Philosophiae Doctor - PhD / Breast cancer is one of the most common cancers among women in South Africa and the second leading cause of cancer death after lung cancer. According to the American Cancer Society 2015, women have a 12% chance of developing invasive breast cancer and a 3% chance of dying from it. Despite the wide variety of breast cancers e.g. lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS), many share the same etiology and target tissue. Estrogen related carcinogenesis with regard to breast cancer typically results from the activation of distinct signalling pathways. These pathways are not mutually exclusive and are often constituted by receptor mediated stimulation of cell proliferation caused by specific transcriptional gene activation, reactive oxygen species (ROS) formation causing DNA damage and consequently mutations. The molecular pathways that cause drug resistance are not fully understood and the search continues to find novel targets for treatment. The effects of non-toxic triterpenes, oleanolic acid and ursolic acid and the role of autophagy and apoptosis as mechanisms to overcome drug resistance in breast cancer were studied in vitro in MCF-7 breast cancer cells and MCF10A breast cells. In this study the first aim was to establish the influence of OA and UA on cell growth and to see if opposing proliferation patterns could observed between the presumably ERɑ negative (ERɑ/ß -/+) MCF-10A and ERɑ positive (ERɑ/ß +/+) MCF-7 cells. This was followed by morphology studies to establish the possible presence of cytotoxicity and examination of molecular pathways contributing to the anti-cancerous properties of UA and OA and their validity as therapeutic agents. The MCF-7 breast cancer cell line and the immortalized normal mammary cell line, MCF-10A were treated with different concentrations of UA and OA for 6hrs, 12hrs, 24hrs, 48hrs, and 72hrs respectively. Cell morphology was studied in hematoxylin and eosin as well as Hoechst and acridine orange stained cells and viability was measured using crystal violet staining. Molecular techniques employed included the Tali® Apoptosis - and the cellROX assays, flow cytometry and western blotting. Morphological, viability and apoptotic studies have shown that at their lowest concentration, both UA and OA have anti-proliferative and apoptotic effects on MCF-7 and to a lesser extent on MCF-10A. Flow cytometric analysis of treated cells has demonstrated cell arrest in the S- and G2/M phase. The MCF-7 and MCF-10A cells growth inhibition effect may be due to increased autophagy and apoptosis as an alternative to decreased proliferation in MCF-7 cells. This possibility should be evaluated in further studies. The results showed that UA was more effective OA in decreasing cell numbers and it may be applied as treatment for breast cancer. Our observation has shown the treatment with OA and UA increased cell death in MCF-7 cells.The opposing proliferation patterns observed between the presumably ERɑ negative (ERɑ/ß -/+) MCF-10A and ERɑ positive (ERɑ/ß +/+) MCF-7 cells could possibly be ascribed to ERß forming homodimers that may facilitate proliferation, whereas ERɑ/ß heterodimers (expressed in 59% of breast cancers) are frequently associated with the ERɑ antagonising actions of ERß. The results indicate a trend towards biphasic and anti- proliferative effects of the reactants in breast cancer cells which may contribute towards the development of anti- cancer therapies. However, further work is must be done to identify the OA and UA mechanism(s) responsible for anticancer activity. / Libyan Embassy

No description available.

Background: Osteoarthritis (OA) in the knee is one of the most common joint diseases in the world. The symptoms include local joint pain, joint stiffness, crepitation etc. Treatment follows national clinical guidelines which includes patient education, exercise and weight loss. Manual therapy can be used as an additional treatment and has shown a positive effect on pain, range of motion (ROM) and function but the method is not studied enough. Purpose: To investigate the effect of manual mobilization with the OMT Nordic System method as a complement to exercise and patient education for patients with knee OA on pain, Quality of Life (QoL) and ROM. Method: A Single subject experimental design study with 4 participants was conducted. Participants underwent a standardized patient education followed by a 6-week baseline of physical exercise, then a 3-week intervention phase which added manual therapy of the knee joint two times a week for the entire phase. The data was analysed regarding changes in both trend and level. Result: All participants had a significant positive change in level of pain and one participant had a positive change in trend. QoL varied among the participants, two had no change in level, one had a significantly positive change and one had a significantly negative change. Only one participant had a positive change of trend in QoL. ROM increased significantly in level in three out of four participants and the trend changed positively among two of the participants Conclusion: This study indicates that OMT Nordic system as a complement to physical exercise and patient education have a positive effect on pain and ROM in patients with knee OA in the short term. However, since not both level and trend were all over significant the result lacks in significance. Due to the study’s design the results should not be generalized on a group level. To be able to draw general conclusions further studies needs to investigate the effect of the OMT Nordic System with more participants and in different settings.

