Neste trabalho foram analisados 30 casos de linfomas de células B da região oral, fixados em solução de formaldeído e incluídos em parafina, através da técnica de imuno-histoquímica para as proteínas c-Myc, Bcl-2, Bcl-6 e ciclina D1. Dos casos analisados 40% foram positivos para a marcação para c-Myc, 33,3% para a marcação para ciclina D1, 83,3% para a marcação para Bcl-2 e 53,3% para a marcação para Bcl-6. Todos os casos foram diagnosticados como linfomas difusos de grandes células B, o subtipo de linfoma com a maior casuística. A análise destas proteínas é de fundamental importância para o diagnóstico e direcionamento do tratamento de doenças hematopoiéticas, pois estão envolvidas em vários processos de controle da transcrição gênica, do ciclo celular e dos processos apoptóticos e o aumento do conhecimento sobre sua ação em diferentes subtipos de linfomas pode corroborar outros estudos. / In this study, 30 cases of formalin-fixed and paraffin-embedded B-cell lymphomas of the oral region were submitted to immunohistochemistry for the detection of proteins c-Myc, Bcl-2, Bcl-6 and cyclin D1. Fourty percent (40%) of the studied cases were positive for c-Myc, 10% for cyclin D1, 83.3% for Bcl-2 and 53.3% for Bcl-6. The analysis of these proteins has fundamental importance for the diagnosis and treatment course of hematopoietic diseases, because they are involved in various processes controlling gene transcription and cell cycle. All cases were diffuse large B-cell lymphomas, the subtype with the highest incidence. The analysis of these proteins is very important for the diagnosis and treatment course of hematopoietic diseases, because they are involved in various processes controlling gene transcription, cell cycle and apoptotic processes and an increase in the knowledge of their action in different subtypes of lymphomas can corroborate to other studies.

Neste trabalho foram analisados 30 casos de linfomas de células B da região oral, fixados em solução de formaldeído e incluídos em parafina, através da técnica de imuno-histoquímica para as proteínas c-Myc, Bcl-2, Bcl-6 e ciclina D1. Dos casos analisados 40% foram positivos para a marcação para c-Myc, 33,3% para a marcação para ciclina D1, 83,3% para a marcação para Bcl-2 e 53,3% para a marcação para Bcl-6. Todos os casos foram diagnosticados como linfomas difusos de grandes células B, o subtipo de linfoma com a maior casuística. A análise destas proteínas é de fundamental importância para o diagnóstico e direcionamento do tratamento de doenças hematopoiéticas, pois estão envolvidas em vários processos de controle da transcrição gênica, do ciclo celular e dos processos apoptóticos e o aumento do conhecimento sobre sua ação em diferentes subtipos de linfomas pode corroborar outros estudos. / In this study, 30 cases of formalin-fixed and paraffin-embedded B-cell lymphomas of the oral region were submitted to immunohistochemistry for the detection of proteins c-Myc, Bcl-2, Bcl-6 and cyclin D1. Fourty percent (40%) of the studied cases were positive for c-Myc, 10% for cyclin D1, 83.3% for Bcl-2 and 53.3% for Bcl-6. The analysis of these proteins has fundamental importance for the diagnosis and treatment course of hematopoietic diseases, because they are involved in various processes controlling gene transcription and cell cycle. All cases were diffuse large B-cell lymphomas, the subtype with the highest incidence. The analysis of these proteins is very important for the diagnosis and treatment course of hematopoietic diseases, because they are involved in various processes controlling gene transcription, cell cycle and apoptotic processes and an increase in the knowledge of their action in different subtypes of lymphomas can corroborate to other studies.

