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UCLA
1.
Wang, Jiexin.
The paraspeckle protein Pspc1 promotes adipogenesis through differentiation-dependent nuclear export of adipogenic RNAs.
Degree: Cellular & Molecular Pathology, 2016, UCLA
URL: http://www.escholarship.org/uc/item/52p3n3tq 
► Adipocyte differentiation is accompanied by a robust program of cell-type specific gene expression. Although transcriptional regulators of this process are well defined, the contribution of…
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▼ Adipocyte differentiation is accompanied by a robust program of cell-type specific gene expression. Although transcriptional regulators of this process are well defined, the contribution of posttranscriptional factors to the establishment of the adipocyte phenotype is poorly understood. This thesis presents the RNA-binding protein paraspeckle protein 1 (Pspc1), a component of the paraspeckle complex, that promotes adipogenesis in vitro and is important for mature adipocyte function in vivo. Cross-linking and immunoprecipitation followed by RNA sequencing revealed that Pspc1 binds to intronic and 3′ untranslated regions of a battery of adipocyte RNAs, including that encoding the transcriptional regulator Ebf1. Purification of the paraspeckle complex from adipocytes further showed that Pspc1 associates with the RNA export factor Ddx3x in a differentiation-dependent manner. Remarkably, Pspc1 relocates from the nucleus to the cytoplasm during differentiation, coinciding with enhanced export of adipogenic RNAs. Mice lacking Pspc1 in fat show reduced lipid storage and adipose tissue mass and are resistant to diet-induced obesity and insulin resistance due to a compensatory increase in energy expenditure. These findings highlight a role for Pspc1-dependent RNA maturation in the posttranscriptional control of adipose development and function.
Subjects/Keywords: Pathology
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APA (6th Edition):
Wang, J. (2016). The paraspeckle protein Pspc1 promotes adipogenesis through differentiation-dependent nuclear export of adipogenic RNAs. (Thesis). UCLA. Retrieved from http://www.escholarship.org/uc/item/52p3n3tq
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):
Wang, Jiexin. “The paraspeckle protein Pspc1 promotes adipogenesis through differentiation-dependent nuclear export of adipogenic RNAs.” 2016. Thesis, UCLA. Accessed November 19, 2019.
http://www.escholarship.org/uc/item/52p3n3tq.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wang, Jiexin. “The paraspeckle protein Pspc1 promotes adipogenesis through differentiation-dependent nuclear export of adipogenic RNAs.” 2016. Web. 19 Nov 2019.
Vancouver:
Wang J. The paraspeckle protein Pspc1 promotes adipogenesis through differentiation-dependent nuclear export of adipogenic RNAs. [Internet] [Thesis]. UCLA; 2016. [cited 2019 Nov 19].
Available from: http://www.escholarship.org/uc/item/52p3n3tq.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wang J. The paraspeckle protein Pspc1 promotes adipogenesis through differentiation-dependent nuclear export of adipogenic RNAs. [Thesis]. UCLA; 2016. Available from: http://www.escholarship.org/uc/item/52p3n3tq
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
McGill University
2.
Pareek, Swati.
RelB regulation of cigarette smoke-induced pulmonary inflammation.
Degree: MS, Department of Pathology, 2018, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile160960.pdf
► Inflammation is a response to injury and infection. Although protective under physiological conditions, excessive and persistent inflammation is linked to disease. As the lungs are…
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▼ Inflammation is a response to injury and infection. Although protective under physiological conditions, excessive and persistent inflammation is linked to disease. As the lungs are continuously exposed to the external environment and subjected to injury by irritants, it is particularly liable to inflammation. RelB is a member of the non-canonical NF-κB pathway that may control lung inflammation and cell death caused by cigarette smoke (CS), a potent irritant and a leading cause of morbidity and mortality around the world. Our lab has previously shown that RelB protects against CS-induced apoptosis and inflammation in vitro, but less is known about pulmonary RelB in vivo. We hypothesized that RelB protects against acute CS-induced pulmonary inflammation. To investigate our hypothesis, we exposed wild-type (RelB+/+) and RelB-deficient mice (RelB-/-) mice to CS using an acute full-body regime. We found that CS-exposure caused a sustained decrease in airway granulocytes in RelB-/- mice; this decrease in granulocytes was predominated by neutrophils. Pulmonary inflammation caused by other irritants, including chlorine, ovalbumin (to mimic features of asthma) and lipopolysaccharide was unaffected by RelB. Differential cytokine analysis via multiplex assay suggests that alterations in chemotactic cytokines do not fully account for the CS-specific decrease in RelB-/- granulocytes. Flow cytometric analysis of the bronchoalveolar lavage and bone marrow cells also reveal that it is unlikely that the sustained decrease is caused by excessive cell death or decreased hematopoiesis from the bone marrow. Overall, our results indicate that RelB regulates acute CS-induced pulmonary inflammation through an unidentified mechanism. Understanding how RelB regulates CS-induced inflammation may potentiate the discovery of new therapeutic strategies for many of the inflammatory diseases caused by CS.
Le système immunitaire produit de l'inflammation en réponse à une blessure ou une infection. Bien que l'inflammation aiguë a un rôle protecteur, l'inflammation chronique peut entraîner des lésions persistantes dans les tissus et les organes. Par exemple, les poumons sont vulnérables aux irritants provenant de l'environnement extérieur et sont donc susceptibles de développer des lésions et de l'inflammation. RelB est un membre de la voie non-canonique du facteur transcriptionel NF-κB qui joue un rôle important dans l'inflammation et la mort cellulaire. Notre laboratoire a précédemment montré que RelB protège contre l'apoptose et l'inflammation induites in vitro par la fumée de cigarette ; un puissant irritant et une cause majeure de morbidité et de mortalité dans le monde. Cependant, le rôle protecteur de RelB dans les poumons est moins connu. Nous avons émis l'hypothèse que RelB protège contre l'inflammation pulmonaire induite par la fumée de cigarette. Pour valider notre hypothèse, nous avons exposé des souris de type sauvage (RelB+/+) ou déficientes en RelB (RelB-/-) à la fumée de cigarette Nous avons trouvé que l'exposition à la fumée…
Advisors/Committee Members: Carolyn Baglole (Internal/Supervisor).
Subjects/Keywords: Pathology
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McGill University
3.
AlGhamdi, Sarah.
Modeling intra-abdominal high grade serous ovarian cancer of human origin in nude mice.
Degree: MS, Department of Pathology, 2018, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile161234.pdf
► Background: Ovarian cancer is the deadliest disease of the female reproductive tract. At the time of diagnosis, in most cases the disease has already progressed…
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▼ Background: Ovarian cancer is the deadliest disease of the female reproductive tract. At the time of diagnosis, in most cases the disease has already progressed beyond the confines of the ovaries and into adjacent pelvic structures and various other sites within the peritoneal cavity. High-grade serous ovarian cancer (HGSOC) is the most common reported subtype, accounting for almost 70% of all ovarian cancer cases. Having a HGSOC mouse model with a phenotype of disease as close as it develops in humans, should allow a better assessment of preclinical therapeutic options as well as better understanding of the progression of the disease. Orthometastatic mouse models of peritoneal HGSOC are poorly described in the literature. Most of the ovarian cell lines studied in immunocompromised mice have been implanted subcutaneously instead of intraperitoneally thus not reflecting the nature of the disease, and, consequently, not allowing for a clear assessment of treatment responses. Moreover, most studies published utilized ovarian cancer cell lines that have low genetic fidelity with HGSOC. Hence, we created mouse models of HGSOC using cell lines with genetic fidelity to HGSOC aiming to allow better assessment of preclinical therapeutic options as well as better understanding of the progression of the disease. Methods: Athymic nude mice were injected intraperitoneally with one of the following cell lines: OVCAR-4, PEO14, or OVSAHO. The three cell lines showed expression of ARID1A, PAX8 and mutant p53, with variable expression of CA125 and WT1. We contrasted among the models the time needed for the disease to develop, the tissues being targeted, and the histopathological abnormalities detected. We also ran functional assays to test and compare the ability of the cell lines for migration and invasion. Results: The elapsed time for the disease to develop for all cell lines ranged from 4 to 11 months. This result stands in contrast with the less than 3 months it takes for the disease to evolve in the peritoneal cavity when injecting cells of unlikely HGSOC fidelity, such as SKOV-3 or A2780. Within the three cell lines used, we found commonalities and differences in terms of in vivo behavior. Among the commonalities, all cells homed to the omental-spleen-pancreatic area, liver base, mesentery and diaphragm. Among the differences, PEO14 cells developed sizable masses not invading the abdominal organs. OVSAHO cells developed more discrete masses closely surrounding yet not invading the organs. Finally, OVCAR-4 cells caused full invasiveness within the organs of the abdominal cavity in addition to developing micro-metastases in the lung. Animals injected with OVCAR-4 cells showed abundant bloody ascites heavily populated with multicellular structures (MCS). Animals injected with OVSAHO or PEO14 cells accumulated reduced volume of ascites fluid. In functional studies, OVCAR-4 has the highest migration and invasion capacity concordant with the in vivo behavior. Other cell lines have variable degree of heterogeneity of their invasion…
Advisors/Committee Members: Carlos Telleria (Supervisor).
Subjects/Keywords: Pathology
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4.
Star, Gregory.
The relationship between the bone morphogenic protein system and production of endothelin-1 by human lung microvascular endothelial cells: relevance to pulmonary arterial hypertension.
Degree: PhD, Department of Pathology, 2016, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile138823.pdf
► Introduction: Despite many advances in identifying its molecular basis and pathogenesis, pulmonary arterial hypertension (PAH) remains incompletely understood. It mainly affects women with a female…
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▼ Introduction: Despite many advances in identifying its molecular basis and pathogenesis, pulmonary arterial hypertension (PAH) remains incompletely understood. It mainly affects women with a female to male ratio of 3:1, and it often presents during the prime years of life with a mean age at diagnosis of 45 years. Lungs affected by PAH feature muscularization of proximal pulmonary arteries, endothelial cell growth resulting in obliteration of the microvascular lumen and the presence of inflammatory cells in the vascular walls. Endothelial cell (EC) dysfunction is a central feature of PAH. The ECs display dysregulated growth, which has been compared to a local neoplasia. The normal balance of endothelial-derived vasoconstrictors and dilators is tilted towards constriction and mitogenicity, as evidenced by a decrease in both nitric oxide and prostacyclin (PGI2), and an increase in production of the potent vasoconstrictor and smooth muscle mitogen endothelin-1 (ET-1). PAH can be familial. Mutations in the type II TGF beta family receptor, bone morphogenic protein receptor type II (BMPRII), are the most frequent mutations found in heritable PAH, accounting for approximately 80% of familial cases and 15-20% of idiopathic PAH (IPAH) cases. More recently, mutations in other TGF beta family signalling members such as activin-like-kinase receptor 1 (ALK1) and their intracellular signalling protein SMAD8 have been described as well. Results: Although abundant evidence now links BMP/TGF beta family signaling and PAH development, the effects of the mutations on production of endothelial mediators has not been studied in detail. Since endothelin-1 is an important mediator in PAH, we studied how BMP/TGF beta signalling affects the control of endothelin-1 production. In the first study of this thesis (chapter 2), we demonstrate that BMP9 is an extremely potent stimulator of ET-1 production in cultured lung microvascular ECs. This is an important finding, since previous studies have demonstrated that BMP9 is the most important ligand of ALK1 and it also binds to BMPR2. As described in chapter 3, we explored several mechanisms whereby BMP might control ET-1 production. Using knockdown of BMPR2 expression by siRNA, we assessed the effects on BMPR2 signaling and ET-1 levels. BMPR2 knockdown alone sufficed to increase ET-1 levels and, surprisingly, also increased downstream BMP receptor signaling. Exposure to BMP7, a ligand of BMPR2, increased ET-1 production. Co-knockdown of BMPRII with ALK2 prevented the increase in signaling and ET-1 production and also inhibited the BMP7-induced stimulation. The compound FK506, has recently been shown to stimulate SMAD signalling through ALK2. We show for the first time that FK506 can restore the downstream signalling for BMPR2 even when BMPR2 is knocked down. FK506 increased SMAD signaling and ET-1 production. This was completely prevented with ALK2 knockdown, further demonstrating the importance of ALK2 in ET-1 stimulation.Conclusion: The studies in this thesis provide insights into the role of the…
Advisors/Committee Members: David Langleben (Supervisor).
Subjects/Keywords: Pathology
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McGill University
5.
Lasiste, Jade Marie Edenvirg.
Metformin inhibits epithelial-to-mesenchymal transition in lens epithelial cells.
