Thesis (M.Sc.D.)--Boston University School of Graduate Dentistry, May 20, 1966. / Bibliography included.

O carcinoma escamoso basalóide (CEB) tem sido considerado uma das variantes mais agressivas do carcinoma espinocelular (CEC), acometendo preferencialmente a base da língua, a hipofaringe e a laringe. Um total de 776 carcinomas espinocelulares primários de boca, cirurgicamente excisados entre 1970 e 2000, foram revisados dos arquivos dos Departamentos de Patologia e de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia do Hospital do Câncer A.C. Camargo. Dezessete CEBs foram identificados e analisados comparativamente a 27 CECs pouco diferenciados com estadiamento e localização equivalentes, quanto ao gênero, idade, raça, tabagismo, etilismo, localização do tumor primário, classificação pelo sistema TNM, tratamento, ocorrência de recidiva tumoral, metástases em linfonodos regionais, a distância e de segundo tumor primário. Analisaram-se a morfologia tumoral e a expressão dos marcadores de proliferação celular e apoptose: PCNA, p53, Bax e Bcl-X. As probabilidades de sobrevida, acumuladas nos períodos de 5 e 10 anos para ambos grupos tumorais, foram calculadas pelo método de Kaplan-Meier, sendo a influência das variáveis clínicas e microscópicas no prognóstico avaliada pelo modelo de regressão de Cox. Morfologicamente, a maioria dos CEBs apresentou configuração tumoral sólida/lobular, disposição em paliçada das células periféricas, espaços císticos, comedonecrose, hialinização intra e peritumoral, disjunção epitélio tumoral/conjuntivo e associação com o componente escamoso. Nenhuma diferença estatística foi detectada entre os grupos CEB e CEC quanto às características demográficas, clínicas e quanto à expressão dos marcadores PCNA, p53 e Bcl-X. O CEB apresentou, comparativamente ao CEC, maior expressão da proteína Bax (p=0,031). As probabilidades de sobrevida global, sobrevida específica e sobrevida livre de doença acumuladas em 5 e 10 anos para os pacientes com CEB e com CEC foram semelhantes. O estadiamento clínico N constituiu um fator prognóstico independente para os pacientes com carcinoma escamoso basalóide e carcinoma espinocelular pouco diferenciado na mucosa bucal. A morfologia tumoral, bem como a expressão dos anticorpos PCNA, p53, Bax e Bcl-X, não foram fatores prognósticos significativos. Estes resultados sugerem que, o CEB e o CEC pouco diferenciado com localização e estadiamento clínico equivalentes na boca, apresentam comportamento clínico e biológico similares. Assim sendo, os pacientes acometidos por estes tumores podem ser submetidos aos mesmos protocolos terapêuticos. / Basaloid squamous cell carcinoma (BSCC) has been recognized as an agressive variant of conventional squamous cell carcinoma (SCC), that arises predominantly in the base of the tongue, hypopharynx and larynx. A total of 776 cases of surgically excised primary oral squamous cell carcinomas from the files of Otohinolaryngology, Head and Neck Surgery, and Pathology Departments of the Cancer Hospital A.C. Camargo, from 1970 to 2000 were retrospectively reviewed. Seventeen cases of BSC were identified and clinically compared with 27 poorly differentiated SCC, with equivalent localization and clinical stage using the following parameters: patient gender, age, race, tobacco and alcohol abuse, stage by the TNM-UICC, localization, lymph nodes involvement, treatment, local and cervical recurrences, distant metastasis and second primary tumors. In addition, we investigated the morphologic features and the expression of proliferative and apoptose markers: PCNA, p53, Bax and Bcl-X. The 5 and 10-year survival rates were calculated by Kaplan-Meier method and the prognostic value of the clinical and microscopic variables was obtained by Cox regression models. The histopathologic analysis showed that BSCC was arranged in solid lobules with abundant comedo-type necrosis, peripheral cells with nuclear palisading, microcystic spaces, stromal and intratumoral hialinosis, tumor/stroma disruption and association with squamous cell component. No statistically significant differences were found between group BSSC and SCC, with regard to clinical features and immunohistochemical reactivity for antibodies PCNA, p53 and Bcl-X. In comparison with SCC, BSCC group showed higher Bax score (p=0,031). The 5-year and 10-year overall survival, cancer specific survival and disease free survival rates showed no significant differences between BSC and SCC groups. The N clinical stage presented an independent prognostic factor for the oral BSC and SCC patients. The histological features and immunohistochemical markers: PCNA, p53, Bax , and Bcl-X, showed no prognostic value. These results suggest that the clinical and biologic course of BSCC is similar to the SCC when clinical stage, site and treatment are matched. In this way, patients presenting these tumors can undergo the same therapeutical protocols.

