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Tang, Chi-wai Sydney. "The many facets of the renal proximal tubular epithelial cell in human." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31992468.
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Colgin, Lorel Melanie. "Spontaneous mutations in aging human renal epithelia in vivo /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/6318.
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Orphanides, Chrystalla. "Hypoxia is a pro-fibrogenic stimulus for human renal tubular epithelial cells." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314192.
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Shah, Nileshkumar. "Expression and regulation of cadherin of human renal proximal tubule epithelial cells." Thesis, St George's, University of London, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754076.
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Cadherins are a family of trans-membrane junctional proteins important in maintenance of cell-cell junction, phenotype regulation, tissue organisation and embryonic development. The proteins form calcium dependent homophilic cell junctional complexes and bind internally to the actin cytoskeleton and regulate intracellular signalling via the p- catenin pathway. Altered cadherin expression is essential for embryonic development, tissue repair or healing, fibrosis, cancer and metastasis. Much interest has developed in cadherin expression and its regulation along with signalling in renal proximal tubule epithelial cells (PTECs), an important cell type in the development of tubulointerstitial fibrosis and a potential source of myofibroblasts.
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Oates, Jeremy Edward. "Isolation and characterisation of an enriched side-population from human renal epithelial cells." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/isolation-and-characterisation-of-an-enriched-sidepopulation-from-human-renal-epithelial-cells(712fe1d5-12c4-4222-b6dc-687171450f86).html.
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Browne, James Alexander. "The expression and function of the atypical MAP kinase ERK5 in human renal epithelial cells." Thesis, St George's, University of London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511895.
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Winn, Simon. "An investigation of the actions of connective tissue growth factor on human renal epithelial cells." Thesis, St George's, University of London, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754078.
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Introduction. Connective tissue growth factor (CTGF) is the only CCN member recognized as a mediator of chronic fibrotic disease. Accumulating evidence suggests that CTGF is important as a downstream effector of transforming growth factor (TGFβ) in modulating a sustained pro-fibrotic signal in in vivo models. Moreover, in cultured human proximal tubule epithelial cells (PTECs) CTGF mRNA is readily upregulated by TGFP and the nascent protein accumulates extracellularly. How pro-fibrotic signalling occurs is yet to be ascertained but it likely involves extracellular interactions with secreted CTGF. The tetra-modular structure of CTGF has been shown to possess multiple binding sites for ligands present in the extracellular milieu including matrix proteins, growth factors including the TGFβ superfamily and cell surface receptors. As such, CTGF can behave as a bridge between matrix and cell. Moreover, individual modules possess intrinsic biologic activity. Materials and Methods. Experiments were performed in cultured renal human renal epithelial cells. Recombinant human CTGF protein was generated in-house following plasmid transfection into context relevant PTECs. Immunoblotting and ELISA techniques were used to investigate protein expression in response to incubation with study protein in isolation or in combination with TGFP superfamily members. Protein-protein binding was investigated using surface plasmon resonance (SPR) in order to elucidate how CTGF might regulate TGFβ superfamily cell signalling. Additional experiments with an alternative CCN member, CCN3, were performed. Results. Both full-length and C-terminal CTGF bind to TGFβ and BMP7 and in human renal epithelial cells, this binding modulates the downstream Smad signalling pathways associated with fibrosis. In cultured human podocytes, CTGF drives TGFβ-dependent signalling in the absence of exogenous TGF(3 suggesting activation of latent TGFβ. Moreover, C-terminal CTGF increases the generation of pro-fibrotic markers aSMA and fibronectin, both of which are subsequently blocked by inhibiting the TGFp receptor. Unlike CTGF, an alternative CCN member CCN3 reduces TGFβ-induced signalling in PTECs. Conclusion. CTGF protein has multiple binding sites and modulates the cellular responses of TGFp superfamily members on human renal epithelial cells. Both full-length and C-terminal CTGF bind to TGFβ and BMP-7. CTGF also appears to bind to the receptors of the TGFβ superfamily. C-terminal CTGF has intrinsic profibrotic activity that differs from the full-length protein as demonstrated in cultured human podocytes. The pro-fibrotic activity is suppressed by CCN3 in the CTGF rich environment of the cultured PTEC. The interplay of different CCN proteins in modulating fibrotic pathways in renal epithelial cells warrants further investigation.
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Ho, Sau-kwan, and 何秀鈞. "Interactions of anti-dsDNA antibodies with human proximal renal tubular epithelial cells in the pathogenesis of lupus nephritis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197161.
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Lupus nephritis is characterized by the production of anti-dsDNA antibodies, deposition of immune complexes within the kidney parenchyma, proliferation of resident renal cells and induction of inflammatory and fibrotic processes. Approximately 70% of patients with lupus nephritis show immune aggregates along the tubular basement membrane, which is accompanied by an influx of infiltrating cells and increased intra-renal expression of IL-6. Much attention has focused on the inflammatory processes in the kidney during pathogenesis of lupus nephritis whereas mechanisms of fibrogenesis are less well characterized.
Tubulo-interstitial injury is a key indicator of poor prognosis of renal function. Given that the tubulo-interstitium occupies over 80% of the kidney volume, injury to this compartment will have a major impact on renal function. There is evidence to show that proximal tubular epithelial cells (PTEC) undergo epithelial-to-mesenchymal transition (EMT) during pathological disorders and adopt a fibroblastic morphology with increased fibrogenic potential. We have previously demonstrated that anti-dsDNA antibodies bound directly to the surface of PTEC through cross-reactive proteins, which were subsequently internalized and translocated to the nucleus where they induced functional changes. Using a proteomic approach, this study identified the cross-reactive antigens that mediated anti-dsDNA antibody binding and intracellular localization in PTEC and the functional consequences thereafter, focusing on EMT and fibrogenic events.
Human polyclonal anti-dsDNA antibodies isolated from patients with lupus nephritis bound to Ku70 in plasma membrane extracts isolated from PTEC, and to Ku70, Ku80 and major vault protein in cytosolic and nuclear fractions. Anti-dsDNA antibodies increased synthesis of Ku70, Ku80 and major vault protein in PTEC in a time-dependent manner. Expression of these proteins was localized to proximal tubules especially those undergoing atrophy, and staining was more prominent in renal biopsies from patients with lupus nephritis compared to non-lupus renal disease or control specimens.
Binding of anti-dsDNA antibodies to PTEC increased phosphorylation of MAPK and PKC signaling pathways that was accompanied by a concomitant increase in IL-6, IL-8 and TGF-1 secretion and synthesis of β-catenin, fibroblast specific protein-1, fibronectin and laminin. Inhibition of MAPK and PKC signaling pathways with specific inhibitors revealed differential regulation of inflammatory and fibrotic processes by these signaling pathways. In this respect, increased ERK, p38 MAPK, JNK and PKC phosphorylation in PTEC following anti-dsDNA antibody stimulation enhanced IL-6, IL-8 and fibronectin synthesis, whereas increased ERK and JNK phosphorylation upregulated TGF-β1 secretion. Increased β-catenin synthesis was mediated through JNK and PKC phosphorylation.
Taken together, our data suggest that PTEC contribute to the pathogenesis of renal inflammation and fibrosis in lupus nephritis. We hypothesize that anti-dsDNA antibodies bind to Ku70 on the plasma membrane of PTEC to mediate inflammation, cell activation and increased fibrogenesis. Although synthesis of EMT markers was increased in PTEC after anti-dsDNA antibody stimulation, transition to a fibroblastic morphology was not observed under our experimental setting suggesting that induction of the EMT cascade is an early event before phenotypic alterations.published_or_final_version
Medicine
Master
Master of Philosophy
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Veerasamy, Mangalakumar. "The role of Id proteins 1 and 2 in regulating phenotypic changes by TGFB1 and BMP7 in human renal epithelial cells." Thesis, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589773.