Degree: MS, Department of Pathology, 2017, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile147093.pdf
► Purpose: Posterior capsule opacification (PCO) is the most common complication after cataract surgery, affecting up to 50% of patients 2-5 years post-operatively. Epithelial-to-mesenchymal transition (EMT)…
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▼ Purpose: Posterior capsule opacification (PCO) is the most common complication after cataract surgery, affecting up to 50% of patients 2-5 years post-operatively. Epithelial-to-mesenchymal transition (EMT) is the main pathophysiology underlying PCO. Metformin, a drug with an excellent safety profile used primarily for diabetes, has been shown to suppress EMT. The objective of this study was to test the effectiveness of metformin in inhibiting EMT in an in vitro model of PCO. Methods: The human lens epithelial cell (LEC) line HLE-B3 was exposed to transforming growth factor-beta (TGF-β) and fibroblast growth factor (FGF) to induce EMT. Subsequently, the effect of metformin on the following cellular parameters were determined: (1) survival, using a viability assay and drug concentrations ranging from 0-100 mM; (2) expression of epithelial (Pax6, E-cadherin) and mesenchymal (α-smooth muscle actin or α-SMA, fibronectin) markers via Western blot; (3) morphology, via microscopy and image analysis; (4) and migration, using the wound assay. The presence of the metformin uptake receptor SLC22A1 in the cell line and the ratio of active to inactive protein kinase B (pAkt/Akt) were assessed via Western blot. SLC22A1 expression was confirmed with immunohistochemistry on donor eyes. Statistical analysis of variance (ANOVA) with Tukey post-hoc test was done for analysis of cytotoxicity, morphology and migration data. Results: Metformin is lethal to half (LC50) and all cells at 30 and 80 mM, respectively. A decrease in viability (P<0.05) was noted at 5 mM. Compared to untreated cells, EMT-induced LECs treated with 1 mM metformin showed increased Pax6 and E-cadherin and decreased α-SMA and fibronectin expression. LECs treated with metformin also maintained the roundness and circularity consistent with an epithelial phenotype. In addition, migration was significantly inhibited with 0.5 mM metformin (P<0.05). The HLE-B3 cell line and lens ocular epithelium in donor eyes were found to express SLC22A1, and treated HLE-B3 cells showed a decreased pAkt/Akt ratio. Conclusion: Metformin inhibits EMT in LECs, decreasing survival and migration and maintaining the epithelial phenotype. These findings suggest that metformin entry into the cell is through the SLC22A1 receptor, and its action mediated via decreased Akt activation. Metformin thus has potential as an adjunct to treatment. Toxicity to proximal eye tissues and effectiveness in vivo must be tested to determine dose, route and timing of administration.
Objectif: L'Opacification de la capsule postérieure (OCP) est la complication la plus courante suite à la chirurgie d'une cataracte et affecte environ la moitié des patients dans les 2-5 années suivant l'opération. Un phénomène appelé transition épithéliale-à-mésenchymale (TEM) est le principal mécanisme sous-jacent l'OCP. La metformin, un médicament principalement utilisé chez les diabétiques et ayant un excellent profil thérapeutique, est reconnue pour sa capacité d'inhibition de la TEM. L'objectif de cette étude est de…
Advisors/Committee Members: Miguel Noel Burnier (Internal/Supervisor).
Subjects/Keywords: Pathology
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McGill University
6.
Mastromonaco, Christina.
Intraocular lens biocompatibility: a novel, objective approach to understanding posterior capsular opacification.
Degree: MS, Department of Pathology, 2017, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile146786.pdf
► Posterior capsular opacification (PCO) is the leading complication following cataract surgery. Understanding factors that contribute to PCO development is a significant public concern as treatment…
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▼ Posterior capsular opacification (PCO) is the leading complication following cataract surgery. Understanding factors that contribute to PCO development is a significant public concern as treatment can lead to complications. PCO depends on the biocompatibility of the patient and the artificial lens; known as an intraocular lens (IOL), implanted within the capsular bag of the eye after cataract surgery. In order to prevent PCO, a better understanding of IOL characteristics, including design and material, and how it interacts with patients is required. Herein, this study investigates three main objectives: to invent a new objective PCO quantification system in post-mortem eyes, to validate this methodology, and to perform a retrospective multivariable analysis to determine which factors (IOL and patient-based) are least likely to result in PCO. The ultimate goal is to find the optimum IOL platform for patients. In total, 180 post-mortem eyes with implanted IOLs were collected from the Minnesota Eye Bank, along with their clinical history, including date of cataract surgery and IOL model number. The capsular bag (CB) with the IOL implant was removed from all eyes to obtain digital images. PCO outcome was quantified on CB images using an objective, novel automated custom image analyzer. The software measured intensity and area of the opacification within the IOL optic edge, intra-optic edge (IOE= intensity/area), and the opacities found within the capsular bag just outwards of the IOL optic, known as Soemmering's ring (SR= intensity/area). Software-derived PCO outcomes were statistically analyzed with previously used subjective PCO grading to verify validity. Epidemiologic analysis determined which IOL characteristics and patient-related factors correlated with PCO. IOL factors included material, edge design, lens filter, decentration and time of IOL implantation. Patient factors included sex, age and diabetes mellitus, among others.The software PCO grading system correlated well with previous scoring methods. Multivariate analyses showed non-diabetic patients had less SR (P= 0.05). Individuals 50-80 years old compared to 80+ had lower SR PCO (P= 0.01). Square and frosted optic edge design had lower SR and IOE PCO rates compared to OptiEdge (P= 0.001, 0.03). Patients with an IOL implanted for less then 25 months had lower SR and IOE PCO. (P= 0.0001, 0.004). In order to generate a lens that does not develop PCO, it is critical to understand the IOL- and patient-related factors that lead to PCO development. Based on our data, the most susceptible patients are elderly and diabetic, and it may be preferable to implant a square and frosted edge lens.
L'opacification capsulaire postérieure (OCP) est la principale complication après une chirurgie de la cataracte. Les éléments qui contribuent au développement de l'OCP sont une préoccupation majeure du public car le traitement peut provoquer des complications. L'OCP dépend de la biocompatibilité du patient envers la lentille artificielle; appelée lentille intraoculaire (LIO).…
Advisors/Committee Members: Miguel Noel Burnier (Internal/Supervisor).
Subjects/Keywords: Pathology
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Boston University
7.
Varian, Bernard.
The impact of delay to fixation on PD-L1 expression in human tissue.
Degree: MS, Pathology, 2017, Boston University
URL: http://hdl.handle.net/2144/20793
► The effects of tissue preservation techniques are known to have meaningful impact on diagnostic and prognostic variables. This study aims to evaluate and improve the…
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▼ The effects of tissue preservation techniques are known to have meaningful impact on diagnostic and prognostic variables. This study aims to evaluate and improve the quality of biospecimens utilized in cancer research. Protein Death Ligand 1 (PD-L1) is a cell surface molecule with an important role for immune suppression. Its utility lies within providing a basis for limiting the immune response. We aimed to evaluate the expression levels of PD-L1 in tissues that had varying lengths of delay to fixation. 21 placenta, renal, and colon surgical specimens were collected and divided into delay to fixation cohorts. Samples were then evaluated through Hematoxylin and Eosin (H and E), PD-L1 Immunohistochemistry (IHC), and for the colon samples Microsatellite Instability (MSI) Status. A total of 75% of slides were positive for PD-L1 expression. In relation to Placenta all were positive for PD-L1 expression. While colon samples were 41.25% positive for PD-L1 expression. Finally 49.5% of renal samples were positive for PD-L1 expression. Of the three colon samples one was MSI Low status while the remaining were Microsatellite Stable (MSS). PD-L1’s status as a utile biomarker for prognostic and diagnostic reasons remains uncertain. The stability of PD-L1 expression across tissue type and sample delay shows the stability of the biomarker. Therefore our work shows that a delay while significant in affecting other biomarkers does not significantly alter PD-L1 expression.
Subjects/Keywords: Pathology
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APA ·
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APA (6th Edition):
Varian, B. (2017). The impact of delay to fixation on PD-L1 expression in human tissue. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/20793
Chicago Manual of Style (16th Edition):
Varian, Bernard. “The impact of delay to fixation on PD-L1 expression in human tissue.” 2017. Masters Thesis, Boston University. Accessed November 19, 2019.
http://hdl.handle.net/2144/20793.
MLA Handbook (7th Edition):
Varian, Bernard. “The impact of delay to fixation on PD-L1 expression in human tissue.” 2017. Web. 19 Nov 2019.
Vancouver:
Varian B. The impact of delay to fixation on PD-L1 expression in human tissue. [Internet] [Masters thesis]. Boston University; 2017. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/2144/20793.
Council of Science Editors:
Varian B. The impact of delay to fixation on PD-L1 expression in human tissue. [Masters Thesis]. Boston University; 2017. Available from: http://hdl.handle.net/2144/20793
University of Cape Town
8.
Mohamed, Abdel Rahman Ahmed Nada.
The control of Foxp3+ regulatory T cell by interleukin-4 receptor alpha-mediated signaling.
Degree: PhD, Pathology, 2018, University of Cape Town
URL: http://hdl.handle.net/11427/29830
► T regulatory (Treg) cells play a pivotal role in the maintenance of self-tolerance and immune homeostasis. Forkhead box P3 (Foxp3)+ Treg function is controlled by…
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▼ T regulatory (Treg) cells play a pivotal role in the maintenance of self-tolerance and immune homeostasis. Forkhead box P3 (Foxp3)+ Treg function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. Recently, Interleukin (IL)-4 has been shown to play an important role in determining the fate of Foxp3+ Tregs. In vivo, IL-4-mediated signaling via Interleukin-4 receptor alpha (IL4Rα) was convincingly shown to mediate Treg transdifferentiation into ex-Foxp3 Th2 or Th17 cells, suggesting a negative regulation of Foxp3+ Tregs by IL-4Rα-mediated signaling. Puzzlingly, however, IL-4-mediated signaling was also independently found to reinforce the Foxp3+ Tregs, counter-arguing for the positive regulation of Foxp3+ Tregs by IL-4Rα-mediated signaling. In the face of such a conundrum, the present work was set forth as an attempt to unambiguously and conclusively decipher the bases of the regulation of Foxp3+ Treg by IL-4Rα-mediated signaling using transgenic murine models. It was first noted that Foxp3+ Treg cells do express IL-4Rα under steady-state. Furthermore, in vitro, purified CD25+ Tregs were prompted to higher Foxp3 expression and increased survival upon stimulation with IL-4 arguing for a potentiating role of IL-4Rα mediated signaling on Foxp3+ Treg cells. To better address the need for the host Foxp3+ Treg cells to express IL-4Rα as observed, we generated Foxp3-specific IL-4Rα deficient mice where IL-4Rα is specifically deleted from Foxp3+ T cells in the whole organism. Even though naïve Foxp3cre IL-4Rα -/lox mice model at homeostasis did neither reveal any significant alteration of the cellular, tissular and phenotypic profile nor development of spontaneous inflammatory disorder when compared to wild-type mice, under S. mansoni infection impairment IL-4Rα-mediated signaling on Foxp3+ Tregs resulted in heightened activation marker expression and elevated T cell effector functions as indicated by increased cytokines production and greater T cell proliferation rate. This heightened immune responsiveness translated overall into an exacerbated parasitic egg-driven fibrogranulomatous inflammation in the liver and the gut of schistosomiasis-diseased Foxp3cre IL-4Rα-/lox mice. Furthermore, in another model of helminth infection with the parasitic nematode, Nippostrongylus brasiliensis, Foxp3cre IL-4Rα-/lox mice showed a higher level of mucus and exaggerated emphysematous
pathology in the lungs. Interestingly, the impairment of IL-4Rα signaling within the Foxp3+ Treg population in Foxp3cre IL-4Rα-/lox mice led to a reduced recruitment of Foxp3+ Tregs and a diminished expression of Foxp3, and other associated Treg suppressive markers (i.e. IRF4 and Helios) during the course of these helminth infections. Taken together, our findings supported a role for IL-4Rα signaling in the positive regulation of Foxp3+ Tregs function and thus, the suppression of inflammatory responses during helminth infections. In conclusion, this work demonstrated a positive role for IL-4Rα mediated signaling in…
Advisors/Committee Members: Brombacher, Frank (advisor), Komguep Nono, Justin (advisor).
Subjects/Keywords: Pathology
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APA ·
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MLA ·
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CSE |
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APA (6th Edition):
Mohamed, A. R. A. N. (2018). The control of Foxp3+ regulatory T cell by interleukin-4 receptor alpha-mediated signaling. (Doctoral Dissertation). University of Cape Town. Retrieved from http://hdl.handle.net/11427/29830
Chicago Manual of Style (16th Edition):
Mohamed, Abdel Rahman Ahmed Nada. “The control of Foxp3+ regulatory T cell by interleukin-4 receptor alpha-mediated signaling.” 2018. Doctoral Dissertation, University of Cape Town. Accessed November 19, 2019.
http://hdl.handle.net/11427/29830.
