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Heinrich, Marie-Christine [Verfasser]. "Die PSCA Expression ist mit günstigen Tumoreigenschaften und reduziertem PSA Rezidiv bei operiertem Prostatakarzinom assoziiert / Marie-Christine Heinrich." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/1221084798/34.
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Nguyen, Minh-Triet [Verfasser]. "PSCA als DNA-Vakzine zur Behandlung des duktalen Pankreaskarzinoms / Minh Triet Nguyen." Bonn : Universitäts- und Landesbibliothek Bonn, 2012. http://d-nb.info/104351094X/34.
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Günes, Serap. "MODIFICATION OF VESICULAR STOMATITIS VIRUS G PROTEIN FOR TARGETED GENE DELIVERY INTO PSCA-POSITIVE TUMOR CELLS." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2007. http://nbn-resolving.de/urn:nbn:de:swb:14-1182861723404-04537.
Повний текст джерелаАнотація:
Gene therapy is a promising treatment option for cancer. Ideally, a therapeutic gene is delivered specifically into tumor cells sparing the neighboring normal cells. For this purpose gene delivery vectors are designed that can recognize structures, which are exclusively expressed on tumor cells (i.e. the tumor-associated antigens -TAA-). Retroviral vectors are commonly used for gene therapy by modifying the envelope protein responsible for the recognition of the target cell. The Vesicular Stomatitis Virus G protein (VSV-G) is a well-liked choice for pseudotyping the retroviral vectors since it confers on the viral particle stability to allow concentration to high titers necessary for the clinical applications. However, the main drawback of VSV-G, the ubiquitously expressed receptor and thus the broad target range, hinders the use of this protein for targeted gene therapy. In this thesis, we aimed to modify the VSV-G for targeted gene therapy against Prostate Stem Cell Antigen (PSCA) -expressing tumors. Therefore we followed two approaches. The first approach comprised of the fusion of a single-chain antibody fragment against PSCA to the N-terminus of VSV-G. In the second approach the VSV-G was modified by insertion of a small epitope. We could demonstrate that two positions in the N-terminal region of VSV-G protein permit insertion of a ten amino acid long epitope. These mutant VSV-G proteins were successfully assembled into retroviral particles. We demonstrated that the mutant retroviral particles can be used for targeting to PSCA-positive cells using nanobeads. The nanobeads were chemically coupled to antibodies against the epitope in the VSV-G protein and PSCA on the tumor cell. These bispecific nanobeads allowed the recruitment of mutant retroviral particles to the PSCApositive cells. Our results point out the potential of these mutant retroviral particles in targeted gene delivery. Further studies will be necessary to assess the efficiency of in vivo targeted gene therapy using these mutant retroviral particles.
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Michen, Susanne. "Armierung von NK-Zellen mit den PSCA-spezifischen chimären Antigenrezeptoren NKp46-αPSCA und NKp46-KiBAP-αPSCA". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-160333.
Повний текст джерелаАнотація:
Bei den konventionellen Krebstherapien kommt es häufig zu einer Wiederkehr des Tumors, da meist einzelne Tumorzellen und abgesiedelte Metastasen im Körper verbleiben. Vor diesem Hintergrund hat die Entwicklung neuer Behandlungsmethoden, die spezifisch die Tumorzellen erkennen und eliminieren und zudem gesunde Körperzellen schonen, eine große Bedeutung in der heutigen Krebsforschung. Eine erfolgsversprechende Strategie ist die Generierung von tumorspezifischen, zytotoxischen Immuneffektorzellen, zum Beispiel T-Lymphozyten und Natürlichen Killerzellen, durch die genetische Modifikation mit einem chimären Antigenrezeptor (CAR). Dabei gibt es bereits weitreichende Studien mit T-Lymphozyten, so dass sich nun das Forschungsinteresse immer mehr auf die NK-Zellen richtet. Im Gegensatz zu CAR-armierten T-Lymphozyten sind sie in der Lage ihr antitumorales Potenzial nicht nur gegen Antigen-positive sondern auch MHC-Klasse I-negative Tumorzellen zu richten. Mögliche Zielstrukturen der CAR sind tumorassoziierte Antigene, wie das Prostata-spezifische Stammzellantigen (PSCA). Es wird auf über 94 % der humanen primären Prostatakarzinome und deren Knochenmetastasen verstärkt exprimiert, jedoch kaum auf Normalgewebe. PSCA ist somit ideal für eine Immuntherapie geeignet. Die bisher in Studien verwendeten CAR-armierten NK-Zellen wiesen eine feststehende Spezifität gegenüber einem bestimmten Tumorantigen auf. Allerdings ist die Expression von Tumorantigenen innerhalb des Tumors sehr heterogen oder wird durch Tumorevasionsmechanismen herunterreguliert. Dies begrenzt die Reaktivität CAR-armierter NK-Zellen. Durch die Generierung eines CAR, dessen Spezifität gegenüber einem Tumorantigen ausgetauscht werden kann, wäre der universelle Einsatz CAR-armierter NK-Zellen in der adjuvanten Immuntherapie von Tumorerkrankungen möglich.
Im Hauptteil dieser Arbeit wurden die permanente NK-Zelllinie YTS und primäre humane NK-Zellen mittels lentiviralen Gentransfers mit einem PSCA-spezifischen CAR, bestehend aus dem gegen PSCA gerichteten Einzelkettenantikörper αPSCA und dem aktivierenden NK-Zellrezeptor NKp46, armiert. Die generierten NK-Zellen wiesen eine über längere Zeiträume stabile Oberflächenexpression des CAR αPSCA-NKp46 auf. Die Kreuzvernetzung des CAR mit seinem Antigen führte zunächst zu keiner selektiven Immunantwort der CAR-armierten YTS und primären NK-Zellen gegenüber histogenetisch verschiedenen, PSCA-exprimierenden Tumorzelllinien. Erst nach gleichzeitiger Überexpression des mit NKp46 assoziierten Signaladaptermoleküls CD3-ζ wurde eine Aktivierung der Effektorfunktionen der YTS NK-Zellen induziert. Dies zeigte sich zum einen in der Expression von CD107a als Degranulationsmarker sowie der Freisetzung des inflammatorischen Zytokins IFN-γ. Zum anderen wiesen die CAR-armierten und CD3-ζ-exprimierenden YTS NK-Zellen eine spezifische Zytotoxizität gegenüber MHC-Klasse I- und PSCA-exprimierenden Tumorzellen auf. Im anschließenden Teil der Arbeit wurde ein modular aufgebauter CAR generiert, bei dem der Einzelkettenantikörper und folglich die Spezifität gegenüber Tumorantigenen austauschbar ist. Dazu wurden YTS NK-Zellen durch lentiviralen Gentransfer mit dem biotinylierbaren NKp46-NK-Zellrezeptor NKp46-KiBAP modifiziert, der über mehrere Monate stabil auf der Oberfläche exprimiert wurde. Die exogene als auch endogene Biotinylierung des Rezeptors wurde mittels einer Biotinproteinligase demonstriert. Unter Ausnutzung der sehr starken Biotin-Avidin-Bindung wurde die Assoziation mit einem Einzelkettenantikörper nachgewiesen. Dafür wurde exemplarisch der gegen PSCA gerichtete, biotinylierbare Einzelkettenantikörper αPSCA-BAP verwendet.
Diese Arbeit zeigt, dass eine spezifische Erkennung und effiziente Lyse von PSCA-exprimierenden Tumorzellen durch die generierten CAR-armierten NK-Zellen erfolgte, wobei zum ersten Mal NKp46 als Bestandteil eines CAR verwendet wurde. Zudem wurde ein modular aufgebauter CAR generiert, dessen Spezifität gegenüber Tumorantigenen austauschbar ist. Diese neuartige Strategie ermöglicht erstmalig eine flexible Armierung von NK-Zellen und stellt damit einen wesentlichen Vorteil bei der Behandlung verschiedener Krebserkrankungen dar.
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Günes, Serap. "Modifikation of vesicular stomatitis virus G protein for targeted gene delivery into PSCA-positive tumor cells." [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:swb:14-1182861723404-04537.
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CREMONESE, Giorgia. "Prostate Stem Cell Antigen (PSCA): a putative target for immunotherapy and diagnosis in prostate, pancreatic and bladder carcinoma." Doctoral thesis, Università degli Studi di Verona, 2010. http://hdl.handle.net/11562/342880.
Повний текст джерелаАнотація:
L’immunoterapia basata sull’utilizzo di anticorpi non coniugati, coniugati a tossine o radiomarcati, che riconoscono antigeni associati a tumore, è promettente per la cura di tumori solidi o ematici. Un possibile target per l’immunoterapia potrebbe essere il prostate stem cell antigen (PSCA), un antigene appartenente alla famiglia delle “GPIanchored protein”. Il PSCA è un antigene di superficie espresso a bassi livelli nel tessuto prostatico sano ed over espresso nel tumore prostatico, pancreatico e della vescica. L’espressione di PSCA è inoltre correlata positivamente a “Gleason score” e allo stadio della patologia nel tumore prostatico.
