cÃlulas tumorais humanas. Dentre esses, quatro compostos [5-(acridin-9-il-metileno)-3-(4-metil-benzil)-tiazolidina-2,4-diona, AC4; 5-(acridin-9-il-metileno)-3-(4-bromo-benzil)-tiazolidina-2,4-diona, AC7; 5-(acridin-9-il-metileno)-3-(4-cloro-benzil)-tiazolidina-2,4-diona, AC10; e 5-(acridin-9-il-metileno)-3-(4-flÃor-benzil)-tiazolidina-2,4-diona, AC23] foram ativos, especialmente em HCT-8 (cÃlon) e SF-296 (glioblastoma), com valores de CI50 variando de 2,3 a 5,3 Âg/mL. Os compostos apresentaram seletividade para cÃlulas tumorais, desde que nÃo inibiram (IC50 > 25 Âg/mL) a proliferaÃÃo de cÃlulas monocucleares de sangue perifÃrico humano (CMSPH), bem como, nÃo foram capazes de induzir dano ao DNA dessas cÃlulas. Nenhum dos compostos mostrou atividade hemolÃtica contra eritrÃcitos de camundongos (EC50 > 200 Âg/mL), o que sugere uma citotoxicidade por mecanismos mais especÃficos. A fim de determinar o mecanismo envolvido na citotoxicidade seletiva dos compostos, foi realizada uma seqÃÃncia de experimentos in vitro, usando a linhagem HCT-8 como modelo. As cÃlulas foram tratadas em diferentes concentraÃÃes dos compostos (2,5; 5 e 10 Âg/mL) por 12 e 24 horas. Todos os compostos foram capazes de reduzir a viabilidade (teste do azul de tripan) e a proliferaÃÃo (ensaio do BrdU) de cÃlulas HCT-8 apÃs o tratamento. A induÃÃo de apoptose pelos derivados acridÃnicos foi determinada por citometria de fluxo (integridade da membrana, fragmentaÃÃo do DNA internucleosomal e potencial transmembrÃnico) e por anÃlise morfolÃgica das alteraÃÃes celulares (brometo de etÃdeo/laranja de acridina e hematoxilina/eosina). A anÃlise por citometria de fluxo revelou que os compostos avaliados promoveram despolarizaÃÃo mitocondrial, o qual evidencia a ativaÃÃo da apoptose pela via intrÃnseca nas cÃlulas HCT-8. Na anÃlise do screening em 3 diferentes linhagens mutantes de Saccharomyces cerevisiae, foi observado que a linhagem Top1Δ (sem topoisomerase I) mostrou moderada resistÃncia aos compostos acridÃnicos testados na concentraÃÃo de 50 Âg/mL. AlÃm disso, as acridinas inibiram parcialmente o relaxamento do DNA por topoisomerase I, sugerindo que os compostos AC4, AC7, AC10, AC23 tem o potencial antiproliferativo, em parte, relacionado a inibiÃÃo da atividade catalÃtica desta enzima. Esses dados apontam o potencial anticÃncer dos compostos testados.
Acridines are planar aromatic polycyclic molecules that have the ability to progress in nuclear DNA. Many of its representatives have antibacterial, antiparasitic and antitumor. This study evaluated the cytotoxic potential of 22 new acridine compounds in strains of human tumor cells. Among these, four compounds [5-(acridin-9-yl-methilene)-3-(4-methyl-benzyl)-thiazolidine-2,4-dione, AC4;…
Advisors/Committee Members: HÃlio Vitoriano Nobre JÃnior, Ivan da Rocha Pitta, ClÃudia do à Pessoa.
