Universiẗat, Diss., 2000--Kaiserslautern.

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Submitted by admin tede (tede@pucgoias.edu.br) on 2018-06-19T18:25:16Z No. of bitstreams: 1 DANIEL RODRIGUES DE BASTOS.pdf: 1922893 bytes, checksum: 51e3aa82ceb630f944c3c65627dcffaa (MD5) / Made available in DSpace on 2018-06-19T18:25:16Z (GMT). No. of bitstreams: 1 DANIEL RODRIGUES DE BASTOS.pdf: 1922893 bytes, checksum: 51e3aa82ceb630f944c3c65627dcffaa (MD5) Previous issue date: 2017-05-04 / Introduction: Breast cancer is the most frequent neoplasm among women worldwide and represents the leading cause of death in this population. Important biomarkers have been studied in order to better define the prognosis of patients affected by this cancer. MicroRNAs are small molecules of non-coding RNAs composed of 21 to 25 nucleotides that play an important role in the post-transcriptional regulation of several genes. Objective: The objective of this study was to evaluate the expression of microRNAs (miRNAs: hsa-miR-7 and hsa-miR-10b) and BRCA1 protein in breast cancer samples, as well as the possible associations between expression of these markers with clinicopathological and prognostic aspects. Method: The study included 92 cases of breast carcinoma from Hospital Araújo Jorge, Associação de Combate ao Câncer em Goiás. Formalin fixed paraphin embedded samples were used for the analisis. MicroRNA was extracted from the samples and used for cDNA synthesis. The cDNA samples were adjusted to the same concentration and submitted to quantitative real-time PCR (qRT-PCR). Samples were further evaluated by immunohistochemistry for BRCA1 expression. Results: From a group of 234 immunohistochemical records, 56 cases of non-triple-negative and 36 triple-negative breast carcinomas were selected. Five-year overall survival was significantly associated to triple negative phenotype (p = 0.044), advanced stages (p = 0.005), lymph node involvement (p = 0.038), presence of distant metastasis (p = 0, 0008) and absence of BRCA1 expression (p = 0.039). Significant associations were demonstrated between the absence of BRCA1 and the triple-negative phenotype (p = 0.0346), as well as the absence of estrogen receptor expression (p = 0.006) and absence of progesterone receptor expression (p = 0.0163). The analysis by qRTPCR demonstrated different levels of miR-10b and miR-7 expression in the tumors, with significant associations with triple-negative phenotype (p = 0.021, p = 0.042) and the absence of BRCA1 (p = 0.039, p = 0.006). The comparison between absence and presence of human epidermal growth factor receptor expression showed a significant difference for miR-7 (p = 0.031), and the expression of miR-10b in these cases was not statistically different (p = 0.926). Conclusion: Significant associations were demonstrated between the absence of BRCA1 and the triple-negative phenotype. Five-year overall survival was reduced for the triple-negative phenotype patients, clinical stages III and IV, the presence of lymph node metastasis, the presence of distant metastasis and the absence of BRCA1 expression. This study also demonstrated that hsa-miR-7 and hsa-miR-10b are significantly associated with the absence of BRCA1 expression and triple-negative phenotype, with poorer survival in these patient profiles. Studies with more cases and