Para que ocorra a transição do epitélio normal de laringe para carcinoma escamoso é necessário um processo de múltiplas etapas tal como exposição prolongada ao fumo e álcool e uma possível associação à infecção pelo HPV. Vários tipos de marcadores moleculares vêm sendo estudados na carcinogênese da laringe, entre eles proteínas associadas a apoptose (bcl-2 e PARP-1) assim como proteínas envolvidas em múltiplos processos biológicos como a Galectina-3. Neste estudo foram realizadas análise imunoistoquímica quantitativa e qualitativa para bcl-2, PARP-1 e galectina-3 em 65 pacientes diagnosticados com câncer de laringe subdivididos em: carcinoma de laringe in situ (CLIS), carcinoma de laringe com metástase (CLM), sem metástase (CLS) e linfonodos cervicais (LC). A detecção e tipificação do HPV foram realizadas pela reação em cadeia da polimerase (PCR) e os tipos de HPV avaliados foram HPV 6, 11, 16, 18, 31 e 33. Na avaliação quantitativa de galectina-3 observou-se um significativo aumento de expressão no carcinoma invasivo de laringe (CLS e CLM) quando comparado com carcinoma in situ (CLIS), podendo concluir que essa proteína seria um bom marcador pra progressão de câncer de laringe. Para as proteínas PARP-1 e bcl-2 não houve diferença nos níveis de expressão nos grupos analisados. Na análise qualitativa PARP-1 apresentou uma homogeneidade de marcação tanto alta como baixa entre os grupos. Em relação à Galectina-3 observou-se um predomínio de casos com alta expressão, diferentemente da proteína bcl-2 onde o predomínio foi de baixa expressão em todos os casos de carcinoma de laringe e seus respectivos linfonodos metastáticos. Dos 65 pacientes, 55 (84,6%), foram positivos para beta-globina e 7 (12.7%) dos 55 pacientes foram positivos para HPV. Não foi possível verificar quaisquer correlações entre as proteínas Galectina-3, bcl-2 e PARP-1 e o HPV devido ao baixo índice de casos positivos. / To occur the transition from normal epithelium to squamous cell carcinoma is a necessary a for multiple stages process, such as smoking and alcohol abuse and a possible association with HPV infection. Several types of molecular markers have been studied in cancer of larynx, including proteins associated with apoptosis (bcl-2 and PARP-1) and proteins involved in many biological process such as galectin-3. In this study, analyses of qualitative and quantitative immunohistochemistry was performed for bcl-2, PARP-1 and galectin-3 in 65 patients diagnosed with laryngeal squamous cell carcinoma divided into in situ laryngeal carcinomas(LSCCS), laryngeal squamols cells carcinomas without metastases (LSCCWT) and with metastasis (LSCCW) and cervical lymph nodes (CL). HPV detection and typing was performed by PCR and the HPV types evaluated were HPV 6, 11, 16, 18, 31 and 33. In quantitative of galectin-3 there was observed a significant increase of expression in invasive laryngeal squamous cell carcinoma (LSCCWT and LSCCW) compared with in situ laryngeal carcinomas (LSCCS), may indicating that this protein could be a good marker for progression of laryngeal carcinoma. For PARP-1 and bcl-2 protein there was no difference in the levels of expression in all groups studied. In qualitative analysis PARP-1 showed a homogenous immunolabeling in both high and low among the groups. In relation to Galectin-3, it was observed a predominance of cases with high expression, unlike the protein bcl-2 where the expression prevalence was low in all cases of laryngeal carcinoma and their metastatic lymph nodes. Of the 65 patients, 55 (84.6%) were positive for beta-globin and 7 (12.7%) of 55 patients were positive for HPV. Because of a low incidence of HPV in the cases studied, it was not possible correlate the proteins bcl-2, PARP-1 and Galectin-3 with the presence of HPV.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1999. / Bibliography: leaves 98-114.

No description available.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 5 uppsatser.

Thesis (Ph.D. in Pharmacology) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 112-125). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

La formation de cancers est liée à des dérèglements de la progression du cycle cellulaire ou de l’apoptose. L’identification des acteurs cellulaires mis en jeu dans la maladie et l’élucidation des mécanismes responsables de ces dysfonctionnements sont à la base de nouveaux traitements anticancéreux. Ainsi, en vue du développement de thérapies ciblées, les kinases Pim et les protéines anti-apoptotiques de la famille des Bcl-2, surexprimées dans de nombreux types de cancers et associées à des phénomènes de chimiorésistance, constituent des cibles pertinentes. Les kinases Pim (Pim-1,-2 et -3) sont une famille de sérine / thréonine kinases qui jouent un rôle fondamental dans les processus de survie, de prolifération ou de différenciation cellulaire. Bien qu’elles possèdent un substrat commun avec les autres protéines kinases, l’ATP, des différences structurales permettent de les différencier et de les inhiber sélectivement. En tenant compte de ces spécificités, nous nous sommes intéressés à la synthèse de nouveaux inhibiteurs sélectifs des kinases Pim, compétitifs de l’ATP. Parmi les autres agents impliqués dans la formation de tumeurs, les protéines de la famille des Bcl-2, responsables du phénomène d’apoptose ou mort cellulaire programmée, font l’objet d’un domaine d’étude récent. Elles se classent en deux familles selon leur fonction : les protéines pro-apoptotiques et les protéines anti-apoptotiques dont la surexpression est observée dans de nombreux cancers. Nous avons poursuivi l’étude de relations structure-activité initiée au laboratoire à partir de trimères d’alkoxyquinoléines, inhibiteurs micromolaires des protéines anti-apoptotiques Bcl-2 et Bcl-xL, en préparant de nouveaux analogues. / Cancer development is associated with dysfunctions in cell cycle progression or apoptosis. The identification of cellular agents involved in this disease, and the elucidation of mechanisms responsible for these dysfunctions provide the basis for the development of novel anti-cancer drugs.Thus, Pim kinases and Bcl-2 anti-apoptotic proteins which are overexpressed in many malignancies and contribute significantly to chemoresistance are of great interest for the development of targeted cancer therapy. Pim kinases (Pim-1,-2 and -3) belong to a family of serine / threonine kinases which play a key role in cell survival, proliferation and differenciation. Although all protein kinases share ATP as a common substrate, the structure of the ATP-binding pocket of Pim kinases is unique and offers an opportunity for a selective inhibition. Taking account of these specificities, we were interested in the synthesis of novel selective ATP competitive Pim kinase inhibitors. Among the other agents involved in tumorigenesis, Bcl-2 family proteins, which govern apoptosis (or programmed cell death), are subject of a recent interest. These proteins are divided in two classes depending on their function : pro-apoptotic and anti-apoptotic members that are overexpressed in a variety of cancers. In a preliminary work in the laboratory, alkoxyquinoline trimers have demonstrated micromolar inhibition against antiapoptotic proteins Bcl-2 and Bcl-xL. Therefore, we carried on this structure-activity relationship study with the synthesis of novel analogues.

