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1
BADIOLA, SANGA ALEXANDRA. "Study of the role of the SOX2 transcription factor in neural and mammary cancer stem cells using SOX2 conditional knock-out in mouse." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/52431.
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The stem cell-determining transcription factor Sox2 is required for the maintenance of normal stem cells. In this study, we investigated the requirement for Sox2 in neural and breast cancer stem-like cells. In the first case, using a conditional genetic deletion mutant in a mouse model of platelet-derived growth factor-induced malignant oligodendroglioma. Taken together, our results showed that Sox2 is essential for tumor initiation by mouse pHGG cells, and we illustrated a Sox2-directed strategy of immunotherapy to eradicate tumor-initiating cells. In the second case, we used a Sox2 conditional deletion by an MMTV-Cre transgene (active in mammary tissue) to address Sox2 requirement within a widely studied mouse model of mammary tumor, produced by expression of a transgene encoding a mutated ErbB2/Neu oncogene, driven to mammary tissue by the MMTV promoter. Our results point to a heterogeneity within mammary tumors regarding Sox2 expression and function, in particular within ErbB2/Neu-positive tumors, that it will be important to consider when hypothesizing therapy approaches.
2
Eger, Glenda. "Regulation and Function of MAP Kinases in PDGF Signaling." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-301057.
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Platelet-derived growth factor (PDGF) is a family of signaling molecules that stimulates cell growth, survival and migration. PDGF is recognized by specific transmembrane proteins, the PDGF receptors, which relay the signals to the cell activating the Mitogen-activated protein (MAP) kinases and other signaling pathways. Aberrant activation of these pathways is frequently detected in cancer. Hence, the study of these processes is essential for identifying potential drug targets or diagnostic markers. In paper I, we identified Receptor Subfamily 4 Group A Member 1 NR4A1 to be regulated by PDGF via MAP kinases, clarifying the role of Extracellular signal–regulated kinases (Erk) 1/2, Erk5 and Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in its regulation. NR4A1 was found to be important for the tumorigenic potential, measured as anchorage-independent growth, of glioblastoma cells. Since the cellular responses elicited by PDGF result from the balance between phosphorylation and dephosphorylation events, we investigated the role of the dual specificity phosphatases DUSP4/MKP-2 and DUSP6/MKP-3. In paper II, we describe the crucial role of Erk1/2 and p53 in the expression of DUSP4/MKP2. Moreover, we observed that DUSP4/MKP-2 downregulation decreases Erk5 activation and accelerates PDGFRβ internalization and downregulation resulting in a specific inhibition of Signal transducers and activators of transcription (Stat) 3, Src and protein kinase C (PKC), and partially of p38, Stat1/5 and Phoshoplipase Cγ (PLCγ). In paper III, we report that DUSP6/MKP-3 creates a negative cross-talk between Erk1/2 and Erk5 and an auto-inhibitory feedback loop on the PI3-kinase/Akt pathway. In paper IV, we identify a new regulative mechanism of the PDGF pathway. PDGF induces Erk5 expression and activation that modulates the PDGFRβ activity. After Erk5 downregulation, the receptor undergoes to a faster and stronger activation that results in a faster internalization and degradation. In conclusion, we present a mechanism through which the PDGF/MAP kinases support tumor growth, and elucidate different regulatory pathways involved in PDGF signaling.
3
Zhang, Xiao-Qun. "Functional Studies on the PDGFR α gene promoter and effects of autocrine PDGF-A stimulation in vivo." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1455.
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Platelet-derived growth factor receptor α (PDGFRα) plays an important role during embryogenesis. After implantation, the patterns of expression of Pdgfrα and its ligand Pdgf-A undergo an "autocrine-paracrine transition", in that Pdgf-A becomes expressed in the ectoderm and epithelia, while Pdgfrα is expressed in the adjacent mesenchymal tissue. In human tumors, such as malignant glioma, both PDGF and PDGFRα are overexpressed within the same tissue, indicating that an autocrine PDGF loop is generated in the tumors. This thesis is focused on the in vivo functionality of the PDGFRα gene (PDGFRA) promoter, arid on the effect of autocrine PDGF-A stimulation in transgenic n-iice during embryogenesis. To test the in vivo promoter function of a human PDGFRA 2.2 kb 5' flanking fragment, we generated transgenic mouse lines and found that the 2.2 kb fragment was able to promote lacZ reporter gene expression in most of the endogenous Pdgfra expressing tissues. Absence of expression and "ectopic" expression of the transgenic lacZ were also observed. To investigate the autocrine PDGF effect, we produced autocrine PDGF-As (A short-chain) transient transgenic embryos. These transgenic embryos carried a 6 kb mouse Pdgfra 5' flanking sequence linked to a human PDGF-As cDNA. The pattern of expression of the PDGF-As transgene mRNA was similar to that of lacZ. Some of the transgenic embryos exhibited severe abnormal phenotypes, such as midline fusion defects in the cephalic and craniofacial region and small body size, and these embryos die at mid-gestation stage. These findings indicate that a paracrine pattern of expression and the dosage of PDGF are important for sustaining normal embryo development, especially with regard to the middline fusion in craniofacial regions. The possible signaling pathways that may be involved in regulating Pdgfra activity were also studied by comparison of patterns of mRNA expression of Gli, Ptc, and Paxl with that of Pdgfra. The results pointed to the possibility that the Shh signaling pathway may be involved in the regulation of Pdgfra expression for example during early bone and foregut development. The specific regulatory mechanisms may vary for different tissues.
4
Ma, Haisha. "Regulation of Platelet-Derived Growth Factor Receptor Signaling and its Targeting in Cancer Therapy." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248172.
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Overactivity of platelet-derived growth factor receptor (PDGFR) is a frequent event in many types of solid tumors. Therefore, it is of great importance to uncover the mechanisms that regulate PDGF/PDGFR signalling, to develop efficient inhibitors targeting this pathway. The first step of downregulation of PDGFR activity upon ligand binding is internalization; thus we investigated how endocytosis pathways affect PDGFR signaling. We showed that in Ras-transformed fibroblasts, the internalization of PDGFR is shifted from the routine clathrin-dependent endocytosis to macropinocytosis, which results in enhanced PDGFR activity and subsequent downstream signalling, promoting anchorage-independent growth. We were also interested in how intracellular trafficking regulates signalling attenuation of PDGFR. We found that His-domain containing protein tyrosine phosphatase (HD-PTP) positively regulates phosphorylation level of the ubiquitin-ligases c-Cbl and Cbl-b; consistently, silencing of HD-PTP led to a decreased level of PDGFR ubiquitination (paper II). Consequently, internalized PDGFR could not be sorted properly and escaped degradation. This resulted in enhanced activation of phospholipase C γ (PLCγ) and changed kinetics of signal transducer and activator of transcription (STAT) 3 signalling, which further increased colony formation of HD-PTP silenced cells in soft agar, indicating a tumor suppressor role of HD-PTP. Activation of PDGFR leads to stimulation of downstream pathways. We identified Fer kinase as a critical signal transducer downstream of PDGFR in a proteomic screen. We showed that Fer kinase is essential for PDGF-induced STAT3 activation; as a result (paper III), Fer depletion severely blunted the ability of PDGFR signalling to promote anchorage-independent growth in soft agar and delayed tumor initiation in a mouse model. The crosstalk between host and tumor plays a critical role in tumor progression. At present most anti-cancer drugs are targeting tumor cells; we were interested in how targeting tumor host cells affects the efficacy of anti-tumor therapy. We found that selective PDGFRβ inhibition in host cells exerted tumor inhibitory effects on growth and vascularization of tumors with autocrine PDGF signaling, whereas tumors lacking such stimulation show only minor response on tumor growth (paper IV). Meanwhile, we demonstrated that PDGF/PDGFRβ signalling promotes expression of NG2, a marker for pericytes.
5
Willetts, Karen Eve. "PDGF A and PDGF Rα in mammalian development." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318900.
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Hoflack, Bernard, Pierre Jurdic, Thilo Riedl, Anne Gallois, and Maria Arantzazu Sanchez-Fernandez. "Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-184120.
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BACKGROUND:
Bone remodeling relies on the tightly regulated interplay between bone forming osteoblasts and bone digesting osteoclasts. Several studies have now described the molecular mechanisms by which osteoblasts control osteoclastogenesis and bone degradation. It is currently unclear whether osteoclasts can influence bone rebuilding.
METHODOLOGY/PRINCIPAL FINDINGS:
Using in vitro cell systems, we show here that mature osteoclasts, but not their precursors, secrete chemotactic factors recognized by both mature osteoblasts and their precursors. Several growth factors whose expression is upregulated during osteoclastogenesis were identified by DNA microarrays as candidates mediating osteoblast chemotaxis. Our subsequent functional analyses demonstrate that mature osteoclasts, whose platelet-derived growth factor bb (PDGF-bb) expression is reduced by siRNAs, exhibit a reduced capability of attracting osteoblasts. Conversely, osteoblasts whose platelet-derived growth factor receptor beta (PDGFR-beta) expression is reduced by siRNAs exhibit a lower capability of responding to chemotactic factors secreted by osteoclasts.
CONCLUSIONS/SIGNIFICANCE:
We conclude that, in vitro mature osteoclasts control osteoblast chemotaxis via PDGF-bb/PDGFR-beta signaling. This may provide one key mechanism by which osteoclasts control bone formation in vivo.
7
Hoflack, Bernard, Pierre Jurdic, Thilo Riedl, Anne Gallois, and Maria Arantzazu Sanchez-Fernandez. "Osteoclasts control osteoblast chemotaxis via PDGF-BB/PDGF receptor beta signaling." PLOS one, 2008. https://tud.qucosa.de/id/qucosa%3A28994.
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BACKGROUND:
Bone remodeling relies on the tightly regulated interplay between bone forming osteoblasts and bone digesting osteoclasts. Several studies have now described the molecular mechanisms by which osteoblasts control osteoclastogenesis and bone degradation. It is currently unclear whether osteoclasts can influence bone rebuilding.
METHODOLOGY/PRINCIPAL FINDINGS:
Using in vitro cell systems, we show here that mature osteoclasts, but not their precursors, secrete chemotactic factors recognized by both mature osteoblasts and their precursors. Several growth factors whose expression is upregulated during osteoclastogenesis were identified by DNA microarrays as candidates mediating osteoblast chemotaxis. Our subsequent functional analyses demonstrate that mature osteoclasts, whose platelet-derived growth factor bb (PDGF-bb) expression is reduced by siRNAs, exhibit a reduced capability of attracting osteoblasts. Conversely, osteoblasts whose platelet-derived growth factor receptor beta (PDGFR-beta) expression is reduced by siRNAs exhibit a lower capability of responding to chemotactic factors secreted by osteoclasts.
CONCLUSIONS/SIGNIFICANCE:
We conclude that, in vitro mature osteoclasts control osteoblast chemotaxis via PDGF-bb/PDGFR-beta signaling. This may provide one key mechanism by which osteoclasts control bone formation in vivo.
8
Pontén, Annica. "Biological activities of novel platelet-derived growth factors, PDGF-C and PDGF-D /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-013-3/.