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Tubulo-interstitial fibrosis (TIF) is a key feature of chronic kidney diseases (CKD). Epithelial mesenchymal transition of PTECs is considered to contribute to the interstitial fibroblast pool which secretes excessive matrix proteins seen in TIF. TGFpl plays a crucial role in TIF including mediating EMT. In animal models of CKD treatment with bone morphogenic protein 7 (BMP 7), a member of TGF superfamily improved the histology and renal function. However, the cellular signalling mechanisms involved in the anti- fibrotic effects of BMP 7, in particular whether BMP 7 inhibits TGFp 1 mediated EMT of human PTECs have not been studied. Experiments were performed in HKC 8 cells; a virally transformed human PTEC model. The expression of cell surface receptors for TGF superfamily and phosphorylation of TGFp 1 and BMP 7 Smads were studied by immunoblotting, and the nuclear translocation of Smad proteins was studied by immunofluorescence. The expressions of E-cadherin and (l-SMA were studied with TGFp 1 and BMP 7 treatment individually and in combination. siRNAs were used to knock-down Smadl and 5 proteins, to identify their role in BMP 7 regulation of markers of EMT. TGFp 1 and BMP 7 regulation of Id2 expression was studied at the protein level and the Smad signalling regulating this process was studied by '. silencing their expression with siRNA. siRNAs were used to study the role of Id2 on the expression of E-cadherin and (l-SMA with TGFp 1 and BMP 7 stimulation. Plasmid vector expressing Id2 was used to overexpress Id2 to study its role in TGFp 1 regulation of , markers ofEMT. Idl expression was studied at the protein level with BMP 7, and the Smad signalling involved in this process was studied by silencing their expression with siRNAs. The role of Id 1 in BMP 7 regulation of E-cadherin and (l-SMA was studied by silencing its expression by siRNA. The interaction of Idl and Id2 with E2A gene products was studied by nuclear co-immunoprecipitation. HKC 8 cells express TGF type 11, Alkl, Alk2, Alk3, Alk5 and Alk6 receptors. TGFpl and BMP 7 activated their respective receptor Smads concurrently during combined treatment. The nuclear translocation of their respective receptor Smads was not inhibited by the other during combined treatment. BMP 7 do~egulated E-cadherin, and it had an additive effect with TGFp 1 in this process and this was a Smad 1/5 dependent event. BMP 7 inhibited TGFp 1 induction of (l-SMA through Smad 1/5 signalling. TGFp 1 downregulated Id2 through Smad2/3 signalling and BMP 7 counter-regulated this through Smad1/5 signalling. IV Id2 gene silencing prevented BMP 7 inhibition of TGF~ I mediated a-SMA' expression. Id2 overexpression prevented TGF~ I mediated a-SMA expression. BMP 7 increased expression of Idl through non-Smadl/5 pathway and Id l gene silencing resulted in induction of a-SMA with BMP 7 stimulation. Both Idl and Id2 were co- immunoprecipitated with EI2 and E47 in the nuclear extract. In conclusion, these studies show that the anti-fibrotic effect of BMP 7 is mediated by inhibition of TGF~ 1 mediated induction of a-SMA and the myofibroblastic transition of PTECs in this in vitro model. The activation of Smadl/5 and Id2 signalling is involved in this counter-regulation. Although BMP 7 itself downregulated E-cadherin through Smadl/5 signalling, the concurrent induction of Idl through non-Smadl/5 pathway prevented de novo induction of a-SMA and myofibroblastic transition of PTECs. Id I and Id2 were shown to bind with E2A gene products, but their role in the expressions of markers of EMT in this model needs further confirmation.
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Sheremet, Andriy. "Bioinspired polyethersulfone-based hollow fiber membranes as the scaffolds in renal assist device for protein-bound toxins removal from blood." Master's thesis, Faculdade de Ciências e Tecnologia, 2014. http://hdl.handle.net/10362/13308.
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Dissertation for obtaining the Master degree in Membrane EngineeringErasmus Mundus Master in Membrane Engineering
Using bioartificial kidney is the promising approach for removal of non-dializable, proteinbound uremic toxins, which are responsible for high mortality and morbidity in treating kidney failure related conditions. Additionaly, bioartificial kidney device could perform the physiological roles of the kidney such as metabolic replacement, endocrine function and immunomodulation. In the current work two commercial polyethersulfone-based membranes, Gambro HCO 1100 and Membrana MicroPES TF10 used in haemofiltration and plasma separation applications respectively were investigated. To provide adequate cytocompatibility of the membrane biomimetic, biomimetic double layer coating was developed. First, the membranes were coated with musselinspired synthetic polydopamine film, following with the coating of Collagen Type IV. Transport properties of the coated and native membranes were investigated. Increase in pure water permeability of the coated HCO 1100 membranes was observed. Membrane surface hydrophilization was assumed as the major factor responsible for the effect. Membrane permeabilities for bovine serum albumin and immunoglobulin G solutions were studied. Significant increase in protein rejection was observed for double coated HCO 1100 membranes with small or no effect of the double coated MicroPES TF10 membranes. Next, formation of confluent monolayers of the renal epithelial cells on the membrane scaffolds was studied. Cell seeding strategy was developed and two seeding conditions were tested. Specifically, the cells were allowed to adhere to the biomimetic membranes passively, and the negative pressure was applied to facilitate cell adhesion. After cultivation in semi-batch conditions the monolayer formation was examined. Confluent monolayers were observed for the conditions with passive cell adherence for the both membranes. Cell contacts formation and cell polarization were confirmed with the staining for ZO-1 protein. Applying the pressure to facilitate cell adhesion, on the contrary, resulted in the loss of cell ability to form functional monolayers.
EM3E Master is an Education Programme supported by the European Commission, the European Membrane Society (EMS), the European Membrane House (EMH), and a large international network of industrial companies, research centres and universities
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Fougeray, Sophie. "Rôle du stress du réticulum endoplasmique et de l’autophagie dans la régulation des réponses immune et angiogénique activées par des stress ischémiques et inflammatoires dans l’épithélium rénal humain." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05P618/document.
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Dans le cadre de situations pathologiques, le rein peut être soumis à de multiples agressions toxiques, ischémiques et immunologiques pouvant favoriser la survenue d’une maladie rénale chronique et le développement d’une insuffisance rénale. En réponse à ces stress, les cellules du parenchyme rénal vont activer des processus biologiques adaptatifs permettant le maintien de la viabilité cellulaire et l’homéostasie de l’organe. Ces réponses adaptatives peuvent également activer l’immunité innée et induire le remodelage tissulaire (fibrogenèse et angiogenèse). Cependant, les mécanismes précis de cette régulation sont mal connus. L’objectif de ce travail a été de caractériser les mécanismes de régulation et les conséquences microenvironnementales (inflammation et angiogenèse) de l’activation de la réponse UPR (Unfolded Protein Response) et de l’autophagie, en réponse à des stress ischémiques et immunologiques. Dans un premier travail, nous avons montré que la réponse UPR est impliquée dans la génération d’une réponse inflammatoire induite par un stress métabolique dans des cellules tubulaires rénales. Le stress métabolique, caractérisé par une carence en glucose, induit un stress du RE et active la réponse UPR. Ce stress active le facteur NF-.B et favorise la transcription de cytokines et chimiokines pro-inflammatoires. La voie PERK/eIF2 : - n’est pas nécessaire à l’activation de l’inflammation mais amplifie l’expression des cytokines alors que la voie IRE1 - est impliquée dans la génération de cette réponse inflammatoire. De plus, l’ischémie aigue active le stress du RE et l’inflammation dans les reins de rat. Enfin, à partir de biopsies de déclampage de greffons rénaux, l’expression de GRP78, marqueur du stress du RE, et de NF-.B p65/RelA dans les tubules rénaux, est significativement plus élevée en comparaison avec des biopsies de greffons rénaux stables, à distance de la greffe. Dans un second travail, nous avons montré que la réponse UPR régule l’angiogenèse dans les cellules tubulaires rénales lors d’une carence en glucose. La voie PERK est un régulateur majeur de l’expression des facteurs angiogéniques (VEGFA, bFGF et angiogénine). De plus, l’expression de l’angiogénine est modulée par les voies PERK et IRE1.. Enfin, l’ischémie aigue induite chez le rat, active la réponse UPR parallèlement à l’augmentation de l’expression de VEGFA, bFGF et de l’angiogénine. Dans un troisième travail, nous avons mis en évidence un nouveau mécanisme par lequel l’interféron. (IFN.) active l’autophagie dans les cellules tubulaires rénales. Nous avons montré que l’IFN. entraine une déplétion en tryptophane, active la voie GCN2, une kinase eIF2., ce qui conduit à l’augmentation