The ErbB family of receptors are key regulators of growth, differentiation, migration and survival of epithelial cells. CI-1033 is an irreversible pan-ErbB tyrosine kinase inhibitor that has the ability to inhibit EGFR function but has shown limited therapeutic efficacy. Lovastatin targets the activity of HMG-CoA reductase, the rate-limiting step in the mevalonate pathway. In this study, the ability of lovastatin to potentiate the cytotoxic effects of CI-1033 was evaluated. The combination of lovastatin and CI-1033 exhibited some cooperative cytotoxic activity in a squamous cell carcinoma–derived cell line. This combination resulted in enhanced cell death by induction of a potent apoptotic response. Furthermore, this drug combination inhibited EGF-induced EGFR autophosphorylation and activation of the downstream signaling effectors, ERK and AKT. These findings suggest that combining lovastatin and tyrosine kinase inhibitors may represent a novel combinational therapeutic approach in squamous cell carcinoma of the head and neck.

No description available.

Thesis (M.S.)--University of Southern California, 1998. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (D.Sc.(Odontology))--University of Pretoria, 2003. / "Published work submitted to the University of Pretoria for the degree of Doctor of Science in Odontology (Oral pathology)". Includes bibliographical references. Also available online.

Thesis (M.S.)--University of Southern California, 1998. / Includes bibliographical references.

Made available in DSpace on 2015-05-14T12:56:03Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2601299 bytes, checksum: 03c727557f510c297974aa71ae47105c (MD5) Previous issue date: 2014-02-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The oral cancer is a major cause of morbidity and mortality worldwide. In Brazil, 15,000 new cases are expected for the year 2014. Lip squamous cell carcinoma features are similar to skin lesions and have as main etiological agent, the chronic sun exposure. The galectins -1, -3 and -7 are proteins involved in tumorigenesis and have been investigated due to changes in their expressions in oral cancer. The objective of this study was to evaluate the expression by Immunohistochemistry of galectins-1, -3 and -7 in 30 cases of lip squamous cell carcinoma, making the correlation with clinical data, histological grading of malignancy through the proposed systems for Bryne (1998) and WHO (2005). The parameters analyzed and expression of galectins -1, -3 and -7 were subjected to statistical analysis (Chi-square, Fisher exact test and test for comparison of Binomial proportions). There was no expression of galectin -1 in 93.3% of cases, showing statistically significant correlation (p = 0.0356) between histological grading of malignancy proposal by WHO and the marked cell type. There was no statistically significant correlation between the galectin -3 with none of the evaluated parameters. Expression of galectin-7 was present in all cases evaluated and showed statistical significance between the marked cell type and regional metastasis (p=0,0000) and between the marked cell type and histological grading proposal for Bryne. Changes in the expression of galectinas -1, -3 and -7 suggest the participation of these proteins in carcinogenesis. We conclude, through the results of this research, that the expression of these proteins in squamous cell carcinoma of lip can act as a marker of biological behaviour of this type of lesion. / O câncer oral é uma importante causa de morbidade e mortalidade em todo o mundo. No Brasil, são esperados quinze mil novos casos para o ano de 2014. O carcinoma epidermóide de lábio apresenta características semelhantes a lesões de pele e tem como principal agente etiológico a exposição solar crônica. As galectinas -1, -3 e -7 são proteínas envolvidas na tumorigênese e têm sido investigadas devido a mudanças em suas expressões em casos de câncer oral. O objetivo deste estudo foi avaliar a expressão através da imunoistoquímica das galectinas -1, -3 e -7 em 30 casos de carcinoma epidermóide de lábio, fazendo a associação com os dados clínicos, gradação histológica de malignidade através dos sistemas propostos por Bryne (1998) e OMS (2005). Os parâmetros analisados e a expressão das galectinas -1, -3 e -7 foram submetidas a análise estatística (teste do qui-quadrado, teste exato de Fisher e teste Binomial para a comparação de proporções). Houve expressão da galectina -1 em 93,3% dos casos, apresentando associação estatisticamente significativa (p=0,0356) entre a gradação histológica de malignidade proposta pela OMS e o tipo celular marcado. Não houve associação estatisticamente significante entre a galectina -3 com nenhum dos parâmetros avaliados. A imunoexpressão da galectina -7 esteve presente em todos os casos avaliados e exibiu significância estatística entre o tipo celular marcado e metástase regional (p=0,0000) e entre o tipo celular marcado e a gradação histológica proposta por Bryne. Alterações na expressão das galectinas -1, -3 e -7 sugerem a participação dessas proteínas na carcinogênese. Concluímos, através dos resultados da presente pesquisa, que a imunoexpressão dessas proteínas em carcinoma epidermóide de lábio possa atuar como marcador do comportamento biológico deste tipo de lesão.