MLA Handbook (7th Edition):
Mohamed, Abdel Rahman Ahmed Nada. “The control of Foxp3+ regulatory T cell by interleukin-4 receptor alpha-mediated signaling.” 2018. Web. 19 Nov 2019.
Vancouver:
Mohamed ARAN. The control of Foxp3+ regulatory T cell by interleukin-4 receptor alpha-mediated signaling. [Internet] [Doctoral dissertation]. University of Cape Town; 2018. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/11427/29830.
Council of Science Editors:
Mohamed ARAN. The control of Foxp3+ regulatory T cell by interleukin-4 receptor alpha-mediated signaling. [Doctoral Dissertation]. University of Cape Town; 2018. Available from: http://hdl.handle.net/11427/29830
Boston University
9.
Jang, Sunyoung.
Characterization of the recruitment of intimal smooth muscle cells in vascular disease.
Degree: 2014, Boston University
URL: http://hdl.handle.net/2144/14329
► Intimal hyperplasia occurs as a response to a variety of vascular insults and results in vascular stenosis, and organ ischemia. This process represents a fundamental…
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▼ Intimal hyperplasia occurs as a response to a variety of vascular insults and results in vascular stenosis, and organ ischemia. This process represents a fundamental component of atherosclerosis, venous graft stenonsis, and allograft arteriopathy in solid organ transplants. Smooth muscle cells (SMCs), and their associated extracellular matrix (ECM) form major components of intimal hyperplasia. We hypothesize that chemokines play a critical role in SMC migration into such intimal lesions. A number of chemokine-chemokine receptor interactions that mediate inflammatory cell recruitment have been characterized. However, the specific chemokine- chemokine receptor pathways that contribute to SMC recruitment are not known. The aims of this study are to examine the expression of C-C chemokine receptor 1 (CCR1) on medial SMCs (MSMCs), and to test its functionality in SMC recruitment. SMCs were derived from murine aortas; cultures were >95% SMC as demonstrated by the expression of smooth muscle α-actin (SMA), calponin, smooth muscle myosin heavy chain (SM-MHC). Interferon-gamma (IFN-γ) and Tumor necrosis factor- alpha (TNF-α) - stimulated MSMCs express CCR1 with a peak expression between 30 h and 48 h after cytokine stimulation. The functionality of receptors was initially demonstrated by agonist-induced calcium mobilization: the addition of CCR1 ligands, Regulated on activation, Normal T cell expressed and secreted (RANTES) and Macrophage inflammatory protein -1α (MIP-1α) to MSMCs caused an increase in intracellular Ca2+ concentration. Blockade of CCR1 by BX471, a CCR1 antagonist, inhibited the Ca2+ mobilization induced by RANTES and MIP-1α. The results suggest that up-regulation of CCR1 expression on cytokine-stimulated SMCs may facilitate recruitment into intimal lesions through endothelial-derived chemokine expression.
Subjects/Keywords: Pathology
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APA ·
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APA (6th Edition):
Jang, S. (2014). Characterization of the recruitment of intimal smooth muscle cells in vascular disease. (Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/14329
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):
Jang, Sunyoung. “Characterization of the recruitment of intimal smooth muscle cells in vascular disease.” 2014. Thesis, Boston University. Accessed November 19, 2019.
http://hdl.handle.net/2144/14329.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jang, Sunyoung. “Characterization of the recruitment of intimal smooth muscle cells in vascular disease.” 2014. Web. 19 Nov 2019.
Vancouver:
Jang S. Characterization of the recruitment of intimal smooth muscle cells in vascular disease. [Internet] [Thesis]. Boston University; 2014. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/2144/14329.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jang S. Characterization of the recruitment of intimal smooth muscle cells in vascular disease. [Thesis]. Boston University; 2014. Available from: http://hdl.handle.net/2144/14329
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cape Town
10.
Majara, Lerato Charlotte.
HIV-1 strain-specific neutralizing antibody responses and the dynamics of viral evolution.
Degree: Image, Clinical Laboratory Sciences, 2016, University of Cape Town
URL: http://hdl.handle.net/11427/28263
► It is widely held that for an HIV-1 vaccine to provide sterilizing immunity, it would need to elicit broadly neutralizing antibodies (bnAbs). However, factors underlying…
(more)
▼ It is widely held that for an HIV-1 vaccine to provide sterilizing immunity, it would need to elicit broadly neutralizing antibodies (bnAbs). However, factors underlying the development of these antibodies are not clear. There is evidence to suggest that in some individuals who develop bnAbs, the development of breadth is influenced by the co-evolution of the transmitted/founder (t/f) virus and earlier strain-specific neutralizing antibody (ssnAb) responses. Here we characterized the viral evolution, ssnAb and bnAbs responses in CAP292, an HIV-1 infected woman who developed bnAb responses from one year post infection. We used single genome amplification (SGA) to characterize viral evolution at four time points: at acute infection; after the development of strain-specific neutralizing responses; at the first detection of the broadly neutralizing antibody response; and lastly, at the peak of the broad response. We identified the t/f virus, and generated chimeric viruses from this to determine the targets of the ssnAb responses. A panel of site-directed mutant viruses were used to map the specificity of the bnAb responses. Our data indicated that infection was most likely founded by a single virus and that the first wave of ssnAbs emerged at 14 weeks post infection (w.p.i), targeting the V1V2 loop of Envelope (Env). A second wave of ssnAbs, possibly targeting the C3V4 region, emerged by 30 w.p.i. Two distinct viral clusters were detected by the time the bnAb response peaked, suggesting the presence of distinct escape pathways. Mapping of the bnAb specificities indicated that CAP292 produced PGT128-like bnAb responses targeted toward the 332 glycan.
Advisors/Committee Members: Williamson, Carolyn (advisor), Anthony, Colin Scott (advisor).
Subjects/Keywords: Pathology
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APA (6th Edition):
Majara, L. C. (2016). HIV-1 strain-specific neutralizing antibody responses and the dynamics of viral evolution. (Thesis). University of Cape Town. Retrieved from http://hdl.handle.net/11427/28263
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):
Majara, Lerato Charlotte. “HIV-1 strain-specific neutralizing antibody responses and the dynamics of viral evolution.” 2016. Thesis, University of Cape Town. Accessed November 19, 2019.
http://hdl.handle.net/11427/28263.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Majara, Lerato Charlotte. “HIV-1 strain-specific neutralizing antibody responses and the dynamics of viral evolution.” 2016. Web. 19 Nov 2019.
Vancouver:
Majara LC. HIV-1 strain-specific neutralizing antibody responses and the dynamics of viral evolution. [Internet] [Thesis]. University of Cape Town; 2016. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/11427/28263.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Majara LC. HIV-1 strain-specific neutralizing antibody responses and the dynamics of viral evolution. [Thesis]. University of Cape Town; 2016. Available from: http://hdl.handle.net/11427/28263
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cape Town
11.
Logan, Erin.
Early-life immunity and susceptibility to Mycobacteria.
Degree: PhD, Pathology, 2018, University of Cape Town
URL: http://hdl.handle.net/11427/29195
► The naïve and not-yet developed infant immune system exhibits heightened susceptibility to external factors (e.g pathogens), and is shaped by these and others, such as…
(more)
▼ The naïve and not-yet developed infant immune system exhibits heightened susceptibility to external factors (e.g pathogens), and is shaped by these and others, such as maternal immunity. However, we do not yet fully understand their impact on development of infant immunity. A better understanding of these effects would benefit children world-wide, but especially those in low-middle income countries (LMIC), where increased exposure to pathogens due to poorer living conditions highlights the necessity of robust early-life immunity. Mycobacterium tuberculosis (Mtb) and helminths are pathogens co-endemic in many LMIC and cause significant morbidity and mortality in children. Infant immune responses to these pathogens, whether during standalone infection, co-infection or resulting from maternal infection are not fully understood. To contribute to this knowledge gap, we investigated early-life immune responses, how they relate to childhood Mtb/helminth infection and how they are affected by maternal infectious history and immunity. Analysis of clinical humoral responses revealed total IgG that increased significantly between baseline and tuberculosis (TB) investigation in infants who did not acquire Mtb infection; these infants also exhibited raised levels of measles-specific IgG and BCG-specific IgG2. No active helminth infections were detected, but the presence of Ascaris lumbricoides- and Trichuris trichiura-specific class-switched antibodies indicated prior exposure. No association was found between helminth-specific humoral responses and risk of Mtb infection, nor with maternal helminth-specific humoral responses. Conversely, data from murine experiments revealed a protective effect of maternal helminth infection (Nippostrongylus brasiliensis) on BCG infection in offspring, with reduced lung bacterial burden and increased numbers of activated CD4+ T cells and B cells. Maternal Nb infection may have a synergistic effect on BCG vaccination, as BCGvaccinated/infected pups from Nb-infected mothers had reduced lung bacterial burdens, increased CD4+ T cell and B cell responses and increased IFNγ-producing CD4+ T cells. Findings from this study suggest that childhood vaccines could provide heterologous protection against unrelated pathogens such as Mtb. The murine data suggest a protective effect of maternal helminth infection against BCG infection in offspring, but no similar finding was observed with the clinical data. The clear protective effect of maternal Nb infection during offspring BCG infection warrants a more in-depth clinical study addressing the functional effects of maternal helminth infection on Mtb infection outcome in infants.
Advisors/Committee Members: Horsnell, William (advisor), Hatherill, Mark (advisor), Cunningham, Adam F (advisor).
Subjects/Keywords: pathology
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APA (6th Edition):
Logan, E. (2018). Early-life immunity and susceptibility to Mycobacteria. (Doctoral Dissertation). University of Cape Town. Retrieved from http://hdl.handle.net/11427/29195
Chicago Manual of Style (16th Edition):
Logan, Erin. “Early-life immunity and susceptibility to Mycobacteria.” 2018. Doctoral Dissertation, University of Cape Town. Accessed November 19, 2019.
http://hdl.handle.net/11427/29195.
MLA Handbook (7th Edition):
Logan, Erin. “Early-life immunity and susceptibility to Mycobacteria.” 2018. Web. 19 Nov 2019.
Vancouver:
Logan E. Early-life immunity and susceptibility to Mycobacteria. [Internet] [Doctoral dissertation]. University of Cape Town; 2018. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/11427/29195.
Council of Science Editors:
Logan E. Early-life immunity and susceptibility to Mycobacteria. [Doctoral Dissertation]. University of Cape Town; 2018. Available from: http://hdl.handle.net/11427/29195
University of Cape Town
12.
Reiche, Michael Anton.
Visualising the Mycobacterial Mutasome.
Degree: Image, Pathology, 2018, University of Cape Town
URL: http://hdl.handle.net/11427/28381
► An SOS-inducible DNA repair system has been linked to transient hyper-mutation and the development of drug resistance in Mycobacterium tuberculosis. Previous work has established that…
(more)
▼ An SOS-inducible DNA repair system has been linked to transient hyper-mutation and the development of drug resistance in Mycobacterium tuberculosis. Previous work has established that this “mycobacterial mutasome” comprises the specialist DNA polymerase, DnaE2, and accessory factors of unknown function, ImuA′ and ImuB. However, the molecular interactions and sub-cellular recruitment dynamics enabling mutasome function remain poorly understood. Here, a panel of fluorescent strains of M. smegmatis was developed to investigate expression and subcellular localization of ImuA′ and ImuB in live mycobacteria exposed to genotoxic agents. Using fluorescence microscopy, it was observed that, during prolonged genotoxic stress, single M. smegmatis cells exhibited an elongated cell phenotype and apparent aneuploidy – potentially providing an environment for recombination between differentially mutated chromosomes. Furthermore, ImuB was seen to associate with the dnaNencoded β clamp in discrete foci during mutagenic DNA repair. In contrast, ImuA′ did not exhibit similar localization and instead appeared to diffuse throughout the bacillus. A mutant ImuB protein deficient in the β clamp-binding motif failed to colocalize with the β clamp, reinforcing the inferred essentiality of the ImuB-β clamp protein-protein interaction for mutasome recruitment and induced mutagenesis. Additionally, exposure of M. smegmatis to griselimycin, a novel β clamp-targeting natural product antibiotic, prevented ImuB-β clamp co-localization during SOS induced mutagenesis, an observation confirmed by superresolution, threedimensional interferometric photo-activated light microscopy. These results establish the capacity of griselimycin to inhibit DNA replication as well as prevent DNA damage-induced mutagenesis by disrupting mutasome assembly and activity. Notably, this differentiates griselimycin from other inhibitors of DNA metabolic function which carry the often-unavoidable liability of accelerating drug-resistance by inducing mutagenic DNA repair. In turn, it suggests the potential application of griselimycin as an anti-evolution agent in novel therapeutic regimens designed to protect existing tuberculosis drugs.