Il presente lavoro di tesi descrive la generazione e caratterizzazione di un anticorpo monoclonale murino anti PSCA (mAb), ottenuta tramite la tecnologia dell’ibridoma, e del suo frammento anticorpale a singola catena (scFv), generato clonando la regione variabile della catena leggera (VL) e della catena pesante (VH) nel vettore di espressione pHEN-2. Tramite citofluorimetria è stato dimostrato che l’anticorpo monoclinale possiede una buona affinità e specificità di legame all’antigene. Il potenziale diagnostico dell’anticorpo è stato dimostrato tramite Western Blot su lisati di tessuti neoplastici di prostrata e pancreas, in cui l’anticorpo è in grado di legare l’antigene denaturato e glicosilato, e tramite ELISA, in cui l’anticorpo si lega all’antigene espresso da cellule precedentemente fissate. Il potenziale terapeutico dell’anticorpo è stato valutato tramite saggio di proliferazione: l’anticorpo da solo non è in grado di indurre morte cellulare tramite un meccanismo diretto, mentre in seguito a coniugazione chimica con la catena A della ricina (RTA) rivela effetto citotossico su cellule PC-3 hPSCA con IC50 (concentrazione in grado di inibire la massima proliferazione cellulare del 50%) pari a 1.3x10-9, valore 100 volte più piccolo di quello ottenuto con la sola tossina RTA.
Il frammento scFv è stato prodotto nel ceppo batterico E. Coli. Mediante analisi citofluorimetrica su cellule PSCA positive e saggio immunoenzimatico sull’antigene ricombinante è stato verificato che il frammento anticorpale mantiene le stesse caratteristiche di specificità di legame all’antigene dell’anticorpo monoclinale parentale, ma possiede affinità minore. Quando l’ scFv viene reso bivalente, tramite il cross-linking dei monomeri utilizzando un anticorpo anti-myc, l’affinità raggiunge quasi quella dell’anticorpo parentale.
Successivamente l’scFv è stato unito attraverso fusione genetica al dominio enzimatico della tossina batterica Pseudomonas aeruginosa exotoxin A (PE40). L’immunotossina risultante è espressa nel ceppo batterico E. Coli e si accumula nei corpi d’inclusione. L’analisi citofluorimetrica su cellule PSCA positive fatta utilizzando i corpi d’inclusione rinaturati e contenenti l’immunotossina di fusione ha confermato che l’interazione tra l’scFv e l’antigene viene conservata in seguito alla fusione con la tossina PE40.
L’effetto citotossico dell’immunotossina purificata scFv-PE40 verrà valutata prima in vitro su linee cellulari PSCA positive e negative e poi in modelli in vivo che permetteranno di valutare anche eventuali effetti collaterali.Antibody-based therapy using unconjugated, toxin-conjugated or radiolabeled immunoglobulins recognizing tumor-associated antigens has proven beneficial for solid and hematolymphoid neoplasms. A suitable target could be prostate stem cell antigen (PSCA), a member of the “GPI-anchored protein”. PSCA is a cell surface-antigen expressed at low levels in normal prostate tissue and over expressed in prostate, pancreatic and bladder carcinomas. Moreover PSCA expression is positively correlated with Gleason score and with pathologic stage in prostate cancer. The present thesis describes the generation and characterization of the murine anti PSCA monoclonal antibody (mAb), obtained by hybridoma technology, and its fragment single chain (scFv), generated by cloning the variable heavy (VH) and light (VL) chain sequences in the expression vector pHEN-2. The mAb showed the ability to recognize with good affinity and specificity the native PSCA by flow cytometry. The diagnostic potential of the mAb was demonstrated by Western Blot performed with prostate and pancreatic neoplastic tissue lysates, showing the binding to denaturated and glycosylated PSCA, and by ELISA performed with fixed cells. The mAb was also assessed for its possible use in the therapeutic approach: the cell-proliferation assay demonstrated that the antibody alone is not able to induce cell death through a direct mechanism, while when it is conjugated to the ricin A chain toxin (RTA) by chemical linkage it can poison PC-3 hPSCA cells with an IC50 (i.e. concentration inhibiting 50% of the maximal cell proliferation) of 1.3x10-9 M, value 100 fold lower than the IC50 of the RTA toxin alone. The scFv was produced in E. Coli bacteria; flow cytometric analysis on PSCA-positive cells and immunoenzymatic assay on the recombinant antigen proved that the antibody fragment maintains the binding specificity of the parental monoclonal antibody. The affinity of the scFv is lower than the affinity of mAb but it is partially recovered making the scFv divalent by cross-linking the scFv monomers via an antibody-mediated myc- Tag interaction. To create a fusion immunotoxin (IT) the scFv was later genetically fused to the enzymatic domain of Pseudomonas aeruginosa exotoxin A (PE40). The resulting IT was expressed in E. Coli bacteria and it is accumulated in the inclusion bodies. The flow cytometric analysis on PSCA-positive cells performed with the whole refolded inclusion bodies extract containing the fusion IT confirmed that the interaction of scFv with the PSCA is preserved after fusion to PE40. The efficacy of purified scFv-PE40 will be analyse in vitro on positive and negative cell lines and subsequently in vivo models which also will be useful to study the side effects of this new drug.
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Leyton, Victor Jeffrey. "Engineered antibody fragments for the targeting and imaging of prostate stem cell antigen (PSCA)- expressing xenografts in vivo by microPET." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1624118821&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Quinaud, Manuelle. "Étude structurale et fonctionnelle de PscE : PscF : PscG? un hétérotimère nécessaire à la biogenèse de l'aiguille de sécretion de type III de Pseudomonas aeruginosa." Grenoble 1, 2007. http://www.theses.fr/2007GRE10138.
Повний текст джерелаАнотація:
Le système de sécrétion de type III est présent chez plusieurs pathogènes à Gram négatif chez qui cette véritable nanomachine est impliquée dans le transport de molécules de virulence directement des bactéries vers le cytoplasme des cellulescible. Ce système de sécrétion est composé d'une base ancrée dans la membrane bactérienne et d'une structure creuse en forme d'aiguille qui pointe vers l'extérieur de la bactérie. Pseudomonas aeruginosa, bactérie dont l'aiguille de sécrétion de type III est étudiée dans cette thèse, est responsable de nombreuses maladies nosocomiales ainsi que d'infections chez les patients atteints de mucoviscidose. Dans le cytoplasme bactérien, la protéine PscF qui forme l'aiguille de type III chez P. Aeruginosa est stabilisée avant sa sécrétion par 2 chaperonnes distinctes; PscE et PscG. Ceci est nécessaire à la fonctionnalité du système de sécrétion de type III. La structure cristallographique à 2. 0 A de résolution du complexe hétérotrimérique PscE:PscF55-85_PscG révèle que le domaine C-terminal de la protéine de l'aiguille B PscF, impliqué dans le processus de polymérisation, est enfoui dans une cavité hydrophobe de la protéine PscG. La rupture des interactions spécifiques entre PscG et PscF entraîne une forte baisse de la cytotoxicité de la bactérie envers une lignée de macrophages, ce qui indique que cet hétérotrimère essentiel, qui possède des homologues chez une grande variété de pathogènes, est une cible thérapeutique attractive pour le développement de nouveaux médicamentsType III secretion systems are found in several Gram-negative bacteria. These nanomachines are involved in the transport of virulence effectors directly into the cytoplasm of Target cells. Pseudomonas aeruginosa, whose type III secretion needle is studied here, is the causative agent of a large number of nosocomial and chronic infections in cystic fibrosis patients. This system is composed of a base anchored in the double bacterial membrane and a hollow needle formed by a single polymerized protein (PscF in Pseudomonas aeruginosa). Within the bacterial cytoplasm, PscF requires two distinct chaperones for stabilisation before its secretion, without which the entire system is nonfunctionnal. The 2. 0 A X-ray crystal structure orthe PscE:PscF55-85 :PscG ternary complex reveals that the C-terminus of the needle protein PscF, which is essential for needle polymerisation, is engulfed within the hydrophobic groove of the TPR-like molecule PscG. This indicates that the macromolecular scaffold necessary to stabilize the needle protein is totally distinct from T chaperoned complexes between pilus- or flagellum- forming molecules. Disruption of specific PscG:PscF interactions leads to impairement of bacterial cytotoxicity toward macrophages, indicating that This essential heterotrimer, which possesses homologs in a wide variety of pathogens, is an attractive therapeutic Target for the development of novel drugs
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Michen, Susanne [Verfasser], Hanns Achim [Akademischer Betreuer] Temme та Gerold [Akademischer Betreuer] Barth. "Armierung von NK-Zellen mit den PSCA-spezifischen chimären Antigenrezeptoren NKp46-αPSCA und NKp46-KiBAP-αPSCA / Susanne Michen. Gutachter: Hanns Achim Temme ; Gerold Barth. Betreuer: Hanns Achim Temme". Dresden : Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://d-nb.info/1069093149/34.
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Morgenroth, Agnieszka. "Herstellung chimärer Rezeptoren zur tumorspezifischen Armierung polyklonaler, zytotoxischer T-Lymphozyten." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2005. http://nbn-resolving.de/urn:nbn:de:swb:14-1134590060614-48883.