Subjects/Keywords: FARMACOLOGIA; Compostos AcridÃnicos; Citotoxicidade; Inibidor de Topoisomerase I; Dano ao DNA; Apoptose; Acridine Compounds; Cytotoxicity; Topoisomerase I inhibitor; DNA Damage; Apoptosis
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APA ·
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APA (6th Edition):
Barros, F. W. A. (2010). Estudo do potencial anticÃncer de novos derivados acridÃnicos sintÃticos em modelos experimentais in vitro. (Masters Thesis). Universidade Federal do Ceará. Retrieved from http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4750 ;
Chicago Manual of Style (16th Edition):
Barros, Francisco Washington AraÃjo. “Estudo do potencial anticÃncer de novos derivados acridÃnicos sintÃticos em modelos experimentais in vitro.” 2010. Masters Thesis, Universidade Federal do Ceará. Accessed February 25, 2021.
http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4750 ;.
MLA Handbook (7th Edition):
Barros, Francisco Washington AraÃjo. “Estudo do potencial anticÃncer de novos derivados acridÃnicos sintÃticos em modelos experimentais in vitro.” 2010. Web. 25 Feb 2021.
Vancouver:
Barros FWA. Estudo do potencial anticÃncer de novos derivados acridÃnicos sintÃticos em modelos experimentais in vitro. [Internet] [Masters thesis]. Universidade Federal do Ceará 2010. [cited 2021 Feb 25].
Available from: http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4750 ;.
Council of Science Editors:
Barros FWA. Estudo do potencial anticÃncer de novos derivados acridÃnicos sintÃticos em modelos experimentais in vitro. [Masters Thesis]. Universidade Federal do Ceará 2010. Available from: http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4750 ;
24.
Panagopoulou, Vasiliki.
Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτισή τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση.
Degree: 2014, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ)
URL: http://hdl.handle.net/10442/hedi/42537
► Effect of Angiotensin Converting Enzyme Inhibitors on In-Stent Restenosis andRelation to Plasma Apoptosis Signaling MoleculesTheory: Angiotensin-converting enzyme inhibitors have been reported to inhibit instentrestenosis. To…
(more)
▼ Effect of Angiotensin Converting Enzyme Inhibitors on In-Stent Restenosis andRelation to Plasma Apoptosis Signaling MoleculesTheory: Angiotensin-converting enzyme inhibitors have been reported to inhibit instentrestenosis. To assess the effect of angiotensin-converting enzyme inhibition onin-stent restenosis and its relation to apoptosis, we studied patients with chroniccoronary artery disease and significant stenosis in left anterior descending coronaryartery.Methods:116 patients with chronic coronary artery disease who required stentimplantation in the left anterior descending coronary artery or a major diagonal branchwere studied. Patients were randomized to receive angiotensin converting enzymeinhibitors orally (n = 58) or a placebo (n = 58). Drug therapy was initiated 1 weekbefore initial stenting and continued for 6 months. Plasma levels of the apoptoticsignaling molecules soluble Fas ,soluble Fasligandand sTRAIL obtained from blooddrawn from the left anterior descending coronary artery were measured just beforeinitial stenting and 6 months later, at the time of repeat coronary angiography.Results: In-stent restenosis was present in 9.3% of patients in the ACE inhibitor groupand 25.6% of patients in the placebo group (p =0.047). Mean late luminal loss was0.15[0.12-0.20]mm in the ACE inhibitor group and 0.22 [0.14-0.26] mm in the placebogroup (p = 0.002). There were no significant differences in plasma soluble Fas orsoluble Fas ligand levels at baseline. At 6 months, the change in plasma soluble Faslevel was significantly higher in the quinapril group (0.72 ±1.24 ng/ml) than in theplacebo group (0.28 ± 0.72 ng/ml)(p =0.024). The change in plasma soluble Fas ligandlevels at 6 months was significantly higher in the quinapril group (7.43 ±12.2 pg/ml)than in the placebo group (0.06 ± 6.8 pg/ml) (p =0.002).Also for the sTRAIL levelsthere was significant difference;in the ACE inhibitor group values were: 104[78-139]pg/ml vs 63[45-100] pg/ml, in the placebo group (P<0.001)Conclusion: the angiotensin-converting enzyme inhibitors leads through thesignificant increase of sFas, sFasL and sTRAIL plasma levels in important inhibitionof in-stent restenosis and reduction of the late lumen loss phenomenon afterpercutaneous intervention.
Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτιση τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση Θεωρητικό υπόβαθρο: Η χορήγηση των αναστολέων του μετατρεπτικού ενζύμου της αγγειοτενσίνης έχει προαναφερθεί πως αναστέλλουν την εντός του stent επαναστένωση. Για να εκτιμήσουμε την επίδραση της αναστολής του μετατρεπτικού ενζύμου στην επαναστένωση εντός του stent και να τη συσχετίσουμε με το φαινόμενο της απόπτωσης μελετήσαμε ασθενείς με χρόνια στεφανιαία νόσο και σημαντικού βαθμού στένωση στον πρόσθιο κατιόντα κλάδο.Μέθοδοι: 116 ασθενείς με χρόνια στεφανιαία νόσο οι οποίοι έχιζαν τοποθέτησης stent στον πρόσθιο κατιόντα…
Subjects/Keywords: Αναστολείς μετατρεπτικού ενζύμου αγγειοτενσίνης; Απόπτωση; Επαναστένωση εντός της ενδοστεφανιαίας πρόσθεσης; Angiotensin converting enzyme inhibitor; Apoptosis; in- stent restenosis
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APA (6th Edition):
Panagopoulou, V. (2014). Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτισή τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση. (Thesis). National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Retrieved from http://hdl.handle.net/10442/hedi/42537
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):
Panagopoulou, Vasiliki. “Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτισή τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση.” 2014. Thesis, National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ). Accessed February 25, 2021.
http://hdl.handle.net/10442/hedi/42537.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Panagopoulou, Vasiliki. “Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτισή τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση.” 2014. Web. 25 Feb 2021.
Vancouver:
Panagopoulou V. Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτισή τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση. [Internet] [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2014. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10442/hedi/42537.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Panagopoulou V. Επίδραση της αναστολής του μετατρεπτικού ενζύμου αγγειοτενσίνης σε δείκτες αποπτωτικής δραστηριότητας στη στεφανιαία κυκλοφορία και συσχέτισή τους με την επαναστένωση εντός στεφανιαίων ενδοπροσθέσεων, σε ασθενείς οι οποίοι έχουν υποβληθεί σε διαδερμική στεφανιαία παρέμβαση. [Thesis]. National and Kapodistrian University of Athens; Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών (ΕΚΠΑ); 2014. Available from: http://hdl.handle.net/10442/hedi/42537
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of KwaZulu-Natal
25.
Ramharack, Pritika.
HMG-CoA reductase inhibitor, atorvastatin induces apoptasis in human lung adenocarcinoma cell (A549).
Degree: 2015, University of KwaZulu-Natal
URL: http://hdl.handle.net/10413/14680
Subjects/Keywords: Lung cancer.; Apoptosis and p53.; HMG-CoA reductase inhibitor.
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APA ·
Chicago ·
MLA ·
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to Zotero / EndNote / Reference
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APA (6th Edition):
Ramharack, P. (2015). HMG-CoA reductase inhibitor, atorvastatin induces apoptasis in human lung adenocarcinoma cell (A549). (Thesis). University of KwaZulu-Natal. Retrieved from http://hdl.handle.net/10413/14680
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):
Ramharack, Pritika. “HMG-CoA reductase inhibitor, atorvastatin induces apoptasis in human lung adenocarcinoma cell (A549).” 2015. Thesis, University of KwaZulu-Natal. Accessed February 25, 2021.
http://hdl.handle.net/10413/14680.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ramharack, Pritika. “HMG-CoA reductase inhibitor, atorvastatin induces apoptasis in human lung adenocarcinoma cell (A549).” 2015. Web. 25 Feb 2021.