Advisors/Committee Members: Warner, Digby (advisor).
Subjects/Keywords: pathology
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APA (6th Edition):
Reiche, M. A. (2018). Visualising the Mycobacterial Mutasome. (Thesis). University of Cape Town. Retrieved from http://hdl.handle.net/11427/28381
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):
Reiche, Michael Anton. “Visualising the Mycobacterial Mutasome.” 2018. Thesis, University of Cape Town. Accessed November 19, 2019.
http://hdl.handle.net/11427/28381.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Reiche, Michael Anton. “Visualising the Mycobacterial Mutasome.” 2018. Web. 19 Nov 2019.
Vancouver:
Reiche MA. Visualising the Mycobacterial Mutasome. [Internet] [Thesis]. University of Cape Town; 2018. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/11427/28381.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Reiche MA. Visualising the Mycobacterial Mutasome. [Thesis]. University of Cape Town; 2018. Available from: http://hdl.handle.net/11427/28381
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cape Town
13.
Mbobo, Buchule.
Modelling neuroimmune interactions using organotypic slice cultures.
Degree: Image, Division of Chemical Pathology, 2017, University of Cape Town
URL: http://hdl.handle.net/11427/24907
► Tuberculosis predominantly manifests in the form of a pulmonary infection, but may spread out into other parts of the body and is then referred to…
(more)
▼ Tuberculosis predominantly manifests in the form of a pulmonary infection, but may spread out into other parts of the body and is then referred to as extrapulmonary tuberculosis (EPTB). One form of EPTB is an infection of the central nervous system (brain & spinal cord), CNS-TB. Although CNS-TB is relatively rare, accounting for about 5% of EPTB, it is characterised by high morbidity and mortality, particularly for children and immunosuppressed individuals. To examine the effects of a Mycobacterium tuberculosis infection of neural tissue, researchers have hitherto relied on two animal models namely, in vivo intracranial infections or in vitro culturing with dissociated neural cells. Both models have yielded crucial insights concerning CNS-TB but each have limitations e.g. lack of access to the brain during infection in vivo and absence of the 3D organizational tissue structure in vitro. This study investigated the effect of the vaccine strain for tuberculosis, Bacille Calmette-Guerin (BCG) on neural tissue using the model of organotypic hippocampal slice cultures; an in vitro model that overcomes the previously mentioned obstacles. The study sought to expound on immunological and electrophysiological responses to the infection. A viable and moderate BCG infection was established in the hippocampal slice cultures, confirmed by colony forming units enumeration and immunohistochemistry. However, immunological analysis using ELISA found that BCG infection did not change the production levels of cytokines and elicit a distinguishable immune response. To examine the neuronal function during BCG infection, whole-cell patch clamp technique was applied to the hippocampal slice cultures. The neuronal intrinsic properties were not significantly different between infected and non-infected slices. However, tuberculin PPD (M. tuberculosis extract) moderately and transiently had a depolarizing effect when 'puffed' directly onto neurons. In conclusion, organotypic slice cultures are suitable for the investigation of cellular interactions and neural functions in CNS-TB, and the neuronal impact of PPD warrants further investigation.
Advisors/Committee Members: Jacobs, Muazzam (advisor).
Subjects/Keywords: Pathology
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Export
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Manager
APA (6th Edition):
Mbobo, B. (2017). Modelling neuroimmune interactions using organotypic slice cultures. (Thesis). University of Cape Town. Retrieved from http://hdl.handle.net/11427/24907
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):
Mbobo, Buchule. “Modelling neuroimmune interactions using organotypic slice cultures.” 2017. Thesis, University of Cape Town. Accessed November 19, 2019.
http://hdl.handle.net/11427/24907.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Mbobo, Buchule. “Modelling neuroimmune interactions using organotypic slice cultures.” 2017. Web. 19 Nov 2019.
Vancouver:
Mbobo B. Modelling neuroimmune interactions using organotypic slice cultures. [Internet] [Thesis]. University of Cape Town; 2017. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/11427/24907.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Mbobo B. Modelling neuroimmune interactions using organotypic slice cultures. [Thesis]. University of Cape Town; 2017. Available from: http://hdl.handle.net/11427/24907
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
14.
Birbrair, Alexander.
PERICYTE SUBTYPES AT THE INTERSECTION BETWEEN TISSUE REGENERATION AND PATHOLOGY.
Degree: 2014, Wake Forest University
URL: http://hdl.handle.net/10339/39384
► Normal tissue homeostasis as well as tissue regeneration and repair after damage rely on resident stem cells. Incomplete regeneration in mammals has been attributed to…
(more)
▼ Normal tissue homeostasis as well as tissue regeneration and repair after damage rely on resident stem cells. Incomplete regeneration in mammals has been attributed to an insufficient number of stem cells and a rapid fibro/adipocytic infiltration after wounding. Excessive scar formation compromises tissue function and can lead to organ failure. Cells called pericytes, located around blood vessels, act as stem cells. Some studies suggest that pericytes may contribute to regeneration in various organs as well as fibrous tissue and fat formation in response to aging and pathologies. Based on markers and morphology, pericytes have been identified as heterogeneous. However, the differentiation capability of pericyte subtypes has not yet been explored. Here we distinguish two bona fide pericyte subpopulations based on molecular markers, Nestin-GFP-/NG2-DsRed+/ PDGFRâ+ (type-1) and Nestin-GFP+/NG2-DsRed+/ PDGFRâ+ (type-2). This thesis characterizes heretofore their unknown specific roles. Only type-2 pericytes have the potential, under optimized culture conditions, to generate neural cells. Additionally, type-2 pericytes participate in muscle regeneration; while type-1 contribute to fat accumulation. Type-1 pericytes deposit fibrous tissue in an organ-dependent manner in response to tissue injury. Moreover, only type-2 pericytes participate in normal and pathological angiogenesis. Our discoveries provide novel central cellular targets susceptible to signaling manipulation and pharmacological modulation in many diseases. Based on this work, we expect to limit deleterious pericytes' functions while preserving their healthy functions.
Subjects/Keywords: pathology
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APA (6th Edition):
Birbrair, A. (2014). PERICYTE SUBTYPES AT THE INTERSECTION BETWEEN TISSUE REGENERATION AND PATHOLOGY. (Thesis). Wake Forest University. Retrieved from http://hdl.handle.net/10339/39384
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):
Birbrair, Alexander. “PERICYTE SUBTYPES AT THE INTERSECTION BETWEEN TISSUE REGENERATION AND PATHOLOGY.” 2014. Thesis, Wake Forest University. Accessed November 19, 2019.
http://hdl.handle.net/10339/39384.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Birbrair, Alexander. “PERICYTE SUBTYPES AT THE INTERSECTION BETWEEN TISSUE REGENERATION AND PATHOLOGY.” 2014. Web. 19 Nov 2019.
Vancouver:
Birbrair A. PERICYTE SUBTYPES AT THE INTERSECTION BETWEEN TISSUE REGENERATION AND PATHOLOGY. [Internet] [Thesis]. Wake Forest University; 2014. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/10339/39384.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Birbrair A. PERICYTE SUBTYPES AT THE INTERSECTION BETWEEN TISSUE REGENERATION AND PATHOLOGY. [Thesis]. Wake Forest University; 2014. Available from: http://hdl.handle.net/10339/39384
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Columbia University
15.
Woo, Seung-Hyun.
Identification and characterization of epithelial progenitor niches in skin.
Degree: 2011, Columbia University
URL: https://doi.org/10.7916/D82231Q9
► The skin contains a highly regionalized stem and progenitor cell niche system, where a particular epithelial progenitor population primarily displays unipotent or bipotent behavior by…
(more)
▼ The skin contains a highly regionalized stem and progenitor cell niche system, where a particular epithelial progenitor population primarily displays unipotent or bipotent behavior by contributing to their local niche under homeostatic conditions. Some of these populations, however, can also contribute to lineages beyond their local niche in response to wounding or other traumas. The goal of this thesis was to identify additional epithelial progenitor niches in the skin and characterize them. I focused on identifying and investigating the role of epithelial progenitors residing in two discrete compartments, the upper isthmus (UI) of the hair follicle and the touch dome (TD) in the epidermis, during skin development and homeostasis. The UI niche was identified by immunofluorescence studies based on the expression profile of a6 integrin low, Sca-1 negative, CD34 negative cells. The progenitor characteristics of UI keratinocytes were confirmed using skin reconstitution and in vitro colony formation assays. The transcriptional profiling of UI cells led to the identification of Tbc1d10c, one of the uniquely upregulated genes in UI cells. The comprehensive characterization of the UI niche by immunofluorescence led to the identification of a neural complex called palisade nerve endings (PN) present outside of the UI. Further investigation of PN using immunofluorescence and animal models revealed the presence of a glutamate transport to the HF via sensory nerve fibers. I elucidated that the presence of glutamate was critical for the organization of Schwann cells in the developing HF. Although the relationship between UI keratinocytes and PN still needs to be investigated, the presence of PN in the UI niche implicates that there is more function ascribed to UI cells in addition to serving as epithelial progenitors. The next epithelial progenitor niche I identified and characterized was the touch dome (TD) in the epidermis of hairy skin. The TD is a specialized niche, in which both epidermal Merkel cells and TD keratinocytes reside. The unexpected and exclusive presence of both Tbc1d10c and CD200 proteins in TD keratinocytes eventually led us to find that they were epidermal Merkel cell progenitors. Their progenitor characteristics were validated using skin reconstitution assay and in vivo lineage tracing by EdU incorporation. Our results collectively suggested that TD keratinocytes were bipotent progenitors that gave rise to both squamous and neuroendocrine epidermal lineages. Lastly, I generated a UI-specific Cre transgenic mouse line driven by the Tbc1d10c promoter, which will be utilized for further characterization of UI keratinocytes, including in vivo lineage tracing. I also generated Tbc1d10c complete knockout mice, which I will investigate to determine whether Tbc1d10c plays a role during skin development and homeostasis.
Subjects/Keywords: Pathology
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APA ·
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MLA ·
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APA (6th Edition):
Woo, S. (2011). Identification and characterization of epithelial progenitor niches in skin. (Doctoral Dissertation). Columbia University. Retrieved from https://doi.org/10.7916/D82231Q9
Chicago Manual of Style (16th Edition):
Woo, Seung-Hyun. “Identification and characterization of epithelial progenitor niches in skin.” 2011. Doctoral Dissertation, Columbia University. Accessed November 19, 2019.
https://doi.org/10.7916/D82231Q9.
MLA Handbook (7th Edition):
Woo, Seung-Hyun. “Identification and characterization of epithelial progenitor niches in skin.” 2011. Web. 19 Nov 2019.
Vancouver:
Woo S. Identification and characterization of epithelial progenitor niches in skin. [Internet] [Doctoral dissertation]. Columbia University; 2011. [cited 2019 Nov 19].
Available from: https://doi.org/10.7916/D82231Q9.
Council of Science Editors:
Woo S. Identification and characterization of epithelial progenitor niches in skin. [Doctoral Dissertation]. Columbia University; 2011. Available from: https://doi.org/10.7916/D82231Q9
Wayne State University
16.
Bottrell, Alyssa.
The Role Of Pdgf C And Its Splice Variant In Breast Cancer.
Degree: PhD, Pathology, 2014, Wayne State University
URL: https://digitalcommons.wayne.edu/oa_dissertations/1285
► The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as…
(more)
▼ The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C encoding the truncated PDGF C protein (t-PDGF C). Specific aims of this dissertation are to determine the role of full-length PDGF C (FL-PDGF C) and t-PDGF C in breast cancer and to characterize their subcellular localizations. This study found that although t-PDGF C presumably lacks the signal peptide, it is secreted as a heterodimer with FL-PDGF C which can undergo extracellular proteolytic activation. Furthermore, PDGF C was found in the nuclear fraction of breast cancer cells, suggesting an uncharacterized function in breast cancer. A putative nuclear localization sequence in PDGF C showed little effect on its nuclear localization as determined by the point mutagenesis assay. Interestingly, we found that the serine protease cleavage site in the hinge region plays a critical role for both extracellular proteolytic processing and nuclear accumulation of PDGF C, suggesting that the biochemical processing and the subcellular localization are co-regulated. For the functional study, we established in vitro cell models engineered to overexpress PDGF C isoforms or inhibit its expression. This study found that PDGF C expression correlates with cell proliferation, invasive phenotype and anchorage-independent growth in vitro. Importantly, t-PDGF C expression further promoted PDGF C-induced phenotypic transformation. PDGF C downregulation decreased tumor growth and metastatic potential in vivo. Taken together, this study identified PDGF C and its splice variant as key signaling molecules in breast cancer. In addition, once thought of as primarily an extracellular signaling molecule, nuclear localization marks a potentially important paradigm shift in PDGF C biology.