Повний текст джерелаАнотація:
Die Effizienz einer Tumortherapie durch einen Transfer von ex vivo aktivierten Tumor-spezifischen zytotoxischen T-Lymphozyten wird durch zahlreiche Faktoren wie geringe Anzahl der isolierten spezifischen T-Zellen, schnelles Abklingen der Aktivität und kurzzeitige Persistenz der transferierten Effektorzellen im Empfängerorganismus stark limitiert. Eine Möglichkeit zur Überwindung dieser Einschränkungen bietet die Entwicklung einer neuen Strategie zur Armierung der zytotoxischen T-Lymphozyten mit Tumor-spezifischen chimären Rezeptoren. Ziel dieser Arbeit war es, die Grundlagen für eine solche immuntherapeutische Strategie zu erarbeiten. Da das Prostatakarzinom die am meisten diagnostizierte maligne Erkrankung und die dritt häufigste Todesursache des Mannes ist, wurde das auf der Oberfläche von Prostatakarzinomzellen exprimierte PSCA (prostataspezifisches Stammzellantigen) als Zielantigen gewählt. Neben der therapierefraktären Spätstadien des Prostatakarzinoms bedürfen die früh entstehenden Mikrometastasen (minimale Resterkrankung) einer neuen adjuvanten Behandlungsoption. Das PSCA ist ein membranständiges Tumor-assoziiertes Antigen, das in mehr als 80 % der primären Prostatakarzinome überexprimiert wird. PSCA wird als besonders aussichtsreiches Zielantigen einer Immuntherapie bei fortgeschrittenen Prostatakarzinomen angesehen, weil sein Expressionsniveau mit der Tumorprogression und der Entwicklung zum androgenunabhängigen Wachstum ansteigt. In der vorgelegten Arbeit wurde zunächst ein neuer monoklonaler PSCA-spezifischer Antikörper generiert, der als Grundlage für die Konstruktion eines Einzelkettenantikörpers (scFv) verwendet wurde. Aus einem Hybridomklon, der sich durch sehr hohe Bindungsstärke auszeichnete, wurden mittels degenerierter Primer die kodierenden Sequenzen für die variablen VH und VL Domänen des Antikörpers amplifiziert. Durch die Verbindung der beiden VH und VL Domänen mittels eines Linkers wurde der PSCA-spezifische Einzelkettenantikörper generiert. Die mit gereinigtem scFv durchgeführten Bindungsanalysen bestätigten die Funktionalität des rekombinanten Proteins und seine Anwendbarkeit zur Chimerisierung eines membranständigen Rezeptors. Nach dem ?Zwei-Signal-Modell? benötigen T-Zellen für eine effiziente Antigen-spezifische Aktivierung neben dem T-Zell-Rezeptorsignal ein zusätzliches kostimulatorisches Signal. Daher wurden chimäre Rezeptoren auf der Basis der Beta-Kette des T-Zell-Rezeptors und des CD28-Moleküls generiert. Bei der Konstruktion des chimären T-Zell-Rezeptors wurde die konstante Domäne der Beta-Kette mit der CD3 -Kette fusioniert. Neben einer starken Oberflächenexpression des Rezeptors wurde auch die effiziente Bindung von löslichem PSCA nachgewiesen. Die Bindung des Rezeptors an das PSCA führte zur Phosphorylierung der ITAM-Sequenzen der heterodimeren -Kette, was die Funktionalität des chimären Rezeptors bestätigte. Die Stimulation der Zellen über den anti-CD3 Antikörper resultierte ebenfalls in der Phosphorylierung der heterodimeren -Kette, was ein Hinweis auf eine mögliche Interaktion der chimären Kette mit dem endogenen CD3-Komplex lieferte. Um die kostimulatorische Wirkung über das selbe Antigen zu erzielen, wurde das CD28 Molekül N-terminal ebenfalls mit dem Einzelkettenantikörper modifiziert. Die durch Bindung des löslichen Proteins induzierte Phosphorylierung der Akt-Kinase bewies die Funktionalität der chimären CD28 Kette als PSCA-spezifischer Rezeptor. Diese Arbeit demonstriert die Generierung eines hochaffinen PSCA-spezifischen Einzelkettenantikörpers als eine Antigen-erkennende Struktur eines chimären Rezeptors. Die Armierung polyklonaler zytotoxischer T-Lymphozyten mit den funktionsfähigen chimären Rezeptoren stellt den ersten Schritt einer neuen Strategie zur Eliminierung hormon-refrektärer und metastasierender Prostatakarzinomzellen dar.
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Arêas, Ana Paula de Mattos. "Estudo do efeito adjuvante de CTB em fusões com as proteínas pneumocócicas PsaA e PspA no desenvolvimento de vacinas protéicas contra Streptococcus pneumoniae." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-16092007-181850/.
Повний текст джерелаАнотація:
A colonização da mucosa respiratória é a primeira etapa na patogênese de Streptococcus pneumoniae, bactéria causadora de pneumonia, meningite, e otite média, responsável por mais de um milhão de mortes por ano no mundo. As proteínas de superfície PsaA e PspA têm sido investigadas como candidatos vacinais para estas doenças. CTB é a porção não tóxica da toxina colérica (CT), responsável pela ligação da toxina ao receptor celular GM1 e descrita como adjuvante de mucosas. Neste trabalho, estes genes de S. pneumoniae foram clonados em pAE, um vetor de expressão de E. coli, que utiliza o promotor T7, ou a 3\' de ctxB no plasmídeo pAE-ctxB. As proteínas recombinantes CTB, PsaA, CTB-PsaA, PspA1, CTB-PspA1, PspA3 e CTB-PspA3 foram expressas em E. coli BL21 (SI) e purificadas através de coluna carregada com níquel. Ensaios de ligação ao receptor GM1 mostraram que CTB e a porção CTB das proteínas de fusão foram obtidas na forma funcional. Imunização por via intranasal com CTB-PsaA e, por via intranasal e intradérmica com CTB-PspA1 e CTB-PspA3 induziu a produção de IgG no soro. Em compensação, somente a imunização com a fusão CTB-PsaA induziu produção de IgA nas secreções de mucosa. Ensaios de colonização da nasofaringe de camundongos BALB/C e C57BL/6 mostraram que a imunização intranasal com CTB-PsaA resulta em diminuição de colonização por S. pneumoniae. Desafios letais com linhagem virulenta de S. pneumoniae mostraram que a imunização intradérmica com CTB-PspA3, ao contrário da imunização intranasal, é capaz de proteger os animais. Uma vez que estas proteínas de fusão induziram resposta imune protetora, estas deverão ser investigadas como componentes de uma nova vacina para infecções causadas por S. pneumoniae.The colonization of the respiratory mucosa is the first step in the pathogenesis of Streptococcus pneumoniae, bacterium that causes pneumonia, meningitis and otitis media. It is responsible for more than one million deaths per year worldwide. The surface proteins PsaA and PspA have been investigated as vaccine candidates against these diseases. CTB is the non-toxic portion of cholera toxin (CT), responsible for the toxin binding to the cellular receptor GM1 and described as mucosal adjuvant. In this study, these genes from S. pneumoniae were cloned in pAE, an E. coli expression vector that uses T7 promoter, or downstream to ctxB gene in the pAE-ctxB plasmid. The recombinant proteins CTB, PsaA, CTB-PsaA, PspA1, CTB-PspA1, PspA3 and CTB-PspA3 were expressed in E. coli BL21 (SI) and purified through a chelating resin charged with nickel. GM1 binding assays showed that CTB and CTB portion of the fusion proteins were functional. Intranasal immunization with CTB-PsaA and, intranasal and intradermal administration of CTB-PspA1 and CTB-PspA3 induced IgG production in the serum. On the other hand, only CTB-PsaA fusion protein induced IgA in the mucosal secretions. Nasopharyngeal colonization assays in BALB/C and C57BL/6 mice showed that intranasal immunization with CTB-PsaA results in a decrease of colonization by S. pneumoniae. Lethal challenges with S. pneumoniae virulent strains indicated that intradermal immunization with CTB-PspA3, in contrast to the intranasal immunization, is able to protect mice. Since the fusion proteins induced a specific immune response, they should be further investigated as components of a new vaccine against infections caused by S. pneumoniae.
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Silva, Marcelo da. "Clonagem, expressão e purificação das proteínas de superfície, PsaA e fragmentos de PspA de Streptococcus pneumoniae." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-27102005-163558/.
Повний текст джерелаАнотація:
Streptococcus pneumoniae é o principal causador da pneumonia bacteriana. As vacinas atualmente disponíveis contêm polissacarídeo capsular conjugado ou não com proteínas carreadoras. No entanto, elas apresentam elevado custo ou proteção reduzida nos grupos de risco (crianças abaixo de 5 anos de idade e idosos). Proteínas de superfície de S. pneumoniae, como a PsaA e PspA, são consideradas fortes candidatas vacinais. Com o objetivo de se desenvolver uma vacina de ampla cobertura e baixo custo contra pneumococos, os genes psaA e pspA foram clonados em vetores de expressão em E. coli, pAE e pET e as proteínas expressas foram purificadas por cromatografias de afinidade e de troca aniônica. O rendimento de proteína recombinante obtido com a construção baseada em pET foi 3 vezes maior que o obtido com pAE. Condições de cultivo foram estabelecidas utilizando meio definido com indução por IPTG e/ou por lactose. As cepas recombinantes estão adequadas para serem usadas em estudos para escalonamento da produção em biorreatores.Streptococcus pneumoniae is the main causative agent of bacterial pneumonia. The current vaccines available contain capsular polysaccharide conjugated or not with carrier proteins. However these are either too expensive or do not protect the high-risk groups. Surface proteins of S. pneumoniae, such as PsaA and PspA, are considered strong vaccine candidates. With the aim of developing a broad-coverage and low-cost vaccine against pneumococcus, the psaA and pspA genes were cloned in E. coli expression vectors, pAE and pET and the expressed proteins were purified through affinity and anion exchange chromatography. The yield of the recombinant protein obtained with the construction based in pET was 3-fold higher than that obtained with pAE. Culture conditions were established using defined media with IPTG and/or lactose induction. The recombinant strains are now ready to undergo studies for scale-up of production in bioreactors.
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Ceci, Francesco <1983>. "Prediction Nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for Prostate Cancer." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2020. http://amsdottorato.unibo.it/9186/1/PhD%20Thesis_PSMA_DEF_Only%20Thesis.pdf.