Primary cell culture is limited by the increase in cellular levels of p16INK4a in response to an in vitro culture environment and, in conjunction with telomere shortening following cell division, presents a barrier to cellular proliferation. The use of transformed cell lines is limited for studies wherein the aim is to generate data akin to an in vivo environment as commonly such cell lines achieve their immortal benefits by down regulating important tumour suppressive mechanisms and inhibiting cell cycle checkpoints. Normal Human Oral Keratinocyte (NHOK) cells expressing shp16+hTERT were generated and compared to NHOK cells expressing Bmi1 +hTERT using an optimized retroviral transduction protocol and compared simultaneously to an epidermal control. Population doubling assessment of cell lines revealed that shp16+hTERT was not sufficient to extend replicative lifespan in the absence of p53 whilst cell lifespan extension was observed not only in cells expressing Bmi1+hTERT, but also in cells transduced with Bmi1 alone. Upon characterization, cells showed expression of p53 and responsiveness to UVB-induced apoptosis as demonstrated by an increase in p53 expression. NHOKBmi1+hTERT displayed adaptability to serum free culture when weaned into keratinocyte serum free media (KSFM) and retained the ability to stratify into multiple layers when supported by feeders on polycarbonate membrane inserts. The cell line NHOKBmi1+hTERT will be beneficial for in vitro studies looking to utilise an alternative to transformed or spontaneously derived cell lines and holds potential for further development and optimization into a well characterized SSE in a user friendly, and reproducible system for the testing for oral products.

South Asians residing in the UK are known to be significantly different in terms of socio-economic and cultural influences from the UK population in general. They are at substantially higher risk of developing oral cancer (OSCC) and the potentially malignant disorder (PMD) oral submucous fibrosis (OSF). To overcome barriers to conventional health service use, a mobile dental unit was the base for screening within the South Asian community. Bilingual advocates ensured cultural acceptability and actively recruited high-risk individuals for screening as well as being involved at the secondary referral centre to facilitate attendance for definitive diagnosis of positive screened individuals. In total 1596 high-risk individuals were screened and 5.4% referred with suspicious lesions. No OSCC was detected in any positive screened individuals but PMDs were confirmed in 29%, with dysplasia (15%) and OSF (9%) the commonest lesions referred. Due to the complex presentation of OSCC the most appropriate gold standard screening outcome is the detection of individuals who cannot be discharged from long-term follow-up at the secondary referral centre. On this basis screening specificity was 99% and Positive Predictive Value (PPV) 79%. The low PPV was attributed to the high prevalence of complex oral mucosal lesions (46%) that cannot be definitively diagnosed as benign by visual examination alone, which indicates diagnostic aids are required for screening this high-risk population. 4 Compliance with referral for positive screened individuals was only 76% and immediate incisional biopsy of positive screened individuals would be needed to improve this. In addition to histological detection of dysplasia, molecular markers of disease could readily be investigated by immunohistochemistry and the expression of keratins are ideal candidates due to their responsiveness to pathological signalling and abnormal expression in oral (pre)cancer. Analysis of 28 fresh frozen OSF samples and 6 site-matched controls, using a panel of 22 monoclonal antibodies, revealed changes in keratin 17 expression which correlated with disease severity. A mobile dental unit staffed by suitably experienced dentists and cultural advocates and equipped for immediate histological diagnosis of positive screened individuals is required in order to undertake effective and ethical oral cancer screening in high-risk UK based South Asian populations.