Advisors/Committee Members: Hyeong-Reh C. Kim.
Subjects/Keywords: Pathology
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APA (6th Edition):
Bottrell, A. (2014). The Role Of Pdgf C And Its Splice Variant In Breast Cancer. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/1285
Chicago Manual of Style (16th Edition):
Bottrell, Alyssa. “The Role Of Pdgf C And Its Splice Variant In Breast Cancer.” 2014. Doctoral Dissertation, Wayne State University. Accessed November 19, 2019.
https://digitalcommons.wayne.edu/oa_dissertations/1285.
MLA Handbook (7th Edition):
Bottrell, Alyssa. “The Role Of Pdgf C And Its Splice Variant In Breast Cancer.” 2014. Web. 19 Nov 2019.
Vancouver:
Bottrell A. The Role Of Pdgf C And Its Splice Variant In Breast Cancer. [Internet] [Doctoral dissertation]. Wayne State University; 2014. [cited 2019 Nov 19].
Available from: https://digitalcommons.wayne.edu/oa_dissertations/1285.
Council of Science Editors:
Bottrell A. The Role Of Pdgf C And Its Splice Variant In Breast Cancer. [Doctoral Dissertation]. Wayne State University; 2014. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1285
McGill University
17.
Lisio, Michael-Anthony.
Evaluation of platinum-sensitivity in a cell line model of high grade serous ovarian cancer and the induction of re- sistance from a chemo-sensitive cell line through the re- population of cells following short-term cisplatin treatment.
Degree: MS, Department of Pathology, 2019, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile163705.pdf
► Introduction Resistance to platinum-based therapy develops in most patients treated for High Grade Serous Ovarian Cancer (HGSOC), a fact that largely accounts for this disease's…
(more)
▼ Introduction Resistance to platinum-based therapy develops in most patients treated for High Grade Serous Ovarian Cancer (HGSOC), a fact that largely accounts for this disease's elevated mortality. It was previously shown by Cooke and colleagues (Oncogene, 2010) that platinum (Pt) resistance results from the expansion of sub-clonal populations of resistant cells present prior to treatment. Current in vitro models of Pt-resistance may be confounded by a lack of fidelity to the genetic signature of HGSOC, or by the methods used to elicit the onset of resistance which may lack clinical relevance. This project aims to address whether Pt-resistance can be evolved from a population of Pt-sensitive cells exposed to cisplatin (CDDP) in a clinically relevant manner using patient-derived cell lines such as PEO1. The central aim was to uncover what heterogeneity might exist within this cell line and to determine if in vitro derived Pt-resistance can result from the selection of pre-existent subsets of cells as occurs in vivo. Methods The Pt-sensitivity of the cell lines used, was established by exposing cells in culture to CDDP for 1 hr. Live cell number and percent viability were assessed 72 hours after drug removal using Guava microcytometry. Long-term assessment of Pt toxicity was provided by use of the clonogenic survival assay. To achieve Pt-resistance in vitro, a culture of PEO1 was exposed to 10 µM CDDP for 1 hour and allowed to repopulate. These cells were passaged and used to establish a novel cell line (PEO1X) with 20-fold diminished Pt-sensitivity confirmed via the clonogenic survival assay. PEO1X cells were assayed for histopathological and cell-fate markers by immunohistochemistry and compared to PEO1. Migratory capacity was assessed via the Boyden chamber method, while cell cycle status 72 hours after CDDP exposure was interrogated using propidium iodide staining. Doubling time was also determined, and a partial genetic signature was established by sequencing a panel of 33 cancer-related genes. Results PEO1 exhibits morphological asymmetry, with a dichotomy between epithelial and mesenchymal phenotypes. This is further evidenced by the heterogeneous expression of markers such as E-Cadherin, Vimentin and CA125. Although similar to PEO1 in proliferation rate, PEO1X cells possess obvious differences in morphology, being smaller and more homogenously rounded in appearance with altered expression of markers such as E-Cadherin, Vimentin, CA125 and CD133. Unlike PEO1, the cell cycle status of PEO1X is barely altered 72 hrs following CDDP exposure even at 10 µM. PEO1X also possesses a more migratory phenotype than PEO1 with significantly more cells transiting through the pores of the Boyden chamber membrane in 30 hrs. Sequencing revealed heterogeneity in the status of P53 in PEO1 with PEO1X being slightly enriched in P53 WT expressing cells. Interestingly, the gene NF1, encoding the tumor-suppressor neurofibromin was found to contain an indel mutation in PEO1 and PEO1X while containing a different…
Advisors/Committee Members: Carlos Telleria (Internal/Supervisor).
Subjects/Keywords: Pathology
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McGill University
18.
Guerrina, Necola.
Reduced aryl hydrocarbon receptor (AhR) expression drives the pathogenesis of cigarette smoke-induced emphysema.
Degree: PhD, Department of Pathology, 2019, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile163747.pdf
► Chronic Obstructive Pulmonary Disease (COPD) is a prevalent and complex respiratory disorder primarily caused by inhalational exposure to cigarette smoke (CS). However, only approximately 15%…
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▼ Chronic Obstructive Pulmonary Disease (COPD) is a prevalent and complex respiratory disorder primarily caused by inhalational exposure to cigarette smoke (CS). However, only approximately 15% of cigarette smokers develop COPD, suggesting that genetic or epigenetic factors may contribute to disease susceptibility. One feature of COPD is emphysema, which is characterized by permanent alveolar wall destruction leading to airspace enlargement. The alveolar wall destruction in emphysema is a consequence of multiple pathogenic mechanisms including chronic inflammation, a protease: anti-protease imbalance and the upregulation of cell death programs such as apoptosis, autophagy and endoplasmic reticulum (ER) stress. However, molecular mechanism(s) that regulate these pathogenic events, and thus the development of emphysema, are poorly understood. This regulation may involve the aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor whose involvement in COPD pathogenesis is unknown. Our lab has previously published that AhR-deficiency exacerbates CS-induced cell death and inflammation in lung structural cells. Thus, we hypothesized that AhR-deficiency would promote the development of CS-induced emphysema and COPD pathogenesis.Using a preclinical model of CS-exposure, we demonstrate that AhR deficiency worsens the development of a CS-induced emphysema-like phenotype in the murine lung. AhR ablation promoted the CS-induced: (1) upregulation of pathogenic mechanisms underlying emphysema development (i.e. inflammation, an antiprotease imbalance, and the activation of cell death machinery), (2) lung parenchymal destruction, and (3) declines in lung function. In COPD subjects, there was less pulmonary and systemic AHR expression. In humans, systemic AHR mRNA levels also positively correlated with lung function. There was no alteration in the frequency of AHR single nucleotide polymorphisms (SNPs) that could explain this decrease in AHR in COPD subjects. However, elevated expression of the AhR Repressor (AHRR), which is a negative regulator of the AHR, in the COPD lung may contribute to reduced AHR expression in these subjects.We also utilized an in vitro model of CS exposure to evaluate if the AhR attenuation of CS-induced cell death in lung structural cells involves its regulation of cell death modalities such as autophagy and/or ER stress. We show that the expression of the autophagy and ER stress protein LC3II was significantly elevated in cigarette smoke extract (CSE)-exposed AhR-deficient lung structural cells; these cells were primary mouse lung fibroblasts (MLFs), mouse lung epithelial cells (MLE12) and alveolar epithelial cells (A549). Heightened LC3II expression could not be explained by the transcriptional upregulation of key autophagy genes (Gabarapl1, Beclin1, Lc3b), upregulation of upstream autophagic machinery (ATG5-12, ATG3) or impaired autophagic flux. This suggested that elevated LC3II in CSE-treated AhR-deficient cells is likely mediated by an autophagy-independent mechanism. This was…
Advisors/Committee Members: Carolyn Baglole (Supervisor).
Subjects/Keywords: Pathology
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McGill University
19.
Redpath, Margaret.
Unraveling the role of the X chromosome in cancer: characterization of FOXP3 Isoforms and PR70 in cutaneous melanoma.
Degree: PhD, Department of Pathology, 2019, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile163214.pdf
► Many cancers have a different incidence, behavior and response to treatment in men and women. Traditionally these sex-specific variations have been attributed to differences in…
(more)
▼ Many cancers have a different incidence, behavior and response to treatment in men and women. Traditionally these sex-specific variations have been attributed to differences in habits, occupational exposures and hormones. More recently it has been recognized that some of the dissimilarities can be attributed to genetics. We were particularly struck by the significant increase in the incidence and mortality of melanoma in men. The objective of this project was to characterize how the X chromosome contributes to this effect. Global analysis of genomic alterations revealed that a somatic loss of one X chromosome in females was significantly associated with a worse prognosis in melanoma. We further showed that it was the inactive X that was lost in all cases. This led to the hypothesis that an activating mutation of an oncogene, or inactivating mutation of a tumor suppressor gene, on the remaining X chromosome in these patients was contributing to tumor aggressiveness. PR70 and FOXP3 were identified as warranting further investigation as candidate X-linked tumor suppressors in melanoma based on their behaviour in other tumor types. The PPP2R3B gene (Xp22.33) encodes for PR70, the regulatory subunit of a protein phosphatase that plays a critical role in cell cycle progression. In melanoma a strong correlation is demonstrated between low levels of PR70 mRNA expression and poor distant metastasis-free survival by multivariate analyses. In line with this, no or low PR70 protein expression is associated with poor overall survival in three independent sample sets of melanoma. Endogenous and exogenous PR70 expression levels are shown to have an inverse correlation with the rate of melanoma cell proliferation. Exogenous PR70 overexpression decreases tumor take and growth in nude mice compared to shRNA-mediated downregulation that increases it. The FOXP3 gene (Xp23.11) encodes a transcription factor that is important for T-regulatory cell development. Interestingly, FOXP3 was also found to be expressed in the majority of our melanoma cell lines at both the mRNA and protein level. All five of the known isoforms of FOXP3 were shown to localize to the nucleus in melanoma cell lines and demonstrated isoform- and cell line-specific effects on gene transcription. Both PR70 and FOXP3 are associated with a dose-dependent decrease in melanoma cell proliferation with an accumulation of cells in the G1 phase of the cell cycle. These findings are significant because proliferative rate is one of the strongest independent prognostic factors in melanoma.
De nombreux cancers ont une incidence, un comportement et une réponse au traitement différents chez les hommes et chez les femmes. Traditionnellement, ces variations spécifiques liées au sexe ont été attribuées à des différences entre les sexes dans les habitudes, l'exposition professionnelle et le statut hormonal. Plus récemment, il a été reconnu que certaines de ces différences peuvent être attribuées à la génétique. Nous avons été particulièrement frappés par l'augmentation…
Advisors/Committee Members: Alan Spatz (Supervisor).
Subjects/Keywords: Pathology
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University of Manitoba
20.
Bay, Diane.
Serrated polyps of the colon: the Winnipeg experience.
Degree: Pathology, 2011, University of Manitoba
URL: http://hdl.handle.net/1993/4885
► BACKGROUND: The pathological distinction between hyperplastic polyps and sessile serrated adenoma/polyps of the right colon is often difficult and may result in misdiagnosed polyps. OBJECTIVE:…
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▼ BACKGROUND: The pathological distinction between hyperplastic polyps and sessile serrated adenoma/polyps of the right colon is often difficult and may result in misdiagnosed polyps.
OBJECTIVE: To review the proportion and accuracy of serrated polyp diagnosis within a one year retrospective review of colorectal polyp samples, focusing on hyperplastic polyps of the right colon, using criteria set forth by previous studies.
MATERIALS & METHODS: 4096 Winnipeg patient cases from January 2009 to December 2009 were reviewed. The proportion of sessile serrated adenoma/polyps, traditional serrated adenoma and serrated adenoma were determined in the patient population. Additionally, pathological morphological variables were reassessed by two study pathologists to determine the frequency of sessile serrated adenoma/polyp initially diagnosed as hyperplastic polyps within the right colon.
RESULTS: Approximately 5% of all polyps in the patient population where diagnosed as non-hyperplastic serrated polyps (SSA/P, TSA and SA) and 12.5% as hyperpalstic polyps. Of the non-hyperplastic serrated polyps, a majority were diagnosed as SA. Upon reassessment of right sided HP (n=121), 34% were re-classified as SSA/P.