du flux autophagique. De plus, la supplémentation entryptophane et l’utilisation d’ARN interférence dirigés contre GCN2 inhibent l’autophagie induite par l’IFN. Enfin, l’autophagie intervient dans la régulation de la sécrétion de cytokines inflammatoires et de facteurs de croissance en réponse à l’IFN.. En conclusion, nous avons caractérisé dans ce travail des mécanismes originaux de régulation d’une réponse inflammatoire et angiogénique par la réponse UPR et l’autophagie en réponse à des stress ischémiques et immunologiques au sein de l’épithélium tubulaire rénal humainUnder pathological conditions, kidney is subjected to multiple toxic, ischemic and immunological failures that promote the occurrence of chronic kidney disease and the development of acute kidney injury. In response to stress, renal parenchymal cells activate biological adaptive processes permitting the maintenance of cell viability and renal homeostasis. These adaptive responses can also activate innate immunity and induce tissue remodeling (fibrogenesis and angiogenesis). However, accurate mechanisms of this regulation are still unclear. The aim of this work was to characterize regulation mechanisms and micro environmental consequences(inflammation and angiogenesis) of the activation of the UPR (Unfolded Protein Response) and autophagy, in response to ischemic and immunological stress. In a first study, we demonstrated that the UPR is involved in the generation of inflammatory response induces by metabolic stress in tubular renal cells. Metabolic stress, characterized by glucose deprivation, induces an ER stress and activates the UPR. This stress activates NF-.B and promotes the transcription of pro inflammatory cytokines and chemokines. The PERK signaling is not required for the induction of inflammation but amplifies cytokine expression whereas IRE1 is involved in the generation of inflammatory response. Moreover, acute ischemia activates ER stress and inflammation in rat kidneys. Finally, from kidney transplant biopsies performed before implantation, the expression of GRP78, an ER stress marker, and NF-.B p65/RelA in renal tubules is significantly increased in comparison with stable human kidney transplant biopsies. In a second study, we showed that the UPR regulates angiogenesis in tubular renal cells during glucose deprivation. The PERK pathway is a major regulator of angiogenic factors expression (VEGFA, bFGF and angiogenin). Furthermore, angiogenin expression is modulated by PERK and IRE1. pathways. Finally, acute ischemia activates the UPR and, in parallel, increases VEGFA, bFGF and angiogenin expression in rat kidneys. In a third work, we identified a novel mechanism by which IFN. activates autophagy in human kidney epithelial cells. We showed that IFN. promotes tryptophan depletion, activates the eIF2. kinase GCN2, and leads to an increase of the autophagic flux. Moreover, tryptophan supplementation and RNA interference directed against GCN2 inhibit IFN.-induced autophagy. Finally,autophagy regulates the secretion of inflammatory cytokines and growth factors in response to IFN..In conclusion, we characterized in this work original mechanisms that regulate inflammatory and angiogenic responses by the UPR and autophagy in response to ischemic and immunological stress in tubular renal human epithelium
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Cui, Ju, and 崔菊. "Kinesin-1 in pancreatic beta cell and renal epithelial cell." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hdl.handle.net/10722/197835.
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Kipari, Tiina Marika Johanna. "Inflammatory macrophages and renal tubular epithelial cell apoptosis." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/29197.
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Macrophages play a key role in renal inflammation and may be cytotoxic to resident cells within tissues. I begin this thesis by examining the effect of macrophages upon the level of apoptosis and proliferation in tubular epithelial cells in vitro. I then went on to examine the role of NO in vivo in the murine model of unilateral ureteric obstruction (UUO) characterised by tubular cell apoptosis and interstitial fibrosis. The specific iNOS inhibitor L-NIL (control D-NIL) was administered between days 5 to 7 following UUO. Mice were sacrificed at day 7 and the obstructed kidney removed for histological analysis. L-NIL treatment did not affect macrophage infiltration but did reduce both tubular and interstitial cell apoptosis. Proliferation of tubular cells and interstitial cells was unaffected. Interstitial fibrosis was significantly increased by L-NIL treatment. I also investigated the effect of conditional macrophage ablation in the UUO model. The conditional macrophage ablation mice used in these studies are transgenic for the human diphtheria toxin receptor (DTR) under the CD11b promoter (CD11b-DTR mice). Intraperitoneal (IP) administration of diphtheria toxin (DT) to DTR mice results in the rapid and specific depletion of monocytes and macrophages. DTR mice underwent UUO at day 0 and either DT or PBS was administered IP on days 5, 6 and 7. Mice were sacrificed at day 7 and the obstructed kidney removed for histological analysis. Administration of DT resulted in a 3-fold reduction in interstitial macrophage accumulation in obstructed kidneys. However, macrophage depletion had no effect upon proximal or distal tubular cell proliferation or apoptosis. Interestingly, macrophage depletion had no effect upon the accumulation of myofibroblasts but attenuated interstitial fibrosis.
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Gloulou, Basma. "Identification et caractérisation des cellules tumorales circulantes dans le cancer rénal à cellules claires." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00806775.
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La diffusion dans le sang des cellules tumorales circulantes (CTC) à partir de la tumeur primitive est un signe précoce d'invasivité tumorale et du risque de développer des métastases. Par conséquent, la capacité à les détecter de façon très sensible et spécifique est censée constituer un test cliniquement important pour le pronostic du cancer, le suivi des patients et la personnalisation de la thérapie. Les CTC sont des cellules rares, et plusieurs méthodes ont été proposées pour leur détection. La technique ISET (Isolation by Size of Epithelial/Tumor cells) se base sur la différence de taille des CTC par rapport aux cellules leucocytaires et a montré une très grande sensibilité d'isolement et spécificité d'identification des CTC. Elle permet l'analyse cytopathologique, immunologique et moléculaire des cellules isolées.Le cancer du rein représente 3% des cancers de l'adulte, dans 75% des cas il s'agit d'un carcinome rénal à cellules claires (RCC). Sur le plan génétique, il est un des rarissimes cancers solides caractérisé par des variations de l'ADN, il s'agit de mutations au niveau du gène VHL.Ce projet de recherche vise l'analyse comparative, moléculaire et cytopathologique, des CTC isolées à partir des patients avec RCC dans le but d'évaluer, par une approche moléculaire, les critères cytopathologiques diagnostiques des CTC. Notre étude a porté sur 29 patients ayant bénéficié de l'isolement des CTC par ISET avant toute intervention chirurgicale.L'analyse cytopathologique a été réalisée utilisant les critères décrits par l'équipe de P. Hofman pour définir les CTC (CNHC-MF) et les Cellules Atypiques Circulantes " CAC " (CNHC-UMF). L'analyse génétique par séquençage du gène VHL a été réalisée avec succès sur l'ADN de 205 cellules individuelles, sur l'ADN issu du tissu tumoral et sur l'ADN génomique de chaque patient.Sur les 29 tumeurs étudiées, 25 étaient caractérisées par des mutations du gène VHL. Cent soixante et une cellules, CTC et CAC, isolées à partir du sang de ces 25 patients, ont présenté des variations génétiques du gène VHL identiques à l'ADN issu du tissu tumoral. Il s'agit de 18 mutations différentes affectant les 3 exons de ce gène. Nous avons trouvé des CTC/CAC dans 29/30 des patients avec CCRC analysés. Des mutations VHL ont été trouvées dans 25 des 29 tumeurs CCRC correspondantes. Nous avons obtenu des résultats spécifiques VHL dans 205 des 327 CTC/CAC microdisséquées, comprenant 64 CTC et 141 CAC, selon l'analyse cytopathologique. Les mutations VHL ont été détectées en aveugle dans 57/64 CTC et dans 125/141 CAC. Cependant, nous avons observé que les 8 et 16 CTC et CAC restantes, respectivement, avaient été isolées de patients sans mutations VHL détectables dans le tissu tumoral.Conclusion : Ceci est la première étude comparative de diagnostic génétique et cytopathologique des CTC/CAC chez des patients avec un cancer solide, le CRCC. Nos résultats suggèrent que des critères cytopathologiques élargis pourraient être appliqués au diagnostic des CTC chez les patients avec CCRC. Bien que des études complémentaires et plus élargies soient maintenant nécessaires, cette méthode ouvre la voie à une approche génétique pour le diagnostic des Cellules Tumorales Circulantes
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Lehman, Teresa Ann. "Studies in human skin epithelial cell carcinogenesis /." The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487332636474889.
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Hooker, Erika. "Negative regulators of the Src family kinases in renal epithelial cells." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116932.
