Thesis (Ph.D.) - University of Queensland, 2002. / Includes bibliography.

Thesis (doctoral)--Umeå University, Sweden, 1995. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (M.Phil.) - University of Queensland, 2005. / Includes bibliography.

Perineural invasion (PNI) in cutaneous squamous cell carcinoma (cSCC) and desmoplastic melanoma (DM) may be a negative prognostic finding, and likely contributes to increased rates of local recurrence. The biological mechanisms underlying PNI remain unclear, although several lines of evidence implicate neurotrophins and their receptors. Expression of the high affinity nerve growth factor (NGF) receptor TrkA has been shown to be associated with PNI in numerous malignancies, although literature in cutaneous neoplasms is sparse. Given this, we sought to ascertain the incidence of PNI in a cohort cSCCs using double immunostaining (DIS), and to investigate PNI's relationship with TrkA expression and established histopathologic prognosticators. In DMs we investigated the relationship between TrkA and PNI. In DM we additionally analyzed expression of the low affinity NGF receptor (p75NGFR) and the presence of a functional polymorphism in the glial cell line-derived neurotrophic factor (GDNF) receptor RET (RETp) as they relate to PNI. In this IRB approved study, cSCCs from the head and neck (H&N) and 53 from non-H&N areas were immunohistochemically analyzed for PNI (DIS with S100 and p63) and TrkA expression. For DM, 43 cases were immunohistochemically evaluated for TrkA and p75NGFR expression while RETp was detected by direct DNA sequencing. The presence of each was correlated with histologically observed PNI. In cSCCs, comparing H&N versus non-H&N areas; using hemotoxylin and eosin (H&E) PNI was detected in 11% versus 6% of cases respectively and using DIS, in 23% versus 15% respectively, with significant disagreement between both methods (𝜅=0.47, p=0.002). There was a 2.33 fold increase in PNI detection with DIS compared to H&E (95%CI: 1.12-4.87; p=0.02). TrkA expression was 2.9 times more frequently observed in cSCCs from the H&N compared to those from non-H&N areas (p=0.01). Regardless of site, TrkA expression was associated with decreased degree of differentiation (OR=6.46, p=0.0006) and high-risk morphologic variants (OR = 6.53, p=0.002). TrkA expression was not significantly associated with PNI (p=0.33). In DM, PNI was present in 67% of cases. On univariate analysis; p75NGFR was associated with PNI (expression detected in 79% of PNI-positive cases compared to 36% of PNI-negative cases, p=0.005), increased Breslow's depth and greater Clark's Level (p= 0.007 and p= 0.01 respectively). RETp was noted in 28% of cases but was not significantly associated with PNI (p=0.27) or other histopathologic variables. TrkA expression was absent in all cases. PNI was associated with increased Breslow's depth and Clark's Level (p=0.01 and p=0.009 respectively). Controlling for the association between p75NGFR and depth, p75NGFR remained associated with an increased propensity for PNI (OR=4.68, p=0.04). In conclusion, increased PNI detection with DIS in cSCCs underscores the adjunctive utility of immunohistochemistry in microstaging. Although unlikely to play a role in the development of PNI, TrkA's association with cSCCs from H&N and select histopathologic parameters suggests a role for the NGF-TrKA axis in tumorogenesis while its absent expression in DM suggests that expression is lineage-related. Lastly, In DM, p75NGFR expression is significantly associated with PNI and a more locally aggressive phenotype.

Magister Scientiae Dentium - MSc(Dent) / Background: Recent epidemiological reports established that there is an increase in the incidence of oral squamous cell carcinoma in young patients. Some report this to be in the absence of contributing habits such as smoking and alcohol use. Few reports of such a nature have reported a similar trend in South Africa. Aim: Describe the epidemiological pattern of oral squamous cell carcinoma seen at the Tygerberg academic complex. Method: Histopathological biopsy reports of patients diagnosed by the oral pathology department of Tygerberg hospital from 1996 to 2013 were electronically retrieved and included. Patients were grouped by age into two groups, one included patients 40 years and younger, the other included patients older than 40 years. Descriptive analysis was performed for age, sex, smoking and alcohol habits and oral site of tumor. Frequency of OSCC patients was calculated manually from the total number of oral biopsies. Chi- square or Fisher’s exact tests were used as appropriate. Probabilities of less than 0.05 were regarded as significant. Results: The total number of OSCC patients over the 18-year period was 2220. The mean age was 57.6years.The male to female ratio was 2.9:1 for all age groups and 2.2:1 for young patients. The majority of patients (96%) were above 40 years old. Smoking and alcohol were commonly reported for all age groups (91.3%) and (83.8%) for young patients. The tongue was the commonest site for all age groups (30.8%) followed by oropharynx (27.3%) while in younger patients, the oropharynx was the commonest site (30.3%) followed by tongue (29.2%). Conclusion: The study confirmed that OSCC is still an affliction of people older than 40 years and males are predominantly affected. Smoking and alcohol are strong risk factors for OSCC irrespective of patient's age. OSCC among people older than 40 years may have no great difference from the same disease affecting younger ones in terms of sex, oral habits and tumor site.