Повний текст джерелаАнотація:
Objective The objective of this study was to develop a clinical nomogram to predict gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11-PET/CT) positivity in different clinical settings of PSA failure.
Materials and methods Seven hundred three (n = 703) prostate cancer (PCa) patients with confirmed PSA failure after radical therapy were enrolled. Patients were stratified according to different clinical settings (first-time biochemical recurrence [BCR]: group 1; BCR after salvage therapy: group 2; biochemical persistence after radical prostatectomy [BCP]: group 3; advanced stage PCa before second-line systemic therapies: group 4).
First, we assessed 68Ga-PSMA-11-PET/CT positivity rate. Second, multivariable logistic regression analyses were used to determine predictors of positive scan. Third, regression-based coefficients were used to develop a nomogram predicting positive 68Ga-PSMA-11-PET/CT result and 200 bootstrap resamples were used for internal validation. Fourth, receiver operating characteristic (ROC) analysis was used to identify the most informative nomogram’s derived cut-off. Decision curve analysis (DCA) was implemented to quantify nomogram’s clinical benefit.
Results 68Ga-PSMA-11-PET/CT overall positivity rate was 51.2%, while it was 40.3% in group 1, 54% in group 2, 60.5% in group 3, and 86.9% in group 4 (p < 0.001). At multivariable analyses, ISUP grade, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p ≤ 0.04). A nomogram based on covariates included in the multivariate model demonstrated a bootstrap-corrected accuracy of 82%. The nomogram-derived best cut-off value was 40%. In DCA, the nomogram revealed clinical net benefit of > 10%.
Conclusions This novel nomogram proved its good accuracy in predicting a positive scan, with values ≥ 40% providing the most informative cut-off in counselling patients to 68Ga-PSMA-11-PET/CT. This tool might be important as a guide to clinicians in the best use of PSMA-based PET imaging.
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Gallo, Michal. "Model Stirlingova motoru v PSCAD." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2016. http://www.nusl.cz/ntk/nusl-242000.
Повний текст джерелаАнотація:
This dissertation about the Stirling engine deals with the history and formation of the heat engine. At the beginning of this work, fundamental parts and their functions are described, elucidating the principle of operation explained by the thermodynamic cycle and subsequently comparing the ideal and the real Stirling cycle and last but not least provides various modifications whilst describing their differences. The mathematical model of the Stirling engine is processed by Schmidth’s theoretical analysis and thereafter is created in PScad v46. The process of creating a model is shown in one of the chapters of this dissertation. The results were taken into account in the design of 3D models in Inventor Professional by Autodesk. The work concludes with the evaluation of the computational model and its functionality as well as the documentation of the 3D model.
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Schwickardi-Jerrentrup, Maren. "Freies PSA und PSA-Quotient in der Diagnostik des Prostatakarzinoms." [S.l.] : [s.n.], 2005. http://archiv.ub.uni-marburg.de/diss/z2005/0091/.
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Hunt, Jannine M. "A psbA phylogeny for selected rhodophyceae /." Electronic version (PDF), 2006. http://dl.uncw.edu/etd/2007-2/huntj/janninehunt.pdf.
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Eriksson, Carl. "Osäkerhetsanalys av PSA-resultat : Metodutveckling och parameterinventeringför osäkerhetsanalys av PSA-resultat." Thesis, Uppsala universitet, Tillämpad kärnfysik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-336256.
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This master thesis examines the possibility of performing asimplified uncertainty analysis on a probabilistic safety assessment(PSA) of the Oskarshamn 3 nuclear power plant. The aim of the thesiswas divided in two parts, first to examine the uncertainty parametersof a PSA-model for Oskarshamn 3 and the second part was to developand examine a simplified method of uncertainty analysis as comparedto a more regular method of Monte Carlo-simulation. The thesis ismostly concerned with examining the core damage frequency. Theexamination of uncertainty parameters showed that many parameterswere missing from the model and thus further investigation areneeded, if a full Monte Carlo is to be performed. The simplifiedmethod for uncertainty analysis that was developed consisted ofassuming a lognormal distribution for the frequency of basic eventsand then using the minimal cutset-list to calculate an approximationto the end distribution. The simplified method was then compared tothe Monte Carlo-analysis for Oskarshamn 2 for different MCS-lists anda preliminary uncertainty analysis was performed for Oskarshamn 3.
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Lores, Lazara Elena Santiesteban. "Síntese, caracterização e avaliação imunológica de conjugados do sorotipo 6B de Streptococcus pneumoniae à proteína A de superfície pneumocócica (PspA)." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-19062017-151232/.
Повний текст джерелаАнотація:
As vacinas conjugadas contra Streptococcus pneumoniae mostram-se eficazes na redução da doença pneumocócica, no entanto depois de sua introdução tem se verificado a substituição de sorotipos. Para evitar estes problemas o emprego de proteínas da própria bactéria como carreadoras tem sido usado. Neste trabalho a PspA foi conjugada ao sorotipo 6B de S. pneumoniae por dois métodos de conjugação. Inicialmente a PspA clado 1 e 3 foram purificadas, recuperando as proteínas com mais de 90% de pureza. A conjugação intermediada pelo agente ativador cloreto de 4-(4,6-dimetoxi-1,3,5-triazin-2-il-)-4-metilmorfolino (DMT-MM) permitiu rendimentos de Ps entre 20 e 30%, no entanto este tipo de conjugado não foi imunogênico resultando na não indução de anticorpos anti-PspA. Por outro lado a conjugação por aminação redutiva possibilitou obter rendimentos de Ps entre 50 e 60% e os conjugados induziram elevados títulos de anticorpos anti-PspA em camundongos Balb/c, que foram capazes de promover a fagocitose da bactéria; no entanto, a resposta de anticorpos anti-Ps 6B foi baixa.Conjugate vaccines against Streptococcus pneumonaie have had an important public health benefit; nevertheless after its introduction it has been observed a serotype replacement. To solve this problems conjugate vaccines using pneumococcal surface proteins as carriers has been studied. In this work, Pneumococal surface protein A (PspA) was employed as a carrier protein, conjugated to serotype 6B. Initially PspA clade 1 and PspA clade 3 were purified; both proteins were recovered with more than 90% purity. The conjugation mediated by the activating agent 4- (4,6-dimethoxy-1,3,5-triazin-2-yl -) - 4-methylmorpholine chloride(DMT-MM) allowed Ps yields between 20 and 30%, however this conjugation chemistry had a negative impact on the immunogenicity of the protein. On the other hand conjugation by reductive amination led to Ps yields between 50 and 60% and induced high anti-PspA antibodies titers in Balb /c mice that were able to promote phagocytosis of the bacterium; however, polysaccharide 6B induced low antibody titers.
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Krhut, Štěpán. "Zušlechťování bioplynu metodou PSA." Master's thesis, Vysoké učení technické v Brně. Fakulta strojního inženýrství, 2017. http://www.nusl.cz/ntk/nusl-318663.
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This work deals with bio gas cleaning by a PSA method and modernizing of a laboratory unit. Raw bio gas contains many unwanted elements like carbon dioxide mostly which lowers its energy potential then. To extend the possibilities of usage of bio gas it is necessary to remove such elements. One of the well-known method for eliminating CO2 out of the bio gas is the method called Pressure Swing Adsorption (PSA). This work describes PSA method and compares it with other methods for cleaning the bio gas. In the following part of my work I am introducing the original laboratory PSA unit which is placed in the laboratory of UPI institution for research purposes. The modernization of the method was made by changing the manual valves for electromagnetic ones and there was also designed a new control system unit for two control modes. For manual and for automatic. The essential function is based on remote controlling the valves either by switches or by a program. The electric control panel was created for such required modes. The automated process was controlled by Arduino programming platform which was integrated into the panel. In the case of the next measurement and reading there was created a detailed description for user on how to operate the control panel and also the comments for control program of automatization.
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Moreira, Horácio Alvarenga. "Um novo índice para detecção do câncer de próstata (razão entre densidade do PSA e PSA livre sobre o PSA total)." Universidade Estadual de Londrina. Centro de Ciências da Saúde. Programa de Pós-Graduação em Ciências da Saúde, 2015. http://www.bibliotecadigital.uel.br/document/?code=vtls000200881.
