316 research outputs found
Sigma receptor ligands: novel applications in cancer imaging and treatment
No full textSigma receptoren (subtypes sigma-1 en sigma-2) zijn unieke bindingsplaatsen die een aanzienlijk hogere expressie vertonen in kanker dan in gezond weefsel. Hoewel de endogene agonisten niet met zekerheid geïdentificeerd werden, zijn vele kunstmatige liganden beschikbaar voor onderzoek van de normale en pathofysiologische functie van sigma receptoren. Van therapeutische doseringen van zulke verbindingen (met name sigma-1 antagonisten en sigma-2 agonisten) is bekend dat zij de proliferatie en overleving van kankercellen doen afnemen maar nauwelijks invloed hebben op normale cellen.
Het onderzoek dat in dit proefschrift wordt beschreven was gericht op de verdere ontwikkeling van sigma liganden voor diagnostische beeldvorming en als chemotherapeutica in de oncologie.
We presenteren gegevens die erop wijzen dat competitie door steroïdhormonen variabiliteit van de opname van sigma liganden tijdens PET-imaging kan veroorzaken. Met name progesteron competeert met 11C-SA4503 voor binding aan sigma receptoren in kankercellen. We tonen ook aan dat sigma-1 receptoren in spontane hypofysetumoren tot overexpressie komen en dat 11C-SA4503-PET een geschikte methode kan zijn om zulke laesies aan te tonen.
We rapporteren dat het anti-kankereffect van sigma liganden wordt bepaald door de sigma-2 receptorbezetting in kankercellen. Cytotoxiciteit gaat gepaard met opvallende, vroege veranderingen van het metabolisme in zulke cellen. Meting van de sigma-2 receptor bezetting in menselijke tumoren d.m.v. PET kan wellicht worden gebruikt om de therapeutische dosis te voorspellen. Een combinatie van sigma liganden en cytokine-gebaseerde therapie werd getest en bleek robuste anti-kanker effecten te veroorzaken in melanoma cellijnen en in primair materiaal van ovariumcarcinoom afkomstig van kankerpatiënten.
Sigma receptors (subtypes sigma-1 and sigma-2) are unique binding sites showing a considerably higher expression in cancerous compared to non-cancerous tissues. Although the endogenous agonists have not been identified with certainty, many artificial ligands are available to study the function of sigma receptors in health and disease. Therapeutic doses of such compounds (particularly sigma-1 antagonists and sigma-2 agonists) are known to decrease proliferation and survival of cancer cells, but minimally affect non-cancer cells.
Research described in this thesis was aimed at further development of sigma ligands as diagnostic imaging agents and therapeutic drugs in oncology.
We present evidence indicating that competition by steroid hormones accounts for variability of sigma ligand uptake during PET imaging. Specifically, progesterone competes with 11C-SA4503 for binding to sigma-1 receptors in cancer cells. We also show that sigma-1 receptors are overexpressed in spontaneous pituitary tumors and that 11C-SA4503-PET may be a suitable method for detection of such lesions.
We report that sigma receptor occupancy in cancer cells determines the observed anti-cancer effect of sigma ligands. Cytotoxicity is accompanied by striking, early changes of metabolism in such cells. Assessment of sigma-2 receptor occupancy in human tumors with PET may be employed for prediction of the therapeutic dose. A combination of sigma ligands and cytokine-based therapy was tested and found to display robust anti-cancer effects in melanoma cell lines and in patient-derived primary samples of ovarian carcinoma.
Exploiting the inter-strain divergence of Fusarium oxysporum for microbial bioprocessing of lignocellulose to bioethanol
No full textpeer-reviewedMicrobial bioprocessing of lignocellulose to bioethanol still poses challenges in terms of substrate catabolism. A targeted evolution-based study was undertaken to determine if inter-strain microbial variability could be exploited for bioprocessing of lignocellulose to bioethanol. The microorganism studied was Fusarium oxysporum because of its capacity to both saccharify and ferment lignocellulose. Strains of F. oxysporum were isolated and assessed for their genetic variability. Using optimised solid-state straw culture conditions, experiments were conducted that compared fungal strains in terms of their growth, enzyme activities (cellulases, xylanase and alcohol dehydrogenase) and yield of bioethanol and the undesirable by-products acetic acid and xylitol. Significant inter-strain divergence was recorded in regards to the capacity of studied F. oxysporum strains to produce alcohol from untreated straw. No correlation was observed between bioethanol synthesis and either the biomass production or microbial enzyme activity. A strong correlation was observed between both acetic acid and xylitol production and bioethanol yield. The level of diversity recorded in the alcohol production capacity among closely-related microorganism means that a targeted screening of populations of selected microbial species could greatly improve bioprocessing yields, in terms of providing both new host strains and candidate genes for the bioethanol industry
Résultats à long terme de neuf cas d'allongement du cubitus dans le traitement de la maladie de Kienböck
No full textReclaiming the Raven: Irish-Australian Memory in the Post Modern Moment
No full textThis thesis looks at the processes of memory, imagination and cultural development in a single family of Irish extraction. The line in question derives from a western Irish sept known as the Ui Fiachrach, whose symbol was that of the raven.