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Kowarik, Markus. "Expression, Lokalisation und funktionelle Bedeutung von PDGF und PDGF-Rezeptoren in der Hypophyse und in Hypophysentumorzellen." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-75767.
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Andræ, Johanna. "PDGF in cerebellar development and tumorigenesis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4987-5/.
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Etzel, Nadine. "Einfluss PDGF-Rezeptor-spezifischer Antikörper auf die Chemotaxis mesenchymaler Progenitorzellen und deren Expression von PDGF-Isoformen und -Rezeptoren." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:289-vts-56711.
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12
Ekman, Simon. "Specific signaling through heteromeric PDGF receptor complexes." Doctoral thesis, Uppsala University, Department of Cell and Molecular Biology, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1067.
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Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for mesenchymal cells and exert its effect by binding to two structurally related receptor tyrosine kinases, denoted α- and β-receptors. PDGF binding induces dimerization of its receptors, both homo-and heterodimerization, leading to their autophosphorylation on tyrosine residues and binding of downstream signaling molecules. This thesis describes autophosphorylation and binding of signal transduction molecules to homo- and heterodimeric PDGF receptor complexes.
Heterodimeric PDGF receptor complexes have been found to mediate a stronger mitogenic response than homodimeric receptor complexes. It was found that Tyr771 in the PDGF β-receptor was significantly less phosphorylated in the heterodimeric β-receptor compared to the homodimeric receptor, and this correlated with reduced binding of GTPase activating protein (GAP) for Ras and decreased activation of the Ras/Mitogen activated protein kinase pathway.
The mechanism behind the lowered phosphorylation of Tyr771 in the heterodimeric PDGF β-receptor was investigated. It was found that the SH2 domain-containing tyrosine phosphatase SHP-2 was responsible, at least in part, for the dephosphorylation of Tyr771 in the heterodimeric β-receptor.
PDGF-induced autophosphorylation of tyrosine residues in the receptors has been proposed to occur in trans between the receptor molecules in the dimers. We demonstrated by phosphopeptide mapping that all major autophosphorylation sites can be phosphorylated in trans, both in the PDGF α- and β-receptors. Analyses of the abilities of heterodimeric receptor complexes of one kinase-active and one kinase-inactive receptor to mediate mitogenicity, chemotaxis and activation of mitogen activated protein kinase revealed that the signaling capacities were retained. This illustrates a functional co-operation between the two receptor molecules in the dimer, where one receptor provides a functional kinase and the other acts as a substrate and provides docking sites for downstream signaling molecules.
Elucidating the mechanisms behind the unique signaling properties of the heterodimeric PDGF receptor complex, two heterodimer-specific autophosphorylation sites, Tyr692 and Tyr970, were identified and found to interact with the low molecular weight protein tyrosine phosphatase (LMW-PTP). Mutation of Tyr692 or Tyr970 to phenylalanine residues did not affect PDGF-induced mitogenicity, but the Tyr692 to phenylalanine mutation reduced the chemotactic response mediated by the heterodimeric PDGF receptor complex. A mechanism for the lowered chemotactic response was found to involve an increased RasGAP binding and a decreased SHP-2 binding to the heterodimeric β-receptor.
13
Nilsson, Ingrid. "Hypoxia, PDGF and VEGF in Vascular Development." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6894.
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Enarsson, Mia. "Roles of PDGF for Neural Stem Cells." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4245.
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Bahm, Isabel. "PDGF signalling during Neural Crest Cell migration." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10041758/.
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Neural crest cells are a transient cell population, which migrates through the vertebrate embryonic body, and eventually gives rise to a many different cell types in the adult. Contact inhibition of locomotion (CIL) is a fundamental property of the collective migrating neural crest cells. CIL describes a process by which colliding cells change their direction upon collision and move away from each other, which has been linked to cell dispersion, boundary formation and metastasis. CIL is acquired in neural crest cells during Epithelial-to-Mesenchymal-Transition (EMT), by a switch in the expression of cadherins, from E to N-cadherin. To examine what governs this change I study PDGF signalling during Xenopus laevis cranial neural crest migration. Here I show that PDGFRα and its ligand PDGF-A are expressed in pre-migratory and migrating cranial neural crest cells. Inhibition of PDGF-A/PDGFRα impairs neural crest migration in vivo and cell dispersion in vitro. I find that PDGFRα inhibition leads to a decrease of N-cadherin levels in neural crest cells. Further, I demonstrate that PDGFRα signalling controls N-cadherin dependent CIL. This cellular response is controlled by the PI3K/AKT signalling pathway as a downstream effector of the PDGFRα cellular response in cranial neural crest cells. This data lead me to propose a novel mechanism by which PDGF signalling as a tissue-autonomous regulator of EMT is regulating N-cadherin dependent CIL during cranial neural crest cell migration in Xenopus laevis.
16
Gillnäs, Sara. "PDGF-C signaling is required for normal cerebellar development : An analysis of cerebellar malformations in PDGF-C impaired mice." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-445240.
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Platelet-derived growth factor-C (PDGF-C) and its tyrosine kinase receptor PDGFRɑ have been shown to contribute to several key processes during central nervous system (CNS) development, including normal vascularization and formation of cerebral ventricles and basal membrane of the meninges. Due to redundancy between PDGF-C and PDGF-A, PDGF-C specific roles are sometimes masked and difficult to determine. Using the double mutant Pdgfc-/-;PdgfraGFP/+ mouse (Mus musculus) strain we were able to detect and examine a new, undescribed phenotype of PDGF-C impaired mice, namely cerebellar malformations. These mutant mice displayed an upwards rotation of the cerebellar vermis with a severe posterior vermis hypoplasia and an enlarged fourth ventricle, suggesting PDGF-C/PDGFRɑ signaling as a novel candidate to induce Dandy-Walker malformation (DWM). Due to suspected cerebellar vascular malformation a quantification of diameter, density and number of vessels were performed. A significant increase (P < 0.05) of the number and density of vascular bed in the cerebellar nuclei was detected, however the vessel diameter was not significantly different (P > 0.05) in Pdgfc-/-;PdgfraGFP/+ mice in comparison with the control. Through immunofluorescence staining we detected discontinuation of the ependyma in the acute angle of the ventricular zone adjacent to the rhombic lip, interfacing the fourth ventricle and cerebellar anlagen. We further noted ectopic expression of rhombic lip derived cells in the ventricular zone, suggesting a misguided migration due to ablation of PDGF-C. We conclude that PDGF-C is an essential player in normal cerebellar development.
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Sjöblom, Tobias. "Paracrine and autocrine functions of PDGF in malignant disease." Doctoral thesis, Uppsala University, Ludwig Institute for Cancer Research, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2678.
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Growth factors and their receptors are frequently activated by mutations in human cancer. Platelet-derived growth factor (PDGF)-B and its tyrosine kinase receptor, the PDGF β-receptor, have been implicated in autocrine transformation as well as paracrine stimulation of tumor growth. The availability of clinically useful antagonists motivates evaluation of PDGF inhibition in these diseases.
In chronic myelomonocytic leukemia with t(5;12), parts of the transcription factor TEL and the PDGF β-receptor are fused, generating a constitutively signaling protein. Oligomerization and unique phosphorylation pattern of TEL-PDGFβR was demonstrated, as well as the transforming activity of TEL-PDGFβR, which was sensitive to PDGF β-receptor kinase inhibition.
Dermatofibrosarcoma protuberans (DFSP) is characterized by a translocation involving the collagen Iα1 and PDGF B-chain genes. The COLIA1-PDGFB fusion protein was processed to mature PDGF-BB and transformed fibroblasts in culture. The PDGF antagonist STI571 inhibited growth of COLIA1-PDGFB transfected cells and primary DFSP cells in vitro and in vivo through induction of apoptosis.
Paracrine effects of PDGF-DD, a ligand for the PDGF β-receptor, were evaluated in a murine model of malignant melanoma. PDGF-DD production accelerated tumor growth and altered the vascular morphology in experimental melanomas.
A validated immunohistochemical procedure for PDGF β-receptor detection was established and applied to normal tissues and more than 280 tumor biopsies. Perivascular and stromal expression was detected in 90% and 50%, respectively, of human tumors.
Recently, non-transformed cells in the tumor microenvironment have emerged as targets in cancer therapy. Selective sensitization of tumor fibroblasts to paclitaxel by STI571 was evaluated in vitro and in a xenograft model. Whereas neither drug alone caused growth inhibition, combination of the two significantly reduced tumor growth, suggesting anti-stromal therapy as a possible treatment modality in solid tumors.
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Folestad, Erika Bergsten. "Studies of the novel PDGFs, focusing on PDGF-D /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-770-7/.
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Kumar, Hashethra. "Does PDGF-BB have a role in bone remodelling?" Thesis, St George's, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546797.
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Qin, Yong. "Targeting the Promoter Regions of PDGF Ligand and Receptor." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/194387.
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Aberrant expression of Platelet-derived growth factor A (PDGF-A) and PDGF receptor-β (PDGFR-β) play critical roles in the angiogenesis and proliferation of several malignancies. In this dissertation I explore the transcriptional regulatory role of the Gquadruplex- forming regions in the promoters of human PDGF-A and PDGFR-β, and identify new targets for developing small molecules to modulate their expression in tumors. For PDGF-A promoter, our studies focus on two essential nuclease hypersensitive elements, NHE(PDGF-A) and 5´-end far upstream 5´-SHS. The structural aspects of the intramolecular G-quadruplexes formed in NHE(PDGF-A) and the ligands to stabilize these secondary DNA structures have been investigated by using singlestranded and duplex DNA of the NHE(PDGF-A). We demonstrate that the G-quadruplexinteractive compound, TMPyP4, can selectively inhibit the basal promoter activity of PDGF-A, suggesting that the NHE(PDGF-A) G-quadruplex acts as a repressor in PDGF-A transcription. We also found that the 5´-SHS G-rich strand oligomer can invade the NHE(PDGF-A) and form a unique three-stranded complex in supercoiled plasmids, which is facilitated by potassium ions and TMPyP4. Therefore, we propose a novel molecular mechanism for transcriptional silencing of the NHE(PDGF-A) by 5´-SHS in the PDGF-A promoter, in that the formation of G-quadruplex in the NHE(PDGF-A) provides a platform for the G-rich strand of 5´-SHS to invade and form a partial duplex DNA with the C-rich strand of the NHE(PDGF-A), resulting in displacement of hnRNP K and thus transcription silencing. Prior to the studies describe here, the promoter of human PDGFR-β had not been identified. Herein, we have cloned and characterized the first functional promoter of human PDGFR-β gene. A crucial highly GC-rich region (NHE(PDGFR-β)) in the human PDGFR-β promoter has been identified by its hypersensitivity to the S1 nuclease. Further studies demonstrate that stable G-quadruplex structures can form in the G-rich strand of NHE(PDGFR-β). The G-quadruplex-interactive molecule, telomestatin, can selectively stabilize G-quadruplexes formed in the human PDGFR-β promoter and inhibit its expression in Daoy cells. On the basis of these results, we propose that ligandmediated stabilization of the G-quadruplex structure in the proximal promoter region of human PDGF-A or PDGFR-β can be used to modulate the expression of these protooncogenes.
