Tese (doutorado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Prorgama de Pós-Graduação em Ciências da Saúde, 2015. / Submitted by Ana Cristina Barbosa da Silva (annabds@hotmail.com) on 2015-03-26T16:34:53Z No. of bitstreams: 1 2015_FloraAparecidaMilton.pdf: 14443405 bytes, checksum: 2f69813bfbeca0cccbad7f9286096b83 (MD5) / Approved for entry into archive by Ruthléa Nascimento(ruthleanascimento@bce.unb.br) on 2015-05-04T13:51:55Z (GMT) No. of bitstreams: 1 2015_FloraAparecidaMilton.pdf: 14443405 bytes, checksum: 2f69813bfbeca0cccbad7f9286096b83 (MD5) / Made available in DSpace on 2015-05-04T13:51:55Z (GMT). No. of bitstreams: 1 2015_FloraAparecidaMilton.pdf: 14443405 bytes, checksum: 2f69813bfbeca0cccbad7f9286096b83 (MD5) / A prevalência de obesidade, associada à resistência insulínica e diabetes tipo 2 vem aumentando nas últimas décadas. As tiazolidinadionas (TZDs) são agonistas do receptor gama ativado por proliferadores peroxissomais (PPARγ) com eficiente ação sensibilizadora da insulina. Contudo, o uso das TZDs está associado a efeitos adversos como o ganho de peso, retenção de líquido, edema, insuficiência cardíaca congestiva e perda óssea. GQ-16 é um agonista parcial e específico do PPARγ que melhorou a tolerância à glicose e a sensibilidade à insulina de camundongos submetidos a dieta hiperlipidica de forma semelhante à rosiglitazona, mas, ao contrário dessa, não induziu ganho de peso ou edema. Considerando que um dos principais alvos farmacológicos das TZDs é o tecido adiposo, o objetivo desse estudo foi determinar o efeito de GQ-16 no transcriptoma de adipócitos 3T3-L1 maduros e comparar sua ação com a da rosiglitazona. A análise realizada pela técnica de microarranjo revelou que esses ligantes modificam a expressão gênica de forma diferenciada. Enquanto a rosiglitazona modificou a expressão de 1156 genes, GQ-16 regulou a expressão de apenas 89. Dos 544 genes regulados positivamente pela rosiglitazona (47%), somente 22 (4,2%) foram regulados pelo GQ-16. No mesmo sentido, dos 612 genes regulados negativamente pela rosiglitazona (53%), apenas 24 (4%) foram reprimidos pelo GQ-16. Assim, 46 genes foram regulados simultaneamente pela rosiglitazona e GQ-16, ou seja, uma concordância de somente 4%. Além disso, GQ-16 regulou a expressão de 43 genes (18 ativados e 25 reprimidos) não controlados pela rosiglitazona. A maior semelhança entre o GQ-16 e a rosiglitazona foi sobre a repressão de genes relacionados à resposta inflamatória como o Dcn, Vcam1, Orm2 e Lox, por exemplo. A comparação do GQ-16 com outros agonistas parciais de PPARγ (MRL24 e SR1664) revelou efeitos similares, tanto sobre os genes ativados quanto os reprimidos. Nós propomos que o reduzido efeito sobre genes relacionados à adipogênese e a habilidade do GQ-16 em reprimir eficientemente alguns genes responsivos ao PPARγ relacionados ao processo inflamatório, podem contribuir para o efeito sistêmico sobre a sensibilidade à insulina sem ganho de peso. Novos estudos são necessários para examinar se as similaridades entre a regulação transcricional do GQ-16 e da rosiglitazona estariam envolvidos no efeito terapêutico do GQ-16. / The prevalence of obesity associated with increased insulin resistance and type 2 diabetes has been increasing in the last decades. Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance. However, TZDs have well-established side effects such as weight gain, fluid retention and edema, congestive heart failure and bone loss. GQ-16 is a specific PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in a murine model of obesity and diabetes similarly to rosiglitazone, but does so without inducing weight gain or edema. Since one of the main pharmacological targets of TZDs is adipocyte tissue, the aim of this study was to determine how GQ- 16 influences PPARγ activity at the transcriptome wide level on PPARγ-dependent gene expression in mature 3T3-L1 adipocytes and also to compared these effects with rosiglitazone. Microarray analysis revealed these ligands modify gene expression in a different manner. Rosiglitazone changed the expression of 1156 genes whereas GQ-16 only changed the expression of 89 genes. Of the 544 genes upregulated by rosiglitazone (47%), only 22 (4.2%) were also regulated by GQ-16. Similarly, of the 612 genes repressed by rosiglitazone (53%), only 24 (4%) were by GQ-16. Therefore, just 46 genes were regulated by both ligands. Furthermore, GQ- 16 regulated the expression of 43 genes (18 activated and 25 repressed) that were not controlled by rosiglitazone. Whereas GQ-16 showed weak effects upon most rosiglitazone regulated genes, a subset of weakly rosiglitazone induced and strongly rosiglitazone repressed genes displayed disproportionately stronger responses to GQ-16. The greatest similarity between GQ-16 and rosiglitazone was upon repressed genes related to inflammatory response such as Dcn, Vcam, Orm2 and Lox, for example. Comparison of GQ-16 with other PPARγ partial agonists (MRL24 and SR1664) revealed similar effects on transcriptional repression. We propose that the ability of GQ-16 displays a continuum of partial agonist effects and that the ability of GQ-16 to efficiently repress some PPARγ responsive genes may partly explain systemic effects on insulin sensitivity without weight gain. Further studies are necessary to examine whether the similarities between transcriptional regulation of GQ-16 and rosiglitazone were involved in the therapeutic effect of GQ-16.

