The aims of this thesis were to investigate the long-term effects of adjuvant tamoxifen treatment on breast cancer recurrence and mortality, cardiovascular disease, and the incidence of secondary cancer. Between 1982 and 1992, postmenopausal patients with early stage breast cancer were included in a randomized clinical study of 2 or 5 years of postoperative tamoxifen therapy. The trial was planned by the Swedish Breast Cancer Group, and it included 4610 patients. Follow-up on causes of death, hospitalizations and secondary cancers were obtained from national population-based registries.  All-cause mortality, breast cancer-specific mortality and mortality from coronary heart disease were decreased in the 5-year group, but the incidence of endometrial cancer was increased (Paper I). The incidence and mortality of cerebrovascular diseases were increased during the active treatment phase, and reduced after the active treatment (Paper II). Similar results were seen for subgroups of cerebrovascular diseases such as stroke and ischemic stroke. In the 5-year group, the morbidity from coronary heart disease was reduced during treatment but not after treatment was stopped (Paper III). This was the case also for heart failure and for atrial fibrillation/flutter. For secondary cancers the lung cancer risk was reduced, as well as the lung cancer mortality (Paper IV). An increased risk was observed for endometrial cancer, but appeared to decrease over time. The risk of contralateral breast cancer was reduced, with most of the reduction after treatment was stopped. For distance recurrences the risk was reduced both during treatment and a few years after treatment was stopped. The breast cancer mortality was also reduced, especially during the post-treatment phase.

La carbonatation est une pathologie qui affecte les matériaux à base de ciment tels que les bétons et lesmortiers. Les zones carbonatées du matériau deviennent fragiles et perdent ainsi leur pouvoir deprotection des aciers contre la corrosion. Les produits de corrosion engendrent alors une dégradation dubéton pouvant aboutir à la ruine de la structure.Six types de bétons adjuvantés et deux pâtes de ciments ont été formulés grâce à une étude rhéologiqueafin d'étudier l'effet de la carbonatation accélérée et naturelle sur la durabilité des bétons et des pâtesde ciments à base de ressources algériennes. Pour ce faire, plusieurs méthodes d'investigation sontutilisées, aussi bien à l'échelle macroscopique que microscopique.En conclusion, le modèle rhéologique empirique développé peut être utilisé pour formuler des bétonsrésistants à la carbonatation. L'étude de la carbonatation démontre que le protocole accéléré, peut serévéler moins agressifs que la carbonatation naturelle, notamment pour des pâtes de ciment denses.Dans ce cas, la carbonatation accélérée de la surface tend à combler la microporosité superficielle dubéton, freinant ainsi la diffusion du dioxyde de carbone, contrairement à la carbonatation naturelle quiagit de manière plus diffuse sans totalement obstruer la porosité. Moins les bétons sont compacts, plusle protocole accéléré s'avère effectif.

The advent of prostate-specific antigen (PSA) testing and increased patient awareness has led to patients being diagnosed with prostate cancer at an earlier stage and a younger age than previously. Adjuvant hormonal therapy to radiotherapy or prostatectomy has been shown to reduce the risk of tumour progression, and in some studies survival benefits have been demonstrated. The non-steroidal antiandrogen bicalutamide (‘Casodex’) has undergone extensive evaluation and is currently undergoing clinical trials as immediate therapy, either alone or as adjuvant to treatment of curative intent in patients with localized or locally advanced disease. Data from the first analysis of one of the studies in the Early Prostate Cancer (EPC) programme involving 3,603 patients have shown that, after a median follow-up of 2.6 years, the risk of prostate cancer progression was significantly reduced (by 43%) in patients receiving bicalutamide 150 mg compared with those receiving standard care alone (HR 0.57; 95% CI 0.48, 0.69; p ≪ 0.0001). The risk of PSA progression was also significantly reduced (by 63%). At this stage the survival data are still immature. Side effects of bicalutamide were mostly gynaecomastia and breast pain, which is consistent with its pharmacology. Overall withdrawal rates were similar in the bicalutamide 150 mg and standard care alone groups. In the bicalutamide 150 mg group, withdrawals were mainly due to side effects, whereas in the group receiving standard care alone, withdrawals were mainly due to disease progression. The programme is ongoing, and survival data are awaited. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The guidelines for the curative treatment of prostate cancer presented by the German Society of Urology are discussed. They are based on the current knowledge of the outcomes of surgical and radiotherapeutic treatment for prostate cancer. Radical prostatectomy is recommended as the first-line treatment for organ-confined prostate cancer in patients with an individual life expectancy of at least 10 years. Radiotherapy can be considered as an alternative treatment modality, although current knowledge does not allow a definite assessment of the relative value of radiotherapy compared to radical prostatectomy. Locally advanced cT3 prostate cancer is overstaged in about 20% and curative treatment is possible in selected cases. Guidelines represent rules based on the available evidence. This implies that exceptions must be made whenever appropriate and that guidelines have to be reviewed regularly as new information becomes available. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Vaccination comes second in importance after introduction of clean water as a public health intervention which has largely contributed in the reduction of deaths from infectious diseases. Success in the development of a group A streptococcal (GAS) vaccine is expected to save 517 000 deaths per annum according to a recent independent review commissioned by the world health organization (WHO) and would offer an ideal means to prevent rheumatic heart disease (responsible for the greatest health burden) and other GAS-associated diseases which affect the health of 600 million. Traditional vaccine approaches (killed or live attenuated) have demonstrated great success against many bacterial and viral infectious diseases, crowned by the global eradication of smallpox announce by the WHO in 1980 and near-to-be announced eradication of polio viral disease. However, application of traditional techniques in many cases such as HIV/AIDS, malaria, GAS and Mycobacteria tuberculosis, has not shown the same success. Risk associated with the use of live–attenuated pathogens, such as recurrence of virulence (e.g. HIV), development of autoimmune diseases (e.g. GAS), and difficulties of manufacture hindered the use of such approaches. Other vaccine approaches such as subunit vaccines (recombinant proteins) and carrier conjugated vaccine are also hindered by the lack of suitable adjuvants, carriers and delivery systems. The current thesis focused on the design, synthesis and evaluation of novel adjuvants and vaccine delivery systems against GAS. The first chapter reviews recent approaches in the field of GAS vaccine design and new findings in immunology which represent the basis of our novel strategies. The second chapter describes the design, synthesis and evaluation of a novel library of lipopeptides as self-adjuvanting GAS vaccine candidates, composed of: (i) a universal helper T-cell epitope (P25), (ii) a target GAS B-cell epitope (J14), and (iii) a lipid moiety. Systemic J14-specific IgG antibodies were detected following subcutaneous immunization of BALB/c (H-2d) mice with each construct without the need for an additional adjuvant. The effect of changing the order of P25, J14, and lipid moiety attachment, or incorporation of P25 and J14 into a lipid-core peptide system (LCP) on antibody titers was assessed. The point of lipid moiety attachment had the greatest influence on systemic J14-specific IgG antibody titers. Overall, the best vaccines featured a C-terminal lipid moiety, conjugated through a lysine residue to P25 at the N-terminus, and J14 on the lysine side-chain. Mucosal surface of the nasal-oral route is a primary site of GAS infections. An ideal GAS vaccine would have to elicit both mucosal as well as systemic immune responses and hence would not only prevent the development of GAS-associated diseases but also would prevent primary GAS infections. Therefore, the nasal route is considered a highly promising route of vaccine administration to provide local as well as systemic immune responses against pathogens that utilize mucosal surface as site of infection. The third chapter includes immunological assessment of the lipopeptide vaccine library described in the second chapter following intranasal immunization of B10BR (H-2k) mice. The whole library was first investigated in a small scale experiment (5 mice per group) to select promising candidates which demonstrate the best local and systemic J14-specific antibodies. Four selected lipopeptides were further investigated in a larger scale experiment (15 mice per group) followed by intranasal challenge of vaccinated mice with a virulent GAS M1 strain. The best local and systemic immune responses were demonstrated by a lipopeptide featuring a lipid moiety consisting of two 16 carbon chains incorporated at the C-terminus of the lipopeptide. However, this candidate did not achieve protection against bacterial challenge. The best protection (100%) was shown by a lipopeptide candidate featuring a C-terminal J14, conjugated through a lysine residue to P25 at the N-terminus, and a lipid moiety on the lysine side-chain. A possible explanation for these results was investigated where antibodies elicited by the former candidate was found to better recognize the minimal B-cell epitope in the native p145 sequence of the M protein. Circular dichroism study of lipopeptides used in the previous experiment demonstrated that the former candidate features α-helical conformation which is required to produce protective J14-specific antibodies. Further studies are needed to explain structural features required to achieve both α-helicity and strong mucosal immune responses shown by the previously mentioned two lipopeptides. Signaling through toll-like receptors expressed