The first chapter deals with the origins of the Ui Fiachrach and the impossibility of reaching an “Ur text”. It also critiques the notion of culture, noting that cultural difference (often defined on terms such as ‘blood’) can be a source of conflict. Finally, the problematic nature of the term ‘authenticity’ was explored.
The second chapter is concerned with the politics of ethnographic representation and the uses of English and Gaelic as representational tools.
The third chapter focuses on the differend that existed up till the later part of the 20th century against oral cultures (including Irish culture) and the imagination, as opposed to the realist/positivist/social Darwinist paradigm.
The fourth chapter takes into account the notions of alterity and ambivalence: a brief history of prejudice against the Irish and the dilemma of preserving one’s culture versus fitting in.
The fifth chapter examined the source material gained from research which represents a core sample of my family’s collective memory. The limits of storytelling were delineated, and the motifs classified into themes.
The sixth chapter showed how there is considerable scope and play in the symbol of the raven, in stark contrast to stereotypes typified by Poe’s Raven. In such play is the potential to reclaim the raven as a positive symbol.
The seventh chapter looked at the common characteristics between the visual Irish imagination and the modern genre of magic realism. It also examined the internal dynamics of, and the potential for, continued cultural development into the 3rd millennium
Mindscapes: Laura Riding's poetry and poetics /
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão.Esta tese propõe uma leitura revisionista da poesia contemporânea através do exame do caso de um dos mais esquecidos escritores norte-americanos do século XX: Laura (Riding) Jackson (1901-1991). O objetivo é demonstrar que Riding não apenas possuía uma poética definida e singular, mas que ela permanece uma das instâncias mais extremas e paradoxais do modernismo anglo-americano, a ponto de Riding abandonar a escrita da poesia em 1938. Recorrendo a conceitos de "formação do cânone" bem como às noções de "discurso" e "função do autor", em Foucault, investigo a construção do cânone da poesia moderna anglo-americana, recuperando o contexto e as circunstâncias da ocultação de Riding. Enquanto cubro os "discursos" poéticos em circulação na primeira metade do século XX-o "imagismo" de Pound, a "dissociação da sensibilidade", "impersonalidade" e "tradição" de Eliot, a "unidade orgância" e "ambigüidade" da Nova Crítica-ofereço um panorama crítico de modernismos alternativos sendo articulados à época. Minha intenção é demonstrar que os poemas de Riding são expressões vigorosas de um escritor para quem "a mente pensando se torna a força ativa do poema", para usar a apta formulação de Charles Bernstein. Entre minhas descobertas sobre as várias e complexas razões que levaram à não-canonização de Riding estão a hegemonia da Nova Crítica, o exílio voluntário de Riding da cena literária (onde são feitas ou desfeitas as reputações), sua recusa em ser antologiada, bem como em ser explicada em termos críticos que não os dela. Todos esses fatores, mais a "dificuldade" de sua poesia, contribuíram para fazer de Riding "a maior poeta esquecida da poesia norte-americana", como escreveu Kenneth Rexroth. Ajudado pelos insights de dois importantes críticos de poesia norte-americana, Charles Bernstein e Marjorie Perloff, defendo que a "poesia da mente" de Riding-onde o que está em jogo é que o que pensamos ser a nossa realidade-representa uma mudança radical no paradigma da poética modernista: de uma poesia centrada na imagem para uma poesia centrada na linguagem. Focalizando a experiência consciente e o tempo duracional do pensamento presente em seus poemas, concluo que as "pensagens" de Riding têm o objetivo preciso de constatar um fato universal: enquanto seres humanos e pensantes, estamos numa condição permanente chamada linguagem
Phylogenetic lineages in the Botryosphaeriaceae
No full textBotryosphaeria is a species-rich genus with a cosmopolitan distribution, commonly associated with dieback and cankers of woody plants. As many as 18 anamorph genera have been associated with Botryosphaeria, most of which have been reduced to synonymy under Diplodia (conidia mostly ovoid, pigmented, thick-walled), or Fusicoccum (conidia mostly fusoid, hyaline, thin-walled). However, there are numerous conidial anamorphs having morphological characteristics intermediate between Diplodia and Fusicoccum, and there are several records of species outside the Botryosphaeriaceae that have anamorphs apparently typical of Botryosphaeria s.str. Recent studies have also linked Botryosphaeria to species with pigmented, septate ascospores, and Dothiorella anamorphs, or Fusicoccum anamorphs with Dichomera synanamorphs. The aim of this study was to employ DNA sequence data of the 28S rDNA to resolve apparent lineages within the Botryosphaeriaceae. From these data, 12 clades are recognised. Two of