with cell lines should be performed in order to confirm the role of hsa-miR-7 and hsa-miR-10b in the modulation of BRCA1 expression. / Introdução: O câncer de mama é a neoplasia mais frequente entre as mulheres de todo o mundo e representa a principal causa de morte nesta população. Importantes biomarcadores têm sido estudados, a fim de definir melhor o prognóstico de pacientes acometidas por esta doença. Os microRNAs são pequenas moléculas de RNAs não codificantes, compostos por 21 a 25 nucleotídeos e desempenham importante papel na regulação pós-transcricional de diversos genes. Objetivo: O objetivo do estudo foi avaliar a expressão de microRNAs (miRNAs: hsa-miR-7 e hsamiR- 10b) e da proteína BRCA1 em amostras de câncer de mama, bem como as possíveis associações entre a expressão desses marcadores e os aspectos clinicopatológicos e prognósticos. Método: O estudo foi composto por 92 casos de carcinoma de mama, provenientes do Hospital Araújo Jorge, da Associação de Combate ao Câncer em Goiás. Foram utilizados fragmentos de tumores incluídos em parafina. A extração de microRNA das amostras foi realizada e o produto gerado foi utilizado para a síntese de cDNA. As amostras de cDNA foram ajustadas para igual concentração e submetidas à PCR quantitativa em tempo real (qRT-PCR). As amostras foram avaliadas ainda por meio de imuno-histoquímica para expressão de BRCA1. Resultados: Um total de 234 registros de imuno-histoquímica foi avaliado, resultando em 56 casos de carcinomas de mama apresentando fenótipo não triplonegativo e 36 com fenótipo triplo-negativo. A sobrevida das pacientes em função das características clinicopatológicas demonstrou associações com os casos triplonegativos (p=0,044), estádios mais avançados (p=0,005), acometimento linfonodal (p=0,038), presença de metástase à distância (p=0,0008) e ausência da expressão de BRCA1 (p=0,039). Associações significativas foram demonstradas entre a ausência de BRCA1 e o fenótipo triplo-negativo (p=0,0346), entre a ausência da expressão do receptor de estrógeno e ausência da expressão de BRCA1 (p=0,006), e entre o receptor de progesterona e a ausência da expressão de BRCA1 (p=0,0163). A análise por qRT-PCR demonstrou diferentes níveis de expressão de miR-10b e de miR-7, com associações significativas ao fenótipo triplo-negativo (p=0,021; p=0,042) e à ausência de BRCA1 (p=0,039; p=0,006). A comparação entre ausência e presença da expressão do receptor do fator de crescimento epidérmico humano demonstrou diferença significativa para miR-7 (p=0,031), sendo que a expressão de miR-10b nestes casos não foi estatisticamente diferente (p=0,926). Conclusão: Associações significativas foram demonstradas entre a ausência de BRCA1 e o fenótipo triplo-negativo. A sobrevida em cinco anos foi inversamente associada ao fenótipo triplo-negativo, aos estádios clínicos III e IV, à presença de metástase linfonodal, à presença de metástase à distância e à ausência da expressão de BRCA1. Este estudo demonstrou ainda que hsa-miR-7 e hsa-miR- 10b estão significativamente associados à ausência da expressão de BRCA1 e ao fenótipo triplo-negativo, sendo observada pior sobrevida nestes perfis de pacientes. Estudos com maior número de casos e com linhagens celulares devem ser realizados para constatar o papel de hsa-miR-7 e hsa-miR-10b na modulação da expressão de BRCA1.