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Alabud, Arwa. "Proteasomens roll för ligand inducerad fragmentation av PDGF-β receptorn." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-455265.
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Bakgrund: Platelet derived growth factor receptorn (PDGF receptorn) är en receptor i kroppen som tillhör typ III av Recetor tyrosine kinas (RTK) familjen. PDGF-β receptorn är en typ av dessa receptorer som enligt en studie klyvs i två delar efter ligandbindning med PDGF-BB ligand: till en extracellulär del och en intracellulär del. Hypotesen är att den extracellulära delen går till lysosomen medan den intracellulära delen går till proteasomen efter klyvningen. Syfte: Att undersöka rollen för proteasomen i ligandinducerad fragmentation av PDGF-β receptorn och se om det finns ko-lokalisation mellan receptorns extracellulära del och proteasomen. Dessutom ska det undersökas hur eventuell ko-lokalisering av PDGF receptorns extracellulära fragment med proteasomet påverkas när proteasomerna i cellerna inhiberas. Metod: Bj-hTERT celler stimulerades med PDGF-BB ligand under fyra olika stimuleringstidspunkter (0, 30, 60 och 90 min) och med hjälp av immunofluorescens undersöktes det om det fanns ko-lokalisering mellan proteasomen och PDGF-β receptorns extracellulära del. I ett annat experiment inhiberades även proteasomens aktivitet med inhibitoren MG132 och ko-lokalisationen mättes och jämfördes med kontrollceller behandlat med DMSO för de fyra stimuleringstidspunkterna. Resultat: För det första ko-lokalisationsexperimentet visades ingen större ko-lokalisering mellan proteasomen och receptorns extracellulära del för alla fyra tidspunkter. För det andra ko-lokalisationsexperimentet visades ingen skillnad i ko-lokalisationen mellan proteasomen och receptorns extracellulära fragment för cellerna vars proteasomaktivitet inhiberats och kontrollcellerna. Det visade sig däremot att proteasomen spelade roll för internaliseringen av receptorns extracellulära del in i cellen.
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Higa, Thaís Tiemi. "Imunolocalização de supressores (FOXO3a e PTEN) e ativadores (Akt e phospho-Akt) da transição de folículos primordiais e primários em tecido ovariano humano." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17145/tde-26042018-152648/.
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Mulheres com risco de falência ovariana prematura, assim como aquelas diagnosticadas com câncer que desejam preservar sua fertilidade, têm como opção a criopreservação do tecido ovariano. Esse tecido seria destinado, dependendo do caso, ao reimplante posterior ou para o cultivo in vitro de folículos ovarianos isolados do tecido criopreservado. Nesse contexto, os folículos primordiais são uma população importante tanto por serem mais resistentes ao processo de criopreservação, como por representarem cerca de 90% da população total folicular. Porém o uso destes folículos para procedimentos de Reprodução Assistida ainda é bastante limitado, pois os mecanismos responsáveis pelo seu processo de ativação ainda não são completamente conhecidos. A via de sinalização fosfatidilinositol 3- quinase (PI3K) foi recentemente identificada como determinante para o controle da ativação dos folículos primordiais. Portanto o objetivo deste estudo foi identificar e localizar os fatores componentes da via: supressores (FOXO3a e PTEN) e ativadores (Akt e Phospho-Akt). O que ofereceria uma valiosa ferramenta para elucidar os mecanismos envolvidos na ativação do pool de reserva folicular e permitiria o desenvolvimento de sistemas de cultivo folicular que atuassem diretamente nestes mecanismos. Sendo assim, foi realizado um estudo transversal com amostras de tecido ovariano humano, que foram submetidas à reação imunohistoquímica dos fatores previamente citados. Foram incluídas na casuística 40 pacientes, com idade média de 27,7 anos ± 7,26. Foi realizada uma análise comparativa da expressão dessas proteínas entre os folículos primordiais e primários. Foi encontrada diferença significativa para a proteína Akt, (p<0,05) em que os folículos primordiais (oócito e células da granulosa) manifestaram mais expressão da proteína Akt em comparação aos folículos primários. Também foi encontrada diferença significativa para a proteína phospho-Akt, porém apenas nas células da granulosa, em que houve maior expressão em folículos primordiais comparados aos primários. Enquanto ambos os estágios tiveram marcação negativa para o PTEN e FOXO3a na maioria dos folículos analisados. Sendo assim, neste estudo não foi possível identificar dentre as proteínas escolhidas uma que tivesse expressão claramente característica de uma ou de outra fase folicular, não sendo possível inferir que a atividade de qualquer uma das proteínas fosse estritamente ligada à ativação dos folículo primordiais.Women at risk of premature ovarian failure, as well as those diagnosed with cancer who wish to preserve their fertility, have, as option, the ovarian tissue cryopreservation. This tissue would be destined, depending on the case, to posterior reimplantation, or for the in vitro culture of ovarian follicles isolated from the cryopreserved tissue. In this context, primordial follicles are an important population of cells. As they are more resistant to the cryopreservation process and they represent about 90% of the whole follicular population. However, the use of these follicles for Assisted Reproduction procedures is still quite limited, since the mechanisms responsible for its activation process are not fully understood. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has recently been identified as determinant for the control of primordial follicle activation. Therefore, the aim of this study was to identify and localize the components of this pathway: suppressors (FOXO3a and PTEN) and activators (Akt and phospho-Akt). This would offer a valuable tool to elucidate the mechanisms involved in the activation of the follicular reserve pool and would allow the development of in vitro culture protocols that would act directly in these mechanisms. Thus, a cross-sectional study with samples of human ovarian tissue was performed. These samples were submitted to the immunohistochemical reaction of the previously mentioned factors. Forty patients were included in the study, with a mean age of 27.7 ± 7.26. A comparative analysis of the expression of these proteins was performed between primordial and primary follicles. A significant difference was found for the Akt protein (p<0.05) in which the primordial follicles (oocyte and granulosa cells) showed more Akt expression than primary follicles. Another significant difference was found for the phosphor-Akt protein, but only for the granulosa cells, where there was a greater expression in primordial follicles compared to the primary ones. While both stages were negatively stained for PTEN and FOXO3a in most of the follicles analyzed. Thus, in this study it was not possible to identify among the selected proteins one that had clearly characteristic expression of one or the other follicular phase, and it was not possible to infer that the activity of any of the proteins was strictly linked to the activation of the primordial follicles.
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Valdivia, Maria Alejandra Medina. "Efeitos do PDGF-BB na taxa de proliferação e na adesão de células derivadas da granulação óssea a fragmentos radiculares." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/25/25146/tde-11062018-185848/.
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O objetivo deste estudo foi investigar o papel do fator de crescimento derivado de plaquetas-BB (PDGF-BB) na concentração de 300ng/ml na taxa de proliferação e adesão de células derivadas da granulação óssea humana a fragmentos radiculares periodontalmente comprometidos. Na primeira etapa do estudo, foi estabelecida cultura primária de células da granulação óssea de dois pacientes adultos, sistemicamente saudáveis, não fumantes. Após a expansão celular, as células foram caracterizadas para determinação do fenótipo por meio de ensaios de viabilidade celular, MTT, ensaio de atividade de fosfatase alcalina, ensaio de mineralização e caracterização imunohistoquímica por meio de citometria de fluxo (segunda etapa). Na terceira etapa do estudo, os efeitos da adição de PDGF-BB recombinante humano na concentração de 300ng/ml na taxa de proliferação e adesão de células derivadas da granulação óssea a superfícies radiculares periodontalmente comprometidas foram investigados. A taxa de proliferação celular estimulada pelo PDGF-BB (grupo teste) ou pelo meio de cultura (grupo controle) foi investigada por meio de contagem de células viáveis nos frascos de cultura após 1, 3, 5 e 7 dias do cultivo celular. Foram obtidos 30 fragmentos dentários a partir de dentes extraídos por razões periodontais. Os fragmentos foram raspados com curetas Gracey e condicionados com solução em gel de EDTA a 24% durante 3 minutos, lavados com solução de soro fisiológico, secos e posicionados em placas de 24 poços. Foram incubadas sobre os fragmentos tratados 1x104 células GO por 24 horas, seguido por fixação e preparo para análise por microscopia eletrônica de varredura (MEV). O número de células aderidas sobre os fragmentos foi analisado nas fotomicrografias. O padrão de crescimento das células GO foi compatível com células ósseas, com modificação do padrão do crescimento com o aumento do número de passagens. Houve atividade de fosfatase alcalina em meio osteogênico e convencional, com pico máximo aos 7 dias e atividade de mineralização estimulada ou não por meio osteogênico, com pico máximo aos 21 dias. A análise por meio de citometria de fluxo demonstrou que as células GO não expressaram CD105 e CD166 na 14a passagem, indicando sua diferenciação celular avançada nesse período. A adição de rhPDGF-BB resultou em mudança na taxa de proliferação celular, observando-se pico máximo de crescimento aos 7 dias, com diferenças estatisticamente significantes (p < 0.005; ANOVA post hoc Tukey) em relação aos períodos de 1, 3 e 5 dias. O ensaio de MTT demonstrou maior viabilidade celular no período de 48 hs, comparativamente aos períodos de 24 e 72 horas, quando a densidade óptica celular diminuiu de forma significativa (p< 0.05; Friedmann pósteste Dunn). No ensaio de adesão celular, pode-se observar que a adição de rhPDGFBB aumentou significativamente o número de células aderidas aos fragmentos dentários (p< 0.05; teste t não pareado com correção Welch), com alteração da morfologia celular. Esses resultados sugerem que as células GO tem características compatíveis com linhagem de células osteoblásticas, de fenótipo mais diferenciado após a 12a passagem. A adição de rhPDGF-BB (300ng/ml) resulta em aumento da taxa de proliferação das células GO e do número de células aderidas a fragmentos radiculares, indicando que, nesta concentração, o fator de crescimento é citocompatível, favorecendo a proliferação e adesão celular.The goal of this study was to investigate the effects of recombinant human platelet derived growth factor (rhPDGF-BB) at the concentration of 300ng/ml in the proliferation and adhesion of human bone granulation cells to periodontally diseased root fragments. At the first stage of the study, the granulation tissue existent in healing sockets (21 days after its creation) was collected from two systemically healthy nonsmoking adults to the establishment of primary culture. The in vitro properties of bone granulation (BG) cell lineage were characterized by cell viability, MTT, alkaline phosphatase activity and mineralization assays. The effects of culture medium (control) and rhPGDF-BB 300ng/ml (test) in the proliferation and adhesion of BG cells were investigated. The rate of BG cells proliferation was investigated by the number of viable cells present at 1, 3, 5 and 7 days after platting. Thirty root fragments were obtained from teeth extracted for periodontal reasons. Root fragments were scaled and root planed, conditioned with EDTA 24% for 3 minutes, rinsed in saline solution, air-dryed and positioned in 24-well plates. Each fragment was seeded with 104 BG cells, fixated after 24 hours and prepared for analysis in SEM. The number of cells adhered to the fragments was analysed in photomicrographies. BG cells growth pattern was compatible with osteogenic cell lineage, showing modification with the increasing number of cell passage. GO cells expressed alkaline phosphatase activity in conventional and osteogenic culture medium, with maximum peak at 7 days, as well as mineralization activity stimulated or not by osteogenic or non-osteogenic culture medium, with maximum peak at 21 days. The analysis by flow cytometer showed that BG cells have not expressed CD105 and CD106 at the 14th passage, indicating its advanced cell differentiation. The addition of rhPDGF-BB resulted in modification of proliferation rate, with maximum peak observed at 7 days, significantly different from 1-, 3- and 5-day periods (p< 0.005; ANOVA post hoc Tukey). MTT assay showed greater cell viability after 48 hours than after 24 and 72 hours, when optical density has significantly diminished (p< 0.05; Friedmann post hoc Dunn). At cell adhesion assay, it could be observed that the adhesion of rhPDGF-BB has significantly increased the number of cells adhered to root fragments (p< 0.05; unpaired t test with Welchs correction), and alterations in cell morphology. These results suggest that BG cells present in vitro characteristics compatible with osteoblastic cell lineages, with a more differentiated phenotype after the 12th passage. The addition of rhPDGF-BB (300 ng/ml) results in increase of the rate of BG cell proliferation and in the number of cells adhered to root fragments, indicating that, at this concentration, the growth factor is compatible with BG cells and favors cells proliferation and adhesion.