Orientador: Jacks Jorge Junior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-09T19:48:28Z (GMT). No. of bitstreams: 1 Campagnoli_EduardoBauml_D.pdf: 15962845 bytes, checksum: 0ed7f5d5b20c8803dc7f1a23bf3b1d5d (MD5) Previous issue date: 2007 / Resumo: O carcinoma espinocelular de boca é um dos cânceres mais comuns do mundo, logo a compreensão das vias moleculares envolvidas no processo de carcinogênese poderá auxiliar no desenvolvimento de drogas para o tratamento e prevenção deste tipo de neoplasia. FAS é uma das enzimas metabólicas que participam da síntese endógena de ácidos graxos, enquanto ErbB-2 é um receptor de membrana celular responsável pelo crescimento e diferenciação de vários tipos celulares. Já a proteína p27 é inibidora do ciclo celular e Skp2 é uma ubiquitina ligase que atua na ubiquitinização e degradação de p27. Estudos têm demonstrado que a inibição da FAS desencadeia o processo de apoptose em diversas linhagens de células neoplásicas. Recentemente relatou-se que o Orlistat apresenta efeito inibitório sobre a FAS. Portanto, o objetivo deste estudo foi comparar a expressão de FAS, ErbB-2, p27 e Skp2 em epitélios com displasia leve, moderada, severa e no carcinoma espinocelular quimicamente induzidos, bem como verificar o efeito do Orlistat no processo de carcinogênese bucal. Para tanto, camundongos foram expostos ao 1-óxido 4-nitroquinolina (4NQO) durante 16 semanas e sacrificados ao completarem 16, 18, 20 e 25 semanas. Um dos grupos também recebeu injeção intraperitonial de Orlistat (240 mg/kg) diária, durante quinze dias. Após o sacrifício dos animais, a língua foi removida, emblocada em parafina e cortes histológicos obtidos. Presença de displasias e neoplasias malignas foram avaliadas em lâminas coradas por hematoxilina e eosina. Reações imunohistoquímicas foram realizadas com os anticorpos: Ki-67 (marcador de proliferação celular), FAS, ErbB-2, p27 e Skp2. O índice de proliferação celular (Ki-67) foi de 26,57%, 22,85%, 26,12% e 23,86% nas áreas de displasia leve, moderada, severa e carcinoma invasivo, respectivamente. O epitélio normal teve índice de proliferação celular de 4,31%. ErbB-2 exibiu aumento na expressão tanto nas áreas displásicas como tumorais, sendo que ambas apresentaram mais de 50% de células imunomarcadas. Aumento na expressão da FAS diferiu de modo estatisticamente significante, em relação ao epitélio normal, somente nas áreas com displasia severa e de carcinoma invasivo, embora aumento gradual na expressão desta proteína tenha sido observado durante todo o processo de carcinogênese. A quantidade protéica de p27 aumentou gradualmente durante a carcinogênese, sendo as maiores taxas encontradas nas áreas de displasia severa (57,50% de células imunomarcadas) e carcinoma invasivo (53,55% de células positivas). Para Skp2 verificou-se imunomarcação exclusivamente citoplasmática (Skp2-B), a qual esteve aumentada tanto nas áreas displásicas como tumorais. Os camundongos tratados com Orlistat tiveram área tumoral 67,25% menor do que os animais não tratados. Além disso, houve diminuição na proliferação celular (2,58% de positividade celular), bem como menor número de células imunomarcadas contra as proteínas p27 e Skp2-B. Com base nesses resultados concluiu-se que durante o processo de carcinogênese bucal induzida por 4NQO houve aumento na proliferação celular (Ki-67) e na expressão das proteínas FAS, ErbB-2, p27 e Skp2-B (citoplasmática), sendo que ErbB-2 e Skp2-B tiveram aumento significativo já nos estágios iniciais da carcinogênese. Além disso, o Orlistat apresentou efeito antitumoral e antiproliferativo em carcinomas espinocelulares de língua quimicamente induzidos / Abstract: Squamous cell carcinoma of the oral cavity is one of the most common malignant epithelial neoplasms, and a better understanding of its molecular pathways could help the development of new treatment or preventive agents. Several proteins such as Fatty Acid Synthase (FAS), ErbB-2, p27 and Skp2 are involved in the tumorigenesis process. FAS has an enzyme with multiple functions, including the endogenous synthesis of saturated fatty acids. ErbB-2 is a transmembrane receptor that may have a role in cellular growth and differentiation. p27 is a cyclin-dependent kinase inhibitor and plays an important role on the negative regulation of the cell cycle. On the other hand, Skp2 is an ubiquitin ligase that targets p27 for ubiquitination and degradation. Studies have demonstrated that FAS inhibition induces apoptosis in various neoplastic cells and can suppress tumor cell proliferation. It has been demonstrated that Orlistat has anti-proliferative and anti-tumor properties through blocked FAS activity. Therefore, the aim of the present study was to investigate FAS, ErbB-2, p27 and Skp2 expression in the epithelium with chemically-induced dysplasia and squamous cell carcinoma, and to verify the effect of Orlistat on the carcinogenic process. Lesions were induced by 4NQO in the drinking water to C57BL/6 mice during 16 weeks. The animals were sacrificed after 16, 18, 20 and 25 weeks of treatment. One group also received intraperitonial injection of Orlistat, 240 mg/kg/day, during fifteen days. The tongues were removed and paraffin embedded tissues were cut and stained with hematoxylin and eosin. Dysplastic lesions and squamous cell carcinomas were analyzed in slides stained with hematoxylin and eosin. Immunohistochemistry assays were performed for Ki-67, FAS, ErbB-2, p27 and Skp2. The percentage of cells that reacted with the Ki-67 antibody was 26.57%, 22.85%, 26.12% and 23.86% in areas with mild, moderate, severe dysplasia and invasive carcinoma, respectively. The normal epithelium had low index of cellular proliferation, 4.31%. ErbB-2 showed increase in the expression in dysplastic and tumor areas, for both presented more 50% of positive cells. High expression of FAS was observed in areas with severe dysplasia and squamous cell carcinoma, although gradual increased was observed during all the carcinogenic process. Expression of p27 protein increased gradually during carcinogenesis and the biggest levels were detected in areas with severe dysplasia (57.50% of immunostaining cells) and invasive carcinoma (53.55% of positive cells). Skp2 immunoexpression was strictly cytoplasmic (Skp2-B), and it was increased in tumoral and dysplastic areas. Lesions of mice treated with Orlistat showed a 67.25% reduction when compared with non-treated animals. Moreover, cellular proliferation was reduced (2.58% of cellular immunostaining), and there were less cells immunostained for p27 and Skp2-B. Therefore dysplastic areas showed increased expression of Ki-67 and high expression of FAS, ErbB-2, p27 and Skp2-B, when compared with normal epithelium. ErbB-2 and Skp2-B had increased expression in the early stages of carcinogenesis. Moreover, Orlistat showed anti-tumoral and anti-proliferative effect in chemically-induced quamous cell carcinomas of the tongue / Doutorado / Estomatologia / Doutor em Estomatopatologia