Les recherches actuellement menées dans le domaine de l’Imagerie par Résonance Magnétique (IRM) s’orientent vers l’imagerie dite moléculaire, où l’agent de contraste interagit de manière non covalente avec une biomolécule exprimée dans des conditions pathologiques, modulant ainsi spécifiquement le contraste de la zone concernée. Dans ce but, l’évaluation de l’affinité du contrastophore pour sa cible potentielle est primordiale. Dans ce travail, la technique de « diffusométrie RMN » a été mise en œuvre pour évaluer les interactions non covalentes entre l’albumine sérique humaine (HSA) et différents agents de contraste potentiels pour l’IRM. La HSA présente en effet le double avantage de conférer aux agents de contraste une meilleure efficacité, qui se traduit par une augmentation plus marquée de la vitesse de relaxation des protons de l’eau, ainsi qu’un temps de rémanence vasculaire plus élevé, ce qui les rend propices à une utilisation en angiographie. Cette étude a été réalisée sur trois agents de contraste déjà largement décrits dans la littérature (Gd-DTPA, Gd-EOB-DTPA et MP2269) ainsi que sur trois nouveaux agents de contraste synthétisés dans le cadre de ce travail (Gd-C4-sulfadiméthoxin-DTPA, Gd-C4-sulfaphénazol-DTPA, Gd-C4-thyroxin-DTPA). Ces trois nouveaux contrastophores ont été caractérisés indépendamment en solution aqueuse et en présence d’albumine par deux autres techniques précédemment étudiés au sein de notre laboratoire : la relaxométrie protonique et la spectrométrie de masse electrospray. Les résultats obtenus ont révélé une bonne efficacité de deux des agents de contraste en solution aqueuse, ainsi qu’une affinité élevée pour la HSA dans le cas de ces deux mêmes contrastophores. La technique de diffusométrie RMN pour l’évaluation des interactions non covalentes repose sur la différence entre le coefficient de diffusion du ligand seul en solution (l’agent de contraste IRM dans notre cas) et du ligand lié à la macromolécule étudiée (la HSA). En effet, si le contrastophore se lie à l’albumine et que l’échange entre les deux partenaires est rapide sur les échelles de temps RMN, le coefficient de diffusion observé est une moyenne pondérée entre le coefficient de diffusion du ligand libre et le coefficient de diffusion du ligand lié à l’albumine. Les résultats obtenus ont confirmé les tendances observées lors de précédentes études réalisées avec d’autres techniques et nous ont apporté une information supplémentaire sur la cinétique d’échange entre les deux partenaires de l’interaction. Le travail a permis d’explorer les limites de validité de la méthode.

Diabetes Mellitus (DM) é uma síndrome metabólica complexa, causada pela secreção diminuída ou ausente de insulina pelas células beta pancreáticas, levando a hiperglicemia. A hiperglicemia promove a glicação de proteínas e, conseqüentemente, o aparecimento de produtos finais da glicação avançada (AGEs). Atualmente, os pacientes diabéticos são monitorados pela determinação dos níveis de glicemia e hemoglobina glicada (HbA1c). As complicações geradas pela hiperglicemia podem ser divididas em micro e macrovasculares, representadas por retinopatias, nefropatias, neuropatias e doenças cardiovasculares. A albumina (HSA) é a proteína sérica mais abundante no organismo humano e está sujeita à glicação. A protoporfirina XI (PpIX) é a molécula precursora da síntese do heme, componente estrutural da hemoglobina. Ensaios in vitro e em animais indicaram que a hiperglicemia promove uma diminuição de sua concentração em eritrócitos. A espectroscopia de fluorescência é uma técnica bastante utilizada na área biomédica. A autofluorescência corresponde à fluorescência intrínseca presente em algumas moléculas, estando esta associada à estrutura das mesmas. O objetivo deste trabalho foi utilizar a técnica de espectroscopia de fluorescência para mensurar os níveis de autofluorescência da PpIX eritrocitária e AGE-HSA em pacientes diabéticos e indivíduos saudáveis e compará-los com os níveis de glicemia e HbA1c. Este estudo foi realizado com 151 indivíduos (58 controles e 93 diabéticos). Os dados epidemiológicos de pacientes e controles foram obtidos nos prontuários médicos. Para os indivíduos controle, os valores de glicemia foram adquiridos dos prontuários médicos e os níveis de Hb1Ac obtidos pela utilização de kits comerciais. A determinação