CONCLUSIONS: Winnipeg pathologists diagnose non-hyperplastic serrated polyps with a frequency similar to literature, but are not fully utilizing modern terminology, as majority of non-hyperplastic serrated polyps are reported as SA without further categorisation. Furthermore, a significant proportion of right sided hyperplastic polyps could be re-classified as sessile serrated adenomas on review. Given the difficulty in distinguishing sessile serrated adenomas from hyperplastic polyps, closer endoscopic surveillance should be considered for all individuals with all serrated polyps (including hyperplastic polyps) in the right colon or alternatively all such polyps should be routinely reviewed by two pathologists.
Advisors/Committee Members: Wightman, Robert H. (Pathology) (supervisor), Gartner, John (Pathology) Singh, Harminder (Internal Medicine) Fuczek, Lance (Pathology) (examiningcommittee).
Subjects/Keywords: Pathology
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APA (6th Edition):
Bay, D. (2011). Serrated polyps of the colon: the Winnipeg experience. (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/4885
Chicago Manual of Style (16th Edition):
Bay, Diane. “Serrated polyps of the colon: the Winnipeg experience.” 2011. Masters Thesis, University of Manitoba. Accessed November 19, 2019.
http://hdl.handle.net/1993/4885.
MLA Handbook (7th Edition):
Bay, Diane. “Serrated polyps of the colon: the Winnipeg experience.” 2011. Web. 19 Nov 2019.
Vancouver:
Bay D. Serrated polyps of the colon: the Winnipeg experience. [Internet] [Masters thesis]. University of Manitoba; 2011. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/1993/4885.
Council of Science Editors:
Bay D. Serrated polyps of the colon: the Winnipeg experience. [Masters Thesis]. University of Manitoba; 2011. Available from: http://hdl.handle.net/1993/4885
Boston University
21.
Ambaah, Ekow.
Inhibition of phagocyte killing of bacteria via inhibitory IGG-FCR signaling.
Degree: MS, Pathology, 2019, Boston University
URL: http://hdl.handle.net/2144/36259
► Sepsis is among the leading causes of death in health facilities worldwide. Even with adequate treatment, severe sepsis results in approximately 50% mortality, which indicates…
(more)
▼ Sepsis is among the leading causes of death in health facilities worldwide. Even with adequate treatment, severe sepsis results in approximately 50% mortality, which indicates that the individual response to the infection is variable. (Moitra, Beal, Belikoff, & Remick, 2012)
In a previous paper published by the Remick laboratory it was determined that the presence of pre-existing, plasma IgG antibodies in mice prior to the onset of sepsis could be responsible for differences in their survival. A Plasma Enhanced Killing (PEK) assay was used to calculate the PEK capacity of plasma i.e. the ability of plasma to augment phagocytic killing of bacteria. PEK was calculated as PEK= (1/log (N)) X 100; where N= number of surviving bacteria; a higher PEK indicated better bacterial killing(Moitra et al., 2012). The prior study also determined that inhibitory IgG probably binds inhibitory Fc receptors on phagocytic cells to result in reduced killing of bacteria.
This published work used the value of the PEK to predict which mice would live and which mice would die when subjected to sepsis from cecal bacteria through the method of cecal ligation and puncture (CLP) to induce sepsis.
The goal of this study was to build on what was already found and go further to demonstrate the pathway of how the blocking of IgG occurs via the Fc𝛄R in bacteria. In prior experiments by the Remick lab it was determined that the plasma from the in vitro plasma enhanced killing assay was related to the survival status of septic mice subjected to cecal ligation and puncture (CLP) model of bacterial peritonitis. The PEK assay relies on the presence of pre-existing antibodies in the plasma augmenting the killing of bacterial cells by polymorphonuclear cells. A high PEK value mean the plasma had the capability to kill bacteria and the mice were more likely to survive compared to those with a lower PEK value who were more likely to die from sepsis.
Two sets of plasma were used, plasma collected with Ethylenediaminetetraacetic acid (EDTA) and plasma collected with heparin as anticoagulants. The data showed the likely presence of inhibitory IgG to be present more in the plasma sample collected with heparin than in those collected with EDTA.
Advisors/Committee Members: Remick, Daniel G. (advisor).
Subjects/Keywords: Pathology
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APA (6th Edition):
Ambaah, E. (2019). Inhibition of phagocyte killing of bacteria via inhibitory IGG-FCR signaling. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/36259
Chicago Manual of Style (16th Edition):
Ambaah, Ekow. “Inhibition of phagocyte killing of bacteria via inhibitory IGG-FCR signaling.” 2019. Masters Thesis, Boston University. Accessed November 19, 2019.
http://hdl.handle.net/2144/36259.
MLA Handbook (7th Edition):
Ambaah, Ekow. “Inhibition of phagocyte killing of bacteria via inhibitory IGG-FCR signaling.” 2019. Web. 19 Nov 2019.
Vancouver:
Ambaah E. Inhibition of phagocyte killing of bacteria via inhibitory IGG-FCR signaling. [Internet] [Masters thesis]. Boston University; 2019. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/2144/36259.
Council of Science Editors:
Ambaah E. Inhibition of phagocyte killing of bacteria via inhibitory IGG-FCR signaling. [Masters Thesis]. Boston University; 2019. Available from: http://hdl.handle.net/2144/36259
McGill University
22.
Janssen, Sanne.
Deciphering the role of BORIS/CTCFL in melanoma.
Degree: PhD, Department of Pathology, 2019, McGill University
URL: http://digitool.library.mcgill.ca/thesisfile166872.pdf
► Brother of Regulator of Imprinted Sites (BORIS) is a DNA binding protein that is expressed in the testis and becomes aberrantly expressed in different types…
(more)
▼ Brother of Regulator of Imprinted Sites (BORIS) is a DNA binding protein that is expressed in the testis and becomes aberrantly expressed in different types of cancer, hence the designation of BORIS as a cancer testis antigen. Aberrant BORIS expression in cancer is linked to alterations in gene expression and epigenetic modifications that impact key biological processes. In melanoma, BORIS expression is higher in metastasis compared to primary tumors, indicating a role for BORIS in melanoma progression. Currently, BORIS functions in melanoma remain to be elucidated. Here we set out to investigate the effect of BORIS expression on biological processes involved in melanoma progression.In the first part of this thesis we extend previous work from the laboratory that demonstrated altered gene expression from the X-chromosome upon modified BORIS expression. This is important, as differences in gene expression from the X-chromosome likely contribute to the superior survival of female melanoma patients compared to males. By exploiting single nucleotide polymorphisms in genes located on the X-chromosome we reveal for the first time that ectopic BORIS expression can alter gene expression in an allele-specific manner. More specifically, we show that expression of ZBTB33, a transcriptional regulator involved in cancer cell migration and invasion, is increased from the inactive X-chromosome upon BORIS expression.To address BORIS' involvement in biological processes and pathways in melanoma, we investigated BORIS-induced transcriptional changes and BORIS-interacting proteins using RNA-sequencing and mass spectrometry. We demonstrate that ectopic BORIS expression in melanoma cells promotes phenotype switching from a proliferative to invasive state at the transcriptional and phenotypic level. Using in silico analysis, we identify potential transcriptional regulators that contribute to this switch. Both the BORIS-induced gene expression changes and newly identified BORIS protein partners point to a role for BORIS in the DNA damage response. This finding is supported by our observations that BORIS increases DNA damage, activates the DNA damage response, enhances the sensitivity to DNA damage, and slows the repair process, suggesting that BORIS promotes genomic instability. In the final part of this thesis, we used chromatin immunoprecipitation, bisulfite sequencing and the assay for transposase accessible chromatin (ATAC) to elucidate mechanisms underlying the BORIS-altered gene expression. We demonstrate for six genes that BORIS-induced transcriptional changes are associated with BORIS-DNA binding in the promoter region. For one of these genes, PAX6, we observe that this is not linked to DNA demethylation at the BORIS binding site. Furthermore, we successfully generated ATAC-sequencing data that will be used to assess the effect of BORIS expression on chromatin accessibility.Overall, the work presented in this thesis brings forth new insight into the effect of BORIS expression in melanoma and provides evidence for previously unknown…
Advisors/Committee Members: Alan Spatz (Supervisor).
Subjects/Keywords: Pathology
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Boston University
23.
Langlois, Sarah Elizabeth.
IHC validation in clinical settings; how lab developed assays drive clinical therapies.
Degree: MS, Pathology, 2019, Boston University
URL: http://hdl.handle.net/2144/36575
► Diagnostic laboratory tests are critical to patient care as they help dictate the most appropriate treatments and procedures. To that end, hospitals and laboratories must…
(more)
▼ Diagnostic laboratory tests are critical to patient care as they help dictate the most appropriate treatments and procedures. To that end, hospitals and laboratories must ensure their diagnostic assays are optimized so as to afford patients their best chance for recovery. The
pathology laboratory at Boston Medical Center, like all testing labs, must validate their IHC protocols yearly according to ASCO/CAP guidelines. Furthermore, BMC has a diverse patient population similar to the Atlanta population-based study published by Lund, et al. in 2010. Based on the results of the yearly ASCO/CAP testing and compared with the results of the Atlanta study, it was found that BMC’s HER2 testing was most likely not capturing all positive cases consistently. This prompted an optimization procedure for HER2 to be implemented. In addition to HER2 testing, BMC is looking at ways to optimize and implement PD-L1 IHC protocols as a way to identify those patients who might benefit from more targeted therapy. METHODS: HER2 IHC was performed with an altered protocol to attempt a higher concordance rate with PhenoPath, a reference lab in Seattle, and the Atlanta study data. ER and PR validation IHC protocols were also performed to ensure adequate concordance with required yearly testing. RESULTS: ER and PR protocols were found to be >95% accurate as compared to reference lab results. The new HER2 protocol yielded more vibrant staining results when compared to known positive reference data and previous BMC testing of the same sample. DISCUSSION: Optimizing lab assays is a critical step in ensuring proper clinical therapies are being utilized. Regular testing of a lab’s IHC output must be continuously verified, and continued data collection of the improved HER2 protocol is needed to make sure appropriate standards are being met. Further testing of PD-L1 IHC protocols will be warranted to maintain maximum efficiency.
Advisors/Committee Members: Duffy, Elizabeth (advisor), Andry, Christopher (advisor).
Subjects/Keywords: Pathology
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APA ·
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APA (6th Edition):
Langlois, S. E. (2019). IHC validation in clinical settings; how lab developed assays drive clinical therapies. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/36575
Chicago Manual of Style (16th Edition):
Langlois, Sarah Elizabeth. “IHC validation in clinical settings; how lab developed assays drive clinical therapies.” 2019. Masters Thesis, Boston University. Accessed November 19, 2019.
http://hdl.handle.net/2144/36575.
MLA Handbook (7th Edition):
Langlois, Sarah Elizabeth. “IHC validation in clinical settings; how lab developed assays drive clinical therapies.” 2019. Web. 19 Nov 2019.
Vancouver:
Langlois SE. IHC validation in clinical settings; how lab developed assays drive clinical therapies. [Internet] [Masters thesis]. Boston University; 2019. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/2144/36575.
Council of Science Editors:
Langlois SE. IHC validation in clinical settings; how lab developed assays drive clinical therapies. [Masters Thesis]. Boston University; 2019. Available from: http://hdl.handle.net/2144/36575
University of Missouri – Columbia
24.
Bosanquet, James Percival.
Patients with venous thromboembolism have higher prevalence of obstructive sleep apnea than the general population.
Degree: 2010, University of Missouri – Columbia
URL: http://hdl.handle.net/10355/44845
► Study Objectives: Obstructive sleep apnea (OSA) has been linked to a large number of cardiovascular diseases. However, the link between OSA and venous thromboembolic events…
(more)
▼ Study Objectives: Obstructive sleep apnea (OSA) has been linked to a large number of cardiovascular diseases. However, the link between OSA and venous thromboembolic events (VTE) remains unclear. We sought to study the possible association between VTE and OSA. Design: Retrospective study (August 1999 - April 2009). Setting: University Tertiary Center. Patients: We retrospectively collected data on patients with objectively confirmed VTE. Primary outcome was prevalence of OSA defined as an apnea-hypopnea index (AHI) > 5. Data on demographics and comorbidities were recorded as well as body-mass index was calculated. Measurements and Results: 840 patients were identified as having VTE and analyzed for presence/absence of co-morbidities. Of 840 patients, 130 (15.5%) were also diagnosed with OSA. Compared to the control group (no OSA), those who had OSA were more obese (83.8% versus 43.8%) and had statistically higher prevalence of diabetes, coronary artery disease (CAD), and congestive heart failure (CHF). OSA patients had higher prevalence of pulmonary embolism but similar prevalence of deep vein thrombosis. Conclusions: In this VTE cohort, the prevalence of OSA (15.5%) appears to be higher than that of the general population (2-10%). Our data suggest that patients with both OSA and VTE are more likely to be obese with diagnoses of CAD, CHF, and diabetes than their counterparts with VTE alone. OSA patients had higher prevalence of pulmonary embolism compared to controls. Although OSA has been clearly linked to arterial thrombosis, this study also suggests a link between OSA and venous thrombotic disorders.