Submitted by Caroline Falcao (caroline.rfalcao@ufpe.br) on 2017-04-04T19:21:33Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 2011-Dissertação-RicardoSilva.pdf: 2010474 bytes, checksum: fa5ce1fda4e849fa7743b5d5b4e55481 (MD5) / Made available in DSpace on 2017-04-04T19:21:33Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) 2011-Dissertação-RicardoSilva.pdf: 2010474 bytes, checksum: fa5ce1fda4e849fa7743b5d5b4e55481 (MD5) Previous issue date: 2011-05-30 / Dentre vários compostos sintetizados pelo Laboratório de Planejamento e Síntese de Fármacos (LPSF) da Universidade Federal de Pernambuco, o derivado tiazolidínico (3-(2-Bromo-benzil)-5-(5-bromo-2-metoxi-benzilideno)-tiazolidina-2,4-diona) (LPSF/GQ-113B) apresentou importante atividade antiinflamatória em ratos Wistar. Tal resultado despertou nosso interesse no desenvolvimento e validação de um método bioanalítco para determinação do LPSF/GQ-113B em fluídos biológicos. Nesse contexto, um método bioanalítico sensível e seletivo foi desenvolvido e validado utilizando a técnica de Cromatografia Líquida de Alta Eficiência acoplada a um detector ultravioleta (CLAE-UV) para quantificação do LPSF/GQ-113B em plasma de ratos Wistar. O método envolveu precipitação das proteínas plasmática com acetonitrila e, o LPSF/GQ-113B foi separado utilizando uma fase móvel composta por uma mistura de acetonitrila/água e ácido acético (85:14:1 v/v/v) eluida de forma isocrática através de uma coluna analítica Phenomenex® C18 5μ (150mm x 4.6mm) a uma temperatura de 40 ºC. O comprimento de onda para a detecção foi de 254 nm. A curva de calibração foi linear na faixa de 500-16000 ng/ml/L, com coeficientes de determinação (r²) próximos da unidade (0.997-0.999). Os rendimentos de extração para as concentrações de 1500, 7500 e 13.000 ng/ml/L foram 94.2%, 92.2% e 97.3%, respectivamente. O limite de quantificação para o LPSF/GQ-113B foi de 500 ng/mL. A validação do método incluiu a análise dos parâmetros analíticos de exatidão e precisão intra-dia e inter-dia que se apresentaram dentro dos limites exigidos pela legislação pertinente. Dessa forma, o método proposto pode ser aplicado para determinação quantitativa do LPSF/GQ-113B em plasma de ratos Wistar em estudos farmacológicos, toxicológicos, farmacocinéticos e de biodisponibilidade. / Among several compounds synthesized by the Laboratory of Planning and Synthesis of Drugs, from Federal University of Pernambuco, the thiazolidine derivative (3 - (2-bromo-benzyl) -5 - (5-bromo-2-methoxy-benzylidene)-thiazolidine -2,4-dione) (LPSF/GQ-113B) showed significant antiinflammatory activity in rats. This result has stimulated our interest in the development and validation of a method for determining LPSF/GQ-113B in biological fluids. In this context a fast, sensitive, and selective detection has been developed and validated for quantifying LPSF/GQ-113B in rat plasma by high-performance liquid chromatography coupled UV detector method . A plasma protein precipitation method was used with acetonitrile and, LPSF/GQ-113B was separated using a mobile phase (acetonitrile/water/acetic acid (85:14:1 v/v/v)) on the analytical column Phenomenex ® C18 5μm ( 150mm x 4.6mm) stored into the oven at 40 ºC temperature. The wavelength selected for detection was 254 nm. Over the range 500-16000 ng/mL, the calibration curve was linear with coefficient of determination (r²) were close to unit (0.997564- 0.999765). The recoveries at concentrations of 500, 7500 and 13000 ng/mL were 94.2%, 92.2% and 97.3%. The lower limit of quantification obtained was 500 ng/mL. Validation of the method included analysis of the analytical parameters of accuracy and within-batch and between-batch were inside the limits required by the competent authorities. Thus, the proposed method can be applied for quantitative determination of LPSF/GQ-113B in plasma of Wistar rats in pharmacological studies, toxicological, pharmacokinetic and bioavailability.