Following the end of the Second World War, the late 1940s witnessed a dramatic and rapid transformation in working-class living conditions enacted via the Welfare State, and largely experienced through an enormous expansion in public housing. Ernesettle is a product of this boom. One of seven new estates constructed as part of Plymouth’s programme of reconstruction, it follows a conceptual blueprint laid out in The Plan for Plymouth, a document compiled in 1943 by town planner Patrick Abercrombie and city engineer James Paton-Watson. Designed after a ‘neighbourhood’ model, the Plymouth Plan estates were to provide for life from cradle to grave, incorporating schools, workplaces, clinics, churches, pubs, and shops as well as housing and green space. The progressive social programme propounded by post-war neighbourhood designers strove towards social homogeneity, a strategy that sought to reconcile interests across the class and political spectrum. This thesis examines the results of those ambitions, using oral history accounts of Ernesettle to consider if and how council housing of the 1940s and 50s affected the material and social circumstances of its residents. By focusing on residents’ narratives of daily life between 1950 and 1980, I document a high point in council estate history comprising: a neighbourhood culture of mutual support and lively street life; a domestic culture, closely bound to the nuclear family and the home as a site of consumption; an associational culture of clubs, sports, the church, the pub, and social club; and a working culture of full male employment, collective representation, and increasing employment opportunities for women. The function of the neighbourhood in a process of drawing working-class populations into the mid 20th century cultural mainstream, and its subsequent association with their post-1980s expulsion to the social margins, provides a recurrent research theme underpinning my discussion of Ernesettle life as I explore how changes over time corresponded with the status of residents and their sense of place in society at large.

Oral squamous cell carcinoma (SCC) is a lethal, deforming disease of global significance and rising incidence. In 2011, 6,767 new cases and 2,056 deaths occurred in the UK. Cancers are preceded by oral potentially malignant disorders (PMD), recognizable mucosal diseases harbouring significantly increased risk of carcinoma. These manifestations offer clinicians a ‘therapeutic window’ to intervene during carcinogenesis, although contemporary practice remains unable to predict individual lesion behaviour or quantify risk for malignant transformation. No clear management guidelines exist and available scientific literature is unable to answer the fundamental question whether intervention prevents cancer. This MD thesis includes 7 published papers on oral pre-cancer and 4 observational studies from a specialist PMD service coordinated by the author in Newcastle upon Tyne in Northern England. PMD management involves a complex interaction between patients, clinicians’ views on diagnosis and treatment and histopathological assessment of mucosal biopsy specimens. Uncertainty regarding the ‘potentially malignant state’ remains a pernicious influence throughout. Newcastle PMD patients were profiled as predominantly male, with a median age of 60yrs, and regular users of both tobacco and alcohol. Most presented with single-site disease, primarily leukoplakia on the floor of mouth and ventro-lateral tongue, with over 80% exhibiting epithelial dysplasia on histopathological examination. Approximately 70% underwent interventional therapy using CO2 laser surgery. 840 laser treatments were performed between 1996 and 2015 and the efficacy of laser intervention was examined by reviewing clinico-pathological details and clinical outcome for 590 PMD patients followed for a mean of 7.3yrs. Histopathology required ‘up-grading’ in 36% following definitive examination of laser excision specimens. 74.2% of patients were disease free, primarily younger patients with ‘low-grade’ dysplasia, 9% exhibited persistent disease and were older with gingival lesions often proliferative verrucous leukoplakia (PVL). In 12%, unexpected SCC was identified on excision, whilst 4.8% transformed to malignancy. Interventional laser surgery facilitates definitive diagnosis and efficacious treatment, allows early diagnosis and treatment of SCC, identifies patients at risk of progressive disease and defines clinical outcome categories. Evidence is lacking, however, that intervention halts the progress of carcinogenesis. Multi-centre, prospective, randomized, controlled trials are needed to confirm the efficacy of interventional surgery, to characterise PMD natural history and to disseminate research findings. It is hoped that the clinical work presented in this MD thesis will inform and encourage further research into PMD and lead to a reduction in the incidence of malignancy and improved morbidity and mortality.