Les télomères sont des structures complexes associant des répétitions de séquences nucléotidiques TTAGGG à diverses protéines dont le complexe shelterin. Le TRF2 (Telomeric repeat-binding Factor 2) est un composant majeur de ce complexe, indispensable à la formation de la boucle télomérique T-loop qui permet la protection des extrémités vis-à-vis des exonucléases et systèmes de réparation de l'ADN. Ce facteur est aussi impliqué dans la tumorigenèse de nombreux cancers. Le carcinome épidermoïde oral représente 90% des cancers des Voies Aéro-Digestives Supérieures (VADS) sixième cause de cancer dans le monde avec une incidence de plus de 14000 nouveaux cas en France en 2012. Souvent diagnostiqué par des chirurgiens-dentistes, c'est un cancer de mauvais pronostic traité par chirurgie, radiothérapie, chimiothérapie et thérapies ciblant le R-EGF. Peu d'études se sont intéressées à l'expression de TRF2 dans le carcinome épidermoïde oral et leurs résultats contradictoires ne permettent pas de comprendre son rôle dans leur agressivité.L'expression de TRF2 a été analysée dans les biopsies de 62 patients atteints d'un carcinome épidermoïde oral, à l'aide d'un score de lecture en immunohistochimie. Une forte expression de TRF2 est associé une survie globale significativement plus faible ce qui en fait un facteur pronostique pertinent. In vitro, une faible expression de TRF2 induit une modification du profil sécrétoire des cellules tumorales qui se traduit in vivo par des modifications de l'architecture tissulaire de tumeurs chez la souris nude. Enfin, TRF2 est un marqueur prédictif de réponse aux thérapies ciblées, leur efficacité étant optimale lorsque TRF2 est faiblement exprimé. / Telomeres are composed of tandmely repeated TTAGGG nucleotidic sequences associated with various proteins including shelterin complex. TRF2 (Telomeric repeat-binding Factor 2) is the major component of this complex, necessary for T-loop formation which protects telomeres from DNA damage response and exonucleases. Oral Squamous Cell Carcinoma (OSCC) is the most incident subtype of head and neck cancer (90%), sixth most common cancer in the world with an incidence of 14000 cases in France in 2012. Often diagnosed by dental surgeons,this bad prognosis malignancy is treated by surgery, radiotherapy, chemotherapy and targeted therapies against EGFR. Few studies evaluated TRF2 expression in OSCC and their results are discrepant. TRF2 expression has been assessed in immunohistochemistry in 62 tumoral samples of patients with an history of OSCC. TRF2 overexpression is associated with bad prognosis. TRF2 knockdown changes cells' secretome thus modifying tumoral tissue architecture. Our results showed that TRF2 is predictive for treatment response in targeted therapies in OSCC.