Vancouver:
Ramharack P. HMG-CoA reductase inhibitor, atorvastatin induces apoptasis in human lung adenocarcinoma cell (A549). [Internet] [Thesis]. University of KwaZulu-Natal; 2015. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10413/14680.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ramharack P. HMG-CoA reductase inhibitor, atorvastatin induces apoptasis in human lung adenocarcinoma cell (A549). [Thesis]. University of KwaZulu-Natal; 2015. Available from: http://hdl.handle.net/10413/14680
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
26.
윤, 종호.
Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder.
Degree: 2012, Ajou University
URL: http://repository.ajou.ac.kr/handle/201003/7574
;
http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012163
► X-linked inhibitor of apoptosis protein (XIAP) is associated with tumor genesis, growth, progression and metastasis, and acts by blocking caspase-mediated apoptosis. In the present study,…
(more)
▼ X-linked inhibitor of apoptosis protein (XIAP) is associated with tumor genesis, growth, progression and metastasis, and acts by blocking caspase-mediated apoptosis. In the present study, we sought to evaluate the expression patterns of XIAP in various neoplastic thyroid disorders and determine the association between XIAP expression and clinicopathologic factors. We additionally evaluated the association of XIAP expression and the BRAFV600E mutation and analyzed the association of XIAP expression and tumor recurrence in BRAFV600E prevalent PTC population. Expression of XIAP was evaluated with immunohistochemical staining using monoclonal anti-XIAP in 164 specimens of conventional papillary thyroid carcinoma (PTC) and 53 specimens of other malignant or benign thyroid tumors. The presence of the BRAFV600E mutation was evaluated using PCR amplification and direct sequencing in 164 specimens of conventional PTC. XIAP positivity was observed in 128 (78%) of the 164 conventional PTC specimens. Positive rates of XIAP expression in follicular variant PTC, follicular, medullary, poorly differentiated, and anaplastic thyroid carcinoma specimens were 20%, 25%, 38%, 67%, and 38%, respectively. Six nodular hyperplasia specimens were negative and 1 of 7 follicular adenomas (8%) was positive for XIAP. Lateral lymph node metastases were more frequent in patients negative for XIAP expression (P=0.01). The BRAFV600E mutation was found in 123 of 164 conventional PTCs (75%). XIAP expression was significantly higher in BRAFV600E mutated PTC than that in wild type PTC. (p=0.03). Negative XIAP expression were significantly associated with tumor recurrence in patients with BRAFV600E mutation (p = 0.03). Immunohistochemical staining for XIAP as a novel molecular marker may thus be helpful in the differential diagnosis of thyroid cancer and high XIAP expression in conventional PTC is strongly associated with reduced risk of lateral lymph node metastasis. Moreover, negative XIAP expression was associated with lateral lymph node metastases and an increased risk of recurrence in BRAF mutated PTC patients. XIAP immunohistochemical staining is useful for predicting patient prognosis in in BRAFV600E prevalent PTC population.
ABSTRACT i
TABLE OF CONTENTS ii
LIST OF FIGURES iii
LIST OF TABLES iv
Ⅰ. INTRODUCTION 1
Ⅱ. MATERIALS AND METHODS 2
A. Thyroid samples 2
B. Immunohistochemical analysis of XIAP 2
C. Clinicopathologic features of conventional papillary thyroid carcinoma 3
D. Statistics 4
E. Ethics statement 4
Ⅲ. RESULTS 5
Ⅳ. DISCUSSION 11
Ⅴ. CONCLUSION 14
REFERENCES 15
국문요약 18
Doctor
Advisors/Committee Members: 대학원 의학과, 200824591, 윤, 종호.
Subjects/Keywords: X-linked inhibitor of apoptosis protein; BRAFV600E mutation; papillary thyroid carcinoma; thyroid neoplasms; lymph nodes; metastasis; recurrence
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APA ·
Chicago ·
MLA ·
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CSE |
Export
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Manager
APA (6th Edition):
윤, . (2012). Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/7574 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012163
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):
윤, 종호. “Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder.” 2012. Thesis, Ajou University. Accessed February 25, 2021.
http://repository.ajou.ac.kr/handle/201003/7574 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012163.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
윤, 종호. “Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder.” 2012. Web. 25 Feb 2021.
