Orientador: José Barreto Campello Carvalheira / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T19:07:24Z (GMT). No. of bitstreams: 1 Rocha_GuilhermeZweig_D.pdf: 7543896 bytes, checksum: 5459a8edf8e3ca3315e980f52bbbb876 (MD5) Previous issue date: 2014 / Resumo: Embora a obesidade seja reconhecida como importante causa de diabetes e doença cardiovascular, a associação entre obesidade e diferentes tipos de câncer tem recebido muito menos atenção. A associação entre obesidade e o desenvolvimento de câncer de cólon representa um dos principais avanços conceituais na patogênese do câncer de cólon da última década. Recentemente a atuação da inflamação subclínica da obesidade na carcinogênese ganhou destaque. Mecanisticamente acredita-se que a obesidade atue como promotor tumoral, e seus efeitos pró-tumorigênicos dependam principalmente da resposta inflamatória de baixo grau ocasionada pela obesidade que envolve a produção de citocinas inflamatórias e pró-tumorigênicas (TNF e IL-6). Uma das principais características da inflamação induzida por obesidade é a infiltração de macrófagos no tecido adiposo, produzindo citocinas inflamatórias e outros mediadores que interferem na sinalização insulínica. Inflamação e estresse de retículo que são conectadas em diversos níveis, são sistemas adaptativos de curto período de expressão necessárias para a função e sobrevivência do organismo, e ambas são prejudiciais quando ativadas cronicamente. Neste sentido, a ativação da PKR durante a inflamação e posterior ativação de JNK pela PKR, também interfere e prejudica a via de sinalização da insulina. A relação entre o câncer de cólon e obesidade pode ser devido a ação, em nível molecular, da inflamação subclínica de baixo grau e ao estresse celular causado por essa sinalização inflamatória. Sendo a PKR responsiva à sinalização inflamatória e também à via insulínica em outros tecidos, e relacionada à carcinogênese e à progressão em diversos tipos de câncer, a investigação de sua participação é relevante a medida que propicia o entendimento da fisiopatologia molecular de tumores de cólon. Assim, o objetivo principal do estudo foi avaliar o papel da PKR no desenvolvimento de tumores de cólon em camundongos submetido a dieta hiperlipídica. A ausência de PKR previne a formação de tumores. Além disso, aparentemente a ausência de PKR em células mielóides também confere proteção contra a resistência à insulina induzida por dieta hiperlipídica, reduzindo a inflamação induzida pela obesidade. Essas observações demostram que a PKR pode ser um ponto principal durante a carcinogênese associada à inflamação e pode representar um promissor alvo para a intervenção terapêutica / Abstract: Although obesity is recognized as a major cause of diabetes and cardiovascular disease, the association between obesity and different types of cancer has received much less attention. The association between obesity and the development of colon cancer is one of the major conceptual advances in the pathogenesis of colon cancer in the last decade. Recently the role of subclinical inflammation in obesity and in carcinogenesis gained prominence. Mechanistically it is believed that obesity acts as a tumor promoter, and their pro-tumorigenic effects depend mainly on low-grade inflammatory response caused by obesity, involving the production of inflammatory and pro-tumorigenic cytokines (TNF and IL-6). A key feature of obesity-induced inflammation is the infiltration of macrophages in adipose tissue, producing inflammatory cytokines and other mediators that interfere with insulin signaling. Reticulum stress and inflammation are connected on many levels and work as short period adaptive systems required for the function and survival of the organism, and both are detrimental when chronically activated. In this regard, the activation of PKR during inflammation and subsequent activation of JNK by PKR also interferes and impairs insulin signaling pathway. Thus, PKR can form a metabolically active inflammatory complex which then becomes part of the of insulin pathway and of the pathogens response pathway and control of translation sensible to nutrients. The relationship between colon cancer and obesity may be due to action at the molecular level, subclinical low-grade inflammation and cellular stress caused by this inflammatory signaling. PKR is responsive to inflammatory signaling and also to the insulin pathway in other tissues, and related to carcinogenesis and progression in several types of cancer. Thus, investigation of it's participation is relevant as it provides the understanding of the molecular pathophysiology of colon tumors. Thus, the main objective of the study was to evaluate the role of PKR in the development of colon tumors in mice subjected to a high-fat diet. The absence of PKR prevents the formation of tumors. Moreover, apparently the absence of PKR in myeloid cells also confers protection against resistance to insulin induced by a high-fat diet, reducing inflammation induced by obesity. These observations demonstrate that PKR can be a primary point during carcinogenesis associated with inflammation and may represent a promising target for therapeutic intervention / Doutorado / Fisiopatologia Médica / Doutor em Ciências