Predicting the prognosis of patients with prostate cancer is a clinically important problem. Previous studies have indicated that the expression of haptoglobin-related protein epitopes in samples of breast cancer in early stages was associated with earlier relapses and higher risk for tumor recurrence. Oncogenic antigen 519 (OA-519) is the new marker designation for molecules expressing haptoglobin-related protein epitopes. The objective of this immunohistochemical study was to examine OA-519 expression in prostate cancer samples and its relationship to the established prognostic indicators of tumor grade, tumor volume, and clinical stage. Forty-two consecutive tissue samples of prostate adenocarcinoma were examined using an affinity- purified anti-OA-519 antibody. Twenty specimens (48%) tested positive, whereas 22 (52%) tested negative. No staining was observed in normal or hyperplastic prostate tissue. Staining occurred in 6 of 9 (67%) grade III, 14 of 23 (61%) grade II, and in none of 10 (0%) grade I cases (I vs. II and/or III: Fisher exact test, P < 0.006). Twenty-three of the 42 samples were transurethral resection specimens with cancer; 11 (48%) of these tested positive. The mean percentage of tissue chips with tumor, a measure of tumor volume, was significantly higher in the positive group (57%) than in the negative group (15%) (P = 0.004). The proportion of positively stained cases increased with advancing clinical stage, with 25% of Stage A cases expressing OA-519, and 46%, 67%, and 64% of Stages B, C, and D, respectively, expressing OA-519. OA-519 expression correlates with higher tumor grades, larger tumors, and possibly with advanced stage, and thus, it is potentially of prognostic value in prostate cancer.

No description available.

Introduction: Le principal objectif de cette étude est de mesurer l’effet du GDF-5 sur l’homéostasie du cartilage. Le GDF-5 est un gène de susceptibilité de l’OA faisant partie de la famille des BMPs et qui favorise la synthèse du cartilage. Le but de notre étude a été de déterminer l’effet du GDF-5 sur le métabolisme catabolique ainsi que sur l’équilibre global des chondrocytes, principalement au niveau de l’Aggrécan. Méthode : Des chondrocytes arthrosiques canins et humains OA ont été exposés au GDF-5. L’expression des ARNm et des protéines a été analysée afin d’évaluer la production de l’Aggrécan et le ratio Col-II/Col-I au niveau des facteurs anaboliques et du phénotype. Pour le catabolisme, l’expression et l’activité des aggrécanases ADAMTS-4 et ADAMTS-5 ont été mesurées. Les épitopes NITEGE et CTX-II ont aussi été quantifiés dans le liquide synovial canin après des injections intraarticulaires de GDF-5. Résultats : Le GDF-5 provoque une augmentation de l’activité cellulaire des chondrocytes canins et humains. Pour les ARNm et l’expression protéique, le GDF-5 augmente l’expression de l’Aggrécan alors que les facteurs cataboliques le diminuent. Le phénotype reste inchangé en présence du produit, sauf à haute dose où on augmente le ColI. L’activité des aggrécanases diminue puisque l’épitope NITEGE diminue alors que le CTX-II augmente dans l’articulation. Conclusion : En somme, les facteurs anaboliques du cartilage sont favorisés, alors que les facteurs cataboliques sont diminués par le GDF-5. Cette action double permet d’illustrer l’effet du GDF-5, le classant comme un potentiel médicament modifiant la maladie de l’OA qui mérite d’être étudiée. / Purpose: The objective of this study is to assess the effect of GDF-5 on cartilage homeostasis. GDF-5 is a susceptibility gene for OA and member of the BMP super family. Studies have shown that it can increase expression of anabolic factors in chondrocytes. Therefore, our study indentifies how GDF-5 influences this metabolism and the global homeostasis of chondrocytes, aiming mainly towards Aggrecan. Methods : Osteoarthritic (OA) chondrocytes from canine and human models were exposed to GDF-5. Protein expressions, along with mRNA expression were assessed in order to investigate Aggrecan production and the ratio of Col-II/Col-I, for the anabolic phenotype markers. The aggrecanases ADAMTS-4 and ADAMTS-5 and their global activity were assed for the catabolic factors. The NITEGE and CTX-II epitope were also measured in synovial fluid of Pond-Nuki dogs that received intraarticular GDF-5 injections. Results : GDF-5 increases chondrocyte cellular activity, in our canine and human models. Both mRNA and protein expression of the chondrocytes Aggrecan were increased and the aggrecanases expression and activity were decreased. Collagen ratio did not show a phenotype, except et high dosage where the Col-I production is induced. Aggrecanase activity was lowered while CTX-II was increased. Conclusion : In conclusion, the anabolic cellular activity of OA chondrocytes increases while the catabolic factors decrease in presence of GDF-5. This double action illustrates the global effect of GDF-5, identifying it as a potential disease modifying factor of OA that should be further investigated.