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Watts, Susan Margaret. "Inhibition of neointima formation using the human saphenous vein organ culture model." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264064.
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Vaillant, Pierre. "La platelet-derived growth factor : son role dans la fibrose pulmonaire idiopathique." Nancy 1, 1989. http://www.theses.fr/1989NAN11118.
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Kłosowska-Wardęga, Agnieszka. "Combination Therapies Targeting PDGF and VEGF Signaling Pathways in Solid Tumors." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-119827.
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Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are independently involved in several cancer-associated mechanisms including autocrine stimulation of cancer cells, stimulation of tumor angiogenesis and regulation of interstitial fluid pressure (IFP). The scope of this thesis was to investigate the combinatory effect of anti-VEGF and anti-PDGF treatment on tumor angiogenesis and tumor IFP. Angiogenesis is a process of formation of blood vessels. Based on the tumors dependency on the blood vessels to supply them with oxygen and nutrients, several anti-angiogenic therapies have been tried and shown to have beneficial anti-tumor effects. More recently, anti-angiogenic treatment appeared to transiently “normalize” disorganized tumor vasculature and therefore to improve the uptake of cytotoxic agents. In the first study, treatment was performed on two tumor models that differ only with regard to the degree of maturation of the vasculature, reflected by different number of pericytes that are the target for anti-PDGF treatment in these tumors. The aim was to study the role of pericyte coverage in protecting endothelial cells from anti-VEGF therapies. In the pericyte-rich tumor model the combination treatment gave a more efficient anti-angiogenic effect. Interestingly, it was only a subset of pericytes that was sensitive for the treatment. In the second paper, the effect of anti-VEGF and anti-PDGF treatment on tumor IFP was measured. IFP is elevated in most solid tumors, which is linked to poor prognosis and higher recurrence rate. Additionally, this serves as a problem in ant-cancer therapies since it makes the uptake of cytotoxic agents inefficient. PDGF is known to actively regulate the IFP by regulating the contractile activity of fibroblasts, while VEGF regulates IFP primarily by affecting vessel leakiness. In the current study, combination of anti-VEGF and anti-PDGF therapies was shown to have an additive effect. However, the timing of administration of inhibitors appeared to be crucial. It was only short, but not long term combination treatment that further reduced IFP as compared to monotherapies. Surprisingly, the additive effect on IFP did not translate into an increased efficiency of chemotherapy when comparing combination treatment with monotherapies. The last paper is a follow up of the first study, where it was shown that combination of anti-VEGF and anti-PDGF treatment affect the tumor vasculature. Here we investigated if the anti-angiogenic effect improves treatment efficiency of a cytotoxic agent. There was a significant effect of the combination of anti-VEGF and anti-PDGF on Taxol treatment efficiency in this Taxol resistant tumor model. However, the mechanism for the treatment effect and the relative contribution of the targeted vasculature in the outcome of the therapy remains to be determined, since tumor cells were also sensitized for Taxol in vitro. In summary, we have shown that targeting of PDGF and VEGF signaling pathways simultaneously affect both vasculature and IFP to a higher extent than monotherapies.
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Zhang, Yiqun. "Interpretation of transient temperature data from Permanent Down-hole Gauges (PDGs)." Thesis, Heriot-Watt University, 2015. http://hdl.handle.net/10399/2908.
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With the installation of Permanent Down-hole Gauges (PDGs) during oil field development, a large volume of high resolution pressure, temperature and sometimes flow-rate data are available for real-time and continuous reservoir monitoring. In practice, interpretations of these data can optimize well performance, provide information about the reservoir and continuously calibrate the reservoir model. Although the wellbore is in a non-isothermal environment, heat transfer between the fluid in the wellbore and the formation is often ignored and temperature is usually assumed to be constant in the process of data interpretation, leading to misunderstanding of the pressure profile. Furthermore, the pressure transient analysis (PTA) often fails to determine accurate flow regimes, and may be erroneously applied in nonlinear reservoir-well systems. These problems motivated my detailed analysis of temperature data. In this thesis, firstly, a non-isothermal wellbore model that is capable of predicting the temperature, pressure, and flow-rate profiles under multi-rate and multiphase production scenarios is established. Then this numerical wellbore model is coupled with a reservoir model to reproduce the transient temperature behaviour at gauge locations. Secondly, a new workflow for integrating transient down-hole data processing is introduced. The relationship between temperature change and flow-rate change is interpreted and a new nonlinearity diagnostic function (A_Turc) is presented. Thirdly, new procedures of model-independent transient temperature analysis are performed, followed by diagnosing the wellbore storage regime, verifying the PTA interpretation results, and reconstructing the flow-rate history using transient temperature data. Several case studies are conducted to demonstrate how transient temperature analysis, along with the transient pressure analysis can greatly reduce the uncertainties in well testing interpretation. The applications of both synthetic datasets which are simulated by the fully coupled wellbore-reservoir model and real field datasets demonstrated that the temperature data can provide additional constraints for pressure analysis. Additionally, the reliability of the developed methods which reveal complementary reservoir information from transient temperature data has also been verified.
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Wang, Chun-Chao. "Systematic Analysis of Crosstalk in the PDGF Receptor Signal Transduction Network." NCSU, 2008. http://www.lib.ncsu.edu/theses/available/etd-08072008-162743/.
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Intracellular signal transduction is traditionally characterized in terms of pathways, comprised of serial activation processes. Although it is appreciated that canonical signaling pathways are simply dominant routes of regulation embedded in larger interaction networks, relatively little has been done to quantify pathway crosstalk in such networks. Through quantitative measurements that systematically canvas an array of stimulation and molecular perturbation conditions, together with computational modeling and analysis, we have elucidated crosstalk mechanisms in the platelet-derived growth factor (PDGF) receptor signaling network, in which phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways are prominently activated. We show that, while PI3K signaling is insulated from crosstalk, PI3K enhances Erk activation in multiple ways. Whereas simultaneously blocking Ras and PI3K abolishes PDGF-stimulated Erk phosphorylation, each pathway makes an independent contribution to Erk activation, and PI3K affects Ras activation as well. The magnitudes of these effects depend strongly on the stimulation conditions, subject to saturation effects in the respective pathways and negative feedback loops. Motivated by those dynamics, a kinetic model of the network was formulated and used to precisely quantify the relative contributions of PI3K-dependent and -independent modes of Ras/Erk activation.
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Pinto, Rodrigo Pozza. "Expressão imunoistoquímica do p16 e do PDGFR-beta no adenocarcinoma gástrico." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2005. http://hdl.handle.net/10183/11082.
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O adenocarcinoma de estômago foi a principal causa de morte por neoplasia maligna no mundo durante grande parte do século XX e atualmente é superado somente pelas neoplasias epiteliais malignas de pulmão. Cerca de 750.000 novos casos são diagnosticados anualmente. Apresenta grande variação geográfica, sendo suas maiores incidências encontradas no Japão, América do Sul, Europa Oriental e Oriente Médio. É duas vezes mais freqüente em homens do que em mulheres; é pouco comum antes dos 40 anos e atinge sua maior incidência por volta da sétima década de vida. No Brasil as estimativas para o ano de 2005 apontavam para aproximadamente 23 mil casos novos e 11 mil óbitos. O único tratamento potencialmente curativo é a ressecção completa, macro e microscópica, de toda neoplasia. Mesmo após gastrectomia curativa, a recidiva, regional ou à distância, pode ocorrer em 80% dos casos. Esforços para melhorar estes resultados têm se focalizado no desenvolvimento de terapias pré e pós-operatórias mais efetivas.O oncogene p16 é conhecido por estar implicado na patogênese de muitos tumores humanos e também na regulação do crescimento celular normal, juntamente com as ciclinas, os complexos tirosinoquinases e os fatores de crescimento e transformação tumoral, entre eles o TGF-alfa e beta e os fatores de crescimento derivados de plaquetas (PDGF) e seus receptores (PDGFR alfa e beta). A perda de expressão do p16 no adenocarcinoma gástrico tem sido amplamente estudada. O PDGFR tem sido encontrado ativado e mutado nos tumores gástricos estromais em que o c-KIT, o marcador mais comumente encontrado, está em sua forma selvagem. Os receptores PDGF atuam sobre células de origem estromal e não se expressam em células epiteliais em condições fisiológicas normais. . Isoladamente, o PGDF-beta e o seu receptor ainda não foram objetivamente estudados nem quanto à expressão nem quanto à resposta aos inibidores do crescimento celular no tecido gástrico tumoral quenão de origem estromal.O objetivo deste estudo foi determinar a expressão imunohistoquímica do p16 e do PDGFR-beta no adenocarcinoma gástrico. Foram avaliados no estudo 36 pacientes submetidos à cirurgia por adenocarcinoma de estômago entre os anos de 1998 e 2002 no Complexo Hospitalar Santa Casa de Porto Alegre. As variáveis estudadas foram idade, sexo, localização do tumor, tamanho do tumor, número de linfonodos ressecados, número de linfonodos metastáticos, tipo histológico, tipo de cirurgia e estadiamento patológico (TNM). Não foi detectada expressão do PDGFRbeta em nenhuma das lâminas estudas. O p16 apresentou expressão menor que 10% em 89% dos casos e menor que 1% em 78% dos casos. Não foi detectada correlação entre a perda de expressão do p16 e as variáveis estudadas.Gastric adenocarcinoma has been the main cause of cancer death during most of the twentieth century, now overcame by lung cancer. Annually 750,000 new cases are diagnosed. Great geographic variations are seen and highest incidences can be found in Japan, South America, Eastern Europe and Middle East. It is twice as frequent in men as in women, has o low incidence before the fourth decade with a peak incidence in the seventh decade. In Brazil 23,000 new cases and 11,000 deaths are estimated to 2005. Complete resection of all gross and microscopic disease is the only potentially curative treatment. However, disease recurs in 80% of patients even after curative resection. Efforts to improve these results concentrate on development of new pre and postoperative therapies. Oncogene p16 is implicated in pathogenesis of many human tumors and even in regulation of normal cellular growth, together with cycline, tyrosine kinasis and tumoral transforming and growth factors, like TGF-alpha and -beta and platelet derived growth factors (PDGF) ligands and receptors (alpha and beta). Loss of p16 has been exhaustively studied.PDGFR has been found activated and mutated on gastric stromal tumors where c-KIT, the most commonly marker found, is in wild type. PDGF receptors act over stromal origin cells and are not expressed in epithelial cells under normal physiologic conditions. PDGF-beta and its receptor have not been studied concerning expression and response to cellular growth inhibitors on non-stromal gastric tumors. The aim of this study has been detect immunohistochemistry expression of p16 and PDGFR-beta on gastric adenocarcinoma. Thirty six patients submitted to surgery for gastric adenocarcinoma among 1998-2002 years at Santa Casa de Porto Alegre Hospital have been studied. Variables investigated were: age, gender, tumor size and localization,number of ressected and metastatic nodes, histological type, surgical resection extension and pathological staging. No expression of PDGFR-beta has been detected on surgical specimens. Concerning to p16, loss of expression lower than 10% and 1% has been detected respectively on 89% and 79% of the specimens studied. There has been no correlation among p16 loss and the variables studied.