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The Src kinases are non-receptor tyrosine kinases involved in many epithelial processes in both normal and injured cells. Src was originally identified as a viral oncogene and has since been characterized as an important regulator of cellular proliferation, differentiation, and motility. Our lab has previously demonstrated that the Src kinases are important modifiers of gene expression in tubule cells of the kidney during ischemia-reperfusion injury. The signalling events that control and mediate the Src kinase transcriptional response in renal epithelial cells are not well understood. In this thesis, I have identified two novel negative regulators of the Src transcriptional response in renal epithelial cells. In Manuscript I and II, I demonstrate that the adapter protein Dok-4 can act as an inhibitor of Src-mediated transcription. Unlike most other adapter proteins, several members of the Dok family are primarily characterized by their inhibitory actions downstream of active tyrosine kinases. Despite being the most ubiquitously expressed Dok family member, Dok-4 function has remained elusive as few interacting proteins have been identified. In Manuscript I, we found that the previously defined boundaries of the Dok-4 PTB domain needed to be extended for proper function. We demonstrate that the PTB domain of Dok-4 contains an extended C-terminal alpha helix critical for canonical PTB-mediated interaction and identified the lipid phosphatase Ship1 as a novel partner of this redefined Dok-4 PTB domain. This interaction is greatly increased in the presence of active Src kinases and occurs through a canonical NPXpY motif present in the C-terminal region of Ship1. In contrast to the Dok-4-Ship1 interaction, in Manuscript II we present a non-canonical PTB-mediated interaction between Dok-4 and the nuclear transcription factor, Elk4. This interaction leads to relocalization of Elk4 from the nucleus to the cytoplasm and degradation of full-length Elk4. In renal cells, Dok-4 inhibits Src-mediated activation of Elk4 and represses expression of the immediate early genes, such as egr-1 and fos1, as well as some of their transcriptional targets. In agreement with this data, knock-down of Dok-4 was associated with increased proliferation of renal epithelial cells. During renal ischemia-reperfusion injury, where upregulation of immediate early genes is known to occur, we have for the first time detected a strong activation of the Src kinases and a delayed upregulation of Elk4, suggesting that Elk4 may be not only highly expressed, but also highly active. Dok-4, which is expressed in the kidney, may be essential for limiting damage to the kidney caused by Elk4-induced expression of the immediate early genes. In addition to activating transcription of the immediate early genes, we have previously shown that the Src kinases are responsible for transcriptionally upregulating the receptor tyrosine kinase, EphA2, during renal ischemia-reperfusion injury. In the preliminary manuscript presented here, we observed that while the Src kinases are highly active, the Stat proteins, downstream effectors of the Jak kinases, are dephosphorylated and inactive. As a corollary of this observation, overexpression of all three ubiquitous Jak family members, Jak1, Jak2 and Tyk2 could attenuate Src-mediated activation of the EphA2 promoter. Inhibition of endogenous Jak kinase by siRNA-mediated knock-down or incubation with the pharmacological inhibitor, Jak inhibitor I also activated EphA2 transcription. Surprisingly, Jak-mediated inhibition of EphA2 expression occurs independently of the Stat family and the cytokine receptors. Collectively, this thesis identifies two novel regulators of the Src kinase family in renal epithelial cells, the Dok-4 adapter protein and the family of Jak kinases.Les kinases Src sont des tyrosine-kinases cytosoliques qui sont impliquées dans multiples processus dans les cellules épithéliales et autres. Originalement identifiée comme un oncogène viral, la kinase Src est maintenant caractérisée comme une régulatrice de la prolifération, la différenciation et la motilité cellulaire. Nous avons précédemment montré que les kinases Src sont capables de modifier l'expression génique dans les tubules des reins durant le domage rénal par ischémie et réperfusion. Cependant, les mécanismes de signalisation qui contrôle la réponse transcriptionelle des kinases Src ne sont pas bien compris. La présente thèse décrit deux nouveaux inhibiteurs endogènes de la famille de kinases Src dans les cellules rénale épithéliales.Les deux premiers manuscrits établissent que la protéine adaptatrice Dok-4 fonctionne comme un inhibiteur des kinases Src. Contrairement à la plus part de protéines adaptatrices, la famille Dok est caractérisée par des actions inhibitrices durant la signalisation par les tyrosines kinases. Malgré que Dok-4 soit le membre de la famille Dok exprimé de manière la plus ubiquitaire, sa fonction est encore mal connue. Le premier manuscrit que je présente (Manuscrit I) décrit le domaine PTB de Dok-4. On y a démontré que le domaine PTB contient une extension C-terminal consistant probablement en une hélice alpha et que celle-ci est essentielle pour les interactions canoniques du domaine PTB de Dok-4. De plus, nous avons identifié la phosphatase lipidique Ship1 comme un nouveau partenaire de ce domaine PTB redéfini. Cette interaction est augmentée quand les kinases Src sont actives et elle implique un motif NPXpY dans la région C-terminale de Ship1. Contrairement à l'interaction entre Dok-4 et Ship1, l'interaction décrite dans le deuxième manuscrit (Manuscrit II) entre Dok-4 et le facteur de transcription, Elk4, implique le domaine PTB, mais se fait dans une manière atypique. L'interaction entre Dok-4 et Elk4 induit la relocalisation d'Elk4 du noyau au cytoplasme et cause la dégradation de la protéine Elk4. Dans les cellules rénales, Dok-4 inhibe l'activation d'Elk4 par les kinases Src et réprime l'expression des gènes de réponse précoce ("immediate early genes"), comme egr-1 et fos, et quelques cibles transcriptionelles de ces gènes. En accord avec ces données, suppression de Dok-4 est associée avec une augmentation de prolifération. En utilisant un modèle in vivo d'ischémie-reperfusion rénale, où la surexpression de gène de réponse précoce a déjà été démontrée, nous avons détecté une forte activation des kinases Src suivie d'une augmentation retardée de l'expression d'Elk4 dans les lysates de reins. Ces données suggèrent que dans ce modèle Dok-4 pourrait être critique pour limiter les dommages aux reins causé par l'induction des gènes de réponse précoce par Elk4. En plus d'activer l'expression des gènes de réponse précoce, nous avons précédemment montré que les kinases Src sont impliquées dans l'induction transcriptionnelle du récepteur tyrosine-kinase, EphA2, durant l'ischémie-reperfusion rénale. Dans le manuscrit préliminaire que je présente, nous avons noté que dans un modèle de déplétion et réplétion d'ATP, les kinases Src sont activées et les protéines Stat, des effecteurs des kinases Jak, sont déphsophorylés et inactives. Comme corollaire de cette observation, la surexpression de trois membres de de la famille Jak inhibent l'activation du promoteur d'EphA2 par les Src kinases. En plus, l'inhibition des kinases Jak endogènes par traitement aux siRNA ou par un inhibiteur pharmacologique, Jak Inhibitor I, active le promoteur d'EphA2. Étonnement, l'inhibition de l'expression d'EphA2 par les kinases Jak se fait indépendamment des protéines Stat et les récepteurs à cytokines. Mises ensemble, les données de cette thèse démontrent deux nouveaux inhibiteurs de la famille Src dans les cellules rénales épithéliales, la protéine adaptatrice, Dok-4 et les kinases, Jak1 et Jak2.
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Tang, Chi-wai Sydney, and 鄧智偉. "The many facets of the renal proximal tubular epithelial cell inhuman." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31992468.
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Luxemburg, Michael, and Hanna Jönsson. "Quantum Dot Movement on Human Lung Epithelial Cell Line." Thesis, KTH, Skolan för teknikvetenskap (SCI), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-195672.
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Inhalationsläkemedel är den främsta behandlingsmetoden för lungsjukdomar såsom astma och KOL. Förutom medicinering inandas vi dessutom miljardtals luftmolekyler varje dag varav en del är föroreningar. Hur dessa ämnen påverkar lunghälsan beror i hög grad på spridningen över lungcellerna. För att mediciner ska absorberas effektivt och luftföroreningar inte ska fastna och ackumuleras, krävs ett funktionellt transportsystem över lungcellerna såsom cellernas cilier. Denna studie ämnar undersöka kvantpartiklars spridning på lungceller utsatta för olika förhållanden som har visats påverka ciliers mobilitet. Specifikt undersöks spridning av 3-MPA täckta CdSe-CdS/ZnS kvantprickar på Calu-3-celler odlade med luft-vätska gränssnitt (ALI) och hur väl lämpade dessa celler är för denna typ av studier. Konfokalmikroskop användes för att studera cellerna vid olika temperaturer samt efter inkubering i saltlösning. Som jämförelse utfördes experiment med kvantprickar i vatten och på döda celler odlade med vätska-vätska gränssnitt (LLI). Resultaten visar att spridningen över ALI Calu-3-celler är starkt kopplad till fluktuationer i cellagret snarare än de olika ciliemodulerande förhållandena. Vi drar därför slutsatsen att ALI Calu-3-celler inte är optimala för studier av ciliers funktion kopplad till spridningshastighet.