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A boca pode ser acometida por doenÃas, variando de alteraÃÃes de desenvolvimento à neoplasias malignas agressivas e metastatizantes. O conhecimento destas condiÃÃes auxilia no diagnÃstico diferencial realizado pelo clÃnico. Este trabalho tem como objetivo realizar uma anÃlise epidemiolÃgica das lesÃes de cavidade oral em cinco laboratÃrios de anÃtomo patologia da cidade de Fortaleza, CearÃ, Brasil. MÃtodos: Coleta de dados a partir de laudos histopatolÃgicos de lesÃes orais, no perÃodo de 2001 a 2005, oriundos de cinco laboratÃrios, de anatomia patolÃgica, pÃblicos e privados. As variÃveis utilizadas foram sexo, idade, raÃa, localizaÃÃo anatÃmica e laudo histopatolÃgico. As lesÃes analisadas foram agrupadas em nÃo-neoplÃsicas, neoplÃsicas e laudos descritivos. Resultados: No perÃodo analisado, foram coletadas 6231 lesÃes orais, das quais 41,41% oriundas de laboratÃrios particulares e 58,59% de laboratÃrios pÃblicos. O sexo feminino foi o mais acometido, com proporÃÃo homem:mulher de 1:1,68. As lesÃes ocorreram em uma ampla faixa etÃria, variando de 0 a 100 anos, com pico de incidÃncia entre 31 e 60 anos. As lesÃes nÃo-neoplÃsicas representaram 64,89% dos casos, com as lesÃes inflamatÃrias/reativas sendo as mais prevalentes, seguidas pelas lesÃes inflamatÃrias de glÃndula salivar, cistos e hiperplasias epiteliais sem atipias. As neoplasias representaram 30,80% dos casos, das quais 59,52% eram benignas, 32,45% malignas e 8,03% eram lesÃes prÃ-malignas. A hiperplasia fibroepitelial foi a lesÃo mais prevalente em todo o estudo e o carcinoma de cÃlulas escamosas, a neoplasia maligna mais comum, com 23,14% e 8,52% respectivamente ConclusÃo: As lesÃes foram mais comuns no sexo feminino, na faixa etÃria economicamente ativa, representadas principalmente por lesÃes inflamatÃrias/reativas. Apesar da alta ocorrÃncia de lesÃes inflamatÃrias/reativas neste estudo, a prevalÃncia de lesÃes malignas foi significativa, demonstrando a necessidade do conhecimento destas lesÃes pelo cirurgiÃo dentista e a criaÃÃo de polÃticas pÃblicas que enfatizem a prevenÃÃo e o diagnÃstico precoce das mesmas / A wide range of diseases can affect the oral cavity, from developmental defects to metastasizing malignant neoplasms. The knowledge on Oral Pathologies`s prevalence helps the clinician making differential diagnosis. The aim of this study was to perform an epidemiological survey of oral lesions in five anatomopathological laboratories in Fortaleza, CearÃ, Brazil. Methods: The sample was obtained from histopathology reports of oral lesions diagnosed between the years of 2001 to 2005 in five anatomopathological laboratories. Data regarding sex, race, age, anatomical site and histopathological diagnosis were registered. Lesions were categorized in non-neoplastic, neoplastic and descritive reports. Results: During the five-year period, 6231 oral lesions reports were collected, 41,41% from private laboratories and 58,59% from public laboratories. Female were more affected, with a male:female ratio of 1:1,68. Lesions occurred in a wide age range, varying from 0 to 100 years old, with an incidence peak between 31 to 60 years. Non-neoplastic lesions represented 64,89% of cases, with inflammatory/reactive lesions being the most prevalent group, followed by inflammatory lesions of salivary glands, cysts and non-atypical epithelial hyperplasia. Neoplastic lesion represented 30,80% of cases, 59,52% benign, 32,45% malignant and 8,03% pre-malignant lesions. Fibroepithelial hyperplasia was the most common lesion in this study and squamous cell carcinoma was the most prevalent malignant neoplasm, with 23,14% and 8,52%, respectively. Conclusions: Oral lesions were more common among femaleâs reports, in economically active age, mainly represented by inflammatory/reactive lesion. Although, the occurrence of inflammatory/reactive lesions was high, the prevalence of malignant neoplastic and pre-malignant lesion was significant. There dental surgeon must know about the occurrence of such lesions, and public health politics for prevention and early diagnose must be enfasized