da autofluorescência da PpIX foi realizada com excitação de 405 nm e emissão de 632 nm. Para a determinação do AGE-HSA foi realizada excitação de 370 nm e emissão de 455 nm. Aproximadamente 50% dos diabéticos apresentaram lesões micro ou macrovasculares decorrentes da hiperglicemia. Não foram observadas diferenças significativas nos valores de intensidade de emissão de PpIX entre os grupos estudados (P=0,89). Na análise do AGE-HSA observou-se diferenças significativas dos valores de intensidade de emissão entre os dois grupos, sendo este valor 1,45 vezes maior para o grupo de indivíduos diabéticos (P<0,0001). Os pacientes com complicações diabéticas apresentavam intensidade de emissão de fluorescência 1,19 vezes maior que os indivíduos sem complicações decorrentes da doença (P= 0,01), mesmo não havendo diferenças significativas nos valores de HbA1c entre os dois grupos. Concluímos que a espectroscopia de fluorescência foi uma técnica eficaz na identificação da autofluorescência da PpIX e do AGE-HSA. A PpIX não foi um biomarcador eficiente para o acompanhamento do DM. A determinação dos níveis de autofluorescência do AGE-HSA foi eficiente para a discriminação entre os grupos e para o monitoramento da progressão da doença, podendo ser mais eficiente que a dosagem de HbA1c. A espectroscopia de fluorescência é uma técnica simples, rápida e de baixo custo para o acompanhamento de indivíduos diabéticos. / Diabetes Mellitus (DM) comprises a complex metabolic syndrome, caused by reduced or absent secretion of insulin by pancreatic beta cells, leading to hyperglycemia. Hyperglycemia promotes glycation of proteins and, consequently, the appearance of advanced glycation end products (AGEs). Currently, diabetic patients are monitored by determining levels of glucose and glycated hemoglobin (HbA1c). The complications caused by hyperglycemia may be divided into micro and macrovascular complications, represented by retinopathy, nephropathy, neuropathy and cardiovascular disease. Albumin (HSA) is the most abundant serum protein in the human body and is subject to glycation. The Protoporphyrin IX (PpIX) is the precursor molecule of heme synthesis, structural component of hemoglobin. The in vitro and animals studies have indicated that hyperglycemia promotes a decrease in its concentration in erythrocytes. The fluorescence spectroscopy is a technique widely used in biomedical field. The autofluorescence corresponds to the intrinsic fluorescence present in some molecules, this being associated with the same structure. The aim of this study was to use fluorescence spectroscopy to measure levels of erythrocyte PpIX autofluorescence and AGE-HSA in diabetic and healthy subjects and compare them with levels of blood glucose and HbA1c. This study was conducted with 151 subjects (58 controls and 93 diabetics). Epidemiological data of patients and controls were obtained from medical records. For control subjects, blood glucose levels were obtained from medical records and levels of Hb1Ac obtained by using commercial kits. The determination of the PpIX autofluorescence was performed with excitation at 405 nm and emission at 632 nm. Determination of AGE-HSA was performed with excitation at 370 nm and emission at 455 nm. Approximately 50% of diabetic had micro and macrovascular lesions resulting from hyperglycemia. There were no significant differences in the PpIX emission intensity values between groups (P = 0.89). In the analysis of AGE-HSA was observed significant differences in the values of emission intensity between the two groups, and this value was 1.45-fold greater for the group of diabetic (P <0.0001). Patients with diabetic complications had fluorescence emission intensity of 1.19-fold higher than individuals without disease complications (P = 0.01), even with no significant differences in HbA1c values between the two groups. We conclude that fluorescence spectroscopy was an effective technique in the identification of the PpIX autofluorescence and AGE-HSA. The PpIX was not an effective biomarker for the monitoring of diabetes. The determination of AGE-HSA autofluorecência was efficient for the discrimination between groups and monitoring disease progression, may be more effective than HbA1c dosage. The fluorescence spectroscopy is a simple, fast and low cost for the monitoring of diabetic patients.