Advisors/Committee Members: Dabbagh, Ousama (advisor).
Subjects/Keywords: Pathology
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APA (6th Edition):
Bosanquet, J. P. (2010). Patients with venous thromboembolism have higher prevalence of obstructive sleep apnea than the general population. (Thesis). University of Missouri – Columbia. Retrieved from http://hdl.handle.net/10355/44845
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):
Bosanquet, James Percival. “Patients with venous thromboembolism have higher prevalence of obstructive sleep apnea than the general population.” 2010. Thesis, University of Missouri – Columbia. Accessed November 19, 2019.
http://hdl.handle.net/10355/44845.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bosanquet, James Percival. “Patients with venous thromboembolism have higher prevalence of obstructive sleep apnea than the general population.” 2010. Web. 19 Nov 2019.
Vancouver:
Bosanquet JP. Patients with venous thromboembolism have higher prevalence of obstructive sleep apnea than the general population. [Internet] [Thesis]. University of Missouri – Columbia; 2010. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/10355/44845.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bosanquet JP. Patients with venous thromboembolism have higher prevalence of obstructive sleep apnea than the general population. [Thesis]. University of Missouri – Columbia; 2010. Available from: http://hdl.handle.net/10355/44845
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Cape Town
25.
Choshi, Phuti Sophia.
Investigation of neuron T cell interaction in central nervous system tuberculosis.
Degree: Image, Division of Chemical Pathology, 2017, University of Cape Town
URL: http://hdl.handle.net/11427/24881
► Tuberculosis of the central nervous system (CNS TB) is the severest form of tuberculosis. It is classified as extra-pulmonary tuberculosis due to dissemination of Mycobacterium…
(more)
▼ Tuberculosis of the central nervous system (CNS TB) is the severest form of tuberculosis. It is classified as extra-pulmonary tuberculosis due to dissemination of Mycobacterium tuberculosis (Mtb) bacilli from the lung to the brain. It affects mostly children and immune suppressed individuals and high incidents of death occur as a result of missed diagnosis and delayed treatment. Therefore, the is a need for improved therapeutic strategy and a better understanding of the CNS immunity; investigate cells targeted for infection, their respective response to infection and interaction with different cell types to the overall protection of the CNS - as accumulating evidence indicates a dynamic neuronal lymphocyte interplay that defines outcomes of diseases. A novel observation was previously made, that neurons are infected by Mtb during in vitro and in vivo infection. The aim of this study was to further characterize neural responses induced by mycobacteria using hippocampal primary neuron cultures, infected with H37RV and BCG. Secondly, this study investigated the importance of interaction between neurons and immune cells in immunity against mycobacterial challenge using an optimised neuron T cell co-culture model. Investigation included identifying the production levels of neuronal cell surface markers and cytokines induced by Mtb. In flowcytometry and ELISA analyses, infection exhibited a robust inflammatory response with increased neuronal production of cytokines such as IL1β, IL6, TNF and regulatory cytokine IL10 in vitro and in vivo. Neuronal MHC class I expression was upregulated by infection, suggesting possible antigen dependent interactions between neuron and CD8+ T cells. In co-cultures, neurons induced expression of Tbet, RorγT and Gata3 T cell transcription factors through direct contact with T cells. These data highlighted the likelihood of neurons activating T cells upon mycobacterial stimulations. It may potentially be utilised to broaden the understanding of CNS immunity under pathological conditions and possibly lead to identification of novel immunomodulatory targets that could be exploited for new rapid sensitive diagnostics and early opportune intervention against CNS TB – reducing morbidity and mortality associated with the disease.
Advisors/Committee Members: Jacobs, Muazzam (advisor), Hsu, Nai-Jen (advisor).
Subjects/Keywords: Pathology
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Manager
APA (6th Edition):
Choshi, P. S. (2017). Investigation of neuron T cell interaction in central nervous system tuberculosis. (Thesis). University of Cape Town. Retrieved from http://hdl.handle.net/11427/24881
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):
Choshi, Phuti Sophia. “Investigation of neuron T cell interaction in central nervous system tuberculosis.” 2017. Thesis, University of Cape Town. Accessed November 19, 2019.
http://hdl.handle.net/11427/24881.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Choshi, Phuti Sophia. “Investigation of neuron T cell interaction in central nervous system tuberculosis.” 2017. Web. 19 Nov 2019.
Vancouver:
Choshi PS. Investigation of neuron T cell interaction in central nervous system tuberculosis. [Internet] [Thesis]. University of Cape Town; 2017. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/11427/24881.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Choshi PS. Investigation of neuron T cell interaction in central nervous system tuberculosis. [Thesis]. University of Cape Town; 2017. Available from: http://hdl.handle.net/11427/24881
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Boston University
26.
Wei, Yibing.
Utility of an ex vivo human whole blood assay for bacterial killing ability qualification.
Degree: MS, Pathology, 2019, Boston University
URL: http://hdl.handle.net/2144/36729
► Infectious diseases caused by antibiotic resistant bacteria are difficult to treat using traditional antibiotics and have emerged as a global public health problem (Bartlett, Gilbert,…
(more)
▼ Infectious diseases caused by antibiotic resistant bacteria are difficult to treat using traditional antibiotics and have emerged as a global public health problem (Bartlett, Gilbert, & Spellberg, 2013). An alternative strategy to bypass antibiotic resistance in bacteria is to enhance the host immune system (Hancock, & Sahl, 2006), especially innate immunity (Ajesh, & Sreejith, 2009), in order to combat bacterial infections. To verify the augmentation of innate immunity under certain stimuli, a quantifiable measurement of bacterial killing ability is needed. A new method of using heparinized human peripheral whole blood and mild heated blood samples from the same individuals as comparisons has been developed. This assay was used to quantify the bacterial killing ability of phagocytic cells by measuring the bacterial load after co-culturing with the Gram negative bacteria Pseudomonas aeruginosa. The assay shows that peripheral whole blood of healthy humans is capable of being activated ex vivo upon bacterial challenge and suppressing the bacterial load, while blood gently heated at 48 °C for one hour failed to do so. The morphology of the phagocytic cells was examined microscopically. Phagocytosis of bacteria in neutrophils is observed in intact blood, and no such changes were found in heated blood. The level of inflammatory cytokine interleukin 8 (IL-8) was elevated in intact blood after bacteria inoculation, while in the heated blood the cytokine level stayed at baseline, indicating a persistence of leukocyte viability in whole blood and damaged leukocyte activity in gently heated blood. The data show that the human peripheral whole blood assay is suitable as a method for ex vivo bacterial killing quantification with the mildly heated blood sample from the same individual as a comparison. When kept at 37 °C ex vivo, human whole blood can be activated upon bacterial challenge, produce inflammatory cytokines, reduce bacterial load, and phagocytes in the whole blood can successfully maintain their cell viability and capacity to phagocytose bacteria.
Advisors/Committee Members: Remick, Daniel G. (advisor).
Subjects/Keywords: Pathology
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APA (6th Edition):
Wei, Y. (2019). Utility of an ex vivo human whole blood assay for bacterial killing ability qualification. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/36729
Chicago Manual of Style (16th Edition):
Wei, Yibing. “Utility of an ex vivo human whole blood assay for bacterial killing ability qualification.” 2019. Masters Thesis, Boston University. Accessed November 19, 2019.
http://hdl.handle.net/2144/36729.
MLA Handbook (7th Edition):
Wei, Yibing. “Utility of an ex vivo human whole blood assay for bacterial killing ability qualification.” 2019. Web. 19 Nov 2019.
Vancouver:
Wei Y. Utility of an ex vivo human whole blood assay for bacterial killing ability qualification. [Internet] [Masters thesis]. Boston University; 2019. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/2144/36729.
Council of Science Editors:
Wei Y. Utility of an ex vivo human whole blood assay for bacterial killing ability qualification. [Masters Thesis]. Boston University; 2019. Available from: http://hdl.handle.net/2144/36729
Duke University
27.
Bao, Xuhui.
Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors
.
Degree: 2016, Duke University
URL: http://hdl.handle.net/10161/13365
► Glioblastoma is the most common and aggressive malignant brain tumor among all primary brain and central nervous system (CNS) tumors. The median survival time…
(more)
▼ Glioblastoma is the most common and aggressive malignant brain tumor among all primary brain and central nervous system (CNS) tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Medulloblastoma is another major malignant brain tumor that most frequently occurs in children. Although recent advances in surgery, radiotherapy, and chemotherapy have led to an increase in 5-year survival rates of medulloblastoma patients, treatment-related toxicity often has a major impact on long-term quality of survival. As a result, there is an urgent need to develop more efficient and novel therapeutic approaches that specifically target tumor cells while preserving the surrounding normal CNS to improve the poor survival and quality of life of patients with malignant brain tumors. To address this need, we have developed two novel targeted immunotoxins (ITs), D2C7-(scdsFv)-PE38KDEL (D2C7-IT) and NZ-1-(scdsFv)-PE38KDEL (NZ-1-IT). D2C7-IT was developed by fusing the single-chain variable fragment (scFv) of the D2C7 monoclonal antibody (mAb) with domains II and III of Pseudomonas exotoxin A (PE38KDEL), and NZ-1-IT was developed by fusing the scFv of the NZ-1 mAb with PE38KDEL. D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and the EGFR variant III (EGFRvIII), two overexpressed proteins in glioblastomas. NZ-1-IT reacts with podoplanin (PDPN), a protein that has a high expression in glioblastomas and medulloblastomas. In vitro cytotoxicity data shows that both ITs effectively inhibited protein synthesis in a variety of epitope-expressing glioblastoma and medulloblastoma xenograft cells and human tumor cell lines. Furthermore, the direct anti-tumor efficacy of D2C7-IT was examined in orthotopic glioma models in immunocompromised mice, while the direct anti-tumor efficacy of NZ-1-IT was observed in medulloblastoma xenograft-bearing immunocompromised mice. Both immunotoxins showed a robust anti-tumor efficacy in the preclinical brain tumor models. D2C7-IT was first investigated in the subsequent studies to accelerate its translation to the clinic. The preclinical toxicity of intracerebral D2C7-IT infusion was subsequently determined in normal Sprague-Dawley (SD) rats. The maximum tolerated dose (MTD) of D2C7-IT was determined to be between a total dose of 0.10 and 0.35 μg, and the no-observed-adverse-effect level (NOAEL) of D2C7-IT was a total dose of 0.05 μg in SD rats. Both the MTD and NOAEL were utilized as references for the D2C7-IT clinical trial design. In addition to direct tumor cell killing, immunotoxin monotherapy has been shown to induce a secondary anti-tumor immune response through the engagement of T cells. Therefore, the D2C7-IT-induced secondary anti-tumor immune response was investigated using syngeneic mouse glioma models in immunocompetent mice. Moreover, previous studies have demonstrated that immune checkpoint inhibitors have a robust anti-tumor efficacy…
Advisors/Committee Members: Bigner, Darell D (advisor).
Subjects/Keywords: Pathology
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APA (6th Edition):
Bao, X. (2016). Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors
. (Thesis). Duke University. Retrieved from http://hdl.handle.net/10161/13365
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):
Bao, Xuhui. “Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors
.” 2016. Thesis, Duke University. Accessed November 19, 2019.
http://hdl.handle.net/10161/13365.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bao, Xuhui. “Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors
.” 2016. Web. 19 Nov 2019.
Vancouver:
Bao X. Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors
. [Internet] [Thesis]. Duke University; 2016. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/10161/13365.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bao X. Immunotoxin Monotherapy and Combinatorial Therapy With Immune Checkpoint Inhibitors for Malignant Brain Tumors
. [Thesis]. Duke University; 2016. Available from: http://hdl.handle.net/10161/13365
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Iowa
28.
Hall, Sarah Lynne.
Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis.