Foram realizadas 52 entrevistas e um workshop em um período pouco superior a um ano como parte de um projeto de história dos 50 anos de uma agência de fomento. Esse material (a evidência oral) é o material primário utilizado neste presente estudo. Também foram utilizadas 17 entrevistas de um projeto de história dos 40 anos da mesma agência. O material foi lido e foram retirados trechos relacionados a um possível conceito de ciência que poderia ser abstraído dessa evidência oral. Além disso, foram estudados os conceitos de ciência de alguns autores (Donald Stokes, Fernand Braudel, Francis Bacon, Karl Popper, Paul Feyerabend, Thomas Kuhn e Vannevar Bush). Esses conceitos e citações de suas obras foram apresentados (evidência escrita). Em seguida, foram apresentados aproximações e distanciamentos dessas duas evidências. Finalmente, um conceito de ciência resultante, ou o caminho percorrido pelo conceito de ciência, foi apresentado. Conceito este que se baseia primariamente na evidência oral. A possibilidade de formular um conceito de ciência não baseado somente nessa evidência, mas a utilizando primariamente, era o objetivo principal deste estudo. / 52 interviews and a workshop were performed in a period just over a year as part of a 50-year history project of a research funding agency. This material (the oral evidence) is the primary material used in the present study. 17 interviews of a 40-year history project of the same agency were also used. The material was read and excerpts were extracted related to a possible concept of science which could be abstracted from such oral evidence. Moreover, the concepts of science of some authors were studied (Donald Stokes, Francis Bacon, Karl Popper, Paul Feyerabend, Thomas Kuhn e Vannevar Bush). These concepts and quotations from their works were presented (written evidence). Next, similarities and dissimilarities of both evidences were presented. Finally, a resulting concept of science, or the path walked by the concept of science, was presented. Such concept is based primarily on the oral evidence. The possibility of formulating a concept of science not based only on this evidence, but using it primarily, was the main objective of this study.

Esta pesquisa de mestrado se destina a trazer uma reflexão, a partir da proposta de Produção Partilhada do Conhecimento, acerca do encontro entre a diversidade de saberes orais - presente na cultura oral e popular do Brasil -, e as atuais propostas de transformação das pesquisas nas Ciências Humanas. Por meio da História Oral, etnografia e pesquisa participante contextualizamos academicamente como pode acontecer esta parceria para a produção de conhecimento, em diálogo com a história de vida de Mestre Alcides de Lima Tserewaptu e relatos de vivências seus e de parceiras(os) do Centro de Estudos e Aplicação da Capoeira (CEACA), na cidade de São Paulo. A narrativa de sua jornada pela tradição oral e cultura popular em ambientes institucionais de ensino, tais como a Universidade de São Paulo USP e a Escola Municipal de Ensino Fundamental Desembargador Amorim Lima, contando com o congado e a capoeira, manifestações de resistência e luta pela valorização cultura afro-brasileira, proporcionou a análise de possibilidades de caminhos para se pensar a interlocução destes saberes orais com as propostas teóricas nas áreas de história, cultura, antropologia e educação. A antropologia visual foi um dos meios de partilha e registro dos processos da pesquisa (entrevistas, rituais, batizados, reuniões). A prática - já desenvolvida pelo CEACA na produção de material audiovisual -, junto ao reconhecimento de que as tradições das culturas orais não podem ser transpostas para o escrito, garantiram uma colaboração mais coletiva e a legitimação desse método de pesquisa. Um dos resultados do trabalho é um registro audiovisual no qual o Mestre Alcides e algumas pessoas do CEACA colaboraram com a narrativa, inserção de materiais que representam a essência do grupo, seus valores, motivações e práticas em diálogo com as discussões teóricas. / This masters research intends to bring a reflection - from the proposal of Shared Knowledge Production - to the encounter between the diversity of oral knowledge - present