Orientadores: Ricardo Della Coletta, Tuula Anneli Salo / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-21T22:14:14Z (GMT). No. of bitstreams: 1 Pereira_ManoelaCarreraMartinezCavalcante_D.pdf: 2016848 bytes, checksum: 00c1511261259785b77ebe40882c174f (MD5) Previous issue date: 2012 / Resumo: Embora os genes HOX sejam conhecidos por atuarem na regulação de eventos importantes para o desenvolvimento embrionário, incluindo proliferação, diferenciação e migração celular, alterações no padrão de expressão têm sido frequentemente associadas ao desenvolvimento de neoplasias malignas. Estudos em nosso laboratório caracterizaram o perfil de expressão dos 39 membros da família HOX de genes homeobox em amostras orais de mucosa normal e carcinoma espinocelular (CEC), identificando genes diferencialmente expressos. Dentre estes genes destacou-se HOXA10, que tem a sua expressão associada a fenótipos importantes para o desenvolvimento tumoral e ao prognóstico. O objetivo deste estudo foi confirmar os níveis elevados de expressão de HOXA10 em CECs orais em comparação a mucosa oral normal e analisar o efeito da superexpressão e neutralização do gene HOXA10 na modulação dos principais eventos biológicos associados ao fenótipo tumoral. Os níveis de HOXA10 foram avaliados por imuno-histoquímica e qRT-PCR e os efeitos de HOXA10 sobre a proliferação, apoptose, adesão, transição epitélio-mesenquima (TEM), migração e invasão celular foram avaliados em clones celulares de queratinócitos normais HaCaT superexpressando HOXA10 e em clones da linhagem de carcinoma de língua HSC-3 expressando uma sequência de shRNA (short harpin RNA) para neutralizar a expressão de HOXA10. A expressão de HOXA10 foi significantemente maior nas amostras de CEC oral quando comparado com as amostras de tecido normal. A superexpressão de HOXA10 nas células HaCaT significantemente aumentou os níveis de expressão de N-caderina e ?-catenina, sem alteração no perfil protéico. Enquanto a adesão das células HaCaT com superexpressão de HOXA10 foi reduzida na superfície sem tratamento (plástico), na superfície tratada com colágeno tipo I foi significantemente aumentada, condizendo com o maior potencial migratório adquirido por estas células. A neutralização de HOXA10 significantemente reduziu a capacidade proliferativa das células HSC-3. Em adição, o silenciamento de HOXA10 induziu significantemente a expressão de marcadores da TEM, a adesão celular e os potenciais de migração e invasão das células HSC-3. Tanto a superexpressão quanto a neutralização de HOXA10 não modularam as taxas de apoptose. Em conclusão, os resultados deste estudo sugerem que a expressão de HOXA10 modula eventos importantes para o desenvolvimento e progressão dos CECs orais / Abstract: Although HOX genes are known for acting in the regulation of important events during embryogenesis, such as cellular proliferation, differentiation and migration, alterations in their expression patterns have been frequently associated to the development of cancers. Studies in our laboratory characterized the expression profile of the 39 members of the HOX family of homeobox genes in oral samples of normal mucosa and squamous cell carcinoma (SCC), identifying differently expressed genes. Among those genes are HOXA10, which has its expression related to tumor development and prognosis. The aim of the study was to valitade the elevated levels of HOXA10 on oral SCCs comparing to the normal oral mucosa, and to analyze the effects of the overexpression and neutralization of HOXA10 in modulating the main biological events associated to tumorigenesis. The levels of HOXA10 were evaluated by immunohistochemistry and qRT-PCR, and the HOXA10 effects on proliferation, apoptosis, adhesion, epitelial-mesenchimal transition (EMT), migration and invasion were evaluated on HaCaT normal keratinocytes cells overexpressing HOXA10 and on HSC-3 tongue carcinoma cells expressing a shRNA sequence to neutralize HOXA10 expression. The expression of HOXA10 was significantly higher on oral SCC samples when compared to the normal tissue controls. HaCaT cells overexpressing HOXA10 showed higher expression of N-cadherin and ?-catenin mRNA levels, and adhesion and migration were coordinately regulated on those cells. The neutralization of HOXA10 reduced significantly the proliferation capacity of HSC-3 cells, while induced significantly the expression of EMT markers, cell adhesion as well as the migration and invasion of HSC-3 cells. Overexpression and neutralization of HOXA10 did not modulate apoptosis rates. In conclusion, the results of this study suggest that the HOXA10 expression modulates important events associated with development and progression of oral SCCs / Doutorado / Patologia / Doutor em Estomatopatologia