A espectroscopia Raman é uma das tecnologias ópticas que tem ganho cada vez mais destaque na oncologia. Esta tecnologia fornece a composição molecular dos mais variados tipos de amostras, inclusive biofluidos, células e tecidos. Na tentativa de avaliar sua aplicação em lesões bucais, o objetivo deste trabalho foi obter um perfil espectral dos distúrbios epiteliais nãodisplásicos, displásicos, e do carcinoma espinocelular bucal, bem como verificar a possibilidade diagnosticar estas alterações pelos espectros. Inicialmente, foram usados 44 amostras de mucosa bucal em blocos de parafina, com diagnóstico de hiperplasia epitelial, hiperparaceratose, displasia epitelial e carcinoma espinocelular bucal. Da porção epitelial de cada uma destas amostras foram obtidos 10 espectros Raman. A média dos espectros de cada alteração gerou um perfil espectral correspondente à sua composição química. Os resultados desta análise apresentaram picos ou bandas espectrais referentes a moléculas usualmente encontradas nos tecidos biológicos: proteínas, lipídios e DNA. Em seguida, os dados espectrais foram submetidos a análise dos componentes principais (PCA) e análise discriminante linear (LDA), onde foi encontrada uma eficiência de 86,36% no uso da Espectroscopia Raman para o diagnóstico de alterações epiteliais. A validade do método foi comprovada pela Curva Roc resultando em 91% de sensibilidade e 96,9% de especificidade. Em um segundo momento, com a finalidade de avaliar a influência da fixação com formalina nas análises espectrais, a superfície epitelial de uma amostra de tecido bucal fresca ex vivo foi submetida a análise pela Espectroscopia Raman e armazenada em formalina tamponada a 10% por 24h para posteriormente se obter outro espectro. A análise comparativa entre os perfis espectrais de uma mesma amostra antes e após a fixação, demonstraram diferenças em relação aos picos de proteínas e DNA, que podem modificar o perfil espectral da alteração analisada e, portanto, gerar algum erro de classificação. De maneira geral, pelos resultados desta pesquisa, observou-se que a Espectroscopia Raman é uma tecnologia eficiente para identificar a composição molecular de amostras de tecido, seja imediatamente após a excisão cirúrgica, fixação em formalina ou emblocadas em parafina. Entretanto, deve-se considerar que estas a diferentes formas de condicionamento influenciarão diretamente no resultado dos espectros. / Raman spectroscopy (RS) is one of the optical technologies that has garnered a great deal of interest in oncology. This technology provides the molecular composition of various types of samples, including biofluids, cells and tissues. In an attempt to assess its application in oral lesions, the purpose of this study was to obtain a spectral profile of epithelial disorders non-dysplastic, dysplastic, and oral squamous cell carcinoma, as well as checking the ability to diagnose these changes by the spectra. Initially, 44 samples of oral mucosa formali-fixed paraffin embebed were used with epithelial hyperplasia, hyperparakeratosis, epithelial dysplasia and oral squamous cell carcinoma. From the epithelial area of each sample were obtained 10 Raman spectra. The average of the spectra of each change generated a spectral profile corresponding to its chemical composition. Results of this analysis showed peaks or spectral bands related to molecules generally found in biological tissues: proteins, lipids and DNA. Then the spectral data were submitted to principal component analysis (PCA) and linear discriminant analysis (LDA), which was found 86.36% efficiency in the use of Raman spectroscopy (RS) for diagnosis of epithelial changes. The validity of the method was confirmed by Roc curve resulting in 91% sensitivity and 96.9% specificity. In a second step, in order to evaluate the influence of fixation with formalin in the spectral analysis, the epithelial surface of a sample of freshly biopsied oral tissue was subjected to analysis by RS and stored in 10% formalin for 24 hours for later obtain another spectrum. The comparative analysis of the spectral profiles of the same sample, before and after fixation, shows differences relative to spectral peaks of proteins and DNA that can modify the spectral profile of the analyzed change and thus generate some misclassification. In general, the results of this research, it was observed that Raman spectroscopy is an efficient technology to identify the molecular composition of tissue samples, either immediately after surgical excision, either after fixation in formalin and embedded in paraffin. However, it should be considered that these different means of conditioning will influence the outcome of the spectra.