Vancouver:
윤 . Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder. [Internet] [Thesis]. Ajou University; 2012. [cited 2021 Feb 25].
Available from: http://repository.ajou.ac.kr/handle/201003/7574 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012163.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
윤 . Expression of X-linked Inhibitor of Apoptosis Protein in Neoplastic Thyroid Disorder. [Thesis]. Ajou University; 2012. Available from: http://repository.ajou.ac.kr/handle/201003/7574 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000012163
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
27.
Lau, Rosanna.
cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function
.
Degree: 2012, University of Ottawa
URL: http://hdl.handle.net/10393/22845
► The cellular inhibitor of apoptosis protein (cIAP)-2 plays an important role in the protection against apoptosis by inhibiting the endogenous IAP inhibitor Smac, thus allowing…
(more)
▼ The cellular inhibitor of apoptosis protein (cIAP)-2 plays an important role in the protection against apoptosis by inhibiting the endogenous IAP inhibitor Smac, thus allowing other members of the IAP family, such as XIAP to block caspases. Additionally, cIAP2 functions as a ubiquitin ligase and mediates survival/proliferative signaling through NF-κB. cIAP2 is overexpressed in many human cancers and is believed to play an oncogenic role. This led to the development of small molecule IAP antagonists aimed at eliciting apoptosis in cancer cells. However, the loss of cIAP2 is also associated with multiple myeloma, in which constitutively active NF-κB signaling contributes to pathogenesis of the disease and suggests that cIAP2 may also perform a tumour suppressive function.
We demonstrate a novel role for cIAP2 in maintaining p53 levels in mammary epithelial cells that express wildtype p53. Downregulation of cIAP2 resulted in activation of IKKs, which led to increased Mdm2-mediated degradation of p53. cIAP2 depletion also led to increased phosphorylation of ERK1/2. Reduction of p53 levels, in combination with survival signaling provided by NF-κB and MEK-ERK pathways were associated with increased colony formation in vitro and increased DMBA-induced adenocarcinomas in cIAP2-null mice.
Treatment of cells with IAP antagonists resulted in significant cytotoxicity only in p53-mutant MDA-MB-231 cells, which was associated with autocrine production of TNF-α. We propose that the transcription of TNF-α is potentiated by gain-of-function mutation in p53 since downregulation of mutant p53 in MDA-MB-231 cells decreased TNF-α mRNA. Downregulation of cIAPs in p53-mutant cells resulted in a decrease in nuclear IKK-α, which may result in decreased IKK-α-mediated survival signaling. In contrast, cIAP downregulation in p53-wildtype cells resulted in no change in nuclear IKK-α, degradation of the corepressor SMRT and cell survival. We show that the effects of cIAP2 downregulation are context-dependent. Downregulation of cIAP2 in p53-wildtype cells results in a decrease in p53 and an increase in survival and proliferative signaling. These results suggest a tumour suppressor function for cIAPs that may account for cIAP mutation-associated cancers such as multiple myeloma. Moreover, our data also defines gain-of-function p53 mutation as a possible contributor to IAP antagonist sensitivity.
Subjects/Keywords: Inhibitor of apoptosis;
Cancer;
Cell signaling;
p53
…pathways ........................................................ 3
1.2
Inhibitor of apoptosis… …protein
cIAP1
cellular inhibitor of apoptosis protein 1
cIAP2
cellular inhibitor of… …heat shock protein
IAP
inhibitor of apoptosis protein
ID4
inhibitor of DNA binding 4… …phosphatase 1
XIAP
X-chromosome-linked inhibitor of apoptosis protein
ACKNOWLEDGEMENTS
First and… …describe a few pathways governing apoptosis that are commonly deregulated in
cancer.