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Paré, Martin. "L’implication de SHP-1 en condition élevée de glucose inhibe la signalisation de l’insuline et du PDGF-BB dans les cellules musculaires lisses vasculaires hypoxiques." Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/9502.
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Résumé : Bien que l’hypoxie soit un puissant inducteur de l’angiogenèse, l’activation des facteurs de croissance est perturbée en hyperglycémie au niveau du pied et du cœur. Cette perturbation entraîne la perte de prolifération et de migration chez les cellules endothéliales, musculaires lisses vasculaires et péricytes empêchant la formation de nouveaux vaisseaux qui mènera à l’amputation des membres inférieurs chez les patients diabétiques. Une étude a démontré qu’une augmentation de la protéine tyrosine phosphatase Src homology-2 domain-containing phosphatase-1 (SHP-1) en condition hyperglycémique chez les péricytes entraînait l’inhibition de la signalisation du PDGF-BB, ce qui résultait en le développement d’une rétinopathie diabétique. Nous avons alors soulevé l’hypothèse que l’expression de SHP-1 dans les cellules musculaires lisses vasculaires affecte la prolifération et la migration cellulaire par l’inhibition de la signalisation de l’insuline et du PDGF-BB en condition diabétique. Nos expérimentations ont été effectuées principalement à l’aide d’une culture primaire de cellules musculaires lisses primaires provenant d’aortes bovines. Comparativement aux concentrations normales de glucose (NG : 5,6 mM), l’exposition à des concentrations élevées de glucose (HG : 25 mM) pendant 48 h a résulté en l’inhibition de la prolifération cellulaire par l’insuline et le PDGF-BB autant en normoxie (20% O2) qu’en hypoxie (24 dernières heures à 1% O2). Lors des essais de migration cellulaire, aucun effet de l’insuline n’a été observé alors que la migration par le PDGF-BB fut inhibée en HG autant en normoxie qu’en hypoxie. L’exposition en HG à mener à l’inhibition de la signalisation de la voie PI3K/Akt de l’insuline et du PDGF-BB en hypoxie. Aucune variation de l’expression de SHP-1 n’a été observée mais son activité phosphatase en hypoxie était fortement inhibée en NG contrairement en HG où on observait une augmentation de cette activité. Finalement, une association a été constatée entre SHP-1 et la sous-unité bêta du récepteur au PDGF. En conclusion, nous avons démontré que l’augmentation de l’activité phosphatase de SHP-1 en hypoxie cause l’inhibition des voies de l’insuline et du PDGF-BB réduisant les processus angiogéniques des cellules musculaires lisses vasculaires dans la maladie des artères périphériques.Abstract : Even though hypoxia is a strong angiogenic inducer, pro-angiogenic factor signaling pathways in peripheral limb and heart are altered by hyperglycemia. This disruption leads to loss of endothelial cells, vascular smooth muscle cells and pericytes proliferation and migration preventing new blood vessel formation which results in amputation of lower extremities in diabetic patients. A study has shown that increase expression of the protein tyrosine phosphatase Src homology-2 domain-containing phosphatase-1 (SHP-1) in hyperglycemic condition in pericytes caused PDGF-BB signaling inhibition resulting in the development of diabetic retinopathy. Our hypothesis is that SHP-1 expression in vascular smooth muscle cells inhibits cell proliferation and migration induced by insulin and PDGF-BB in diabetic condition. Our experiments were performed using primary culture of vascular smooth muscle cells (SMC) from bovine aortas. As compared to normal glucose concentrations (NG:5,6 mM), high glucose level (HG: 25 mM) exposure for 48h inhibited SMC proliferation induced by insulin and PDGF-BB in both normoxia (20% O2) or hypoxia (1% O2 for the last 24h). During cell migration assays, no effect of insulin was observed while PDGF-BB action of SMC migration was reduced in HG in both normal and low oxygen concentrations. HG exposure lead to inhibition of insulin- and PDGF-BB-stimulated PI3K/Akt signaling pathway in hypoxia. No variation of SHP-1 expression was observed in HG condition. However, SHP-1 phosphatase activity was elevated in HG condition during hypoxia as compared to NG concentrations. Finally, our data showed an association between SHP-1 and the PDGF receptor beta subunit. In conclusion, our results demonstrated that the increase of SHP-1 phosphatase activity in hyperglycemia and hypoxia environment caused inhibition of insulin and PDGF-BB signaling pathways reducing angiogenic processes in vascular smooth muscle cells contributing to peripheral arterial disease in diabetes.
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Vassilikioti, S. "Studies on antisense inhibition of PDGF #beta#-receptor expression in cultured cells." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319894.
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Shibuya, Hideyuki. "TNFα, PDGF and TGFβ synergistically induce synovial lining hyperplasia via inducible PI3Kδ." Kyoto University, 2015. http://hdl.handle.net/2433/199195.
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Karlsson, Susann. "T-Cell Protein Tyrosine Phosphatase, a Regulator of the PDGF Signaling Pathway." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107674.
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Keilhack, Nikolas [Verfasser]. "PDGF-BB fördert die Redifferenzierung in vitro expandierter humaner Gelenkchondrozyten / Nikolas Keilhack." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/1010798057/34.
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Aravapalli, Kiran. "The effect of triiodothyronine on the expression of PDGF-BB in fibroblasts." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12046.
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Thesis (M.A.)--Boston UniversityThe thyroid gland consists of two types of cells that develop from distinct tissues. The parafollicular C-cells are derived from neural crest tissue and produce calcitonin, while the follicular cells produce thyroid hormone and are derived from endodermal tissue; thyroid hormone is the focus of this study. In the follicular cells, iodide is eventually metabolized into T4 and T3, with T4 being the primary production. Deiodinase 2 processes T4 into T3 because T3 serves the greatest physiological function. Thyroid hormone is crucial in maintaining basal metabolic rate and has a major effect on many organs, so in order for the body to optimally operate, thyroid hormone must be produced and utilized in a proper manner. However, the role of thyroid hormone in wound healing has not been properly addressed. The main steps in wound healing involve migration, proliferation, remodeling, and angiogenesis. Fibroblasts play a key role in all of these steps and hence, were the cells of choice in this study. Platelet derived growth factor- BB is critical in wound healing because it is potent in causing both the proliferation and migration of fibroblasts. In this study, we dosed fibroblasts with different concentrations of thyroid hormone in an attempt to see if the expression of PDGF-BB increased in fibroblasts dosed with thyroid hormone. Fibroblasts were passed, dosed with T3, lysed, and western blots were run to see if the expression of PDGF-BB changed depending on the concentration of T3. Previous studies conducted on mice and guinea pigs showed that an application of topical thyroid hormone cream onto wounds resulted in quicker healing. The next step is to find the individual mechanisms and proteins that thyroid hormone affects, using western blots. The T3 concentrations utilized were 10-7 M and 10-8 M and a control was used that contained fibroblasts with no thyroid hormone. The western blot films clearly showed an increase in the expression of PDGF-BB with the 10-7 M and 10-8 M fibroblasts compared to the control group. Thus, thyroid hormone could affect the migration and proliferation steps of wound healing through the expression of PDGF-BB. Unfortunately, this expression did not appear to be dose-dependent since the samples with less thyroid hormone, 10-8 M, contained an equal or heavier band than the 10-7 M samples. Hence, more experiments need to be run with more concentrations in order to obtain statistically significant data.
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Venalis, Paulius. "Antifibrozinių priemonių paieška preklinikiniuose sisteminės sklerozės modeliuose." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20101001_150707-46435.
Full textAbstract:
Sisteminė sklerozė (SSc) – viena sunkiausių ir fatališkiausių autoimuninių sisteminių reumatinių ligų, o bazinių vaistų stygius, šiai ligai gydyti, itin didelis. Į onkologinę klinikinę praktiką įdiegtas tirozinkinazių inhibitorius – imatinibo mezilatas(IM). IM blokuoja TGF-β ir PDGF intraląstelinio signalo perdavimą ir taip sąlygoja fibrozės prevenciją SSc pelių modelyje. Mums buvo svarbu išsiaiškinti, ar imatinibas gali turėti įtakos ne tik prevencijai, bet ir susiformavusiai fibrozei. Be to TGF-β ir PDGF blokavimas angiogenezėje, galėtų riboti daug žadančio fibrozės inhibitoriaus IM naudojimą gydant SSc. Darbo tikslas: įvertinti imatinibo mezilato poveikį fibrozės procesui ir endoteliui sisteminės sklerozės eksperimentiniuose modeliuose ir ląstelių kultūrose. Darbo uždaviniai: įvertinti imatinibo efektyvumą neuždegiminiame SSc modelyje ir patikrinti imatinibo mezilato efektyvumą uždegiminiame suformuotos fibrozės modelyje; ištirti, ar terapinės imatinibo mezilato koncentracijos daro neigiamą poveikį gyvybinėms endotelio funkcijoms; įvertinti imatinibo mezilato poveikį angiogenezės etapams. Mūsų gauti duomenys rodo, kad: IM ne tik sustabdė bet ir paskatino jau egzistuojančios (bleomicino sukeltos) odos firbrozės regresiją; IM ryškiai sumažino poodžio ir odos storį, bei normalizavo miofibroblastų skaičių Tsk-1 pelėse; IM neturėjo poveikio endotelio ląstelių bazinėms funkcijoms; IM neturėjo neigiamo poveikio angiogenezės etapams.Systemic sclerosis (SSc) – is one of the most complicated and fatal systemic diseases, and the lack of effective therapy is very evident. The tyrosine kinase inhibitor imatinib mesylate (IM) was shown to inhibit TGF-β and PDGF signaling pathways and prevent the development of dermal fibrosis upon challenge with bleomycin in murine model of SSc. The aim of therapy is not only to stop disease progression, but even induce regression of preexisting fibrosis. On other hand, blocking TGF-β and PDGF signaling in angiogenesis might worsen the vascular manifestations of SSc. We found important to evaluate effectiveness of IM for the treatment of pre-established tissue fibrosis and to exclude that the anti-fibrotic effects of IM are complicated by inhibitory effects on endothelial cell functions. Aim of the study: assess the effect of IM on the process of fibrosis and endothelium in experimental models of systemic sclerosis and cell cultures. Objectives of the study: assess the effectiveness of IM on murine models of established fibrosis; evaluate if IM has an effect on basal functions of endothelial cells; assess effect of IM on the process of angiogenesis. We have shown that IM exerts potent antifibrotic effects in two different models of SSc. Imatinib was effective for prevention of fibrosis and for treatment of established dermal fibrosis. We’ve demonstrated that IM does not inhibit major functions of endothelial cells. Thus, IM might not augment further the preexisting vascular... [to full text]
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Venalis, Paulius. "The performance of antifibrotic agents in preclinical models of systemic sclerosis." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20101001_150819-57019.