Diabetes Mellitus (DM) é uma síndrome metabólica complexa, causada pela secreção diminuída ou ausente de insulina pelas células beta pancreáticas, levando a hiperglicemia. A hiperglicemia promove a glicação de proteínas e, conseqüentemente, o aparecimento de produtos finais da glicação avançada (AGEs). Atualmente, os pacientes diabéticos são monitorados pela determinação dos níveis de glicemia e hemoglobina glicada (HbA1c). As complicações geradas pela hiperglicemia podem ser divididas em micro e macrovasculares, representadas por retinopatias, nefropatias, neuropatias e doenças cardiovasculares. A albumina (HSA) é a proteína sérica mais abundante no organismo humano e está sujeita à glicação. A protoporfirina XI (PpIX) é a molécula precursora da síntese do heme, componente estrutural da hemoglobina. Ensaios in vitro e em animais indicaram que a hiperglicemia promove uma diminuição de sua concentração em eritrócitos. A espectroscopia de fluorescência é uma técnica bastante utilizada na área biomédica. A autofluorescência corresponde à fluorescência intrínseca presente em algumas moléculas, estando esta associada à estrutura das mesmas. O objetivo deste trabalho foi utilizar a técnica de espectroscopia de fluorescência para mensurar os níveis de autofluorescência da PpIX eritrocitária e AGE-HSA em pacientes diabéticos e indivíduos saudáveis e compará-los com os níveis de glicemia e HbA1c. Este estudo foi realizado com 151 indivíduos (58 controles e 93 diabéticos). Os dados epidemiológicos de pacientes e controles foram obtidos nos prontuários médicos. Para os indivíduos controle, os valores de glicemia foram adquiridos dos prontuários médicos e os níveis de Hb1Ac obtidos pela utilização de kits comerciais. A determinação da autofluorescência da PpIX foi realizada com excitação de 405 nm e emissão de 632 nm. Para a determinação do AGE-HSA foi realizada excitação de 370 nm e emissão de 455 nm. Aproximadamente 50% dos diabéticos apresentaram lesões micro ou macrovasculares decorrentes da hiperglicemia. Não foram observadas diferenças significativas nos valores de intensidade de emissão de PpIX entre os grupos estudados (P=0,89). Na análise do AGE-HSA observou-se diferenças significativas dos valores de intensidade de emissão entre os dois grupos, sendo este valor 1,45 vezes maior para o grupo de indivíduos diabéticos (P<0,0001). Os pacientes com complicações diabéticas apresentavam intensidade de emissão de fluorescência 1,19 vezes maior que os indivíduos sem complicações decorrentes da doença (P= 0,01), mesmo não havendo diferenças significativas nos valores de HbA1c entre os dois grupos. Concluímos que a espectroscopia de fluorescência foi uma técnica eficaz na identificação da autofluorescência da PpIX e do AGE-HSA. A PpIX não foi um biomarcador eficiente para o acompanhamento do DM. A determinação dos níveis de autofluorescência do AGE-HSA foi eficiente para a discriminação entre os grupos e para o monitoramento da progressão da doença, podendo ser mais eficiente que a dosagem de HbA1c. A espectroscopia de fluorescência é uma técnica simples, rápida e de baixo custo para o acompanhamento de indivíduos diabéticos. / Diabetes Mellitus (DM) comprises a complex metabolic syndrome, caused by reduced or absent secretion of insulin by pancreatic beta cells, leading to hyperglycemia. Hyperglycemia promotes glycation of proteins and, consequently, the appearance of advanced glycation end products (AGEs). Currently, diabetic patients are monitored by determining levels of glucose and glycated hemoglobin (HbA1c). The complications caused by hyperglycemia may be divided into micro and macrovascular complications, represented by retinopathy, nephropathy, neuropathy and cardiovascular disease. Albumin (HSA) is the most abundant serum protein in the human body and is subject to glycation. The Protoporphyrin IX (PpIX) is the precursor molecule of heme synthesis, structural component of hemoglobin. The in vitro and animals studies have indicated that hyperglycemia promotes a decrease in its concentration in erythrocytes. The fluorescence spectroscopy is a technique widely used in biomedical field. The autofluorescence corresponds to the intrinsic fluorescence present in some molecules, this being associated with