Abstract The aim of this population-based cohort study was to evaluate the incidence and relative risk ratios of gynaecological cancers and the mortality of women with at least five children (GM women) compared to the average of Finnish women. We linked together the data of the Population Register (1974–1997), the Finnish Cancer Registry and the national cause-of death files of Statistics Finland (1974–2001) by using a personal identification code. The study population consisted of 86 978 GM women (1974–1997), including 3 752 women with at least 10 children (GGM women). Altogether 7 604 cancer diagnoses and 18 870 deaths were recorded. The incidence (SIR) of breast (0.55, 95% CI 0.52–0.58), endometrial (0.57, 95% CI 0.52–0.63) and ovarian cancer (0.64, 95% CI 0.55–0.73) decreased, and that of cervical cancer (1.13, 95% CI 0.98–1.29) increased in GM women. In multivariate analysis, the increase in parity from five to eight increased the protection against breast and endometrial cancer, but not in ovarian or cervical cancer. A young age at first birth decreased the breast cancer risk, while an older age at first birth decreased the risk for endometrial and cervical cancer. A short premenopausal delivery-free period and a long birth period were risk reducers in women who contracted endometrial cancer after menopause. The mortality (SMR) of breast (0.64, 95% CI 0.59–0.69), endometrial (0.68, 95% CI 0.56–0.80), ovarian cancer (0.68, 95% CI 0.60–0.75) as well as for dementia (0.80, 95% CI 0.72–0.84) decreased. The SMR of kidney (1.38, 95% CI 1.21–1.56) cancer increased in the GM group. The SMR of ischemic heart diseases (1.10, 95% CI 1.08–1.13) and diabetes mellitus (1.42, 95% CI 1.29–1.55) increased. The overall SMR of GM women was 5% less than expected (95% CI 0.94–0.95; deficit 949 deaths), but among GGM women it coincided with the national average (1.01, 95% CI 0.93–1.08). Multiparity affected the spectrum of diseases and causes of death in a specific way: the pregnancy-specific hormonal milieu is responsible for the low SIR and SMR of hormone-dependent cancers, and increased body weight is lightly responsible for the high SMR of cardiovascular and metabolic diseases. These observations advocate for delivering the first child at an age younger than 30 years and to start measures for careful weight control not only during and after pregnancies but even later and permanently.