Contrôle de la signalisation oncogénique du mutant L858R de l'EGFR par la protéine suppresseur de tumeur p14ARF dans les adénocarcinomes pulmonaires. Le récepteur à l'EGF (EGFR) est un oncogène puissant impliqué dans le développement des cancers du poumon. Dans ces cancers, la présence de mutations activatrices de l'EGFR (majoritairement L858R et Del19) est un facteur prédictif de réponse aux agents pharmacologiques qui ciblent spécifiquement ce récepteur (EGFR-TKI). Cependant, l'association entre réponse thérapeutique et mutation est plus complexe que prévue, soulignant la nécessité d'approfondir la compréhension des mécanismes moléculaires impliqués dans développement de ces cancers. Nous avons précédemment montré que la quasi-totalité des tumeurs pulmonaires avec des mutations activatrices de l'EGFR présente une expression faible ou indétectable de la protéine suppressive de tumeur p14ARF. Ces résultats nous ont conduites à émettre l'hypothèse que l'expression de p14ARF était un frein essentiel à l'expansion clonale de ces cellules. Nous décrivons pour la première fois une relation fonctionnelle entre p14ARF et du mutant L858R de l'EGFR dans laquelle p14ARF inhibe la croissance de cellules exprimant ce mutant en induisant leur apoptose. Les effets suppresseurs de tumeur de p14ARF impliquent une fonction pro-apoptotique originale de STAT3 qui conduit à l'inhibition de l'expression de la protéine anti-apoptotique Bcl-2. De plus, nous montrons que les cellules EGFR-L858R maintiennent leur avantage de croissance en inhibant l'expression de p14ARF et la signalisation pro-apoptotique STAT3/Bcl-2 qui en découle. Nos résultats identifient également p14ARF comme une nouvelle cible transcriptionnelle de STAT3, mettant ainsi en évidence une boucle de rétrocontrôle positif entre ces deux protéines qui pourrait entretenir la signalisation pro-apoptotique médiée par STAT3. Sur la base de ces résultats, nous suggérons que la réactivation de la voie p14ARF/STAT3/Bcl-2 pourrait être une nouvelle stratégie thérapeutique dans le traitement de ces cancers. / Control of EGFR-L858R oncogenic signaling pathway by the p14ARF tumor suppressor in lung adenocarcinoma. The EGF receptor (EGFR) is a strong oncogene involved in lung carcinogenesis. In these cancers, sensitivity to inhibitors of the EGFR tyrosine kinase activity (EGFR-TKI) has been shown to be related to the presence of activating mutations in the TK domain of EGFR (mainly L858R and Del19). However, the association between mutations and responsiveness to EGFR-TKI based treatment is more complex than previously envisioned, underlying the pressing need to study thoroughly the molecular mechanisms of lung cancer growth. We previously showed that almost all lung cancer with EGFR activated mutations has very low or undetectable levels of the p14ARF tumor suppressor protein. These results led us to postulate that expression of p14ARF is an efficient break against clonal proliferation of these cells. We report for the first time a relationship between p14ARF and mutant EGFR-L858R in which p14ARF inhibits the growth of EGFR-L858R expressing cells by inducing apoptosis. The p14ARF tumor suppressor effects involve an original STAT3 pro-apoptotic function that drives the inhibition of the anti-apoptotic Bcl-2 protein. Moreover, we show that the EGFR-L858R mutant maintains their survival and proliferation characteristics by inhibiting p14ARF expression and consequently the STAT3/Bcl-2 pro-apoptotic pathway. Our results also identify p14ARF as a new transcriptional target of STAT3, therefore providing evidence of a positive feed-back loop that could maintain STAT3 pro-apoptotic pathway. Based on these data, we suggest that manipulation of this pathway could be a therapeutic strategy for lung cancer treatment.