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Pichitsiri, Watchara. "Renal allograft failure : a study of the drivers of epithelial cell de-differentiation." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2035.
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Kidney transplantation is the gold standard renal replacement therapy for patients with end-stage renal disease. Despite advances in immunosuppressive therapy, chronic allograft dysfunction remains the commonest cause of renal allograft failure in living recipients. The typical pathology of this disease includes chronic inflammation with tubular atrophy and interstitial fibrosis. Although the origin of the excess fibroblasts and myofibroblasts remains controversial, the process of epithelial to mesenchymal transition might play a role. This study was designed to test the linked hypotheses that the immunosuppressive drug, Cyclosporine A and graft infiltrating T cells can induce allograft pathology by alteration of the bioavailability of fibrogenic TGF-β. An initial series of experiments examined the induction of mesenchymal transition by treatment of cultured human renal tubular epithelial cells with immunosuppressive concentrations of Cyclosporine A. Drug treated cells showed characteristic morphological changes associated with increased expression of the mesenchymal marker S100A4 and reduced expression of the epithelial marker E-cadherin; similar changes were induced by the addition of TGF-β1. The phenotypic change induced by Cyclosporine A was not the consequence of an increased response to autocrine TGF-β and could not be inhibited by specific blockade of the ALK5 component of the TGF-β receptor. Further studies showed in vitro that contact between activated T cells and renal tubular epithelial cells could induce mesenchymal transition by a mechanism that was dependent on activation of the TGF-β receptor complex. A final series of experiments defined a mechanism by which T cells activate latent TGF-β allowing subsequent receptor stimulation leading to either T cell or epithelial cells differentiation. The latency associated peptide binds to and inhibits native TGF-β but can be displaced by both thrombospondin-1 and neuropilin-1, producing active TGF-β. In this study it was shown that cytoplasmic thrombospondin-1 is exported and expressed on the surface of activated T cells following brief interaction with renal tubular epithelial cells; neuropilin-1 was also expressed by a mean 18% of activated human T cells. Inhibition of these two molecules with a blocking LSKL peptide sequence inhibited the normal response of activated human T cells to latent TGF-β1. This study demonstrated that both Cyclosporine A and T cells can induce renal epithelial to mesenchymal cell transition. However, the former process seems independent of TGF-β whilst the latter requires TGF-β receptor stimulation and might be regulated in vivo by T cell-mediated activation of latent TGF-β within the allograft.
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Nicholson, Benjamin. "The regulation of high affinity glutamate transport a bovine renal epithelial cell line." Thesis, University of Bristol, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336919.
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Liu, Mengfei, and 刘梦菲. "Epithelial morphogenesis in three-dimensional cell culture system." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208611.
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In human body, the most common structures formed by epithelial cells are hollow cysts or tubules. The key feature of the cysts and tubules is the central lumen, which is lined by epithelial cell sheets. The central lumen allows material exchange, thus it is indispensable for the proper function of the epithelial tissue.
In order to understand the way that the epithelial cells form highly specialized structure, an in vitro three-dimensional (3D) culture system was established. The Caco-2 cells were embedded in reconstituted basement membrane termed matrigel, whose biochemical constitution and physical properties were similar with the in vivo environment. The Caco-2 cells in matrigel spontaneously formed spherical multi-cell cysts, which could continuously expand. The confocal imaging and reconstruction technique helped understand the cyst structure and its formation process. The cysts developed central lumen surrounded by a layer of polarized cells. The apical domain of the cells faced the lumen, while the basal domain attached to the extracellular matrix.
In the mature cysts, fluid was secreted by the cells around the lumen at the apical domain, and accumulated in the central lumen. The laser burning experiment showed that the intraluminal pressure was higher than the outer environment. The intact cell sheet was required to keep the engorged morphology of the cysts. The tension of the cell layer balanced with the intraluminal pressure.
To investigate the effect of pressure on cyst development, the cysts were treated with cholera toxin, which could increase intraluminal pressure through promoting apical secretion. The time-lapse images showed that under cholera toxin treatment, the expansion of the cysts was accelerated. The high intraluminal pressure led to shape change of thecells, followed by increase in cell proliferation rate. Cholera toxin itself could not promote cell growth. In the3D cultured cysts, it was the increased intraluminal pressure that directly induced the acceleration of cell proliferation. It indicated that not only biochemical signals, but also mechanical force, contributed to epithelial morphogenesis.
The mechanical stimulation could be converted into biochemical signals, further affect cell behavior. In response to mechanical stimulation, the focal adhesion kinase was activated in the cells around the cyst lumen. Furthermore, the microarray analysis suggested that multiple signaling pathways were altered under intraluminal pressure stimulation, including the pathways related to cytoskeleton organization, cell cycle and cell adhesion.
Taken together, comparing with the conventional two-dimensional cell culture on rigid surface, the three-dimensional culture system provided the cells a more physiological environment. The 3D culture system allows the epithelial cells to form well-organized hollow structure. It is a convenient model for investigating the process and mechanism of epithelial morphogenesis.published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
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Alam, Tahirah. "Changes in gene expression during human prostate epithelial cell differentiation." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1444338/.
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The prostate is the most common site of disease in the human male. An understanding of its normal growth and development is required in order to elucidate the underlying mechanisms of prostatic diseases, namely benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate epithelium consists of three distinct cells types: basal, luminal and neuroendocrine cells. Several authors have postulated that there is a putative stem cell population in the prostate epithelium that gives rise to all three of these cell types. The stem cells are thought to reside in the basal cell layer and upon cell division give rise to an intermediate, transit amplifying (TA) cell. TA cells undergo rapid proliferation before undergoing terminal differentiation into a luminal or neuroendocrine cell. Despite accumulating evidence for the existence of prostatic stem cells, the regulation of cell growth and differentiation in the normal and diseased prostate is poorly understood. The aims of this research project are to identify genes that are involved in the regulation of growth and differentiation in the normal human prostate. As a model for investigating epithelial cell differentiation, a conditionally immortalised prostate epithelial cell line was employed. BPH cells were conditionally immortalised using a SV40 construct containing the large T antigen to give rise to the prostate epithelial cell line PrE2.8 (Daly-Burns et al., in preparation). These cells exhibit a basal phenotype at the permissive temperature of 33 C and are highly proliferative. When switched to 39 C, growth of the PrE2.8 cells is inhibited and they begin to differentiate. Using the differential display technique and microarray analysis, changes in gene expression between a proliferative and a non-proliferative phenotype were investigated. The protein expression of genes of interest were then confirmed in prostate tissue using immunohistochemistry. These genes may represent early markers of prostate epithelial cell differentiation and may also play a role in the progression of BPH and prostate cancer.
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Kim, Dusik. "The Mechanism of Bicarbonate Secretion in Human Airway Epithelial Cell." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518448.
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Neal, Corey Lekeil. "Snail mediates epithelial mesenchymal transition and cell adhesion in human prostate cancer cell lines." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2011. http://digitalcommons.auctr.edu/dissertations/233.
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Snaill (Snail) transcription factor induces Epithelial Mesenchymal Transition (EMT), in which epithelial cells down-regulate cell adhesion genes such as E-cadherin and up-regulate mesenchymal genes such as vimentin, leading to increased invasion and migration. Maspin is a putative tumor suppressor that is down-regulated in breast and prostate cancer and has been associated with decreased cell motility, while Snail is increased in breast cancer and associated with increased tumor motility and invasion. Very little is known about the role of Snail in cellular adhesion to the extracellular matrix (ECM) and its role in regulation of maspin expression has not been explored. We hypothesized that Snail will lead to decreased cellular adhesion to the extracellular matrix through integrin regulation, concomitant with increased cell migration. Our studies showed that Snail decreases cell adhesion to fibronectin (FN) and collagen I (CGN) matrix through inhibition of cL5 (fibronectin receptor), c~2 (collagen receptor), ~3 1 integrins, while migration to FN and CON was increased. We have also identified an inverse relationship between Snail and rnaspin in normal prostate epithelial cells and prostate cancer cells and shown for the first time that Snail can inhibit maspin expression.