Full textAbstract:
Systemic sclerosis (SSc) – is one of the most complicated and fatal systemic diseases, and the lack of effective therapy is very evident. The tyrosine kinase inhibitor imatinib mesylate (IM) was shown to inhibit TGF-β and PDGF signaling pathways and prevent the development of dermal fibrosis upon challenge with bleomycin in murine model of SSc. The aim of therapy is not only to stop disease progression, but even induce regression of preexisting fibrosis. On other hand, blocking TGF-β and PDGF signaling in angiogenesis might worsen the vascular manifestations of SSc.
We found important to evaluate effectiveness of IM for the treatment of pre-established tissue fibrosis and to exclude that the anti-fibrotic effects of IM are complicated by inhibitory effects on endothelial cell functions.
Aim of the study: assess the effect of IM on the process of fibrosis and endothelium in experimental models of systemic sclerosis and cell cultures.
Objectives of the study: assess the effectiveness of IM on murine models of established fibrosis; evaluate if IM has an effect on basal functions of endothelial cells; assess effect of IM on the process of angiogenesis.
We have shown that IM exerts potent antifibrotic effects in two different models of SSc. Imatinib was effective for prevention of fibrosis and for treatment of established dermal fibrosis. We’ve demonstrated that IM does not inhibit major functions of endothelial cells. Thus, IM might not augment further the preexisting vascular... [to full text]Sisteminė sklerozė (SSc) – viena sunkiausių ir fatališkiausių autoimuninių sisteminių reumatinių ligų, o bazinių vaistų stygius, šiai ligai gydyti, itin didelis. Į onkologinę klinikinę praktiką įdiegtas tirozinkinazių inhibitorius – imatinibo mezilatas(IM). IM blokuoja TGF-β ir PDGF intraląstelinio signalo perdavimą ir taip sąlygoja fibrozės prevenciją SSc pelių modelyje. Mums buvo svarbu išsiaiškinti, ar imatinibas gali turėti įtakos ne tik prevencijai, bet ir susiformavusiai fibrozei. Be to TGF-β ir PDGF blokavimas angiogenezėje, galėtų riboti daug žadančio fibrozės inhibitoriaus IM naudojimą gydant SSc. Darbo tikslas: įvertinti imatinibo mezilato poveikį fibrozės procesui ir endoteliui sisteminės sklerozės eksperimentiniuose modeliuose ir ląstelių kultūrose. Darbo uždaviniai: įvertinti imatinibo efektyvumą neuždegiminiame SSc modelyje ir patikrinti imatinibo mezilato efektyvumą uždegiminiame suformuotos fibrozės modelyje; ištirti, ar terapinės imatinibo mezilato koncentracijos daro neigiamą poveikį gyvybinėms endotelio funkcijoms; įvertinti imatinibo mezilato poveikį angiogenezės etapams. Mūsų gauti duomenys rodo, kad: IM ne tik sustabdė bet ir paskatino jau egzistuojančios (bleomicino sukeltos) odos firbrozės regresiją; IM ryškiai sumažino poodžio ir odos storį, bei normalizavo miofibroblastų skaičių Tsk-1 pelėse; IM neturėjo poveikio endotelio ląstelių bazinėms funkcijoms; IM neturėjo neigiamo poveikio angiogenezės etapams.
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Khouangvichit, Damdouane. "Socio-Economic Transformation and Gender Relations in Lao PDR." Doctoral thesis, Umeå universitet, Kulturgeografiska institutionen, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-33937.
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The aim of this study is to examine socio-economic transformation and gender relations in Lao PDR after the adoption of economic liberalization by the Lao government in the late 1980s. Against a background of general socio-economic transformation in Laos the main focus of the study is on the local level, with emphasis on how people in their everyday lives have engaged with and handled the changes. The application of economic liberalization shaped new conditions for people in local communities, and various livelihoods strategies were adopted under the new circumstances. The study examines gender relations, livelihoods and actors of change in two different contexts of globalization. The first context is the case of foreign direct investment in the Sepone mine, the largest gold-copper mine in the country located in Vilabury district, Savannakhet province. Five villages located close to the mine and directly affected by the operation were chosen as research site. The second case is the context of international tourism development in the small town of Vang Vieng, situated halfway between Vientiane Capital and the world heritage town of Luangprabang. The purpose with the two case studies is to examine how changes take place in different places of the same country under the same political direction and development policy. The study is inspired by theories of space and place and the view that phenomena are place-based and different places are constituted by different socio-spatial relations. The findings show that profound changes took place both in the economic and social-cultural spheres, including in gender relations. The two contexts experienced different processes of changes: in the context of Vilabury district, the transformation was produced through top-down development and created a dependency pattern where new social inequalities and social stratification emerged through unequal access to the new resources of the villagers. In the context of Vang Vieng and the expansion of international tourism, the development process proceeded more through a bottom-up pattern; the villagers perceived they were important actors of development, had more equal access to resources and could define livelihood strategies by themselves.
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Chounlamany, Kongsy, and Bounchanh Khounphilaphanh. "New methods of teaching? : refroming education in Lao PDR." Doctoral thesis, Umeå universitet, Pedagogiska institutionen, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-40938.
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This thesis is about the recent education reform in Laos as a global and a local process. When the economy was deteriorating in Lao People’s Democratic Republic (PDR), the so called New Economic Mechanism (NEM) was introduced and the country opened up for global donors and markets. This also had an effect on the education system. To get hold of financial support there were demands on Lao PDR to replace the previous strong centralised governing of education with more decentralised strategies. There were further demands to replace teacher-led lessons and rote learning with more student-centred classroom practices. The research questions asked in this thesis are: How are education reform and the new methods of teaching governed in policy and through the formal education organisations from ministry level to school level? How do teachers and students in teacher education respond to the education reform and the new methods of teaching? What attention is put to gender and ethnic minorities in these matters? The thesis is inspired by Gita Steiner-Khamsi’s global perspectives on education reform; consensus, conflict and culturalist perspectives. It is also based on a local understanding taking its starting point in a pragmatic approach and a mosaic epistemology and a qualitative inductive methodological approach. The empirical findings are based on 36 documents that govern the education reform, 119 individual interviews with teachers and students in social science and science at teacher education, some observations and a contextual analysis of education, gender and ethnicity in Laos. The findings show that there is a consensus with the international community about bringing education to all people in Lao PDR. However, the political understanding is in conflict between neoliberal and socialist traditions. Democratic centralism is the foundation which built the governing system in Laos; information flows up through the system and decisions down. Even though the system leaves 20 percent autonomy to teachers to develop local curricula in line with the new methods of teaching, there are yet no major signs that such curricula exist. Teacher educators and teacher students understand new methods of teaching mainly as group learning and individual learning with only small variations between the two subjects. According to current policy the goal is to improve access to education for females and ethnic minority students. The ethnic minority students regarded individual studies as difficult because of language problems. They preferred group learning because they could be supported in language issues. Females also felt supported in group learning. However, because of old gender traditions especially females from the dominating Lao Loum group also found individual learning supportive. In individual learning females got opportunities to show individual capacities without being constrained by societal norms. The thesis ends up in a pragmatic tradition where possibilities and constraints with the education reform in Lao PDR are commented on.
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Phommavong, Saithong. "International tourism development and poverty reduction in Lao PDR." Doctoral thesis, Umeå universitet, Kulturgeografiska institutionen, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-50070.
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Santos, Marco Aurélio dos, and 9292212626. "Localização em ambientes internos utilizando PDR e Wi-Fi." Universidade Federal do Amazonas, 2018. https://tede.ufam.edu.br/handle/tede/6517.
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Internal positioning systems allow the localization of people or certain objects indoors, as well as assist in navigation and orientation. Proposals for indoor location systems based on only one technology have achieved unsatisfactory performance in localization, mainly due to the limitations in relation to the conflicting characteristics present in these environments. This work aims at the development of a hybrid location system, integrating the PDR and Wi-Fi technologies, which aims to provide the location of a user in an internal environment, allowing the user to move around and visualize their current location through a representation on a map. The results were satisfactory, including the direct influence of factors such as: physical characteristics (height, body mass, size of the past), smartphone location, speed of the adopted march and adoption of constant movements.
Os sistemas de posicionamento internos permitem a localização de pessoas ou certos objetos em ambientes internos, assim como ajudam na navegação e orientação. As propostas de sistemas de localização para ambientes internos baseados em somente uma tecnologia tem alcançado desempenho insatisfatório na localização, principalmente, devido às limitações em relação às características conflitantes presentes nesses ambientes. Este trabalho tem como objetivo o desenvolvimento de um sistema híbrido de localização, integrando as tecnologias PDR e Wi-Fi, que visa fornecer a localização de um usuário em um ambiente interno, permitindo ao usuário locomover-se e visualizar a sua localização corrente através de uma representação em um mapa. Os resultados obtidos foram satisfatórios, constando-se a direta influência de fatores como: características físicas (altura, massa corporal, tamanho da passada) do usuário, localização do smartphone, velocidade da marcha adotada e adoção de movimentos constantes.
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Patcharanarumol, Walaiporn. "Health care financing for the poor in Lao PDR." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2008. http://researchonline.lshtm.ac.uk/4646530/.