Inhibitor of…
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lau, R. (2012). cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/22845
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):
Lau, Rosanna. “cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function
.” 2012. Thesis, University of Ottawa. Accessed February 25, 2021.
http://hdl.handle.net/10393/22845.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lau, Rosanna. “cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function
.” 2012. Web. 25 Feb 2021.
Vancouver:
Lau R. cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function
. [Internet] [Thesis]. University of Ottawa; 2012. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10393/22845.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lau R. cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function
. [Thesis]. University of Ottawa; 2012. Available from: http://hdl.handle.net/10393/22845
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Florida
28.
Toro, Edgardo J.
Characterization of Enoxacin a Novel Vacuolar H+ ATPase-Directed Osteoclast Inhibitor.
Degree: PhD, Medical Sciences - Molecular Cell Biology (IDP), 2012, University of Florida
URL: https://ufdc.ufl.edu/UFE0044571
► The fluoroquinolone antibiotic enoxacin was recently identified as an inhibitor of an interaction between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments, and of osteoclast…
(more)
▼ The fluoroquinolone antibiotic enoxacin was recently identified as an
inhibitor of an interaction between the B2-subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments, and of osteoclast formation and bone resorption in mouse marrow cultures containing osteoclasts and osteoblasts. Treatment of mouse marrow cultures and Raw 264.7 osteoclast-like cells with enoxacin reduced the amount of B2 subunit and a3 subunit associated with the detergent-insoluble cytoskeleton in differential pelleting assays. The relative levels of a variety of osteoclast marker proteins were not altered by treatment with enoxacin. Bone resorption by fully differentiated osteoclasts was blocked by enoxacin in vitro. To target enoxacin to bone, it was incorporated into a bisphosphonate backbone (bis-enoxacin; BENX). Bis-enoxacin retained its capacity to block interaction between recombinant B2-subunit and pure microfilaments, and also reduced osteoclast formation in either calcitriol-stimulated mouse marrow cultures or receptor activator of nuclear factor kappa B-ligand (RANKL)-stimulated Raw 264.7 cells with an IC50 of 10 µM which was identical to enoxacin. Unlike enoxacin, BENX stimulated caspase 3-mediated
apoptosis. BENX was significantly more effective than enoxacin at reducing bone resorption when bone was present (IC50=1mM). To determine if BENX is an effective
inhibitor of osteoclast resorption, we studied the effect BENX on a rat OTM model. BENX significantly inhibits OTM in vivo when compared to vehicle after 28 days of activation period. In summary, we have utilized a rational approach to identify an anti-osteoclastic agent with a novel mechanism of action that may confer advantages over existing therapeutic agents in the management of osteoclast-related disease. ( en )
Advisors/Committee Members: Holliday, Lexie S (committee chair), Culp, David (committee member), Wallet, Shannon (committee member), Wronski, Thomas J (committee member), Neubert, John K (committee member).
Subjects/Keywords: Actins; Adenosine triphosphatases; Apoptosis; Bone resorption; Bones; Cultured cells; Microfilaments; Orthodontics; Osteoclasts; Tooth movement; bisphosphonate – bone – inhibitor – orthodontic – osteoclast – vatpase
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APA (6th Edition):
Toro, E. J. (2012). Characterization of Enoxacin a Novel Vacuolar H+ ATPase-Directed Osteoclast Inhibitor. (Doctoral Dissertation). University of Florida. Retrieved from https://ufdc.ufl.edu/UFE0044571
Chicago Manual of Style (16th Edition):
Toro, Edgardo J. “Characterization of Enoxacin a Novel Vacuolar H+ ATPase-Directed Osteoclast Inhibitor.” 2012. Doctoral Dissertation, University of Florida. Accessed February 25, 2021.
https://ufdc.ufl.edu/UFE0044571.
MLA Handbook (7th Edition):
Toro, Edgardo J. “Characterization of Enoxacin a Novel Vacuolar H+ ATPase-Directed Osteoclast Inhibitor.” 2012. Web. 25 Feb 2021.