Men are bombarded with contradictory masculine imagery in the media. The perfect man must be aggressive but not violent, sensitive but not emotional, healthy, active and smart without being an idealist, overachiever or too bookish. Heterocentric male focused lifestyle magazines rival women’s magazines in number and availability. Some men look to these images as a tool by which to gauge their masculinity and learn their social role performance. This inquiry includes a content analysis of four major men's lifestyle magazines over a 12-month period in which four new masculinities: certitude, irony, new sexism and double voicing were critiqued. Elements of costume, nonverbal expressions and activity level in the photographs of men and women were examined. The findings indicate that Maxim and Stuff were deluged with displays of certitude of gender roles, irony, "new sexism" and double voicing. Playboy had a high level of gender certitude, marginal levels of new sexism and irony and low levels of double voicing. Lastly, GQ had relatively high levels of gender certitude but it had very low levels of the other masculinities.

<p>Regulators of G protein signaling (RGS) proteins are key negative regulators of Gα signaling, a branch of G-protein-coupled receptor (GPCR)-mediated signal transduction. Approximately 35% of drugs approved by the Food and Drug Administration (FDA) target GPCRs, so it is not surprising that the discovery of RGS proteins has triggered an interest in them as new drug targets. Even though many studies have been shown the involvement of RGS proteins in cancers, there is still a knowledge gap in understanding function and regulation of RGS proteins in these diseases. Consequently, in this thesis, I explored roles of two RGS proteins that have been implicated in cancers.</p> <p>RGS2 is proposed to act as a tumor suppressor in many different cancers, such as breast cancer, bladder, and ovarian cancer. Here, we investigated if RGS2 also plays a tumor suppressor role in UM, whose growth is driven by overactivated Gαq/11 signaling. We found that increased expression levels of RGS2 inhibit cell growth of UM 92.1 and Mel-202 cells. Mechanistically, this cell growth inhibition is dependent on the association between RGS2 and Gαq, but independent of its canonical GTPase-accelerating protein (GAP) activity. Furthermore, RGS2 inhibited the Mitogen-activated protein kinases (MAPK) signaling, downstream of Gαq, while leaving Yes-associated protein 1/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation unaffected. These data indicate a tumor suppressor role for RGS2 in UM and proposes RGS2 stabilization as a potential therapeutic targeting strategy. </p> <p>In contrast to RGS2, RGS20 contributes to cancer progression, particularly in breast cancer. However, how RGS20 is regulated is understudied. Palmitoylation, a reversible post-translational modification, regulates functions of other RGS proteins, and RGS20 is predicted to be palmitoylated. We provided direct evidence of RGS20 palmitoylation in cells and validated the palmitoylation site as the conserved cysteine (Cys148) in the RGS domain. Our results showed that palmitoylation on this site does not affect its GAP activity and subcellular localization, but it affects the association between RGS20 and active Gαo, and inhibition of Gαo-mediated signaling. This study serves as a foundation for future studies in furthering understating the role of palmitoylation in RGS20 function and its possible implications in cancer biology. </p>

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The aim of this study has been to, from a comparative perspective examine how the use of western models in Chinese advertising are perceived by chinese exchange students living in Sweden. The scientific approach in this study has been both with semiotic picture analysis and qualitative interviews. The study's empirical material has consisted of pictures of white models in fashion magazines published in China for example Vouge China. These pictures were presented to the respondents during the interviews, and questions were asked about them and the answers is also a part of this study's empirical material. The theoretical perspectives used in this study is based on theories about whiteness, stereotypes and occidentalism. The results in the study has shown that the whithe models are presented with high status both in the semiotic picture analysis and the qualitative interviews. It has also shown that the respondents prefer asian models over white in advertising in China, especially with products conected to the body and that the white stereotype is almost described identiaclly by all the respondents. Finally the result has found that the ethnicity is connected to picture enviroments, in that way if it is a white model it should be a western enviroment.