Повний текст джерелаАнотація:
Introdução e objetivo: O antígeno prostático específico (PSA) é o mais importante marcador para diagnóstico de câncer de próstata (CaP), porém, em pacientes com níveis intermediários de PSA (entre 2,5 e 20,0 ng/ml), existe uma grande dificuldade para diferenciar casos de CaP daqueles com Hiperplasia Benigna da Próstata (HPB). Apesar do risco considerável de neoplasia, a maior parte destes pacientes, quando investigados por biópsia prostática, apresenta HPB. Desta maneira, biópsias de próstata são realizadas desnecessariamente e as mesmas não são isentas de complicações como prostatite, abscesso, sepses e até óbito. Introduziu-se as porcentagem do PSA livre (%PSAL) e densidade do PSA (DPSA) com o objetivo de aumentar a detecção do CaP (sensibilidade) e diminuir o número de biópsias desnecessárias (especificidade), porém, a utilização isolada destas ferramentas produzem resultados insatisfatórios. Modelos matemáticos como regressão logística com múltiplas variáveis (MRLM) e redes neural artificial apresentam melhores resultados. Entretanto, a complexidade destes cálculos inviabilizam a sua aplicabilidade na prática clínica diária. Baseado na premissa de que quanto menor a porcentagem do PSA e quanto maior a densidade do PSA maior a probabilidade do paciente ter CaP, o objetivo do presente estudo foi avaliar se um NOVO ÍNDICE (NI), obtido pela divisão do valor da densidade do PSA pela relação PSA livre/total, é superior ao uso isolado do PSA, %PSAL, a um MRLM e a DPSA para detecção do CaP. Método: Estudo de avaliação de teste diagnóstico a partir de um banco de dados de três estudos prospectivos, realizados no período de 2002 a 2009, no Hospital Universitário Regional do Norte do Paraná, Hospital do Câncer de Londrina e em cinco clínicas privadas de Londrina-PR, envolvendo 709 homens. Extraiu-se, deste banco de dados, as seguintes variáveis: idade, resultado do exame de toque retal, PSA total, PSA livre, volume da próstata, %PSAL, DPSA e resultado da biópsia de próstata (CaP ou HPB). Dos 709 homens, 466 (162 com CaP e 304 com HPB) tinham dosagem do PSA entre 2,5 e 20 mg/ml e apresentavam, simultaneamente, todas as variáveis acima mencionadas. A capacidade do NI em melhorar a detecção do CaP foi avaliada por análise univariada e multivariada e através de curva ROC. Resultados: O NI apresentou uma acurácia de 76,9% e esta foi superior a do PSA (57,4%), %PSAL (71,2%) e DPSA (73,5%) na discriminação entre CaP e HPB, na faixa de PSA entre 2,5 e 20 ng/ml, aumentando assim a detecção do CaP e diminuindo o número de biópsia de próstata desnecessárias. O NI apresentou uma acurácia semelhante (p=0,2036) a de um MRLM (78,6%). Para uma sensibilidade de 95%, para detecção do CaP, a especificidade (biópsias evitadas) do PSA, %PSAL, DPSA, NI e MRLM foram respectivamente: 8,22%, 18,42%, 20,07%, 20,39% e 26,97%. Conclusão: O NI proporcionou uma melhor discriminação entre CaP e HPB do que o uso isolado do PSA , %PSAL e DPSA. Também apresentou uma acurácia semelhante a de um MRLM, em pacientes com níveis de PSA entre 2,5 e 20 ng/ml.Introduction and objective: Prostatic specific antigen (PSA) is the most important marker for the diagnosis of prostate cancer (CaP). However, in patients with intermediate levels of PSA (between 2.5 and 20, 0 ng/ml), it is difficult to differentiate cases of CaP from those of benign hyperplasia of the prostate (BPH). Despite the considerable risk of neoplasia, most of these patients when investigated by prostate biopsy present BPH. Therefore, unnecessary prostate biopsies are regularly performed and they are associated with complications such as prostatitis, abscess, sepsis and even death. The percentage of free PSA (%PSA) and density (DPSA) were introduced, aiming to increase CaP detection (sensibility) and decrease the number of unnecessary biopsies (specifity). However the utilization of these tools separately, produced unsatisfactory results. Mathematical models with logistic regression with multiple variables (MRLM) and artificial neural network (RNN) present better results, nonetheless, the complexity of these calculations makes its clinical practical applicability limited. Considering the premise that the lower the percentage of the PSA and higher the PSA density greater the probability of the patient of having cancer, the objective of this study was to evaluate whether a new index (NI), obtained by dividing the value of the PSAD by the % PSA, is superior of PSA, %PSA, MRLM and DPSA for detection of CaP. Method: Study of evaluation of a diagnostic test utilizing data obtained from databases of three prospective studies, performed between 2002 and 2009 at Hospital Universitário Regional do Norte do Paraná, Hospital do Câncer de Londrina and five private practice clinics in Londrina, Paraná, which included 709 men. From this database the following variables were extracted: age, description of the digital rectal examination, total PSA, free PSA, prostate volume, %PSAL, DPSA and the result of the prostate biopsy (CaP or BPH). From these 709 men, 466 (166 with CaP and 304 with BPH) had PSA levels between 2.5 and 20 ng/ml and, simultaneously all variables mentioned above were available in their charts. The capacity of this NI to improve CaP detection was evaluated by univariate and multivariate analysis and also by a ROC curve. Results: The NI demonstrated an accuracy of 76.9% which was superior to the PSA(57.8%), %PSA(71.2%) and DPSA(73,5%) in discriminating between CaP and BPH, when PSA was between 2,5 and 20 ng/ml, increasing the detection of CaP e decreasing the number of unnecessary biopsies. The NI showed an accuracy similar (p=0, 2036) to a MRLM (78, 6%). For a sensibility of 95% for the detection of CaP, the specificity (avoided biopsies) of the PSA, %PSAL, DPSA, NI and MRLM were 8,22%, 18,42%, 20,07%, 20,39% and 26,9%, respectively. Conclusion: The NI warranted a better discrimination between CaP and BPH than isolated PSA, %PSA and DPSA. Also, presented accuracy similar to MRLM in patients with PSA between 2,5 and 20 ng/ml.
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Hasan, Kyle R. "PSCAD Modeling and Stability Analysis of a Microgrid." DigitalCommons@CalPoly, 2017. https://digitalcommons.calpoly.edu/theses/1928.
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As power systems are evolving, engineers are facing, and will continue to face, new challenges with respect to maintaining the system in terms of stable operation. Many different forms of generation are becoming prevalent, including; small synchronous generators, photovoltaic generation, and energy storage techniques in the form of battery and ultracapacitor systems. One of the evolutions occurring in the power system is the emergence of microgrids, small power systems capable of isolating from the major power grid in the form of islands. Microgrids use distributed generation to provide power to small communities, and they come with several advantages and disadvantages. This thesis shows the design process employed to model a microgrid, which contains a variety of distributed resources, in PSCAD, as well as investigate the transient instability of the microgrid when transitioning to islanded operation. Modeling techniques for both grid-connected and islanded operation of the microgrid are considered in this study. In addition to modeling techniques, the effectiveness of proper control of energy storage assets in a microgrid is demonstrated through the implementation and comparison between real & reactive power regulation and voltage & frequency regulation.
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Chafee, Meghan E. "Genetic marker for coastal diatoms based on PSBA." View electronic thesis, 2008. http://dl.uncw.edu/etd/2008-1/r3/chafeem/meghanchafee.pdf.
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Melo, Melissa Ely. "Pagamento por serviços ambientais (PSA)." reponame:Repositório Institucional da UFSC, 2016. https://repositorio.ufsc.br/xmlui/handle/123456789/171710.
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Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Jurídicas, Programa de Pós-Graduação em Direito, Florianópolis, 2016.Made available in DSpace on 2016-12-20T03:14:40Z (GMT). No. of bitstreams: 1 342722.pdf: 3656107 bytes, checksum: 8ae370a280d542d890e80ab0f6caedd7 (MD5) Previous issue date: 2016
O objetivo geral da presente Tese é verificar a (in)adequação do instrumento econômico, Pagamento por Serviços Ambientais (PSA), para garantir a proteção dos serviços ecossistêmicos no contexto da crise ambiental. Esta última concebida enquanto questão social, pois marcada pela tensão entre os seres humanos e a apropriação dos recursos naturais. Também percebida enquanto crise do conhecimento, diretamente relacionado com a proliferação da problemática ambiental e incapaz de lhe oferecer solução adequada. No intuito de responder à pergunta fundante: ?O PSA é um instrumento adequado à proteção dos serviços ecossistêmicos no contexto da crise ambiental?? elaborou-se pesquisa bibliográfica e documental com fontes primárias legislativas e estudos acerca do uso real do objeto, buscando-se a compreensão do mundo teórico e da práxis, permitindo conhecer as contradições existentes entre eles. Os objetivos específicos do trabalho foram os seguintes: a) Estudar o processo de transformação do conceito de riqueza dentro do pensamento econômico, a partir da crise ambiental e da marginalização da natureza; b) Investigar as estratégias de internalização das externalidades negativas concebidas pela Economia Ambiental e recepcionadas pelo Direito, diante dos limites oferecidos pela Lei da Entropia; c) Pesquisar as dificuldades conceituais que permeiam os serviços ecossistêmicos e as suas metodologias tradicionais de valoração, confrontando a possibilidade de construção de nova abordagem em termos de valoração de serviços ecossistêmicos, com base na Economia Ecológica; d) Analisar os fundamentos jurídicos, as distintas perspectivas conceituais e as tipologias do Pagamento por Serviços Ambientais (PSA); e) Examinar a experiência de implementação do Pagamento por Serviços Ambientais (PSA) na Costa Rica e no Brasil, delineando perspectivas futuras do instrumento no contexto brasileiro. Cada qual correspondendo a um dos capítulos que ordenaram o tema. A pesquisa confirmou a sua hipótese no sentido de entender pela inadequação do PSA à proteção dos serviços ecossistêmicos no contexto da crise ambiental. Assinalou-se, no entanto, que a Economia Ecológica pode trazer algumas perspectivas no escopo de pensar-se nova concepção para o instrumento, bem como distinta abordagem para a valoração ecossistêmica.