by immune cells was recently shown to result in a robust immune response and was investigated as a possible mode of action for our novel lipopeptides. The fourth chapter introduces our lipopeptide vaccine approach as novel synthetic ligands targeting TLR2. A lipid moiety consisting of two alkyl chains of 16 carbons was found to achieve optimal TLR2 signaling regardless of the position of lipid attachment. Carbohydrates as polyhydroxy compounds provide an easily accessible class of compounds to design scaffolds (carriers) to attach lipids and peptide epitopes in different number and stereochemical positions which makes glycolipopeptides an attractive target for adjuvant research and structure-adjuvanticity relationships studies. The Fifth chapter reports immunological assessment of two series of glycolipopeptides as GAS vaccine candidates and novel vaccine delivery systems. The first series: lipid carbohydrate core peptide system (LCCP); represents a modification of the classical LCP system where polylysine dendrimer is replaced by different monosccharides as carriers for peptide antigens. LCCP analogues induced proper humoral immune responses against incorporated epitopes comparable to the LCP delivery system and as strong as the immune response elicited by CFA mixtures. Moreover, LCCP delivery system has been proved to be tolerant to the use of different epitopes as well as changing carbohydrate cores. Design of novel carbohydrate cores with different orthogonal protecting groups is needed to explore the potential advantage of various stereochemical arrangements provided by monosaccharides. The second series of glycolipopeptides incorporates various glycolipid moieties (self-adjuvanting activity) covalently coupled to the N-terminus of J8 (a model epitope). The new glycolipopeptide vaccine candidates (containing only one copy of J8) bear comparison with an LCP analogue (containing four copies of J8) which would improve the ease of synthesis, purification and cost of vaccine production. The slight difference in immunogenicity among these glycolipopeptides was difficult to be explained due to intervening effects of both the number and orientation of lipids on immunological activity. Further investigation is needed to determine the contribution of each factor.

Vaccination comes second in importance after introduction of clean water as a public health intervention which has largely contributed in the reduction of deaths from infectious diseases. Success in the development of a group A streptococcal (GAS) vaccine is expected to save 517 000 deaths per annum according to a recent independent review commissioned by the world health organization (WHO) and would offer an ideal means to prevent rheumatic heart disease (responsible for the greatest health burden) and other GAS-associated diseases which affect the health of 600 million. Traditional vaccine approaches (killed or live attenuated) have demonstrated great success against many bacterial and viral infectious diseases, crowned by the global eradication of smallpox announce by the WHO in 1980 and near-to-be announced eradication of polio viral disease. However, application of traditional techniques in many cases such as HIV/AIDS, malaria, GAS and Mycobacteria tuberculosis, has not shown the same success. Risk associated with the use of live–attenuated pathogens, such as recurrence of virulence (e.g. HIV), development of autoimmune diseases (e.g. GAS), and difficulties of manufacture hindered the use of such approaches. Other vaccine approaches such as subunit vaccines (recombinant proteins) and carrier conjugated vaccine are also hindered by the lack of suitable adjuvants, carriers and delivery systems. The current thesis focused on the design, synthesis and evaluation of novel adjuvants and vaccine delivery systems against GAS. The first chapter reviews recent approaches in the field of GAS vaccine design and new findings in immunology which represent the basis of our novel strategies. The second chapter describes the design, synthesis and evaluation of a novel library of lipopeptides as self-adjuvanting GAS vaccine candidates, composed of: (i) a universal helper T-cell epitope (P25), (ii) a target GAS B-cell epitope (J14), and (iii) a lipid moiety. Systemic J14-specific IgG antibodies were detected following subcutaneous immunization of BALB/c (H-2d) mice with each construct without the need for an additional adjuvant. The effect of changing the order of P25, J14, and lipid moiety attachment, or incorporation of P25 and J14 into a lipid-core peptide system (LCP) on antibody titers was assessed. The point of lipid moiety attachment had the greatest influence on systemic J14-specific IgG antibody titers. Overall, the best vaccines featured a C-terminal lipid moiety, conjugated through a lysine residue to P25 at the N-terminus, and J14 on the lysine side-chain. Mucosal surface of the nasal-oral route is a primary site of GAS infections. An ideal GAS vaccine would have to elicit both mucosal as well as systemic immune responses and hence would not only prevent the development of GAS-associated diseases but also would prevent primary GAS infections. Therefore, the nasal route is considered a highly promising route of vaccine administration to provide