Introduction: Le principal objectif de cette étude est de mesurer l’effet du GDF-5 sur l’homéostasie du cartilage. Le GDF-5 est un gène de susceptibilité de l’OA faisant partie de la famille des BMPs et qui favorise la synthèse du cartilage. Le but de notre étude a été de déterminer l’effet du GDF-5 sur le métabolisme catabolique ainsi que sur l’équilibre global des chondrocytes, principalement au niveau de l’Aggrécan. Méthode : Des chondrocytes arthrosiques canins et humains OA ont été exposés au GDF-5. L’expression des ARNm et des protéines a été analysée afin d’évaluer la production de l’Aggrécan et le ratio Col-II/Col-I au niveau des facteurs anaboliques et du phénotype. Pour le catabolisme, l’expression et l’activité des aggrécanases ADAMTS-4 et ADAMTS-5 ont été mesurées. Les épitopes NITEGE et CTX-II ont aussi été quantifiés dans le liquide synovial canin après des injections intraarticulaires de GDF-5. Résultats : Le GDF-5 provoque une augmentation de l’activité cellulaire des chondrocytes canins et humains. Pour les ARNm et l’expression protéique, le GDF-5 augmente l’expression de l’Aggrécan alors que les facteurs cataboliques le diminuent. Le phénotype reste inchangé en présence du produit, sauf à haute dose où on augmente le ColI. L’activité des aggrécanases diminue puisque l’épitope NITEGE diminue alors que le CTX-II augmente dans l’articulation. Conclusion : En somme, les facteurs anaboliques du cartilage sont favorisés, alors que les facteurs cataboliques sont diminués par le GDF-5. Cette action double permet d’illustrer l’effet du GDF-5, le classant comme un potentiel médicament modifiant la maladie de l’OA qui mérite d’être étudiée. / Purpose: The objective of this study is to assess the effect of GDF-5 on cartilage homeostasis. GDF-5 is a susceptibility gene for OA and member of the BMP super family. Studies have shown that it can increase expression of anabolic factors in chondrocytes. Therefore, our study indentifies how GDF-5 influences this metabolism and the global homeostasis of chondrocytes, aiming mainly towards Aggrecan. Methods : Osteoarthritic (OA) chondrocytes from canine and human models were exposed to GDF-5. Protein expressions, along with mRNA expression were assessed in order to investigate Aggrecan production and the ratio of Col-II/Col-I, for the anabolic phenotype markers. The aggrecanases ADAMTS-4 and ADAMTS-5 and their global activity were assed for the catabolic factors. The NITEGE and CTX-II epitope were also measured in synovial fluid of Pond-Nuki dogs that received intraarticular GDF-5 injections. Results : GDF-5 increases chondrocyte cellular activity, in our canine and human models. Both mRNA and protein expression of the chondrocytes Aggrecan were increased and the aggrecanases expression and activity were decreased. Collagen ratio did not show a phenotype, except et high dosage where the Col-I production is induced. Aggrecanase activity was lowered while CTX-II was increased. Conclusion : In conclusion, the anabolic cellular activity of OA chondrocytes increases while the catabolic factors decrease in presence of GDF-5. This double action illustrates the global effect of GDF-5, identifying it as a potential disease modifying factor of OA that should be further investigated.