This work utilized normal prostate epithelial cells (PrEC), androgen-dependent LNCaP cells, androgen-independent C4-2, DU145, 22Rvl, ARCaP and PC3 prostate cancer cell lines. Cells with either the endogenous, overexpression or knockdown of the Snail transcription factor were utilized to observe the role of Snail in cell adhesion and migration and to establish its molecular mechanism(s) of action. We have provided direct evidence that the Snail transcription factor negatively impacts prostate cancer cell adhesion and migration to fibronectin and collagen matrices. This activity was regulated through integrins and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we have shown that Snail negatively regulates maspin expression by inhibiting activity at the maspin promoter.
Collectively, these studies define a new role for Snail in cell adhesion to the ECM. Therefore, targeting of Snail may be useful to re-induce expression of maspin putative tumor suppressor, increase cell adhesion to ECM, decrease cell migration and prevent prostate cancer tumor progression and metastasis.
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Goodwin, Mark A. J. "Cell behaviour during epithelial wound closure in the chick extra-embryonic epiblast." Thesis, University of Leicester, 1986. http://hdl.handle.net/2381/34360.
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Light and electron microsope techniques have been used to investigate the normal stage 4-5 epiblast periphery and wound closure at the epithelial margin. The stage 4-5 epiblast is attached to the vitelline membrane by an association of flattened 'edge cells'. Basal 'edge cells' possess lamellipodia oriented in the direction of epiblast expansion. Adjacent cells are connected by junctions and appear to retain their respective positions during the 'gliding' movement of the attached periphery. Fixation at low temperatures produces an alteration in 'edge cell' morphology consistent with a retraction of the epiblast margin. After the excision of approximately 200?m of epiblast periphery, the wound gapes due to tensions within the proximal epithelium. The epiblast cells respond to the trauma of wounding by rounding. Wound closure commences within 1 hour of 'edge cell' excision as epiblast cells at the margins attach to the membrane in distal-proximal sequence. The attached wound margins migrate toward each other across the membrane and close the wound at around 10 hours reincubation. Junctions are not observed at the wound margins and the cells appear to employ a 'rolling and sliding' form of locomotion. These results suggest that 'edge cells' are intrinsically different from those of the proximal epiblast. The normal stage 4-5 epiblast is overlain by a basement membrane. This structure is not observed at the early wound margin. The migrating wound margins deposit extracellular materials on the vitelline membrane and these resemble substances associated with the normal stage 4-5 epiblast basement membrane. Similar materials are also produced by explants and isolated cells of the epiblast periphery when cultured on the vitelline membrane. It is suggested that these materials may represent an attempt to reconstitute a basement membrane during wound closure.
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Sandlund, Johanna. "Angiogenesis in human renal cell carcinoma : hypoxia, vascularity and prognosis." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1331.
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Carter, Jessica. "Epigenetic basis for Tensin3 dysregulation in human renal cell carcinoma." Thesis, University of Portsmouth, 2013. https://researchportal.port.ac.uk/portal/en/theses/epigenetic-basis-for-tensin3-dysregulation-in-human-renal-cell-carcinoma(e39a962d-9c23-4265-8318-bf5fd296148c).html.
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The Tensins are a family of intracellular cytoskeleton interacting proteins that are involved in the regulation of cell motility and migration. Downregulation of Tensins has been observed in several cancers, indicating that it may be advantageous for tumour progression. In this study, an epigenetic basis for the observed downregulation of Tensin3 in human renal cell carcinoma (RCC) has been investigated, specifically the methylation state of the TNS3 gene promoter. The aims of this study were to: 1. Identify and validate a functional promoter for the human TNS3 gene that contains a CpG island within it; 2. quantify the methylation level of this region in RCC; 3. determine whether expression of Tensin3 could be altered through DNA demethylation treatment. Bioinformatic analysis revealed there to be a putative promoter for the human TNS3 gene, housing an 826-bp CpG island. A luciferase reporter assay demonstrated a functional minimal promoter activity for a 2000 bp sequence containing this island. For quantification of methylation in the TNS3 promoter, genomic DNA from RCC patients (tumour and adjacent non tumour) and a normal control group were analysed by bisulphite conversion followed by pyrosequencing analysis. This enabled quantitative determination of DNA methylation of individual CpG dinucleotides within the TNS3 gene promoter, out of a total of 43 analysed. Across the entire CpG stretch, RCC DNA showed significantly higher methylation level than non-tumour kidney DNA and normal control DNA (tumour n=12, non-tumour n=3; normal n=12; P<0.01, tumour vs. non-tumour; P<0.0001, tumour vs. normal). Out of the CpGs analysed, two CpG dinucleotides, CpGs 2 and 8, showed the most pronounced increases in methylation in tumour samples (P<0.0001). Furthermore, CpG 2 methylation negatively correlated with Tensin3 gene expression levels in RCC samples (P<0.005). In addition, pharmacological demethylation of cultured HK2 kidney cells with 5-aza-2’deoxycytidine caused a threefold upregulation of Tensin3 expression as measured by qRT-PCR. In conclusion, these results reveal a differential methylation pattern in the TNS3 promoter region occurring in human RCC, suggesting at least in part an epigenetic basis for the observed aberrant downregulation of Tensin3 in this disease.
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Basora, Nuria. "Involvement of laminin binding integrins in human intestinal epithelial cell functions." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0006/NQ40509.pdf.
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Lan, Li, and 藍莉. "A study of apoptosis in a human epithelial tumour cell line." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B31238762.
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Ouertani, A. "Determinants of cell cycle progression in human mammary epithelial MCF12 cells." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1362848/.
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Cancer of the mammary gland is the most common type of cancer in women worldwide, and the vast majority of breast cancers originate from a cluster of malignant cells in the epithelial tissue of the breast, which initially confines the ductal carcinoma in situ. Research has shown that the signalling pathways that increase differentiation and maintain proliferation in normal epithelial cells are of utmost importance for sustaining this barrier against malignant cells. As a model for normal mammary epithelial cells, the MCF-12A cell line was used to determine factors that are required for cell cycle progression of these cells. A discontinuous treatment assay was developed in which the MCF-12A cells were treated with epidermal growth factor (EGF) and insulin at two distinct times to induce cell cycle re-entry. The use of these chemically defined growth factors enabled us to determine that continuous stimulation with mitogenic factors is not required for these cells to re-enter the cell cycle. An initial activation of the MAP kinase pathway and an up-regulation of the transcription factor c-Myc, followed by activation of the PI3K pathway, resulted in full competence to progress into S phase. The order in which the growth factors were applied, and thus the sequence in which the subsequent proteins were triggered, was of great importance for successful S phase entry. We found that estradiol (E2) was unable to induce the factors necessary for cell cycle progression. Furthermore, we report for the first time that E2 did not affect estrogen-regulated genes which normally are under the control of a ligand-bound estrogen receptor (ER). We suggest that the mechanism by which the ligand-activated ER usually interferes with the estrogen responsive element in the promoter region of the target genes is defective in the MCF-12A cell line. The results presented here may contribute to new approaches in chemotherapy, taking advantage of the diverse molecular mechanism in place for cell cycle progression and proliferation in malignant cells compared to normal mammary epithelial cells.
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Jobson, Timothy M. "Regulation of human colonic sub-epithelial myofibroblast cell number in vitro." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395599.
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Barrett, Martin Andrew. "Transport of cephalosporins across monolayers of some human epithelial cell lines." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300009.
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Harten, Sarah Kay. "Role of the von Hippel-Lindau tumour suppressor gene in regulating renal epithelial cell characteristics." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.490934.
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Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene underlies both VHL disease, an inherited multi-cancer syndrome, and the majority of sporadic clear cell renal cell carcinomas (CCRCCs). The best established function of pVHL is regulation of HIF (hypoxia inducible factor). However, how VHL functions as a renal tumour suppressor gene remains to be fully elucidated. There is extensive evidence that changes in cell-cell adhesion and loss of epithelial cytoarchitecture are pivotal in the progression of tumours of epithelial origin, allowing cell-cell dissociation and subsequent invasion. The main objective of this thesis has been to identify whether VHL regulates epithelial cell characteristics, and, if so, whether this is mediated via HIF. The major findings are as follows: First, VHL loss-of-function has striking effects on the expression and localisation of several tight junction (TJ) components (occludin, claudin 1 and ZO-l) in both VHL defective CCRCC cells and sporadic CCRCC tissue (compared to adjacent unaffected kidney). Secondly disruption of TJs was detected in the earliest lesions of VHL inactivation in VHL patient kidneys, suggesting a potential role in tumour initiation. Thirdly re-expression the adherens junction (AJ) protein E-cadherin did not rescue TJ formation, showing that the TJ defect occurs independently of AJ breakage. Fourthly, VHL is required for formation of the primary cilium, a luminal hair-like structure which senses renal tubular flow and which is disturbed in most renal cystic diseases. Finally activation of HIF promotes dedifferentiation of renal epithelial cells. Dedifferentiation may allow cells to tolerate further mutations and undergo full malignant transformation. I have also shown that HDAC inhibitors can reverse this phenotype and therefore may be of use therapeutically. In summary, the work presented in this thesis provides significant insights into understanding how the VHL/HIF pathway contributes to tumour development in both VHL defective renal cancers and hypoxic non-renal tumours.