Vancouver:
Toro EJ. Characterization of Enoxacin a Novel Vacuolar H+ ATPase-Directed Osteoclast Inhibitor. [Internet] [Doctoral dissertation]. University of Florida; 2012. [cited 2021 Feb 25].
Available from: https://ufdc.ufl.edu/UFE0044571.
Council of Science Editors:
Toro EJ. Characterization of Enoxacin a Novel Vacuolar H+ ATPase-Directed Osteoclast Inhibitor. [Doctoral Dissertation]. University of Florida; 2012. Available from: https://ufdc.ufl.edu/UFE0044571
University of Georgia
29.
Johnson, Melanie E.
Survivin expression in canine and feline cancer.
Degree: 2014, University of Georgia
URL: http://hdl.handle.net/10724/22411
► Survivin is an inhibitor of apoptosis protein that is expressed during embryonic development and several human malignancies but is absent in most adult tissues. Its…
(more)
▼ Survivin is an inhibitor of apoptosis protein that is expressed during embryonic development and several human malignancies but is absent in most adult tissues. Its expression is often associated with a more malignant phenotype and decreased
response to chemotherapeutics. Analysis of the expression profile of transcripts in various cancers identified survivin as one of the top four transcripts upregulated in malignancy. Four human survivin isoforms have been identified that differ in their
ability to inhibit apoptosis. Thus, these isoforms may represent a regulatory balance between apoptosis and inhibition of apoptosis. Intense research is currently under way in human medicine to investigate the role of survivin in cancer. However, nothing
is known in regards to survivin expression in veterinary species. In order to examine survivin expression in canine and feline tissues, immunohistochemistry (IHC) and RT-PCR were performed on dog and cat embryos, normal adult tissues, inflammatory and
hyperplastic tissues, and a variety of neoplastic tissues. Survivin was expressed in fetal tissues, some hyperplastic, inflammatory, and neoplastic tissues, but was absent in most normal, adult tissues. To determine its significance as a prognostic
parameter in canine cancer, survivin expression was determined in neoplastic lymph nodes from dogs undergoing chemotherapy for lymphosarcoma. Survivin expression was shown to be a negative predictor of survival in canine lymphosarcoma. Canine survivin
isoforms have yet to be identified. To explore the possibility of differential expression of canine survivin isoforms, survivin subcellular localization, and proliferative and apoptotic markers were compared between canine mammary adenomas and carcinomas
that were all positive for survivin by IHC. Differences in nuclear survivin expression, Ki-67, and caspase-3 between the tumor types were not observed, thus potential expression of different canine survivin isoforms was not apparent from our data. In
conclusion, results of this work suggest that survivin expression in veterinary species needs to be further investigated, as this protein may prove to be useful in the diagnosis and prognosis of animal cancers. Furthermore, survivin could potentially
become a therapeutic target in veterinary oncology in the future.
Subjects/Keywords: apoptosis inhibitor; cancer; canine lymphosarcoma; canine mammary tumors; caspase-3; cell division; Ki-67; prognostic indicator; review; survivin
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Johnson, M. E. (2014). Survivin expression in canine and feline cancer. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/22411
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):
Johnson, Melanie E. “Survivin expression in canine and feline cancer.” 2014. Thesis, University of Georgia. Accessed February 25, 2021.
http://hdl.handle.net/10724/22411.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Johnson, Melanie E. “Survivin expression in canine and feline cancer.” 2014. Web. 25 Feb 2021.
Vancouver:
Johnson ME. Survivin expression in canine and feline cancer. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Feb 25].
Available from: http://hdl.handle.net/10724/22411.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Johnson ME. Survivin expression in canine and feline cancer. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/22411
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
30.
Brancato, Jennifer M.
Defining the Mechanism of Action of Bromodomain and
Extraterminal Inhibitors in Triple-Negative Breast Cancers.