This thesis widens the application of intersectionality into the study of visual media. This study examines representational patterns on GQ magazine covers issued in the US with specific regards to gender-race-sexuality intersections. Also, this study seeks to grasp what meaning is conveyed via those representational patterns in conjunction with the visual and linguistic modes, and what social effect it imparts. The study employs a mixed-method approach combining the quantitative content analysis with the social semiotics, and the inter-categorical methodological approach to intersectionality. The findings show that GQ magazine employs the same representational patterns acknowledged in culture and the magazines’ market. Those patterns manifest in the sexual objectification of women, racial exclusion, and emphasis on white heterosexual maleness. Additionally, the intersectional analysis revealed that women of colour and sexual minorities are in the least favourable position regarding representational patterns on GQ magazine.

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No description available.

Background: At the time of diagnosis, approximately 75% of all bladder cancers are Non-Muscle Invasive Bladder Cancers (NMIBC) - the standard treatment for these cancers is a Transurethral Resection of the Bladder Tumour (TURBT). Although, the vast majority of these cancers are not life-threatening, they have a high risk of recurrence (and progression, particularly in higher risk NMIBC), despite the use of adjuvant intravesical chemotherapy. Consequently, patients are kept on long term cystoscopic surveillance with endoscopic removal if recurrences are detected - this impacts on patients' quality of life and contributes to the high cost for the healthcare provider. Aims: The fundamental aim of this series of clinical studies, spanning 12 years, was to identify and implement, means of improving the efficiency in both processing and operating on patients with NMIBC to not only reduce recurrence, but also to reduce the duration of follow up and repeat operations. It was an evolutionary process where the findings in the preceding studies formed the basis of the subsequent one - while the aim of the individual studies were different, there was a clear link to the essential principles, thus forming a coherent collection of studies. Methods and results: The project was carried out in 3 phases (with 2 or 3 main studies in each phase, augmented by 1 to 2 linked studies - making the entire submission for PhD by publications a series of 12 studies, to date): Phase 1 (5 studies in this phase): The aim was to demonstrate the natural history of non-invasive bladder cancer and identify sub-categories of patients who could be discharged from surveillance at 5 years. This was initially achieved by evaluating a prospectively maintained cohort of non-invasive bladder cancer patients diagnosed between 1978 and 1984 at the Western General Hospital, Edinburgh. This study identified the importance of the recurrence rate at the first follow up cystoscopy (RRFFC) as an essential prognostic marker. This finding was further validated using 2 separate cohorts from a different Centre (the Royal Infirmary, Edinburgh) managed in the 80s and the 90s, respectively. The data confirmed that over the decades, recurrence patterns do change, possibly as a result of differing techniques and improvements in optics and instruments; however, what remained the same was the prognostic value of the RRFFC. Phase 2 (3 studies in this phase): The early recurrence was deemed to be the result of missed and tumours left behind at the initial TURBT, i.e. a marker of quality. However, RRFFC was only known 3 months after the initial surgery. Since the RRFFC was such an important prognostic factor, the aim of this phase was to determine the surgical factors contributing to the quality of TURBT and subsequently implement changes to the principles in carrying out the surgery to improve this quality. This was achieved by prospective collection of information regarding all patients undergoing TURBT for new bladder cancers, recording the tumour features, surgeon experience, if the resection was deemed to have been complete or not, and the pathological results. We identified that the detrusor muscle in the resected specimen and the experience of the surgeon were independent determinants of TURBT quality. This finding was validated in a further study using cohorts from another time period and another Centre - this allowed me to develop the concept of Good Quality White Light TURBT (GQWLTURBT) as the benchmark for the white light TURBT. Phase 3 (4 studies in this phase): Photodynamic Diagnosis assisted TURBT (PDDTURBT) was demonstrated in randomised controlled trials as a technique that reduces the recurrences in NMIBC. In the absence of evidence with this technique in the 'real life' setting nor comparisons with standardised, benchmarked white light TURBT technique, we performed a prospective controlled study comparing PDD-TURBT and GQ-WLTURBT, evaluating early and delayed recurrence rates in 2 separate studies. I also performed a multicentre UK study on the outcomes with PDD-TURBT and collaborated with other experts in Europe in producing a review article around Photodynamic Diagnosis and the cost effectiveness of this technique. Summary: This coherent series of studies has contributed to knowledge in bladder cancer surgery by, among others: (a) mapping the individual patient natural history of non-invasive bladder cancer; (b) confirming the importance of early recurrence as a strong prognostic indicator; (c) identifying predictors of this early recurrence and the quality of TURBT; (d) introducing the concept of the benchmark Good Quality White Light TURBT and (e) demonstrating the benefits of photodynamic diagnosis within a 'real life' setting.