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Tse, Wan-wai. "A study of genomic DNA methylation in immortalized human epithelial cell lines." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290392.
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Tse, Wan-wai, and 謝韻慧. "A study of genomic DNA methylation in immortalized human epithelial cell lines." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290392.
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Dziasko, M. A. "Localisation of corneal epithelial progenitors and characterization of cell-cell interactions in the human limbal stem cell niche." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1472700/.
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The cornea, the transparent tissue located at the front of the eye, is a highly specialized tissue that transmits and refracts light onto the retina. Maintenance of the corneal epithelium relies on a population of limbal epithelial stem cells (LESCs) that maintain transparency of the ocular surface that is essential for vision. Despite great advances in our understanding of ocular stem cell biology over the last decade, the exact location of the LESC niche remains unclear. After observing a high population of basal epithelial cells expressing stem cell markers within the previously identified limbal crypts (LC), the first aim of this study was to demonstrate by in vitro clonal analysis that these structures provide a niche for the resident LESCs. High-resolution transmission electron microscopy has been further used to image the basal epithelial layer at the limbus. Cells with morphology consistent with stem cells were present within the basal layer of the limbal crypts but not within the basal layer of non-crypt limbal biopsies. Moreover, LESCs appeared proximal to limbal stromal cell extensions that suggested a possible route for direct cell-to-cell interaction. These observations were further confirmed by serial block-face scanning electron microscopy that revealed, for the first time, direct epithelial-stromal interactions in the LESC niche whereas limbal melanocytes maintained the LESC apically. In order to assess the role of limbal melanocytes (hLM) as niche cells for the maintenance of LESC, a novel co-culture system was developed in which hLM were used as a feeder layer for the expansion of limbal epithelial cells in vitro. Interestingly, hLM had the ability to support the clonal growth of LECs that maintained stem cell-like characteristics in 2D and 3D tissue equivalents. Taken together, these observations suggest an important role for melanocytes as niche cells in the native human limbal crypts.
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Reid, Janet Louise. "The mechanism of action of captopril in human renal cell carcinoma /." [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17182.pdf.
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Flores, Joseph. "Human retinal pigment epithelial cell transplantation for the treatment of Parkinson's disease." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/36675.
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Cell replacement therapies have been thoroughly investigated in the hope of finding a long-term, continuous dopaminergic (DAergic) source to treat motor dysfunctions in Parkinson’s disease (PD). However, mixed clinical results, safety and logistical concerns, and ethical issues have led to the interruption of these therapies in the clinic. Human Retinal Pigment Epithelial (hRPE) cells from fetal or neonatal origin have been proposed as a tissue transplant alternative for PD. HRPE cells are of neuroectoderm origin and play an integral part in normal retinal survival and function by providing nutritive, trophic, and anti-inflammatory support. HRPE cells are a potential cell therapy source for PD because of their DAergic properties. In the RPE, dopa is an intermediate product in the melanin biosynthetic pathway, catalyzed by the tyrosine hydroxylase analog tyrosinase. Since tyrosinase-produced dopa can exit the cell through plasma membrane amino acid transporters, RPE implantation into the parkinsonian brain could provide a continuous source of dopa to striatal DA terminals.
Previous reports have shown that hRPE cells attached to biocompatible gelatin microcarriers (hRPE-GM) can successfully ameliorate parkinsonian symptoms in PD patients. However, these observations are empirical in nature; indeed, little is known about long-term hRPE-GM survival or its underlying mechanism of action. The present thesis addresses the hypotheses that 1) hRPE-GM implants ameliorate behavioural deficits, 2) hRPE-GM survive long-term in the host striatum, and 3) the mechanism of action of hRPE-GM implants is not solely due to the in situ production of dopa and may involve alternate mechanisms of action, with an emphasis on anti-inflammatory factors. Using the rodent 6-OHDA model for PD, we investigated the qualitative survival and behavioural effects of hRPE-GM implants combining post mortem immunohistochemistry and non drug-induced behavioural paradigms. Next, we assessed the hypothesized reduction in inflammatory reactions to hRPE-GM implants (in the absence of immunosuppression) by quantifying the inflammatory response using stereological methods. Finally, we described a quantitative timeline of in vivo hRPE-GM survival using our recently developed superparamagnetic labeling techniques and MRI. These studies will provide further support for using hRPE cells as a therapeutic option for PD.
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Darbro, Benjamin Will. "Mechanisms of human epithelial cell immortalization and p16NK4a induced telomere independent sencescence." Diss., University of Iowa, 2007. http://ir.uiowa.edu/etd/183.
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Klatte, Jennifer Elisabeth. "Characterization of the epithelial stem cell niche of the human hair follicle." Giessen : DVG-Service, 2008. http://d-nb.info/989343707/04.
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Allard, David John. "Transcriptional regulation of the human S100A4 gene in breast epithelial cell lines." Thesis, University of Liverpool, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366650.
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Ramos, T. "An in vitro investigation of human ocular surface epithelial stem cell homeostasis." Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3020759/.
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Williams, Stephanie. "The role and regulation of prostaglandins in human tracheal epithelial cell lines." Thesis, University of Bath, 2004. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407486.
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Varughese, Eunice A. "Mechanisms of Cryptosporidium Parvum Invasion Using an Improved Human Epithelial Cell Model." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447688891.
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Ainscough, Sarah Louise. "Improved strategies for the cultivation of human limbal epithelial (HLE) grafts." Queensland University of Technology, 2008. http://eprints.qut.edu.au/18575/.