local as well as systemic immune responses against pathogens that utilize mucosal surface as site of infection. The third chapter includes immunological assessment of the lipopeptide vaccine library described in the second chapter following intranasal immunization of B10BR (H-2k) mice. The whole library was first investigated in a small scale experiment (5 mice per group) to select promising candidates which demonstrate the best local and systemic J14-specific antibodies. Four selected lipopeptides were further investigated in a larger scale experiment (15 mice per group) followed by intranasal challenge of vaccinated mice with a virulent GAS M1 strain. The best local and systemic immune responses were demonstrated by a lipopeptide featuring a lipid moiety consisting of two 16 carbon chains incorporated at the C-terminus of the lipopeptide. However, this candidate did not achieve protection against bacterial challenge. The best protection (100%) was shown by a lipopeptide candidate featuring a C-terminal J14, conjugated through a lysine residue to P25 at the N-terminus, and a lipid moiety on the lysine side-chain. A possible explanation for these results was investigated where antibodies elicited by the former candidate was found to better recognize the minimal B-cell epitope in the native p145 sequence of the M protein. Circular dichroism study of lipopeptides used in the previous experiment demonstrated that the former candidate features α-helical conformation which is required to produce protective J14-specific antibodies. Further studies are needed to explain structural features required to achieve both α-helicity and strong mucosal immune responses shown by the previously mentioned two lipopeptides. Signaling through toll-like receptors expressed by immune cells was recently shown to result in a robust immune response and was investigated as a possible mode of action for our novel lipopeptides. The fourth chapter introduces our lipopeptide vaccine approach as novel synthetic ligands targeting TLR2. A lipid moiety consisting of two alkyl chains of 16 carbons was found to achieve optimal TLR2 signaling regardless of the position of lipid attachment. Carbohydrates as polyhydroxy compounds provide an easily accessible class of compounds to design scaffolds (carriers) to attach lipids and peptide epitopes in different number and stereochemical positions which makes glycolipopeptides an attractive target for adjuvant research and structure-adjuvanticity relationships studies. The Fifth chapter reports immunological assessment of two series of glycolipopeptides as GAS vaccine candidates and novel vaccine delivery systems. The first series: lipid carbohydrate core peptide system (LCCP); represents a modification of the classical LCP system where polylysine dendrimer is replaced by different monosccharides as carriers for peptide antigens. LCCP analogues induced proper humoral immune responses against incorporated epitopes comparable to the LCP delivery system and as strong as the immune response elicited by CFA mixtures. Moreover, LCCP delivery system has been proved to be tolerant to the use of different epitopes as well as changing carbohydrate cores. Design of novel carbohydrate cores with different orthogonal protecting groups is needed to explore the potential advantage of various stereochemical arrangements provided by monosaccharides. The second series of glycolipopeptides incorporates various glycolipid moieties (self-adjuvanting activity) covalently coupled to the N-terminus of J8 (a model epitope). The new glycolipopeptide vaccine candidates (containing only one copy of J8) bear comparison with an LCP analogue (containing four copies of J8) which would improve the ease of synthesis, purification and cost of vaccine production. The slight difference in immunogenicity among these glycolipopeptides was difficult to be explained due to intervening effects of both the number and orientation of lipids on immunological activity. Further investigation is needed to determine the contribution of each factor.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

?rea de concentra??o: Cl?nica Odontol?gica. / Linha de pesquisa: Les?es inflamat?rias, c?sticas e neopl?sicas da cavidade bucal. / Na Folha de Rosto e Ficha Catalogr?fica da obra consta o t?tulo: "Avalia??o dos efeitos anti-inflamat?rio e antiedematog?nico do gel Oxyflower? em modelo de edema de pata induzido por adjuvante completo de Freund em ratos". / Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2018-05-22T17:57:16Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) timilliy_mayra_martins_cruz.pdf: 1084452 bytes, checksum: e81ee908ce5c1b999b746646f5a03878 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2018-06-05T14:41:12Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) timilliy_mayra_martins_cruz.pdf: 1084452 bytes, checksum: e81ee908ce5c1b999b746646f5a03878 (MD5) / Made available in DSpace on 2018-06-05T14:41:12Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) timilliy_mayra_martins_cruz.pdf: 1084452 bytes, checksum: e81ee908ce5c1b999b746646f5a03878 (MD5) Previous issue date: 2017 / Introdu??o: A inflama??o ? um mecanismo de defesa prim?ria que protege o organismo de est?mulos nocivos ou prejudiciais. Os