Full textAbstract:
As in many other developing countries, an official policy of user fees was adopted for the Lao health system in the 1990s. In principle, the poor were to be exempted from paying user fees at public health providers. This study aimed to contribute to policy on financial protection of the poor by (1) improving understanding of health care utilization and strategies adopted by households to deal with costs of Illness; (2) examining attitudes of policy makers and actual practice of public health care providers on fee exemptions of the poor; and (3) proposing better ways of protecting the poor. Both quantitative and qualitative methods were employed. Data were collected from 172 households of 4 villages in Savannakhet Province; 26 public providers in Savannakhet Province and 3 public providers in Vientiane capital; and 22 policy makers in Vientiane capital, between October 2005 and July 2006. The exemption policy has been ineffectively implemented. In practice, criteria for identifying the poor were not specified and no budget was provided to hospitals to finance exemptions. Providers preserved exemptions for 'the destitute'. The payment of user fees could be delayed without interest when 'the poor' had insufficient cash. Villagers strongly believed in the principle of paying user fees to providers either at the point of service or through delayed payment, even though they lived In difficult conditions and their average consumption was below $US1.00 a day. Importantly, they did not perceive exemption from fees to be possible for 'the poor'. The majority of households did not access health care services when III for reasons such as financial and geographical barriers; some of them suffered adverse health consequences as a result such as death or disability. The better the socio-economic group, the better was access to health care services. Among a total of 172 sampled households, twelve households were faced with catastrophic health expenditure, most from the middle and poorest socio-economic group. The villagers managed health crises themselves mainly through drawing on social networks within the community in order to sell assets, borrow, and get other forms of support from neighbours. Although the study of households was small in scale, it was likely to echo households' difficulties elsewhere as the studied villages were similar to other rural areas without roads of Lao PDR. This study suggests that there is an urgent need for the government to improve two main areas: accessibility to adequate health care for everyone, everywhere; and reform of the nationwide policy on health financial risk protection for the poor and the less-poor in order to reduce catastrophic health expenditure.
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AGARBATI, SILVIA. "Generation of human PDGFRα-transgenic mouse: a novel experimental model of skin fibrosis." Doctoral thesis, Università Politecnica delle Marche, 2020. http://hdl.handle.net/11566/274545.
Full textAbstract:
ABSTRACT (Ita)
Introduzione: Il recettore del PDGFα (fattore di crescita derivato dalle piastrine) è un target della risposta autoimmune nella sclerosi sistemica (SSc). Sia le IgG totali purificate da siero (SSc-IgG) che gli anticorpi anti-PDGFRα clonati da cellule B della memoria di pazienti sclerodermici (SSc-Mabs) [Moroncini G. et al., A&R 2015] hanno mostrato la capacità di incrementare la trascrizione del gene del collagene in fibroblasti ottenuti dalla cute di donatori sani e di indurre fibrosi ex vivo, su cute trapiantata in topi SCID [Luchetti M. et al., A&R 2016]. Al fine di riprodurre questi risultati in vivo, abbiamo generato topi transgenici per il PDGFRα umano.
Materiali e Metodi: L’intera sequenza cDNA del PDGFRα umano è stata clonata nel locus ad espressione ubiquitaria Rosa26 a livello del cromosoma 6 murino ed inserita in cellule staminali embrionali (ES) prelevate da topi C57BL/6. I cloni cellulari geneticamente modificati sono stati selezionati per la microiniezione nella blastocisti, con successiva produzione di topi chimerici.
Topi eterozigoti C57BL/6 transgenici per il PDGFRα umano della generazione F2 sono stati utilizzati per stabilire la colonia. Topi maschi di dodici settimane sono stati inoculati a livello della cute del dorso, al giorno 0, 3, 6 e 9, con 0.02 mg/ml di SSc-Mabs (VHPAM-Vκ16F4 or VHPAM-Vκ13B8), o con 2 mg/ml di SSc-IgG o di IgG purificate dal siero di donatori sani (HD-IgG). Parallelamente sono stati inoculati topi controllo con la soluzione veicolo (PBS). Topi C57BL/6 wild type della stessa età e sesso sono stati usati come controlli. Tutti gli animali sono stati sacrificati al giorno 14. Nei tessuti di cute prelevati sono stati analizzati l’espressione del transgene PDGFRα umano e la quantità di collagene. Allo scopo di indurre fibrosi sistemica, sono state inoltre impiantate a livello della cute del dorso degli animali per 28 giorni minipompe osmotiche contenenti 200 μl di PBS come soluzione veicolo o di anticorpo monoclonale SSc-Mab VHPAM-Vκ16F4 (100 μg) o SSc-Mab VHPAM-Vλ16F4 (100 μg) o della miscela di SSc-Mabs VHPAM-Vκ16F4 e VHPAM-Vλ16F4 (50 μg + 50 μg). I topi sono stati sacrificati al giorno 28. Sui tessuti di cute e polmone prelevati sono stati valutati i livelli di collageno, i macrofagi a fenotipo M2 e la deposizione di actina del muscolo liscio (α-SMA).
Risultati: I topi transgenici sono risultati fenotipicamente normali, fertili e non hanno mostrato apparenti caratteristiche patologiche. L’espressione del PDGFRα umano sia come mRNA che come proteina è stata rilevata nella cute di tutti i topi transgenici. L’iniezione intradermica dell’anticorpo monoclonale umano stimolatorio SSc-Mab VHPAM-Vκ16F4 o di SSc-IgG ha determinato un ispessimento del derma ed una aumentata deposizione di collagene, mentre l’anticorpo monoclonale umano non stimolatorio SSc-Mab VHPAM-Vκ13B8 o le HD-IgG non hanno indotto alcuna significativa alterazione della cute rispetto al PBS. I topi C57BL/6 wild type non hanno mostrato alcun cambiamento significativo della cute con tutti gli anticorpi inoculati. La somministrazione continua a livello sottocutaneo dell’anticorpo monoclonale SSc-Mab VHPAM-Vκ16F4 o SSc-Mab VHPAM-Vλ16F4 o della miscela dei due ha determinato un ispessimento del derma ed una aumentata deposizione di collagene a livello della cute. Inoltre nel tessuto polmonare è stato evidenziato un aumento di collagene a livello perivascolare e peribronchiolare, con aree di infiammazione caratterizzate dalla presenza di macrofagi a fenotipo M2 e piccoli capillari con cellule endoteliali α-SMA positive.
Conclusioni: Abbiamo generato un nuovo modello murino umanizzato di fibrosi cutanea grazie alla concomitante espressione del PDGFRα umano e all’inoculo di anticorpi stimolatori anti-PDGFRα umano. Questo modello murino può essere utile per l’identificazione e la validazione preclinica di nuovi approcci terapeutici per la cura della sclerodermia.ABSTRACT (Eng) Background: Platelet Derived Growth Factor (PDGF) Receptor α (PDGFRα) is a target of the autoimmune response in scleroderma (SSc). Both total serum IgG (SSc-IgG) and anti-PDGFRα antibodies cloned from memory B cells of SSc patients (SSc-Mabs) [Moroncini G. et al., A&R 2015] demonstrated the ability to increase collagen gene transcription in healthy donor skin fibroblasts and to induce fibrosis ex vivo, in skin grafts in SCID mice [Luchetti M. et al., A&R 2016]. In order to replicate these findings in vivo, we generated human PDGFRα-transgenic mice. Materials and Methods: Full length human PDGFRα cDNA was knocked-in into the ubiquitously expressed Rosa26 locus on mouse chromosome 6. Correctly targeted C57BL/6 ES cell clones were selected for blastocyst microinjection, followed by chimera production. F2 heterozygous C57BL/6-hPDGFRα transgenic mice were used to establish the colony. Twelve weeks-old male mice were injected into the back skin at days 0, 3, 6 and 9, either with 0.02 mg/ml of SSc-Mabs (VHPAM-Vκ16F4 or VHPAM-Vκ13B8), or with 2 mg/ml of SSc-IgG or IgG purified from serum of healthy donors (HD-IgG). Vehicle only injection control was included. Age- and sex- matched C57BL/6 wild type mice were used as controls. Animals were sacrificed at day 14. Human PDGFRα transgene expression and collagen amount were assessed in explanted skin tissue. To induce systemic fibrosis, osmotic minipumps containing either 200 μl PBS as vehicle or SSc-MabVHPAM-Vκ16F4 (100 μg) or SSc-MabVHPAM-Vλ16F4 (100 μg) or a combination of SSc-Mabs VHPAM-Vκ16F4 and VHPAM-Vλ16F4 (50 μg + 50 μg) were implanted for 28 days on the back skin of animals. Mice were sacrificed at day 28. Collagen amount, M2 macrophages and alpha smooth muscle (α-SMA) deposition were assessed in explanted skin and lung tissue. Results: Transgenic mice were phenotypically normal, fertile, and did not display any apparent pathological features.Human PDGFRα mRNA and protein were detectable in the skin of all examined transgenic mice. Intradermal injection of stimulatory human SSc-Mab VHPAM-Vκ16F4 or SSc-IgG resulted in dermal thickening and increased collagen deposition, whereas non-stimulatory human SSc-Mab VHPAM-Vκ13B8 or HD-IgG did not induce any significant skin tissue alterations compared to vehicle control. C57BL/6 wild type mice did not show any significant skin tissue changes with any antibodies. Subcutaneous continuous administration of SSc-MabVHPAM-Vκ16F4 or SSc-MabVHPAM-Vλ16F4 or the combination of SSc-Mabs VHPAM-Vκ16F4 and VHPAM-Vλ16F4 resulted in dermal thickening and increased collagen deposition in skin tissue. Moreover perivascular and peribronchiolar increased collagen amount were detected in lung tissue, with some inflammatory areas characterized by M2 macrophages and α-SMA endothelial positive cells in small vessels. Conclusions: We generated a novel humanized mouse model of skin fibrosis based on the concomitant expression of human PDGFRα and injection of stimulatory anti-PDGFRα antibodies. This mouse model may be useful for identification and preclinical validation of new therapeutic strategies for SSc.
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Vora, Parvez Firoz. "Molecular regulation of myelination by Oligodendrocyte Progenitor cells." Experimental Neurology (Elsevier), 2010. http://hdl.handle.net/1993/8463.
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Oligodendrocytes (OL) are the myelinating cells of the central nervous system (CNS). A series of complex cell signaling events in the CNS ensures successful myelination. Various molecular cues including growth factors, transcription factors and cytokines regulate myelination by inducing OL migration, proliferation and differentiation. Plateletderived growth factor A (PDGF-A) and fibroblast growth factor 2 (FGF2) are two of the most well characterized regulators of OP migration. The current study hypothesizes that PDGF-A and FGF2 regulate the migration of OP through transient activation of the
extracellular signal-regulated protein kinase (ERK) signaling pathway. The results show that activation of ERK is required for OP migration. It also demonstrates the significance
of threshold levels of growth factors and temporal regulation for OP migration. Furthermore, the chemokine CXCL1 has been shown to play a critical role in regulating
the dispersal of OP during development, although the mechanisms underlying this regulation are unknown. Previous studies have shown that calcium flux is required for
OP migration. CXCL1 induces calcium flux in cells; therefore we hypothesized that CXCL1 inhibition of OP migration was regulated via changes in intracellular calcium
flux. However, our results show that CXCL1 inhibition of OP migration is independent of calcium signaling. In addition, we show that CXCL1 inhibition of OP migration is specific
to PDGF-A induced migration. Lastly, the current study identifies a transcriptional regulator, methyl-CpG-binding protein 2 (MeCP2) as regulating the expression of myelin
specific genes in a transgenic mouse. Interestingly, gene expression of myelin associated proteins myelin basic protein (MBP), myelin associated glycoprotein (MAG)and proteolipid protein (PLP), which play an important role in regulation of OL
differentiation and subsequent formation of myelin of the myelin sheath, where found to be dysregulated. Overall, these findings reveal previously unknown roles of various
intrinsic factors in successive phases of OL development. It aims to provide a better understanding of complexity to myelin development, function and disease.