AIM & OBJECTIVES: Human papilloma virus (HPV) has been related to cervical infection, however, its part in Head and Neck Squamous Cell Carcinoma (HNSCC) is still debatable and is easy to refute. Suspicion of HPV causation is heightened when carcinomas arise in patients that are young and have never smoked. The present UK based study undertaken at Northampton NHS Trust endeavoured to determine the extent to which HPV is an entity in HNSCC in the UK. Furthermore, the study investigated whether sexual behaviour (as measured by sexual health clinic (SHC) attendance) is linked the acquisition of HPV associated HNSCC in young age groups. HNSCC incidences and sexual trends in the UK were collected from publicly available databases to identify if there were any changes at a national level in sexual behaviours and their influence on HNSCC in young age groups. MATERIALS & METHODS: PCR was used to evaluate the presence of HPV in biopsy samples from of 99 patients diagnosed with HNSCC at Northampton Hospital from 2006 to 2014. Patient demographics on age, sex, smoking, alcohol use and SHC attendance were also collected. All HPV PCR positive biopsies were further genotyped using an ABI 3130xl genetic analyser. Databases in the UK; including GLOBOCAN, NATSAL and PHE were searched for data on HNSCC prevalence, sexual behaviour trends and vaccine uptake. Multinomial regression explored the relationship between HPV positivity and sex, age, smoking, drinking, race and SHC attendance. RESULTS: PCR showed that 25.2% (25/99) of biopsies tested were positive for HPV and were all obtained from white participants. Most specimens (23, 92%) were high-risk (HR) HPV 16 positive with a mean age of 56 for HPV positivity and 72% of the cases 50-60 years old. Smokers were 11% in total (11/99) with most 88.9% participants (88/99) being non-smokers. HPV positivity was strongly linked with non-smoking history (p < 0.001); no alcohol abuse (p < 0.001); male gender (p < 0.001); young age less than 60 years (p < 0.001) and SHC attendance (p < 0.001). A Kruskal-Wallis post hoc test affirmed the impact of age on HPV positivity (p= < 0.05). GLOBOCAN and Cancer Research demonstrated a rising UK HNSCC pattern of over 200% for both sexes from 1975 to 2011. The three NATSAL surveys undertaken in 1990-1991, 1999-2001 and 2010-2012 demonstrated an overall increase in opposite and same sex partners. The UK average of individuals engaging in oral sex was in the younger age groups of between 16 and 54 with at least 70% of males and 63% females of that age engaging in oral sex. Finally, NASTAL 1, 2 and 3 surveys reported 20 vs 15; 25 vs 55; 55 vs 65 of males and females respectively with more than 10 sexual partners to have attended the SHC. The UK immunization take-up was over 90% countrywide. CONCLUSION: Few research studies have been conducted to date on HPV as a cause of HNSCC in the UK. The present research showed 25.2% of HNSCC to be caused by HPV, with the high risk (HR) genotype 16 (the leading cause of cervical cancer) accounting for 92% (23/25) of the cases. These outcomes affirmed the high prevalence of HR-HPV in HNSCC, with a rate of 25.2% similar to those reported previously. Routine HPV testing in those aged below 60 is therefore warranted. Smoking and drinking showed negative correlation; the young age of below 60 and attendance of the SHC for both sexes showed a positive correlation with HPV positive HNSCC. NATSAL data showed increased sexually risky behaviour coupled with attending the SHC in younger ages for both sexes. Increased sexually risky behaviour as shown in NASTAL surveys may be the reason why young age and SHC attendance is positively correlated with HPV HNSCC. The study highlights a conceivable relationship between HPV positive HNSCC in those under 60 years with no smoking history who attended the SHC. Smoking and drinking are known risks for HNSCC in those past 65 years of age; the negative association with HPV HNSCC in the young in the present research revealed smoking and drinking to have reduced association with HPV HNSCC. The reported HR-HPV positive HNSCC in young age groups inform future vaccination strategies and consequently decrease the quantity of HPV HNSCC's.