in the oral and popular culture of Brazil -, and the current proposals for the transformation of researches in the Human Sciences. Through Oral History, ethnography and participant research, we seek to contextualize academically how this partnership for the production of knowledge, in dialogue with the life history of Mestre Alcides de Lima Tserewaptu, griô, and among the narratives of his experiences and from his partners at Center for the Study and Application of Capoeira (CEACA), in the city of São Paulo. The narrative of his journey through oral tradition and popular culture in educational institutions such as University of São Paulo and School Amorim Lima, counting on the congado and capoeira, manifestations of resistance and struggle for the valorization of Afro- Brazilian culture, provided the analysis of possibilities of ways to think the interlocution of these oral knowledge with theoretical proposals in the areas of history, culture, anthropology and education. Visual anthropology was one of the means of sharing and recording research processes (interviews, rituals, baptisms, meetings). The practice already developed by CEACA in the production of audiovisual material, allied with the recognition that oral traditions of oral cultures can not be transposed into writing, ensured a more collective collaboration and the legitimation of this method of research. One of the results of the work is an audiovisual record in which Mestre Alcides and some people of CEACA collaborated with the narrative, insertion of materials that represent the essence of the group, their values, motivations and practices in dialogue with the theoretical discussions.

Saquinavir é um medicamento antirretroviral desenvolvido para inibir a protease do vírus da imunodeficiência humana. Este fármaco apresenta várias limitações em função dos seus efeitos colaterais, baixa biodisponibilidade e sensorial não agradável. A nanoencapsulação de fármacos é uma técnica promissora para superar esses problemas. O objetivo deste trabalho é desenvolver suspensões aquosas de nanocápsulas poliméricas contendo saquinavir utilizando uma mistura de poli-ε-caprolactona (PCL) e poli- ε-caprolactone triol (PCL-T) visando uma formulação líquida adequada para o tratamento de crianças infectadas. As nanocápsulas foram preparadas pela técnica de deposição interfacial de polímeros pré-formados. A análise de diâmetro médio de partícula foi realizada por diferentes técnicas, difração a laser, dispersão de luz dinâmica e análise de rastreamento de nanopartículas. O potencial zeta foi determinado por mobilidade eletroforética, o pH por potenciometria e o teor de fármaco e a taxa de encapsulação por cromatografia líquida de alta eficiência com detecção no ultravioleta. O ensaio de liberação in vitro foi realizado com membrana de diálise e coleta das amostras nos intervalos de 0-120 horas, a 37°C. A estabilidade foi verificada nos tempos 0, 15, 30, 60 e 90 dias, ao abrigo da luz, em temperatura ambiente e com o monitoramento do pH, potencial zeta, diâmetro, teor de fármaco e através da análise de retroespalhamento de luz. A morfologia foi observada por microscopia eletrônica de transmissão. A citotoxicidade em linfócitos T humano foi determinada pelo teste de exclusão de azul de tripan e o mascaramento do sabor de saquinavir pela língua eletrônica. Todas as formulações apresentaram tamanho nanométrico entre 172 ± 18 e 225 ± 4 nm e uma boa distribuição de tamanho. A taxa de encapsulação de saquinavir foi maior que 99%. As nanocápsulas apresentaram potencial zeta negativo, valores de pH levemente ácido e morfologia esférica. Os parâmetros avaliados na estabilidade mantiveram-se constantes ao longo do tempo analisado. O ensaio in vitro mostrou uma liberação controlada de saquinavir. As formulações não apresentaram toxicidade in vitro e foram capazes de mascarar o sabor do saquinavir. Portanto, a associação de polímeros é eficaz para a encapsulação de saquinavir, apresentando características nanotecnológicas adequadas para a sua administração. / Saquinavir is an antiretroviral drug designed to inhibit the human immunodeficiency virus protease. This drug presents several limitations regarding side effects, very low