Salley in 1954, (122) was the first worker to use the hamster cheek pouch as a model for experimental carcinogenesis and to produce squamous cell carcinomas in this organ. For a number of reasons, the pouch is most suitable for sequential studies of carcinogenesis, and these include the fact that it is easily accessible and can be everted simply, facilitating macroscopic examination. Furthermore, its anatomic situation makes it a simple model for topical application of any carcinogen. Each animal has two pouches, thus providing its own control. In addition, the pouch serves as a storehouse and is lined only by stratified squamous epithelium with no glands or hair follicles in its wall, thus rendering it less susceptible to cyclic changes than more complex tissues, in which accessory structures are present.

A Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the Degree of Masters of Medicine in the branch of General Surgery, Johannesburg 2018 / Gallbladder cancer (GBCa) has a dismal prognosis, with poor short-term and long-term outcomes, even following surgery and all current adjuvant therapies. Routine submission of all postcholecystectomy gallbladder specimens (GBS) for histopathology to detect cancer is standard practice at all University of the Witwatersrand (Wits) hospitals, as at many institutions globally. The cost-ineffectiveness associated with the results adding no value to overall patient care is debated. The low reported rate of GBCa – between 0.27% and 3.6% of all GBS –prompted advocacy for selective GBS submission based on demographic, clinical, and macroscopic features as indications for evaluation, considered logical from a practical and cost-effective perspective, especially in resource-constrained healthcare systems. Retrospective analysis of histopathology reports of 1194 adult GBS was performed. The histopathology findings of GBS submitted to the National Health Laboratory Service (NHLS) between January 1, 2010 and December 31, 2012 from three Wits hospitals were entered into spreadsheets, categorised into malignant, premalignant, and benign, and analysed, allowing determination of the profile of gallbladder disease. The frequency of GBCa determined, multivariate analysis of demographic and diagnostic subtypes was used to identify associations or risk factors for GBCa. The mean age of adult patients was 46.62 years (standard deviation, 17.81; range, 34-87); 925 (77.5%) female and 269 (22.5%) male. Benign diseases were documented in 1159 (97.1%) adult GBS with acute and chronic cholecystitis, in 705 (59.04%) and 401 (33.58%) specimens, respectively, representing 92.6% of total GBS. Forty-five (4.43%) and 33 (2.7%) specimens were ‘normal’ and benign tumours, respectively. GBCa and premalignant diseases composed 20 (1.67%) and 8 (0.7%) specimens, respectively with incidental GBCa found in 7 (0.59%) of 20 GBCa cases. Surgeon’s macroscopic appearance assessments were inadequately documented, so the value of this practice could not be determined. A small number (48) of GBS were obtained from paediatric patients <18 years of age where-in acute cholecystitis was most commonly diagnosed, no malignancies but one case of cytological atypia detected. The GBS disease profile and incidence of GBCa in this study were consistent with reports from international literature. No single demographic or clinical factor was identified to guide the surgeon in being more selective in submitting GBS. However, with only 7 cases of incidental GBCa in 1194 adult specimens, the routine submission of all GBS specimens to rule out malignancy cannot be justified and is not cost-effective. / XL2018

The purpose of this study was to determine the efficacy and toxicity of amonafide in unresectable or recurrent head and neck cancer and to determine if the degree of toxicity with amonafide correlated with the acetylator phenotype of the patient. Thirty patients were registered on the study and received amonafide, 300 mg/m2, over two hours each day for five consecutive days every 21 days. There was one partial response (3%) which lasted four months. The dose-limiting toxicity was myelosuppression. Acetylator phenotype was determined prior to treatment using HPLC to quantitate caffeine metabolites in urine samples after administration of caffeine. This pharmacokinetic evaluation was performed in 21 patients and revealed that (17/21) 81% of the patients were slow acetylators and 19% of the patients were rapid acetylators. No association was found between acetylator phenotype and toxicity in our patient population. Based on this study, it appears that amonafide given at 300 mg/m2 for 5 consecutive days every 21 days is not active in squamous cell carcinoma of the head and neck, and that acetylator status does not correlate with toxicity.

No description available.