Abstract : The main objective of this thesis is to verify the (in)adequacy of the economic instrument, Payment for Environmental Services (PES) to ensure the protection of ecosystem services in the context of the environmental crisis. The latter conceived as a social issue, marked by the tension between humans and the appropriation of natural resources. It is also perceived as a crisis of knowledge, directly related to the proliferation of environmental problems and unable to offer an adequate solution. In order to answer the founding question: "Is the PES an appropriate instrument for the protection of ecosystem services in the context of the environmental crisis?", it was elaborated a bibliographical and a documental research with legislative primary sources and studies about the actual use of the object, looking for understanding of the theoretical world and the praxis, allowing to know the contradictions between them. The specific objectives were as follows: a) To study the process of transformation of the concept of wealth within the economic thought, from the environmental crisis and marginalization of nature; b) To investigate the internalization of negative external strategies designed by the Environmental Economics and received by the law, on the limits offered by the Law of Entropy; c) To find the conceptual difficulties that permeate the ecosystem services and their traditional evaluation methods, facing the possibility of a new approach for the construction in terms of evaluation of ecosystem services, based on Ecological Economics; d) To analyze the legal basis, the different conceptual perspectives and the types of Payment for Environmental Services (PES); e) To scan the implementation experience of Payment for Environmental Services (PES) in Costa Rica and Brazil, outlining the future prospects of this instrument in the Brazilian context. Each of them corresponding to one of the chapters that ordered the issue. The survey confirmed its hypothesis in order to understand the inadequacy of PES for the protection of ecosystem services in the context of the environmental crisis. It was noted, however, that the Ecological Economics may bring some support in the scope of thinking up new design for the instrument as well as distinctive approach to evaluating ecosystem.
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Woythal, Nadine [Verfasser]. "In vitro Validierung der in vivo PSMA-Expression in der 68Ga-PSMA-PET/CT beim primären Prostatakarzinom durch die Immunohistochemie / Nadine Woythal." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1179778480/34.
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Abdullah, Mohd Halimi. "PSCAD/EMTDC modelling of active filters for HVdc applications." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq23190.pdf.
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Elderkin, Sarah Louise. "Functional analysis of the E.coli phage shock protein PspA." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407101.
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Іванов, Олександр Олександрович, Александр Александрович Иванов, Oleksandr Oleksandrovych Ivanov, О. І. Ігнатова та С. О. Іванов. "Моделювання диференційного струмового захисту в програмному комплексі PSCAD/EMTDC". Thesis, Сумський державний університет, 2014. http://essuir.sumdu.edu.ua/handle/123456789/40025.
Повний текст джерелаАнотація:
В ході виконання наукової роботи був розроблений алгоритм роботи диференційного струмового захисту трансформатора, який було відтворено в програмному комплексі PSCAD/EMTDC. Дане середовище дозволяє в режимі реального часу проводити різноманітні маніпуляції над розробленою схемою та одразу спостерігати результат роботи, а саме процеси, які відбуваються при спрацюванні та до моменту спрацювання захисту. Це значно полегшує процес прийняття рішень, і має величезне значення не тільки для наукового, а й для освітнього процесу.
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Moravčík, Martin. "Modelování a simulace hybridní mikro sítě v prostředí PSCAD." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2012. http://www.nusl.cz/ntk/nusl-219410.
Повний текст джерелаАнотація:
In the opening part of this master´s thesis there is given concept, description, usage and advantages of micro hybrid grids in comparison to micro grids and there are evolution steps towards hybrid grid. There is also a mention about economics of operation of these grids. In the second part of this thesis there are descriptions of devices that are suitable for usage in micro hybrid grids with emphasis on generators and accumulation possibilities. In the next part of this thesis there is given an approach and description for modeling of various components of hybrid grids in PSCAD environment. In the next part of this thesis there are given simulation results that were conducted on created model. Especially power balance in 24 hour operation of the grid with method for determining suitable size of accumulation and installed capacity of photovoltaics. And next there are showed responses from change of power from photovoltaics, next there is a transition to islanded mode and last there is showed the behavior of converter when the limits of accumulation are reached. In the final part of this thesis there are conclusions, fulfillment of goals of this thesis and possibilities of further study.
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Anderle, Franz. "Phosphor-modifizierte Katalysatoren zur PSA-Herstellung." Diss., lmu, 2001. http://nbn-resolving.de/urn:nbn:de:bvb:19-1858.
Повний текст джерела
30
KOPAYGORODSKY, EUGENE M. "MATHEMATICAL MODEL OF ULTRA-RAPID PSA." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1002135981.
Повний текст джерела
31
Mosca, Alessandra. "Structured zeolite adsorbents for PSA applications /." Luleå : Luleå University of Technology, 2009. http://pure.ltu.se/ws/fbspretrieve/3333675.
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32
Barakat, Nermeen H. "TBP recruitment to the U1 snRNA gene promoter is disrupted by substituting a U6 proximal sequence element A (PSEA) for the U1 PSEA." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3329868.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--University of California, San Diego, and San Diego State University, 2008.Title from first page of PDF file (viewed November 19, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
33
Vadesilho, Cintia Fiuza Marques. "Mapeamento de epitopos presentes em variantes dos antígenos vacinais PspA (Pneumococcal surface protein A) e PspC (Pneumococcal surface protein C) de Streptococcus pneumoniae." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/87/87131/tde-06122014-075950/.
Повний текст джерелаАнотація:
S. pneumoniae pode causar infecções do trato respiratório. Uma alternativa às vacinas conjugadas, que conferem proteção sorotipo-específica, seria uma vacina baseada em epitopos de diferentes variantes de antígenos como PspA e PspC. O objetivo deste trabalho foi a identificação de epitopos de variantes de PspA e PspC, utilizando a técnica peptide array, visando a síntese de um antígeno composto por múltiplos epitopos. Os resultados obtidos indicaram que anticorpos contra epitopos lineares de PspA reconhecem as regiões inicial N-terminal e rica em prolinas, mas estes epitopos parecem ser apenas marcadores de exposição ao pneumococo e epitopos conformacionais seriam os de fato protetores, como observado nos experimentos realizados com os Frags de 100 aminoácidos construídos a partir do PspARx1, especialmente aqueles presentes nas regiões dos Frags 2 e 4. Epitopos lineares de PspC parecem ser importantes na região de ligação à sIgA e FH. Assim, uma vacina proteica de ampla cobertura, poderia conter as regiões do Frag 2 de PspA e de ligação de sIgA e FH de PspC.S. pneumoniae can cause respiratory tract infections. An alternative to the conjugate vaccines, which confer serotype-specific protection, would be a vaccine based on epitopes of variants of antigens such as PspA and PspC. The objective of this study was to identify epitopes of variants of PspA and PspC, using the peptide array technique, aiming at the synthesis of a multi-epitope antigen. The results obtained with peptide arrays indicated that antibodies against linear epitopes of PspA recognize the initial N-terminal and proline-rich regions, but these epitopes seem to be only markers of exposure to pneumococcus and conformational epitopes would be in fact protective, as observed in the experiments with fragments of 100 amino acids constructed from PspARx1, especially those present in Frags 2 and 4. Linear epitopes of PspC seem to be important in the regions of sIgA and FH binding. Thus, a protein-based vaccine with broad coverage could contain the regions of Frag 2 of PspA and the regions of sIgA and FH binding of PspC.
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Parthen, Thyra. "Die Wechselwirkung divalenter Kationen mit Strukturelementen der chloroplastenkodierten psbA mRNA." [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=97186473X.
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Canavezes, Alexandre Gonzalez da Rocha Silva. "The topology of the density of the universe using PSCz." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314346.
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36
Hällsten, Christoffer. "Jordfelssimulering och modell-validering med PSCAD av ett impedansjordat distributionsnät." Thesis, Högskolan Väst, Avdelningen för data-, elektro- och lantmäteriteknik, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:hv:diva-7379.
Повний текст джерелаАнотація:
Detta examensarbete har utförts hos Vattenfall Eldistribution på avdelningen Kontroll och Skydd med målsättningen att utforma och utvärdera en nätmodell avsedd för jordslutningssimuleringar i PSCAD. Ombyggnationen från luftledningar till markkablar har medfört att kapacitansen i distributionsnätet ökat, vilket ställer högre krav på jordfelsutrustning och på nätanalyser för att kunna försäkra att en säkerställd frånkoppling kan ske enligt de myndighetskrav som föreligger. Syftet med arbetet har varit att undersöka hur en nätmodell bör utformas för analys av stationära in-svängningsförlopp och utvärdera hur stor noggrannhet som kan förväntas gentemot verkliga jordfelsprov vid felresistanser på främst 3 kΩ och 5 kΩ. Nätmodellen har ut-formats efter ett verkligt impedansjordat mellanspänningsnät med π-länkar i PSCAD och utifrån de nätuppgifter som förekommer i Vattenfalls näthanteringsprogram Netbas. Simuleringsresultaten har jämförts mot resultat från det verkliga nätets jord-felsprover vid olika inställningar på den centrala kompenseringsutrustningen som är placerad mellan den matande transformatorns nollpunkt och jord. Jordslutningssimuleringarna visar, trots antaganden och en viss osäkerhet omkring de verkliga nollföljdskomponenterna, godtyckliga simuleringsresultat vid avstämt och snedavstämt nät motsvarande ± 30 A gentemot ledningarnas kapacitiva strömmar vid en felresistans på 3 kΩ. Jordslutningssimuleringarnas händelseförlopp överensstäm-mer överlag väl mot det verkliga nätet samtidigt som jordslutningar vid 5 kΩ medför en större procentuell avvikelse. Särskilt framträdande avvikelser kunde urskiljas vid analys av fasvinkeln mellan nollföljdsspänning och nollföljdsström. En analys av nätmodellens resultat och troliga orsaker till uppkomna simulerings-avvikelser gentemot det verkliga nätet indikerar på att nätmodellens tillförlitlighet bör kunna optimeras ytterligare om noggrannare hänsyn tas gällande nollföljdsimpedanser, dc-komponenter och de toleranser som förekommer i det verkliga nätets avstäm-ningsutrustning och mätkretsar.This thesis has been carried out at Vattenfall Eldistribution at the department Control and Protection with the objective to design and evaluate a network model for ground fault simulations in PSCAD. The reconversion from overhead lines to underground cables has led to increased capacitances in the distribution network and this places greater demands on the feeder protection unit and network analyzes in order to assure that faulted feeders are disconnected according to regulatory requirements. The aim of this work has been to determine how a network model could be designed for analysis of stationary signal characteristics and evaluate how great accuracy the power system model have compared to real earth fault test results. Earth fault simulations are performed with fault resistances of 3 kΩ and 5 kΩ. The power system model have been created to emulate a real impedance grounded network according to the π-model in PSCAD based on system information from Vattenfalls network management program Netbas. Results from the simulations have been compared against results obtained from real earth faults from the physical network with different settings on the central compensation equipment placed between the transformers neutral and ground. Simulations show, despite assumptions and some uncertainty about the actual zero sequence components similar results when fault resistance was 3 kΩ, both when compensation coil are fully tuned and out of tune ± 30 A corresponding to the feeder capacitance. The overall signal sequence conform quite well to the real network but at the same time simulations with 5 kΩ obtains greater deviations when results are represented in percentage. Particularly prominent abnormalities could be identified in the phase angle between zero sequence voltage and zero sequence current. An analysis of deviations from the simulations in the digital network model against the real system indicates that the model probably could be further optimized if zero sequence impedances, dc components, and tolerances that occur in the real systems reactive compensation equipment and measuring circuits are taken into account.