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Zheng, Wei. "The LAR protein tyrosine phosphatase enables PDGF β-receptor activation and signal transduction." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4364/.
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Many cellular activities including cell survival, proliferation, migration and differentiation are controlled by growth factors and their corresponding tyrosine kinases receptor (RTKs). Growth factor receptor activation is strictly regulated by protein tyrosine phosphatases (PTPs). Here I investigated whether the receptor protein tyrosine phosphatase (RPTP) LAR, which is known to modify the activity of several RTKs, also regulates platelet derived growth factor (PDGF) receptor activity and signalling. Mouse embryonic fibroblasts (MEFs) expressing mutant LAR lacking its phosphatase domains (LARΔP) showed reduced phosphorylation of PDGFβ receptor (PDGFβR) compared with wild type (WT) cells. This was rescued by re-expression of WT LAR. The decreased phosphorylation of the PDGFβR was independent of ligand concentration and occurred on all tyrosine residues, suggesting that LAR is required for full PDGFβR kinase activation. The decreased kinase activity reduced the amplitude or duration of the different signalling pathways activated downstream of the PDGFβR, and resulted in reduced proliferation in response to PDGF-BB. These findings demonstrate, for the first time, that LAR activity is required for PDGF-induced fibroblast proliferation. The inhibition of PDGFβR kinase activity in LARΔP cells was exerted via increased basal activity of the tyrosine kinase c-Abl and its substrate protein kinase Cδ (PKCδ). Ligand-induced PDGFβR dimerization is defective in LARΔP cells, possibly due to the observed increase in the Nherf2 protein associating with the PDGFβR. In summary, I have identified LAR as a new regulator of PDGFβR activity, and propose a novel mechanism where PDGF-induced activation of c-Abl serves as a negative feedback loop to terminate the PDGFβR kinase activity. This may occur via PKCδ activation promoting the association of Nherf2 with PDGFβR, thereby reducing ligand-induced receptor dimerization and kinase activation. In this model, LAR promotes PDGFβR activity by inactivating c-Abl.
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Phouxay, Kabmanivanh. "Patterns of migration and socio-economic change in Lao PDR." Doctoral thesis, Umeå universitet, Kulturgeografiska institutionen, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-37321.
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The aim of the thesis is to investigate patterns and consequences of internal and international migration in Laos during the period 1985-2005 on both a macro-and a micro-level. The thesis focuses on the influences of socio-economic change and government policies on inter-regional and rural-urban migration as well as on crossborder migration from Laos to Thailand. The study also examines the effects of migration and industrial factory work on gender relations during economic transition and consequences of undocumented migration to Thailand. The background consists of a discussion on socio-economic change within the country and on government policies influencing migration patterns, as well as on how socio-economic change, urbanization and industrialization in the region affect internal and international migration in Laos. The thesis consists of three empirical studies which derive from different sources of data; the first is based on Population Censuses in 1995 and 2005 and the second and the third draw from empirical surveys in 2004-2005 and 2006. Paper I focuses on how socioeconomic factors and government policies influence migration patterns in Laos. The paper found that the interregional migration rate decreased in the later census period. This was due to significantly higher rural-rural migration in the earlier period, which in turn was influenced by various types of government policies. Papers II and III are based on micro surveys; paper II focuses on an urban industrial area in Vientiane Capital and explores the current feminization of rural-urban migrations during economic transition with specific focus on the effects of industrial work on gender roles and status of women as industrial workers. Industrial work was seen by the women as temporary jobs for saving money, for sending remittances, and for either returning home or moving to other jobs in Vientiane or Thailand. Paper III is based on surveys in three provinces, and deals with undocumented migration from Laos to Thailand and its consequences. Different income levels, existing social networks, similar language and socio-cultural backgrounds were determinants of cross-border migrations. The study found that migrants who had contacts with informal brokers were highly exposed to risks of human trafficking and violence.
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Bounyasone, Keophouthong, and Ngouay Keosada. "Cultivating educational research in Lao PDR : For a better future?" Doctoral thesis, Umeå universitet, Pedagogiska institutionen, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-42905.
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This thesis looks at the introduction of educational action research as part of the national education reforms in Lao PDR. National policies on education emphasise concepts such as ‘education for all’ and ‘student-centred education’ taken from the globalised education reform agenda. Action research became a tool to implement the new pedagogy of student-centred education that was labelled ‘the five-pointed star’. The thesis contributes to the field of global policy studies. It combines global and contextual aspects in order to analyse how action research travelled from policy to practice. This process was part of a Lao national education reform that developed after the introduction of the new economic mechanism, when the previous socialist planned-economy system was replaced by a globalised market-oriented system. Data were collected from national policy documents, international donor documents, instructional material, and interviews with Lao educators involved with action research in different ways. Furthermore, we carried out action research as part of our own teaching duties in Lao PDR, which were subsequently documented and analysed. In this study of educational reform in Lao PDR we have found that an educational approach like action research that is introduced as part of a taken-for-granted global agenda of change, is reduced to a technical rationality and practices that resemble previous experiences. Our findings are explained from the theoretical perspectives of hidden policy ensembles and policy backlashes. Hidden policy ensembles reduce action research to a technical rationality due to their alien cultural and social connections that are not brought into the open at the reform arena. Policy backlashes become a way for practitioners to create meaning based on previous contextual practices, conceptions, and discourses as a consequence of the technical rationality created by the hidden policy ensembles and the use of the cascade model. The thesis concludes with an outline of a possible future educational development in the form of a critical and educative action research network in Lao PDR that is inspired by cross-cultural dialogue, a critical pedagogy of place, and our own action research experiences.
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Burniston, Stephanie. "Mixed methods analysis of pig associated zoonoses in Lao PDR." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28811.
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Southeast Asia carries a large burden of endemic zoonotic diseases, in livestock and humans, especially in countries where livestock production is increasing among rural households for income generation and poverty reduction. This thesis explores the risk factors for transmission of pig-associated zoonoses – particularly Q fever, brucellosis, hepatitis E, and Japanese encephalitis – in northern Lao PDR, with a view to development of recommendations for “catch-all” control measures to impact on multiple diseases, improving biosecurity and preventing disease transmission to the human population. Research included (i) a qualitative assessment of the knowledge, attitudes, and practices of villagers related to pig-associated zoonoses and their risk factors using focus group methodology; (ii) an assessment of health seeking behaviour at hospital/health centre and village level to examine factors that influence choice of health care provider and determine the impact of health seeking behaviour on illness and treatment costs, and an examination of non-conventional health care sources to understand the complexity of health seeking behaviour and influences on choice of health care provider and, lastly, (iii) health care provider and service delivery assessments to determine healthcare facility routine service delivery procedures and assess capability in diagnosing and treating illness. In terms of disease, the most common illnesses reportedly seen by all those interviewed were respiratory illness, acute febrile illness and diarrhoea, confirming them as the leading causes of morbidity. Knowledge and awareness of the etiological agent of pig-associated zoonoses among villagers, patients, and health care providers was very poor for brucellosis and Q fever, with limited awareness of hepatitis E. Most were aware of Japanese encephalitis. Clinical diagnosis and symptomatic treatment of illness is the normal practice and identification of causative agents in human illness does not often occur. All three empirical assessments identified poor diagnostic capability as a major concern. Focus group discussions revealed that knowledge and awareness of disease risk factors, and of zoonoses in general, was low among villagers. Practices related to food consumption, latrine usage, hand hygiene and sanitation, which are known disease risk factors, were found to be a concern in study villages. Attitudes and practices adopted by villagers in relation to human and animal health and health seeking behaviours were strongly influenced by financial circumstances, access to appropriate healthcare facilities, spiritual beliefs, and a lack of knowledge and resources to maintain the health of both animals and humans. The first point of care when experiencing illness was often the health centre or a local traditional healer or spiritual healer or pharmacist/drug seller, depending on location. This was followed by the district hospital, if nearby. Many villagers described going back and forth between traditional medicine and modern medicine service providers, with 76% (19/25) of participants reportedly seeing more than one type of healthcare provider for a given episode of illness. Self-medication was the most common practice (84% of all participants) irrespective of the care provider consulted. Attendance at a healthcare facility was dependent on available funds and the perceived severity of illness. Overall household costs ranged between no cost, because of the “poor patient” policy that exempts vulnerable groups from paying for care, and $2500 USD for medical treatment, hospital stay, transportation and sometimes food. Healthcare workers at all facility levels (from health centre to provincial hospital) expressed a lack of confidence in making an accurate diagnosis for these pig associated zoonoses due to poor diagnostic capability in their respective facilities. A One Health approach to zoonotic disease surveillance that incorporates transdisciplinary methods and partnerships will lead to improved understanding of the underlining social determinants of health and their impact on health-seeking behaviours, disease transmission and ultimately disease reporting.
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Chaabeni, Sihem. "Les PDG français et leur rôle dans le gouvernement d'entreprise." Toulouse 1, 2003. http://www.theses.fr/2003TOU10063.
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En France, les débats actuels restent centrés sur la réalité du gouvernement d'entreprise (GE) ranimés par la passivité des organes de contrepouvoir. D'autre part, le capitalisme à la Française fortement imprégné de la personnalité publique ne peut qu'affecter l'origine des dirigeants sociaux. Le 1er chapitre est consacré au capitalisme à la française et à l'avènement de la révolution managériale en France. Le 2ème concerne une étude biographique des PDG français via leur origine sociale et leurs cursus. On pourrait ainsi juger de leur mode de recrutement et son adéquation avec le principe de la méritocratie. La durée des mandats est également abordée. Le 3ème chapitre est dédié à la question des rémunérations des dirigeants qui est au coeur des débats et des mécanismes incitatifs. Finalement, nous nous pencherons sur l'état et l'origine du débat sur le GE via l'analyse des conseils d'administration français, notamment du CAC 40 afin de conclure sur leur adéquation avec les principes de bonne gouvernance et les lois NRE promulguées en mai 2001In France, the current debates remain centered on the reality of the corporate governance (CG) revived by the passivity of the power control institutes. In the other hand, the omnipresence of the public personality in French capitalism, can only affect the origin of the managers. The first chapter deals with the French capitalism and with the incoming of the managerial revolution in France. The second chapter is dedicated to a biographical study of the French PDG through their social origin and their cursus. Hence, one could judge their mode of recruitment and its adequation with the principle of meritocraty. Their proxy duration is also treated. The third chapter is dedicated to the leaders remuneration question, which is in the heart of the incentive mechanisms. We finally examine the state and origin of the CG debates via the analysis of the French board directors, especially the CAC 40, and conclude concerning their adequation with the principles of CG and the NRE laws promulgated in May 2001
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Daosavanh, SANAMXAY. "Systematic Study of Flying Squirrels (Mammalia, Sciuridae) in Lao PDR." Kyoto University, 2020. http://hdl.handle.net/2433/252971.
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