bioavailability and sensory not pleasant. The drug nanoencapsulation is a promising technique to overcome these issues. The aim of this work is to develop aqueous suspensions of polymeric nanocapsules containing saquinavir using poly-ε-caprolactone (PCL) and poly-ε-triol caprolactone (PCL-T) towards a liquid formulation suitable for the treatment of infected children. The nanocapsules were prepared using the technique of interfacial deposition of preformed polymers. The characterization study was conducted by examining the average particle diameter by three techniques, the laser diffraction, the dynamic light scattering and the nanoparticle tracking analysis. The zeta potential was evaluated by electrophoretic mobility, the pH by potentiometry and drug content and encapsulation rate by high performance liquid chromatography with UV detection. The in vitro release assay was carried out in a dialysis membrane with analysis at 0-120 hours, at 37 °C. The stability was checked at 0, 15, 30, 60 and 90 days, protected from light, at room temperature and by monitoring the pH, zeta potential, diameter, drug content and by multiple light scattering analysis. The morphology was observed by transmission electron microscopy. The cytotoxicity in human T lymphocytes was determined by exclusion of trypan blue test and the taste masking by the electronic tongue. All formulations presented nanometric size between 172 ± 18 and 225 ± 4 nm and a good size distribution. The drug encapsulation rate was higher than 99%. The nanocapsules presented negative zeta potential, pH values slightly acidic and spherical morphologies. The parameters evaluated in stability remained constant over time analyzed. The in vitro assay showed a controlled drug release from nanocapsules formulations. The developed formulations showed no toxicity and were able to mask the taste of saquinavir. The association of polymers is effective for saquinavir nanoencapsulation presenting suitable nanotechnological features for drug administration.

Foram realizadas 52 entrevistas e um workshop em um período pouco superior a um ano como parte de um projeto de história dos 50 anos de uma agência de fomento. Esse material (a evidência oral) é o material primário utilizado neste presente estudo. Também foram utilizadas 17 entrevistas de um projeto de história dos 40 anos da mesma agência. O material foi lido e foram retirados trechos relacionados a um possível conceito de ciência que poderia ser abstraído dessa evidência oral. Além disso, foram estudados os conceitos de ciência de alguns autores (Donald Stokes, Fernand Braudel, Francis Bacon, Karl Popper, Paul Feyerabend, Thomas Kuhn e Vannevar Bush). Esses conceitos e citações de suas obras foram apresentados (evidência escrita). Em seguida, foram apresentados aproximações e distanciamentos dessas duas evidências. Finalmente, um conceito de ciência resultante, ou o caminho percorrido pelo conceito de ciência, foi apresentado. Conceito este que se baseia primariamente na evidência oral. A possibilidade de formular um conceito de ciência não baseado somente nessa evidência, mas a utilizando primariamente, era o objetivo principal deste estudo. / 52 interviews and a workshop were performed in a period just over a year as part of a 50-year history project of a research funding agency. This material (the oral evidence) is the primary material used in the present study. 17 interviews of a 40-year history project of the same agency were also used. The material was read and excerpts were extracted related to a possible concept of science which could be abstracted from such oral evidence. Moreover, the concepts of science of some authors were studied (Donald Stokes, Francis Bacon, Karl Popper, Paul Feyerabend, Thomas Kuhn e Vannevar Bush). These concepts and quotations from their works were presented (written evidence). Next, similarities and dissimilarities of both evidences were presented. Finally, a resulting concept of science, or the path walked by the concept of science, was presented. Such concept is based primarily on the oral evidence. The possibility of formulating a concept of science not based only on this evidence, but using it primarily, was the main objective of this study.