Degree: MS, Pathology, 2017, University of Iowa
URL: https://ir.uiowa.edu/etd/5769
► Sarcomas are cancers of mesenchymal origin. Though they comprise 15-20% of childhood cancers, and have a 5-year survival rate of 16% for metastatic disease,…
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▼ Sarcomas are cancers of mesenchymal origin. Though they comprise 15-20% of childhood cancers, and have a 5-year survival rate of 16% for metastatic disease, few targeted therapies exist, and the underlying mechanisms of their development are poorly understood. Transcriptional coactivators TAZ and YAP promote cell growth and proliferation, and are constitutively activated in a number of carcinomas. Accompanying TAZ/YAP activation in these cancers is decreased expression of Hippo pathway kinases MST1/2 and LATS1/2. As the Hippo pathway is the primary negative regulator of TAZ/YAP, this provides a potential mechanistic explanation for constitutive TAZ/YAP activation. TAZ and YAP are also thought to play a prominent role in sarcomagenesis, as TAZ-CAMTA1 and YAP-TFE3 gene fusions are the specific initiating events leading to formation of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. However, the mechanisms causing constitutive activation of wild-type TAZ/YAP in sarcomas have not been well-characterized.
The purpose of this study was to determine if Hippo pathway dysregulation occurs in sarcomas with constitutively active, wild-type TAZ/YAP, as well as the mechanisms by which this regulation is lost. We also investigated whether TAZ/YAP could be therapeutically targeted in sarcomas using verteporfin, a small-molecule inhibitor of the TAZ/YAP-TEAD interaction. To address these questions, sarcoma cell lines and patient clinical samples were utilized. Using 159 patient tumor sections, we constructed a tissue microarray, stained for activated (nuclear localized) TAZ/YAP, and Hippo kinases MST1/2 and LATS1/2. A majority of sarcomas contained activation of both TAZ and YAP, while significant decreases in MST1/2 and LATS1/2 expression were observed. Results indicated a majority of tumors which stained positively for nuclear-localized TAZ/YAP also contained loss of expression of at least one of the four kinases evaluated.
All cell lines evaluated via immunofluorescence also had constitutively active (nuclear) TAZ/YAP when grown to confluence, which suggested they were no longer being negatively regulated by the Hippo pathway. In ~50% of lines, protein loss of MST1/2 and LATS2 occurred and mRNA expression of MST1 and MST2 was notably decreased in ~50%, although loss of LATS1 and LATS2 was minimal. Potential mechanisms which could account for Hippo kinase loss were next investigated. It was found that protein degradation diminished MST2 in 25% of cell lines. Regulation by epigenetic modifications was also investigated; hypermethylation accounted for slightly reduced MST1/2, while 67% of lines had histone deacetylation in both kinases. Whether TAZ/YAP can be therapeutically targeted using verteporfin was tested; treatment significantly inhibited anchorage-independent growth, proliferation, and TAZ/YAP transcriptional activity in sarcoma cell lines.
Our results collectively demonstrate TAZ/YAP activity can be targeted in sarcomas with verteporfin, and their constitutive activation is due to loss…
Advisors/Committee Members: Tanas, Munir (supervisor).
Subjects/Keywords: Pathology
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APA (6th Edition):
Hall, S. L. (2017). Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis. (Masters Thesis). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/5769
Chicago Manual of Style (16th Edition):
Hall, Sarah Lynne. “Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis.” 2017. Masters Thesis, University of Iowa. Accessed November 19, 2019.
https://ir.uiowa.edu/etd/5769.
MLA Handbook (7th Edition):
Hall, Sarah Lynne. “Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis.” 2017. Web. 19 Nov 2019.
Vancouver:
Hall SL. Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis. [Internet] [Masters thesis]. University of Iowa; 2017. [cited 2019 Nov 19].
Available from: https://ir.uiowa.edu/etd/5769.
Council of Science Editors:
Hall SL. Characterizing the contribution of hippo pathway dysregulation to sarcomagenesis. [Masters Thesis]. University of Iowa; 2017. Available from: https://ir.uiowa.edu/etd/5769
University of Helsinki
29.
Yin, Miao.
Tumor microenvironment in invasion of fibrosarcoma and melanoma cells.
Degree: Haartman Institute, Department of Pathology, 2013, University of Helsinki
URL: http://hdl.handle.net/10138/42032
► Within cancer, malignant cancer cells extensively interact with stromal components, which mainly consist of extracellular matrix (ECM) and several kinds of stromal cells to acquire…
(more)
▼ Within cancer, malignant cancer cells extensively interact with stromal components, which mainly consist of extracellular matrix (ECM) and several kinds of stromal cells to acquire the ability to proliferate without control, invade surrounding tissue, and metastasize to distant sites. During tumor development and progression, local invasion is a key step for tumor cells to disseminate to sentinel lymph nodes and distant organs. The aim of the present studies was to elucidate the interaction between melanoma cells and stromal components and identify molecules associated with melanoma and fibrosarcoma invasion.
We have analyzed fibrosarcoma cells, which form highly invasive fibrosarcomas in nude mice. We found thymosin β4 (Tβ4) as the gene with the highest upregulation. Interestingly, a sponge toxin latrunculin A, which inhibits the binding of thymosin β4 to actin, was found to profoundly affect the morphology and proliferation of the fibrosarcoma cells and to block their invasion in three-dimensional Matrigel. In addition, our analyses revealed highly significant changes in genes encoding ECM proteins and ECM modifiers, such as versican, tenascin-C (TNC), thrombospondin 1 (TSP-1), cathepsin L(CTSL), and osteopontin (OPN). In the second study, melanoma cells and skin fibroblasts were cultured alone or together in three-dimensional (3D) Matrigel/collagen I gel models, mimicking the in vivo microenvironment to study the effects of skin fibroblasts on melanoma cell invasion. We compared the protease gene expression profiles of benign nevi, thin melanomas (< 2mm), and thick melanomas (≥ 2mm). Various protease inhibitors were then tested using 3D Matrigel invasion assay models. We also examined signaling involved in melanoma cell invasion. We found that the invasion of melanoma cells is promoted and guided by fibroblasts, and that this process is dependent on TGF-β signaling and cysteine cathepsins B/L, but not on MMP activity. Further, we demonstrated significantly increased expression of cathepsins B and L in invasive melanomas. Cathepsin B was predominantly expressed by the melanoma cells and cathepsin L by the fibroblasts. The expression level of cathepsin B was further found to correlate with shortened patient survival.
In the third study, we have explored the role of OPN in promoting the malignant phenotype of melanoma cells cultured in 3D collagen-I gel matrix and the potential mechanisms. Invasive growth of primary melanoma cells overexpressing OPN was significantly stimulated, while apoptosis of OPN transfectants was clearly inhibited. Conversely, knockdown of OPN expression in metastatic melanoma cells caused growth and motility inhibition. Furthermore, we identified inverse expression of OPN and CD9 in melanocytes and melanoma cells.
Paikallinen invaasiokyky on edellytys syöpäsolujen leviämiselle alueellisiin imusolmukkeisiin ja kaukaisempiin elimiin. Tutkimuksessa tarkastelimme fibrosarkooma- ja melanoomasolujen invaasiomekanismeja, pyrimme tunnistamaan näiden kasvainten invaasiokykyyn vaikuttavat…
Subjects/Keywords: pathology; pathology
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APA ·
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MLA ·
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Manager
APA (6th Edition):
Yin, M. (2013). Tumor microenvironment in invasion of fibrosarcoma and melanoma cells. (Doctoral Dissertation). University of Helsinki. Retrieved from http://hdl.handle.net/10138/42032
Chicago Manual of Style (16th Edition):
Yin, Miao. “Tumor microenvironment in invasion of fibrosarcoma and melanoma cells.” 2013. Doctoral Dissertation, University of Helsinki. Accessed November 19, 2019.
http://hdl.handle.net/10138/42032.
MLA Handbook (7th Edition):
Yin, Miao. “Tumor microenvironment in invasion of fibrosarcoma and melanoma cells.” 2013. Web. 19 Nov 2019.
Vancouver:
Yin M. Tumor microenvironment in invasion of fibrosarcoma and melanoma cells. [Internet] [Doctoral dissertation]. University of Helsinki; 2013. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/10138/42032.
Council of Science Editors:
Yin M. Tumor microenvironment in invasion of fibrosarcoma and melanoma cells. [Doctoral Dissertation]. University of Helsinki; 2013. Available from: http://hdl.handle.net/10138/42032
University of Helsinki
30.
Fang, Shentong.
Stem Cells and Their Niches in Angiogenesis : Vascular Endothelial Stem Cells, Hematopoietic Progenitors and Hematopoietic Effector Cells.
Degree: Haartman Institute, 2014, University of Helsinki
URL: http://hdl.handle.net/10138/44017
► Most tissues possess tissue-specific stem cells that allow them to maintain tissue integrity. Stem cell niches provide an ideal regulatory microenvironment to support the maintenance…
(more)
▼ Most tissues possess tissue-specific stem cells that allow them to maintain tissue integrity. Stem cell niches provide an ideal regulatory microenvironment to support the maintenance and proliferation of adult stem cells. However, adult stem cells and stem cell niches have not been identified for all tissues.
Adult stem cells that give rise to the vascular endothelium are still unknown. In this thesis work, we identified a rare population of vascular endothelial stem cells (VESC) on the vascular wall by the phenotype lin-CD31+CD105+Sca-1+c-kit+. A single c-kit expressing VESC with highly proliferative capacity generated functional blood vessels in vivo. A genetic defect in endothelial c-kit resulted in an abolished colony-forming ability of VESCs and impaired tumor angiogenesis and tumor growth. Angiogenesis, the growth of new blood vessels from pre-existing vessels, is actively involved in many physiological and pathological processes such as wound repair, female reproductive cycling, ischemic disease and tumor development. There are two major groups of cells involved in the adult vascular growth, cells that contribute directly by composing the blood vessels, such as vascular endothelial stem cells, and cells that contribute indirectly in a paracrine manner such as infiltrating hematopoietic cells.
Infiltrating hematopoietic cells from the bone marrow contribute to angiogenesis in a paracrine manner by secreting angiogenic factors or by remodeling the extracellular matrix. In this thesis work, we found that transforming growth factor-β (TGF-β) recruited a massive amount of hematopoietic cells to local microenvironment. TGF-β stimulated vascular endothelial growth factor (VEGF) expression on these hematopoietic effectors and thus induced vascular growth. This stimulation was regulated by p38 and p44/p42 mitogen-activated protein kinase (MAPK) signaling pathways. These results together provided evidence for a dual action mechanism for TGF-β-induced angiogenesis in vivo. In malignant tumors, we found that the tumor expressed osteoblastic and vascular hematopoietic stem cell (HSC) niche molecules and enclosed multipotent hematopoietic progenitors. The proliferating hematopoietic progenitors generated hematopoietic effector cells and supported angiogenesis and tumor growth by secreting matrix metalloprotease 9 (MMP-9) and VEGF. HSPCs were found to be in proximity to tumor vasculature. Tumor microenvironment shared features of HSC niche in the bone marrow. Therapeutic ablation of hematopoietic cells including proliferating hematopoietic cells from tumor using AMD3100 in vivo resulted in inhibited tumor angiogenesis and growth.
In conclusion, we identified and characterized a rare population of c-kit expressing VESCs that give rise to the vascular endothelium in adult. Further purification and detailed characterization of VESCs will provide a better understanding of VESCs and hierarchy of endothelial lineage. Our observations on the in vivo angiogenesis induced by TGF-β elucidated the mechanisms of action of TGF-β in…
Subjects/Keywords: pathology; pathology
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APA ·
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MLA ·
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Export
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Manager
APA (6th Edition):
Fang, S. (2014). Stem Cells and Their Niches in Angiogenesis : Vascular Endothelial Stem Cells, Hematopoietic Progenitors and Hematopoietic Effector Cells. (Doctoral Dissertation). University of Helsinki. Retrieved from http://hdl.handle.net/10138/44017
Chicago Manual of Style (16th Edition):
Fang, Shentong. “Stem Cells and Their Niches in Angiogenesis : Vascular Endothelial Stem Cells, Hematopoietic Progenitors and Hematopoietic Effector Cells.” 2014. Doctoral Dissertation, University of Helsinki. Accessed November 19, 2019.
http://hdl.handle.net/10138/44017.
MLA Handbook (7th Edition):
Fang, Shentong. “Stem Cells and Their Niches in Angiogenesis : Vascular Endothelial Stem Cells, Hematopoietic Progenitors and Hematopoietic Effector Cells.” 2014. Web. 19 Nov 2019.
Vancouver:
Fang S. Stem Cells and Their Niches in Angiogenesis : Vascular Endothelial Stem Cells, Hematopoietic Progenitors and Hematopoietic Effector Cells. [Internet] [Doctoral dissertation]. University of Helsinki; 2014. [cited 2019 Nov 19].
Available from: http://hdl.handle.net/10138/44017.
Council of Science Editors:
Fang S. Stem Cells and Their Niches in Angiogenesis : Vascular Endothelial Stem Cells, Hematopoietic Progenitors and Hematopoietic Effector Cells. [Doctoral Dissertation]. University of Helsinki; 2014. Available from: http://hdl.handle.net/10138/44017
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Open Access Theses and Dissertations