medicamentos anti-inflamat?rios tais como os Anti-Inflamat?rios N?o Esteroidais (AINEs) e os corticoster?ides s?o utilizados para tratar os dist?rbios inflamat?rios, por?m, diversos efeitos colaterais t?m sido relatados. Neste contexto, produtos naturais t?m contribu?do bastante para o desenvolvimento de terapias farmacol?gicas modernas e eficazes. Alguns medicamentos naturais apresentam grande potencial terap?utico, como por exemplo, o Oxyflower?. Este rem?dio baseia-se na a??o de ess?ncias florais, por?m seus efeitos biol?gicos ainda n?o foram devidamente investigados. Objetivos: Investigar os poss?veis efeitos anti-inflamat?rio e antiedematog?nico do gel Oxyflower? em modelo animal de inflama??o cr?nica. Metodologia: 25 ratos machos da linhagem Holtzman foram aleatoriamente divididos em 5 grupos experimentais (controle, ve?culo do Oxyflower?, Oxyflower?, triancinolona acetonida e diclofenaco dietilam?nio). A inflama??o foi quimicamente induzida por meio da inje??o de 200 ?L de Adjuvante Completo de Freund (ACF) na pata traseira direita dos ratos. O volume e espessura das patas dos ratos foram mensurados com pletism?metro de pata e paqu?metro digital, respectivamente. Durante 14 dias, os animais foram tratados com os f?rmacos e tiveram acompanhamento de sua massa corporal. Neste per?odo a temperatura das patas traseiras foram avaliadas com um term?grafo digital. Foram realizadas an?lises histol?gicas e leucometria. Os dados foram analisados como m?dia ? erro padr?o ou desvio padr?o da m?dia e apresentados como a varia??o (delta) do volume, espessura e temperatura das patas traseiras. As diferen?as entre os grupos foram analisadas pelos testes de vari?ncia ANOVA (two e one-way), seguidos do post hoc de Tukey e teste Qui-Quadrado. Valores de p< 0,05 foram considerados significativos. Resultados: O gel Oxyflower? promoveu redu??es no volume, espessura e temperatura das patas dos ratos, injetados com ACF, quando comparados aos animais do grupo controle. N?o houve diferen?a em rela??o ao ganho de massa corporal nos diferentes grupos experimentais. Os resultados para leucometria e histologia n?o apresentaram diferen?as significativas entre os grupos. Conclus?o: O gel Oxyflower? apresentou atividade antiedematog?nica semelhante ? Triancinolona e ao Diclofenaco. A termografia infravermelha ? um m?todo aplic?vel na avalia??o da temperatura tecidual associada ao edema, neste modelo experimental. / Disserta??o (Mestrado) ? Programa de P?s-Gradua??o em Odontologia, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2017. / Introduction: Inflammation is a primary defense mechanism that protects the body from harmful or harmful stimuli. Anti-inflammatory drugs such as non-steroidal antiinflammatory drugs (NSAIDs) and corticosteroids are used to treat inflammatory disorders, but several side effects have been reported. Thus, natural products have contributed greatly to the development of modern and effective pharmacological therapies. Some natural medicines have great therapeutic potential, such as Oxyflower?. This drug is based on the action of flower essences, but its biological effects have not yet been properly investigated. Objectives: To investigate the possible anti-inflammatory and anti-infective effects of Oxyflower? gel in an animal model of chronic inflammation. Methods: 25 male rats of the Holtzman strain were randomly divided into 5 experimental groups (control, Oxyflower? vehicle, Oxyflower?, triamcinolone acetonide and diclofenac diethylammonium). Inflammation was chemically induced by injecting 200 ?L of Complete Freund's Adjuvant (CFA) into the right hind paw of rats. The volume and thickness of the paws of the rats were measured with a paw plethysmometer and digital caliper, respectively. During 14 days, the animals were treated with the drugs and had monitoring of their body mass. In this period the temperature of the hind legs were evaluated with a digital thermograph. Histological analysis and leukometry were performed. Data were analyzed as mean ? standard error or standard deviation of the mean and presented as the variation (delta) of the volume, thickness and temperature. The differences between the groups were analyzed by ANOVA (two and one-way) variance tests, followed by Tukey post hoc and Chi-Square test. Values of p <0.05 were considered significant. Results: The Oxyflower? gel promoted reductions in the volume, thickness and temperature of the legs of the rats injected with ACF when compared to the animals of the control group. There was no difference in relation to body mass gain in the different experimental groups. The results for leucometry and histology did not show significant differences between the groups. Conclusion: Oxyflower? gel presented antiedematogenic activity similar to Triamcinolone and Diclofenac. Infrared thermography is an applicable method for evaluation of tissue temperature associated with edema, in this experimental model. Infrared thermography is an applicable method for assessing tissue temperature associated with edema in this experimental model. The antiinflammatory effect of Oxyflower? gel could not be confirmed. However, biomolecular, immunological and immunohistochemical analyzes may help confirm the possible antiinflammatory effect of Oxyflower? gel.