37
Ignatova, O. I., and S. A. Ivanov. "Modeling of distance power protection in software complex PSCAD/EMTDC." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/46898.
Повний текст джерелаАнотація:
Modelling of protective relays offer an economical and feasible
alternative to investigate the performance of relays and protection systems.
To study the performance of the relay characteristics, single line to ground
fault at different zones with and without fault resistances are considered. A
Fast Fourier Transform block in PSCAD/EMTDC has been used to extract
the fundamental component. The test network used in this work is 230kv
transmission line systems.
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Іванов, Олександр Олександрович, Александр Александрович Иванов, Oleksandr Oleksandrovych Ivanov, О. І. Ігнатова та С. О. Іванов. "Моделювання дистанційного захисту лінії електропередач в програмному комплексі PSCAD/EMTDC". Thesis, Сумський державний університет, 2015. http://essuir.sumdu.edu.ua/handle/123456789/41389.
Повний текст джерелаАнотація:
Стійка робота електричних станцій у великій мірі забезпечується за рахунок надійної роботи релейного захисту їх електрообладнання. В даний час, що характеризуються збільшенням числа аварійних
ситуацій, а також зростанням кількості випадків виникнення супутніх ушкоджень, роль релейного захисту постійно зростає. У багатьох випадках через відносну недосконалість релейного захисту не можна
запобігти розвитку аварій, які все частіше протікають по найбільш важкому шляху і супроводжуються значними економічними втратами.
39
Walker, Natalie. "PSMA-1-Doxorubicin Conjugates for Targeted Therapy of Prostate Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554496393458066.
Повний текст джерела
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Razyapova, Aygul. "Tvorba a estimace modelu malé vodní elektrárny v programu PSCAD." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2018. http://www.nusl.cz/ntk/nusl-242038.
Повний текст джерелаАнотація:
This thesis focused on creating a model of a small hydropower plant model (SHPP) and a part of the electricity network in the simulation software "PSCAD" (basing on real sources). The model will be specified on the basis of the data obtained from the measurements to correspond with the real equipment.
41
Frigerio, B. "PSMA-SPECIFIC ANTIBODY FRAGMENTS FOR PROSTATE CANCER IMAGING AND THERAPY." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/221052.
Повний текст джерелаАнотація:
In this study we want to evaluate the potentiality of the use of a single chain Fv (scFv) for molecular imaging and therapy of Prostate Cancer. The target of this scFv is the Prostate Specific Membrane Antigen (PSMA), a type II transmembrane protein overexpressed in advances stages of this disease. In the past we have generated the murine antibody D2B recognizing hPSMA, whose diagnostic specificity has been investigated in xenograft murine models by imaging.
In order to obtain a smaller protein able to better penetrate the tissues we decided to convert the murine monoclonal antibody D2B into a format like scFv. This format, due to its smaller size, have also the advantage, compare to the entire antibody, to have a faster clearance from the blood.
The scFv has been constructed and its functionality has been tested with success on LNCaP cells. Using BIAcore (a technology able to measure the kinetic interaction between two molecules) we showed that the affinity of our scFv is still remarkable despite its monovalent binding.
One goal of the present study is the assessment of potential role of this antibody fragment as diagnostic reagent for the development of radiopharmaceuticals for tumor characterization and molecular imaging. A second goal of the project is the production of a completely human antibody fragment against hPSMA in order to develop a reagent more suitable for therapy. We used phage display technology to convert the murine antibody in a human antibody applying guided selection technology which permits to generate an antibody with the specificity and functionality of the starting rodent mAb.
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Cueva, Chonlon Francisco Iván. "Determinación anatomopatológica de cáncer de próstata en adenomectomías prostáticas. Hospital Nacional Hipólito Unanue - 2010." Bachelor's thesis, Universidad Ricardo Palma, 2010. http://cybertesis.urp.edu.pe/handle/urp/220.
Повний текст джерелаАнотація:
PROBLEMA: ¿Cuál será la frecuencia de cáncer de próstata (CPI), de muestras aparentes de Hiperplasia Prostática Benigna (HPB) obtenidas por adenomectomías prostáticas (APRP)?
OBJETIVOS: Determinar el estadio mediante la escala de Gleason del cáncer de próstata. Correlacionar el cáncer incidental con el PSA, la densidad de PSA, PSA libre y la velocidad del PSA. Correlacionar el CPl con la edad y el antecedente familiar de cáncer de próstata (CaP).
MATERIAL Y MÉTODOS: Estudio descriptivo retrospectivo. Muestra: 1587 pacientes sometidos a APRP con diagnóstico de HPB previo a la cirugía. Criterios de Inclusión: Pacientes del Hospital Hipólito Unanue –Lima-Perú-– servicio de Urología, periodo Enero 2000 - Diciembre 2005, con diagnóstico previo a la cirugía de HPB, sin diagnóstico de cáncer de próstata (CaP) (PSA<4ng/ml y tacto rectal- fibroelastica, no nódulos).
RESULTADOS: Datos de Enero del 2000 - Diciembre del 2005. Se operaron 1159 pacientes (73%) por APRP, y 428 pac. (27%) por Resección Transuretral Prostática (RTU). Hallándose 64 (4%) pac. con CPI con PSA en 8 pacientes (12.5 %) en PSA 0-2 ng/ml y 35 pac. (54.7 %) en 2.1-4 ng/ml. La velocidad de PSA, en el grupo con CPI: 44 (68.7%) pac. Que estuvieron en rango normal y 6 (9.4%) en el rango de 0.76-0.85 ng/ml. Sus edades estuvieron en el rango de edad entre 71 – 80 años a más con 50 pac. (78.1%). Además 11 pac. (17.2%) sin familiares con CaP y 49 pac. (76.6 %) con por lo menos un familiar con CaP y aún mas se encontró 4 pac. (6.25%) que tuvieron 2 o más familiares con el antecedente de CaP. Se halló un Volumen prostático en 20 pac. (31.3 %) entre 31-60 gr. y luego en 26 pac. (40.6 %) en el grupo de 61-80 gr. Presenta en el grupo de 81-100 gr. con 18 pac. (28.1%). y luego disminuye marcadamente en el grupo de 101 a más hasta 0 pacientes.
Se halló 62 pacientes (96.7%) con adenocarcinoma de próstata y 2 pac. (3.3%) con cáncer de tipo transicional. 23 pacientes (37%) presentan un valor de Gleason bajo, 20 pacientes (31%) con Gleason entre 3-4; si observamos en general menos de Gleason 7 son 53 pacientes (82.8%). Con estadío T1a en 44 pac. (68.8 %), mientras que T1b eran solo 20 pac. (31.2%).
CONCLUSIONES: De 1587 pac. operados, 1159 pac. (73%) se operaron por APRP y 428 pac. (27%) por RTU. Hallándose 64 (4%) pac. con CPI frecuentemente del tipo adenocarcinoma de próstata, con Escala de Gleason de bajo grado, (menos de 7). Siendo del tipo T1a la más común. El PSA está en el límite superior de su rango normal en los pacientes con CPI. No hay asociación entre el CPI Y la velocidad de PSA, índice del PSA, edad, tacto rectal, volumen prostático. Hay correlación entre el antecedente familiar y el CPI.
43
Sharpe, Jacob Christopher. "PSC-z determination of the local flow." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311931.
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Mehal, Wajahat Z. "Pathogenetic factors in primary sclerosing cholangitis (PSC)." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386583.
Повний текст джерела
45
Moran, Aaron A. "A PSA Process for an Oxygen Concentrator." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1407928173.
Повний текст джерела
46
Hájek, Martin. "ERP systémy pro terciární sektor ekonomiky - PSA." Master's thesis, Vysoká škola ekonomická v Praze, 2008. http://www.nusl.cz/ntk/nusl-3857.
Повний текст джерелаАнотація:
The main goal of this thesis is to introduce philosophy of PSA (Professional Services Automation) solutions, their benefits, structure and possible future and to describe, why and how were PSA systems developed. Inasmuch as PSA systems originally evolved from ERP systems and their current progress is very similar to the late progress of ERPs, I decided to focus my analyses on ERP systems and to use the relevant conclusions on PSA solutions. The opening chapter of the thesis (chapter 3) introduces and describes philosophy and history of ERP systems, chapter 4 then describes PSA solutions. The fifth part is addressed to the current ERP market, from which a picture of future PSA market can be derived. Practical part 6, which I consider as the primary contribution of this thesis, analyzes some dimensions of PSA in the light of future evolution of this kind of solution. It also defines some factors, that may help to increase positive effects of PSA solutions to service-oriented companies. The thesis is then closed with an example of a real PSA implementation on an engineering company (chapter 7).