La combustion de bois, ou plus largement de la biomasse, est une source de pollution très importante en particules atmosphériques en hiver, particulièrement en France. Si les émissions primaires ont été étudiées depuis de nombreuses années, il existe de grandes incertitudes sur le devenir de ces émissions dans l’atmosphère. Le travail de thèse a donc porté sur l’étude du vieillissement en chambre de simulation atmosphérique de l’aérosol émis par 3 appareillages pour le chauffage au bois (conçus entre 2000 et 2010 et représentatifs de la politique de renouvellement mis en place par l’ADEME), avec un intérêt particulier pour le potentiel de formation d’aérosol organique secondaire (SOA) et la modification de l’empreinte chimique à l’échelle moléculaire au cours du transport atmosphérique. Les expériences ont montré un potentiel de formation de SOA très important. La concentration en OA peut ainsi être multipliée par 7 (1.5 – 7.1) entre l’émission et après un temps de résidence atmosphérique équivalent à 5 h. Cette étude met également en évidence l’impact de l’efficacité de combustion sur les facteurs d’émission et par conséquent le rôle crucial de l’opérateur. L’étude à l’échelle moléculaire a mis en évidence la formation de composés susceptibles de servir de marqueurs de combustion de biomasse âgée, principalement des nitrocatéchols. Enfin, cette étude démontre le rôle clé de la volatilisation du lévoglucosan, principal marqueur organique de la combustion de biomasse, au cours du processus de dilution dans l’atmosphère, et pose clairement la question de la pertinence des constantes cinétiques de dégradation préalablement calculées en chambre de simulation atmosphérique. / Biomass burning is in winter a main source of air pollution by particulate matter, especially in France. While primary emissions have been characterized extensively before, few studies have addressed the aging of these emissions in the atmosphere and large uncertainties remain. Therefore, the objectives of this thesis was to study in a smog chamber the aging of the aerosol emitted by 3 different woodstoves used for residential heating (fabricated from between 2000 and 2010, and representative of the policy engaged by the French environmental agency to renew the appliances across the country), with a specific focus on the Secondary Organic Aerosol (SOA) production potential and the modification of the chemical fingerprint of the emissions at the molecular level during their transport in the atmosphere. The experiments showed the SOA production potential can be significant. The OA concentration can be increased by up to a factor of 7 (1.5 – 7.1) after being aged in the smog chamber with a time equivalent to 5 hours in the atmosphere. The study also further demonstrated the influence of the combustion efficiency on the emissions and implicitly the role of the operator. The study of the composition of the aerosol at the molecular level showed the formation of compounds, likely to serve as markers for aged biomass burning, mainly nitrocatechols. Finally, the work also illustrates the influence of the volatilization of levoglucosan, main marker of biomass burning, during the dilution process occurring in the atmosphere, and challenge the pertinence of the degradation rate constant determined previously in smog chamber.