Degree: PhD, Pharmacology, 2018, Case Western Reserve University School of Graduate Studies
URL: http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411
► Inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers have been extensively studied in a wide range of cancers, and several are being…
(more)
▼ Inhibitors of the Bromodomain and Extraterminal (BET)
family of epigenetic readers have been extensively studied in a
wide range of cancers, and several are being assessed in clinical
trials for their safety and efficacy in both hematologic and solid
tumors. However, we have a very limited understanding of the
mechanism(s) of action of these drugs in cancer. It is important to
determine how BET inhibitors (BETi) elicit their effects in order
to identify patients who will benefit most from the therapy and to
develop effective combination treatments that will provide durable
responses and prevent resistance. Our studies centered on
identifying the mechanism of action of BETi in triple-negative
breast cancer (TNBC), an aggressive disease that lacks effective
targeted therapies. We found that BETi induced multinucleation in
TNBC due in part to the suppression of the critical mitosis
regulators Aurora kinases A/B, and this was followed by
apoptosis
and senescence. The appearance of multinucleated cells coincided
with the suppression of mitosis genes, increased mitotic timing,
and the induction of
apoptosis during mitosis or immediately
following mitotic exit, all of which indicate that BETi induce
mitotic catastrophe. We further discovered that LIN9, a member of
the MuvB transcriptional regulatory complex, is a key mediator of
BETi activity in TNBC. BETi disrupt binding of the BET protein BRD4
to the promoter of LIN9, leading to LIN9 downregulation, which in
turn suppresses expression of mitosis genes and induces
multinucleation. While the selectivity of BETi for cancer cells has
been attributed to the dismantling of super-enhancers (SE) by BETi,
our studies revealed that LIN9 and four other critical mitosis
regulators lacked SEs, indicating BETi-induced mitotic catastrophe
does not rely on the disruption of SEs. Finally, we discovered
TNBCs may be particularly dependent on LIN9 expression. LIN9 is
amplified/overexpressed in two-thirds of TNBCs, and high LIN9
expression is associated with poor survival. Together, these data
reveal that tumors with amplified/overexpressed LIN9 such as TNBCs
may be particularly responsive to BETi. They further suggest that
an effective therapy to treat TNBC could be the combination of BETi
and drugs that increase sensitivity to mitotic
catastrophe.
Advisors/Committee Members: Keri, Ruth (Advisor), Zhang, Youwei (Committee Chair).
Subjects/Keywords: Pharmacology; Oncology; Biomedical Research; Breast cancer; BET protein; BET inhibitor; LIN9; Aurora kinase; apoptosis; senescence; mitotic catastrophe
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APA (6th Edition):
Brancato, J. M. (2018). Defining the Mechanism of Action of Bromodomain and
Extraterminal Inhibitors in Triple-Negative Breast Cancers. (Doctoral Dissertation). Case Western Reserve University School of Graduate Studies. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411
Chicago Manual of Style (16th Edition):
Brancato, Jennifer M. “Defining the Mechanism of Action of Bromodomain and
Extraterminal Inhibitors in Triple-Negative Breast Cancers.” 2018. Doctoral Dissertation, Case Western Reserve University School of Graduate Studies. Accessed February 25, 2021.
http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411.
MLA Handbook (7th Edition):
Brancato, Jennifer M. “Defining the Mechanism of Action of Bromodomain and
Extraterminal Inhibitors in Triple-Negative Breast Cancers.” 2018. Web. 25 Feb 2021.
Vancouver:
Brancato JM. Defining the Mechanism of Action of Bromodomain and
Extraterminal Inhibitors in Triple-Negative Breast Cancers. [Internet] [Doctoral dissertation]. Case Western Reserve University School of Graduate Studies; 2018. [cited 2021 Feb 25].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411.
Council of Science Editors:
Brancato JM. Defining the Mechanism of Action of Bromodomain and
Extraterminal Inhibitors in Triple-Negative Breast Cancers. [Doctoral Dissertation]. Case Western Reserve University School of Graduate Studies; 2018. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411
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