No description available.

A research report submitted to the Faculty of Health Sciences in partial fulfillment of the requirement for the degree Master of Science in Nursing, Faculty of Health sciences, University of the Witwatersrand. Johannesburg, 2018. / Design and Methods A qualitative descriptive design was used for this study and conducted 22 in-depth interviews purposively selected. Sample size was determined by data saturation and qualitative content analysis was used to analyse the data. The inclusion criteria were 18 years and older, ability to speak basic English, identified by the patient as the primary caregiver and willingness to participate. Findings: Participants had different relationships with the sick person; however, caring for a sick mother was the most common. Three themes arose from the data: emotional responses towards the care giver role, personal cost of care giving and spiritual issues relating to care giving. Caring for a person with cancer in the last phase of life was not easy. Participants were overwhelmed by the care responsibilities. Some could not cope with the new role as they were emotionally distressed. Participants were financial burdened by the care needs of the patients; care giving was costly while others sacrificed their source of income to provide care. Most participants used religious practices to cope with their situation. Conclusion: Caring for cancer patients at the last phase of life was not an easy task. Participants were overwhelmed by the responsibilities and demands of caregiving. Most participants were emotionally exhausted and drained and feeling inadequate to perform these responsibilities. The financial burden was related to the care needs of the sick person. The caring role lead to some participants losing their jobs to provide care to their sick loved one. / LG2018

a variety of South African Hospitals: a retrospective study Purpose: To examine the number of lymph nodes present in specimens submitted for histological examination from a variety of South African hospitals; the identification of factors that influence nodal yield and node positivity; determining whether oncological clearance is improved based on the number of nodes examined in high volume centers versus low volume centres; the establishment of guidelines on where surgery for colorectal cancer should ideally be performed. Patients and methods: Pathology reports of resected specimens of colorectal adenocarcinoma in the database of the National Health Laboratory Service Johannesburg laboratory from 2000 to 2005, were examined for patient demographics, referring hospital, tumour specific features of T-stage, degree of differentiation, lymphovascular invasion and adenocarcinoma subtype (mucinous versus non-mucinous), number of lymph nodes identified, number of nodes positive and whether preoperative radiotherapy was administered. Hospitals were grouped into four groups of Charlotte Maxeke Johannesburg Academic Hospital, Helen Joseph Hospital, private hospitals and non-academic public hospitals. Patients were grouped according to the number of lymph nodes retrieved into the following groups: not recorded, no nodes identified,1-7 nodes identified, 8-12 nodes, 13-18 nodes, and greater than 18 nodes identified. Additionally, patients were subdivided into those with nodal metastasis and those without, and into colon and rectal cancer respectively. Multivariate analysis was performed via StatSoft, Inc. (2008) STATISTICA (data analysis software system), version 8.0 on the different lymph node groups versus the abovementioned covariates. Results: Of the 365 patients identified, the mean number of lymph nodes examined per resected specimen was 8.9 (±6.2SD), with significant differences noted between the different resection subtypes (p < 0.001). No statistically significant difference in mean number of nodes identified could be seen between the various hospitals. Alarmingly, in the group of patients where no metastatic nodes could be identified, the recommendation of 12 or more nodes examined per specimen was upheld in only 29% of cases. Factors associated with positive lymph nodes in this study include T-stage, degree of differentiation and lymphovascular invasion by the tumour. No significant benefit in terms of finding metastasis nodes could be demonstrated by examining more than 18 nodes. Conclusions and recommendations: This study highlights a substandard nodal assessment in colorectal cancer specimens overall, including the academic hospitals. More than 70% of node negative patients in this series may have been understaged. Close liaison between the surgeon and examining pathologist is recommended. In the presence of the identified high risk factors for nodal involvement and a substandard nodal assessment, additional measures i.e. fat clearance and immunohistochemistry need employment. A prospective study assessing quality of surgery is necessary, as is the creation of a central database to improve overall quality of cancer care.