Made available in DSpace on 2015-04-14T14:12:21Z (GMT). No. of bitstreams: 1 400803.pdf: 947266 bytes, checksum: 5019355686e387f3f8adc71c7df5ab9c (MD5) Previous issue date: 2008-03-28 / O estudo relativo ? reconstru??o do conhecimento dos alunos sobre o fen?meno natural do ciclo da ?gua por meio de Unidade de Aprendizagem teve como ponto de partida a an?lise de documentos sobre o contexto da investiga??o referente ?s escolas da Regi?o de abrang?ncia do Munic?pio de Erechim, do Estado do Rio Grande do Sul e do Brasil com consulta aos dados dispon?veis no Instituto Nacional de Estudos e Pesquisas Educacionais An?sio Teixeira (INEP/MEC). Essa etapa foi importante para compreender a situa??o atual da Educa??o nessa Regi?o, em especial na ?rea de Ci?ncias. Com base nessas informa??es e a partir da identifica??o dos conhecimentos pr?vios dos alunos de uma turma de 5? s?rie do Ensino Fundamental de uma escola da rede estadual de ensino, durante as aulas de Ci?ncias, a pesquisa buscou compreender de que modo ocorre o processo de reconstru??o do conhecimento desses alunos sobre o fen?meno natural do ciclo da ?gua. Foram coletadas informa??es por meio de um question?rio inicial. Ap?s, os alunos elaboraram perguntas que serviram de base para a organiza??o da Unidade de Aprendizagem. No decorrer do estudo, foram registradas no di?rio de aula as principais observa??es realizadas e, nesse per?odo, os alunos visitaram o Museu de Ci?ncias e Tecnologia da PUCRS, com a finalidade de conhecer os experimentos interativos relacionados ao ciclo da ?gua que integraram a Unidade de Aprendizagem. Na seq??ncia, foi aplicado o question?rio final para identificar o crescimento em rela??o aos conhecimentos pr?vios e para identificar as novas representa??es dos alunos sobre o tema estudado. Foi solicitado, ainda, nos question?rios inicial e final, que os alunos fizessem desenhos sobre o fen?meno estudado, cuja an?lise tamb?m integrou o trabalho. Por ?ltimo, os alunos foram entrevistados para conhecimento de suas percep??es em rela??o ?s experi?ncias vivenciadas ao longo da Unidade de Aprendizagem. Tanto os question?rios quanto as entrevistas e os registros no di?rio de aula foram analisados por meio de an?lise textual discursiva. A investiga??o permitiu concluir que ? preciso conhecer a comunidade escolar, partir dos conhecimentos pr?vios relacionandos ? teoria e ? pr?tica e oferecer atividades diversificadas que contribuam para que os alunos atribuam novos significados aos fen?menos, de modo que os conhecimentos se tornem mais complexos e cient?ficos.

Made available in DSpace on 2015-04-14T14:12:47Z (GMT). No. of bitstreams: 1 433928.pdf: 2102461 bytes, checksum: 712bc3dc76eb20926c82f3f3d21dbedd (MD5) Previous issue date: 2011-03-14 / Este trabalho consistiu em uma investiga??o cujo objetivo foi o de compreender o processo de aprendizagem de conceitos de F?sica e Qu?mica em uma turma de alfabetiza??o, com o aux?lio de uma Unidade de Aprendizagem (UA) focada em cores e vida. Esta investiga??o tem como fundamenta??o te?rica a constru??o e reconstru??o de conceitos e os princ?pios do educar pela pesquisa. O trabalho se desenvolveu com base em uma abordagem qualitativa (natural?stica-construtiva) utilizando como m?todo o estudo de caso e a observa??o participante. Os dados foram coletados por meio de question?rios, para a identifica??o das ideias pr?vias e posteriores ao desenvolvimento da UA, que foram gr?ficos, desenhos e s?mbolos verbais. Al?m disso, no di?rio de campo foram registradas as observa??es da professora. Para a an?lise e interpreta??o dos dados resultantes dos question?rios e das observa??es da professora foi utilizada a metodologia An?lise Textual Discursiva. Este trabalho propiciou que as estrat?gias desenvolvidas na investiga??o resultassem em amplia??o do conhecimento na ?rea de educa??o cient?fica de crian?as em per?odo de alfabetiza??o, possibilitando uma melhor compreens?o sobre como ocorre a aprendizagem neste n?vel, com o uso de experimenta??o no contexto de uma Unidade de Aprendizagem