No description available.

The p63 transcription factor, a member of the p53 family, plays an oncogenic role in squamous cancers, while its expression is often repressed in breast cancers. In the canonical conserved Hippo pathway, known to play a complex role in regulating the growth of cancer cells, the protein kinases Mammalian Ste20 like kinases 1/2 (MST) and Large tumor suppressor kinases 1/2 (LATS) act sequentially to phosphorylate and inhibit the Yes-associated Protein/Transcriptional coactivator PDZ binding transcription factors (YAP/TAZ). We found that in the MCF10A mammary epithelial cell line and insquamous and breast cancer cell lines, expression of deltaNp63 RNA and protein is strongly repressed by inhibition of specific components of the Hippo pathway in a manner that is independent of p53. While the Hippo pathway protein kinases MST1/2 and LATS1 are required for p63 expression, the next step of the pathway namely phosphorylation and degradation of the YAP/TAZ transcriptional activators, is not required for repression of p63. This suggests that regulation of p63 expression occurs by a non-canonical version of the Hippo pathway. Interestingly, we observed that experimentally lowering p63 expression leads to increased Yes Associated Protein protein levels, thereby constituting a feedback loop. In addition, p63 loss reduces the growth of MCF10A and squamous cancer cell lines. These results, which reveal the intersection of the Hippo and p63 pathways, may prove useful for the control of their activities in cancer cells.

Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request