47
Hamborg, Kristin [Verfasser]. "Das freie prozentuale PSA und die PSA-Dichte als prognostische Marker des Prostatakarzinoms : Analyse in 1333 Fällen / Kristin Hamborg." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1035638452/34.
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48
Porfiro, Andrei Oliveira Mota. "Análise de sistemas de transmissão HVDC baseados em conversores modulares multiníveis frente descargas atmosféricas." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/3/3143/tde-18092018-082751/.
Повний текст джерелаАнотація:
Atualmente, em virtude do aumento da demanda energética surgem diversas preocupações devido à escassez dos recursos energéticos tradicionais e os impactos ambientais proporcionados pelos mesmos. Neste contexto, para atender a demanda, diversos investimentos têm sido feitos no desenvolvimento de gerações alternativas e renováveis de energia, bem como na interconexão entre países para exportação de energia. Assim, os estudos exigem soluções mais eficazes para transmissão de energia elétrica, como os sistemas de transmissão High Voltage Direct Current (HVDC), uma alternativa aos sistemas de transmissão atuais, que são predominantemente em Corrente Alternada (CA). Dentre as principais vantagens dos sistemas HVDC, destaca-se a possibilidade de transmissão de grandes montantes de energia a longas distâncias com baixas perdas. Desta forma, eles estão susceptíveis às mais diversas condições meteorológicas e geográficas, em regiões isoladas, o que os tornam vulneráveis a descargas atmosféricas, afetando a segurança do sistema. Assim, neste trabalho, foi simulado um sistema HVDC, utilizando conversores Voltage Source Converter (VSC) do tipo modular multinível, do inglês Modular Multilevel Converter (MMC), frente descargas atmosféricas. Foram analisados diversos casos, visando verificar o comportamento dos conversores e validar a eficácia da utilização de para-raios de óxido metálico, comumente chamado de para-raios de óxido de zinco (ZnO), visto que este é um componente geralmente empregado em sistemas CA. O trabalho apresenta uma revisão acerca dos sistemas VSC-based HVDC (VSC-HVDC), tratando principalmente dos conversores MMC. Também foram descritos todos os modelos utilizados nas simulações, as quais foram realizadas através do software PSCAD/EMTDC. Concluiu-se que o correto dimensionamento e locação dos para-raios operam adequadamente em sistemas Corrente Contínua (CC). Um outro fato interresante é que a sobretensão gerada pelo surto atmosférico se propaga para o lado CA ao incidir no lado CC, mas o contrário não ocorre.Nowadays, due to the increase in energy demand, several concerns arise due to the scarcity of traditional energy resources and the environmental impacts. In this context, to meet the demand, several investments have been made in the development of alternative and renewable generations of energy, as well as in the interconnection among countries for energy exports. Thus, studies require more effective solutions for electric power transmission, such as VSC-HVDC systems, an alternative to current transmission systems, which are predominantly in CA. Among the main advantages of VSC-HVDC systems, we can highlight the possibility of transmitting large amounts of energy over long distances with low losses. In this way, they are susceptible to the most diverse meteorological and geographic conditions, in isolated regions, which make them vulnerable to lightning, affecting the safety of the system. Thus, in this work, an HVDC system was simulated using VSC converters of the multilevel modular type (MMC) in front of lightnings. Several cases were analyzed in order to verify the behavior of the converters and validate the effectiveness of the use of metal oxide arresters, also known as ZnO arresters, since this is a commonly used component in CA systems. The work presents a review about the VSC-HVDC systems, mainly dealing with the MMC converters. We also described all the models used in the simulations, which were performed through the PSCAD/EMTDC software. It was concluded that the correct dimensioning and location of the arresters operate properly in CC systems. Another interresting fact is that the overvoltage generated by the lightning propagates to the AC side when it hits the CC side, but the reverse does not occur.
49
Alcarde, Lais Fernanda. "Estudo de radiomarcação com gálio-68 do inibidor de PSMA baseado em ureia - avaliação comparativa de método automatizado e não automatizado." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/85/85131/tde-30112016-103604/.
Повний текст джерелаАнотація:
Os métodos para o diagnóstico clínico de câncer de próstata incluem o toque retal e a dosagem do antígeno prostático específico (PSA). Entretanto, o nível de PSA encontra-se elevado em cerca de 20 a 30% dos casos relacionados a patologias benignas, o que resulta em falsos positivos e leva os pacientes a realização de biópsias desnecessárias. O antígeno de membrana prostático específico (PSMA), ao contrário, é sobre expresso no câncer de próstata e encontrado em baixos níveis em órgãos saudáveis. Em razão disso, estimulou-se o desenvolvimento de pequenas moléculas inibidoras do receptor de PSMA, que carreguem agentes de imagem ao tumor e que não sejam prejudicadas pela microvasculatura deste. Estudos recentes sugerem que o quelante HBED-CC contribui intrinsicamente para a ligação do peptídeo inibidor de PSMA baseado em ureia (Glu-ureia-Lys) ao grupo farmacofórico. Este trabalho descreve os estudos de otimização das condições de radiomarcação do PSMA-HBED-CC com 68Ga, utilizando sistema automatizado (módulo de síntese) e método não automatizado, buscando estabelecer uma condição adequada de preparação deste novo radiofármaco, com ênfase no rendimento da marcação e na pureza radioquímica do produto. Também objetivou avaliar a estabilidade do peptídeo radiomarcado em condições de transporte e estudar a distribuição biológica do radiofármaco em camundongos sadios. O estudo dos parâmetros de radiomarcação possibilitou definir um método não automatizado que resultou em alta pureza radioquímica (> 95%), sem a necessidade de purificação do radiomarcado. Já o método de marcação automatizado foi adaptado para utilizar módulo de síntese e software já disponíveis no IPEN, e também resultou em rendimento de síntese elevado (≥ 90%) e superior aos descritos em literatura, com a vantagem associada de maior controle do processo produtivo em atendimento aos requisitos de Boas Práticas de Fabricação. O estudo dos parâmetros de radiomarcação permitiu a obtenção do PSMA-HBED-CC-68Ga com atividade específica superior à utilizada em estudos clínicos publicados (≥ 140,0 GBq/μmol), com estabilidade suficientemente longa, que permitirá o transporte às clínicas para aplicação na obtenção de imagens diagnósticas. Os perfis de biodistribuição e farmacocinético do peptídeo radiomarcado foram compatíveis com os encontrados na literatura. Conclui-se que o PSMA-HBED-CC-68Ga, é uma importante ferramenta de diagnóstico do câncer de próstata por imagem PET, pode ser produzido tanto por método automatizado ou não automatizado, com alta pureza radioquímica, alto rendimento de síntese e estabilidade do radiofármaco.The methods for clinical diagnosis of prostate cancer include rectal examination and the dosage of the prostatic specific antigen (PSA). However, the PSA level is elevated in about 20 to 30% of cases related to benign pathologies, resulting in false positives and leading patients to unnecessary biopsies. The prostate specific membrane antigen (PSMA), in contrast, is over expressed in prostate cancer and founded at low levels in healthy organs. As a result, it stimulated the development of small molecule inhibitors of PSMA, which carry imaging agents to the tumor and are not affected by their microvasculature. Recent studies suggest that the HBED-CC chelator intrinsically contributes to the binding of the PSMA inhibitor peptide based on urea (Glu-urea-Lys) to the pharmacophore group. This work describes the optimization of radiolabeling conditions of PSMA-HBED-CC with 68Ga, using automated system (synthesis module) and no automated method, seeking to establish an appropriate condition to prepare this new radiopharmaceutical, with emphasis on the labeling yield and radiochemical purity of the product. It also aimed to evaluate the stability of the radiolabeled peptide in transport conditions and study the biological distribution of the radiopharmaceutical in healthy mice. The study of radiolabeling parameters enabled to define a non-automated method which resulted in high radiochemical purity (> 95 %) without the need for purification of the labeled peptide. The automated method has been adapted, using a module of synthesis and software already available at IPEN, and also resulted in high synthetic yield (≥ 90%) specially when compared with those described in the literature, with the associated benefit of greater control of the production process in compliance with Good Manufacturing Practices. The study of radiolabeling parameters afforded the PSMA-HBED-CC-68Ga with higher specific activity than observed in published clinical studies (≥ 140,0 GBq/μmol), with a sufficiently long stability, which will enable transport to clinics for use in diagnostic imaging. Biodistribution and pharmacokinetic profiles of the radiolabeled peptide were consistent with those founded in the literature. We concluded that PSMA-HBED-CC-68Ga, important diagnostic tool for prostate cancer imaging with PET, can be produced by either automated or not automated method with high radiochemical purity, high synthetic yield and stability of the radiopharmaceutical.
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Marchner, Bartholomäus [Verfasser], and Dirk [Akademischer Betreuer] Hellwig. "Korrelationsanalyse von PSMA-Expression und Mineralisation in Knochenmetastasen von Prostatakarzinomen in vivo gemessen mit Ga-68-HBED-CC-PSMA-PET/CT / Bartholomäus Marchner ; Betreuer: Dirk Hellwig." Regensburg : Universitätsbibliothek Regensburg, 2021. http://d-nb.info/1227039654/34.
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