these lineages clustered outside the Botryosphaeriaceae, namely Diplodia-like anamorphs occurring on maize, which are best accommodated in Stenocarpella (Diaporthales), as well as an unresolved clade including species of Camarosporium/Microdiplodia. We recognise 10 lineages within the Botryosphaeriaceae, including an unresolved clade (Diplodia/Lasiodiplodia/ Tiarosporella), Botryosphaeria s.str. (Fusicoccum anamorphs), Macrophomina, Neoscytalidium gen. nov., Dothidotthia (Dothiorella anamorphs), Neofusicoccum gen. nov. (Botryosphaeria-like teleomorphs, Diapjomera-like synanamorphs), Pseudofusicoccum gen. nov., Saccharata (Fusicoccum- and Diplodia-like synanamorphs), "Botryosphaeria" quercuum (Diplodia-like anamorph), and Guignardia (Phyllosticta anamorphs). Separate teleomorph and anamorph names are not provided for newly introduced genera, even where both morphs are known. The taxonomy of some clades and isolates (e.g. B. mamane) remains unresolved due to the absence of ex-type cultures
The propeptide is required for in vivo formation of stable active yeast proteinase A and can function even when not covalently linked to the mature region
No full textThe PEP4-encoded aspartate protease proteinase A from Saccharomyces cerevisiae is synthesized as a zymogen (Ammerer, G., Hunter, C. P., Rothman, J. H., Saari, G. C., Valls, L. A., and Stevens, T. H. (1986) Mol. Cell. Biol. 6, 2490-2499; Woolford, C. A., Daniels, L. B., Park, F. J., Jones, E. W., van Arsdell, J. N., and Innis, M. A. (1986) Mol. Cell. Biol. 6, 2500-2510). We constructed a mutant form, lacking the propeptide. This form, still containing the signal peptide, was translocated into the endoplasmic reticulum, but the mature region was subsequently completely degraded. When a plasmid encoding only the propeptide after the signal peptide was introduced into a strain producing the mature region, a subpopulation of mature region molecules was rescued from the degradation and gained activity. Increased activity was found when the mature region was co-produced with increased amounts of propeptide, whereas truncated propeptides, lacking residues at its C terminus, were less efficient in the interaction with the mature region. We propose that the mature region of proteinase A cannot fold into its stable active conformation in the absence of the propeptide and that the propeptide can promote folding of the mature region, even when the propeptide and the mature region are not covalently linked
Évaluation clinique rétrospective des traitements arthroscopiques des lésions du complexe triangulaire du poignet
No full textObjectives: The aim of this study is the retrospective clinical evaluation of the arthroscopic treatments for triangular fibrocartilage complex tears. Methods: Between 2003 and 2010, 76 patients with a traumatic lesion (Palmer type 1) and 25 patients with a degenerative lesion (Palmer type 2) of the triangular fibrocartilage complex underwent wrist arthroscopy. Clinical evaluations were based on the Mayo Modified Wrist Score (MMWS), on a compared measurement of the grip force and on a measurement of the different ranges of motion. We also made a subjective evaluation of the benefit brought by arthroscopy and a retrospective evaluation of the pre and postoperative pain. Results: Mean MMWS was 86.3 for traumatic lesions and 83 for degenerative lesions. Mean grip force was 84.8 (Palmer type 1) and 84.2 (Palmer type 2) compared to the controlateral side. Mean ranges of flexion-extension, prosupination and radioulnar motions were 135°, 164° and 56° respectively for traumatic lesions and 130°, 156° and 54° respectively for degenerative lesions. Ninety-four percent of the operated patients reported an improvement of the symptomatology with better results for type 1 (98.7%) compared to type 2 (80%). We noted a clear diminution of the postoperative pain compared to the preoperative's one with frequently some mild persistent pain however. Conclusions: Arthroscopic treatments of the triangular fibrocartilage complex seem to be effective with an improvement of the symptomatology. © 2012
Pharmacogenetics of ophthalmic topical β-blockers
No full textGlaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical β-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical β-blockers. This review summarizes clinically significant polymorphisms that have been identified in the β-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications of polymorphisms in CYP2D6 are also discussed. Although the candidate-gene approach has facilitated significant progress in our understanding of the genetic basis of glaucoma treatment response, most drug responses involve a large number of genes, each containing multiple polymorphisms. Genome-wide association studies may yield a more comprehensive set of polymorphisms associated with glaucoma outcomes. An understanding of the genetic mechanisms associated with variability in individual responses to topical β-blockers may advance individualized treatment at a lower cost
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