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The limbal stem cell population is located in the limbal junctional zone between the cornea and the conjunctiva, and is responsible for maintaining the corneal epithelium. Damage to the limbal stem cell population results in a condition known as limbal stem cell deficiency (LSCD), which is characterised by conjunctivalisation of the cornea, visual impairment and persistent irritation. To treat LSCD, an alternative source of human limbal epithelial (HLE) cells must be transplanted back onto the diseased cornea. Limbal tissue grafts have had a moderate degree of success. However, autologous grafts risk damage to the healthy eye, whilst allogeneic grafts are susceptible to immunological rejection. Cultured HLE grafts offer a promising alternative to whole tissue grafts. The production of cultured HLE grafts involves the removal of a small (1-2 mm2) biopsy from the patient’s healthy limbus, followed by ex vivo expansion to produce an epithelial sheet, which is subsequently transplanted onto the damaged corneal surface. However, the production of cultured HLE grafts usually requires the addition of animal-derived products during cell culture. Animal-derived components, such as foetal bovine serum (FBS) and murine 3T3 feeder cells, introduce the patient to potential crossspecies infection and immune responses to xenogeneic antigens. Consequently, the overall aim of this project has been to develop a culture technique free of xenogeneic products for the establishment and propagation of HLE cells. To achieve this aim, alternatives to FBS in the culture medium and 3T3 feeder cells were pursued. A defined serum-free medium (SFM) containing vitronectin (VN), insulin-like growth factor binding protein 3 (IGFBP3), insulin-like growth factor-I (IGF-I), and epidermal growth factor (EGF) was investigated as an alternative to serumsupplemented medium (SSM) for HLE cell culture. Initial studies focused on the effects of these growth factors on HLE cell metabolic activity and migration. Metabolic activity was primarily stimulated by IGF-I and EGF, with the combination of IGF-I and EGF in solution stimulating metabolic activity to a significantly greater extent than the SSM positive control (p = 0.006). HLE cell migration was also effected by combinations of VN, IGFBP3, IGF-I and EGF. Migration was stimulated above the SFM negative control by the combination of IGFBP3 and IGF-I either with or without the addition of EGF. However, the presence of VN was required for optimal migratory responses (p < 0.003). Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) were also investigated as additional components to the SFM formulation. HGF significantly stimulated HLE cell metabolic activity and migration (p < 0.02). In contrast, KGF did not significantly stimulate either HLE cell metabolic activity or migration. The addition of either HGF or KGF to the SFM supplemented with VN, IGFBP3, IGF-I and EGF did not significantly enhance the metabolic activity of HLE cells. Therefore, HGF and KGF were no longer pursued as additional components to the SFM formulation. Additional studies were conducted to examine the efficacy of replacing murine 3T3 feeder cells with human ocular stromal cells during HLE cell culture. Initially, stromal cells were isolated from the cornea, limbus and sclera to determine whether there were differences between these stromal cell populations. The results indicated that scleral stromal cells had a significantly larger area and perimeter than either corneal or limbal stromal cells (p < 0.001). Scleral stromal cells were also significantly more rounded than either corneal or limbal stromal cells, as determined by the elliptical factor equation (p < 0.001). Immunocytochemistry also revealed that scleral stromal cells expressed significantly more of the myofibroblast marker ..- smooth muscle actin than either corneal or limbal stromal cells (p < 0.001), and significantly less of the fibroblast/myofibroblast marker Thy-1 than corneal or limbal stromal cells (p < 0.001). Therefore, scleral stromal cells were identified as different in comparison to corneal and limbal stromal cells. Primary HLE cells were cultured with irradiated corneal, limbal and scleral stromal cells. HLE cultures established with either corneal or limbal stromal feeder cells contained more cellular protein (as measured by rhodamine B dye absorbance) than cultures established without feeder cells (p < 0.001). The colony forming efficiency (CFE) of HLE cells established with corneal or limbal stromal feeder cells was also significantly greater than HLE cells established without feeder cells (p < 0.001). In contrast, HLE cultures established with scleral stromal feeder cells contained low levels of cellular protein and had a low CFE, which was not significantly different to the HLE cultures established without feeder cells. Immunocytochemistry indicated that HLE cultures established with scleral feeder cells also showed lower expression of the stem cell markers ABCG2 and C/EBP ... These results suggest that freshly isolated HLE cells can be cultured with irradiated corneal or limbal stromal cells as a replacement for murine 3T3 feeder cells. Finally, the SFM supplemented with VN+IGFBP3+IGF-I+EGF was combined with limbal stromal feeder cells, and examined as a culture technique free of animalderived products. Freshly isolated HLE cells established in SFM supplemented with VN+IGFBP3+IGF-I+EGF and limbal feeder cells contained a similar amount of cellular protein (as measured by crystal violet dye absorbance) when compared to the SSM+3T3 positive control. In addition, the CFE of freshly isolated HLE cells established in VN+IGFBP3+IGF-I+EGF and limbal feeder cells was significantly higher than the SSM+3T3 positive control (p = 0.004). However, a live/dead assay revealed a reduced HLE cell viability in SFM supplemented with VN+IGFBP3+IGFI+ EGF and limbal feeder cells after seven days in culture. In addition, immunocytochemistry demonstrated a lower expression of the stem cell markers ABCG2 and C/EBP .. in the SFM treatment with limbal feeder cells. Therefore, freshly isolated HLE cells can be cultured in SFM supplemented with VN+IGFBP3 +IGF-I+EGF and limbal feeder cells. However, this culture technique is less likely to support the growth of immature limbal stem cells when compared to the SSM+3T3 positive control. Overall, this research has attempted to create a culture system free of animal-derived products for the production of cultured HLE grafts to treat limbal stem cell deficiency. The results show that HLE cells respond to a serum-free medium formulation containing VN+IGFBP3+IGF-I+EGF. In addition, this culture medium can be combined with irradiated stromal cells isolated from the limbus to support HLE culture production. However, the combination of VN+IGFBP3+IGF-I+EGF and limbal feeder cells demonstrated a reduced viability, which indicates that further refinement of the formulation is required. This thesis has also demonstrated differences between stromal cells isolated from the cornea, limbus, and sclera, and has generated knowledge which may impact on the understanding of stromalepithelial regulation.
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Braun, Norbert [Verfasser], and Stephan [Akademischer Betreuer] Huber. "UCP-3 Uncoupling Protein Confers Hypoxia Resistance to Renal Epithelial Cells and is Upregulated in Renal Cell Carcinoma / Norbert Braun ; Betreuer: Stephan Huber." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1165506491/34.
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Gharbi, Severine. "Proteomic analysis of ErbB-2 overexpression in human mammary luminal epithelial cell lines." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404418.
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Mercer, John. "Radiation carcinogenesis and delayed lethal damage in a human thyroid epithelial cell line." Thesis, University of St Andrews, 1999. http://hdl.handle.net/10023/9613.
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The human thyroid epithelial cell HTori-3 has been transformed with doses of either chronic and acute x-rays or strontium beta particles. Models of the past have relied upon animal cell systems to mimic in vitro carcinogenesis. The HTori-3 system hoped to overcome the limitations associated with these types of models by using a human thyroid cell line immortalised with the SV40 virus. HTori-3 human thyroid epithelial cells were irradiated in vitro, passaged and then transplanted into nude mice. Tumours that grew over a 2-6 month period were excised and re-established in culture. Samples were stored and all tumours were taken for histological examination. Chromosome spreads confirmed the human nature of all tumours. Following exposure to acute x-rays in the range of 0.25-2.0 Gy 13 tumours were observed in 25 recipients. Following 0.25-2.0 Gy of chronic x-rays 10 tumours from 25 recipients were observed. From a single 2 Gy exposure of strontium beta particles 3 primary tumours from 5 recipients were observed. The largest of these was re-transplanted in nude mice resulting in 100% incidence. All tumours were classified as undifferentiated anaplastic carcinomas. A small number of tumours were observed in the control cell lines, these may be the result of a general instability found with the partial transformed parental cell line. All 2Gy tumours and those previously established from this laboratory after alpha or gamma radiation were used to test for the presence of the delayed lethal death phenotype. A number of cell and molecular endpoints were used. These included plating efficiency, cell adherence, micronucleus formation and p53 status. In all incidences, the reproductive viability of irradiated cells was below that of non- irradiated cells at up to 4 weeks post-irradiation. The HTori-3 cell line and the techniques used to study the delayed effects of radiation may be applicable to other cell systems and may be a useful model to study the long-term effects of radiation induced genomic instability.
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Jönsson, Hanna. "The Search for Cilia Beat in a Cultured Human Airway Epithelial Cell Line." Thesis, KTH, Tillämpad fysik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-210050.
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Murray, Kathryn. "The role of mechanotransduction in the regulation of human alveolar epithelial cell function." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/25010.
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The aims of the study were i) to identify whether a reproducible protocol for isolation of type II pneumocytes from human lung tissue could be developed to study mechanical effects on these cells; ii) to establish whether an immortalised cell line, NCI-H441, expressed a phenotype similar to that of human type II pneumocytes, allowing its use in an in vitro model system of mechanotransduction; and iii) to investigate the effect of matrix substrate and mechanical stimulation on the production of inflammatory cytokines by NCI-H441. Human type II pneumocytes were successfully isolated from clinical resection samples, utilising a trypsin, DNase, discontinuous percoll gradient and differential attachment procedure. Isolated cells were found to demonstrate blunt microvilli, abundant lamellar bodies characteristic of type II pneumocyte under electron microscopic evaluation. The percentage of the cell isolations positively identified as type II pneumocyte with the modified haematoxylin staining ranged from 26.50 – 71.35% of the total preparations. Many of the morphological and antigenic characteristics of type II pneumocytes were shared with the NCI-H441 cell line. A cyclic mechanical stimulation regime was applied to cells using an in house system with a regime of 20 minutes stimulation at 0.25 Hz, 5000 μstrain. Significant membrane hyperpolarisation responses were elicited in cyclin mechanical stimulated primary human type II pneumocytes seeded on fibronectin and NCI-H441 cells seeded on collagen IV and fibronectin. A significant membrane depolarisation response was demonstrated by NCI-H441 when seeded on bovine serum albumin. NCI-H441 cells express interleukins (IL) 4, 6 and 8, suppressor of cytokine signalling – 3 (SOCS3) and surfactant specific protein – A (SP-A). Six hours after the application of cyclic mechanical stimulation NCI-H441 cells seeded on bovine albumin serum demonstrated a reduction in mean relative SOCS3 gene expression compared with controls. Cyclic mechanical stimulation of NCI-H441 cells seeded on fibronectin resulted in an increase in mean relative IL-8 gene expression levels an hour after stimulation.