the same structure. The aim of this study was to use fluorescence spectroscopy to measure levels of erythrocyte PpIX autofluorescence and AGE-HSA in diabetic and healthy subjects and compare them with levels of blood glucose and HbA1c. This study was conducted with 151 subjects (58 controls and 93 diabetics). Epidemiological data of patients and controls were obtained from medical records. For control subjects, blood glucose levels were obtained from medical records and levels of Hb1Ac obtained by using commercial kits. The determination of the PpIX autofluorescence was performed with excitation at 405 nm and emission at 632 nm. Determination of AGE-HSA was performed with excitation at 370 nm and emission at 455 nm. Approximately 50% of diabetic had micro and macrovascular lesions resulting from hyperglycemia. There were no significant differences in the PpIX emission intensity values between groups (P = 0.89). In the analysis of AGE-HSA was observed significant differences in the values of emission intensity between the two groups, and this value was 1.45-fold greater for the group of diabetic (P <0.0001). Patients with diabetic complications had fluorescence emission intensity of 1.19-fold higher than individuals without disease complications (P = 0.01), even with no significant differences in HbA1c values between the two groups. We conclude that fluorescence spectroscopy was an effective technique in the identification of the PpIX autofluorescence and AGE-HSA. The PpIX was not an effective biomarker for the monitoring of diabetes. The determination of AGE-HSA autofluorecência was efficient for the discrimination between groups and monitoring disease progression, may be more effective than HbA1c dosage. The fluorescence spectroscopy is a simple, fast and low cost for the monitoring of diabetic patients.

Compostos de cobre(II) dinucleares, contendo ligantes nitrogenados, foram preparados, caracterizados por diversas técnicas espectroscópicas (UV/Vis, IV e EPR) e tiveram sua reatividade frente a células melanomas (B16F10 e TM1) verificada. Estes compostos são miméticos da tirosinase, enzima contendo em seu sítio ativo dois íons de cobre, presente em bactérias, plantas, animais e humanos, sendo responsável pela oxidação de fenóis a catecóis e destes às correspondentes quinonas. São enzimas relacionadas também à melanogênese, isto é, síntese de melanina, com formação de polímeros eumelanina e feomelanina, responsáveis pela pigmentação de nossa pele, olhos e cabelos. Os compostos mononucleares correspondentes foram também preparados e estudados, para efeito de comparação. Os resultados indicaram que os complexos dinucleares são mais ativos, tanto como miméticos da tirosinase, quanto em relação à citotoxicidade frente a melanomas, que os análogos mononucleares, mostrando que a estrutura é um fator determinante de ambas as atividades biológicas aqui estudadas. Ensaios de interação com as biomoléculas DNA e albumina humana (HSA) através de espectroscopia de UV/Vis e dicroísmo circular (CD) respectivamente, também foram realizados e complementaram os estudos. Atividade nuclease significativa foi observada para os complexos dinucleares, em presença de peróxido de hidrogênio, através de ensaios de clivagem em gel de agarose, buscando uma possível elucidação dos mecanismos de ação dos complexos em estudo. / Dinuclear copper(II) complexes with nitrogenated ligands were prepared, characterized by spectroscopic techniques (UV/Vis, IR and EPR) and had their reactivity verified towards melanoma cells (B16F10 and TM1). These compounds are tyrosinase mimics, an enzyme present in bacteria, fungi, animals and humans, capable of catalyzing the oxidation of phenols to catechols, and catechols to the corresponding quinines, and containing two copper ions in its active site. Tyrosinases are also enzymes related to melanogenesis, assisting the formation of eumelanin and pheomelanin polymers, responsible for the colour of our eyes, skin and hair. The corresponding mononuclear copper(II) complexes were also prepared and comparative studies were performed. The results indicated that the dinuclear species are more reactive than the mononuclear ones, both as tyrosinase mimics as in cytotoxicity damage to melanoma cells, showing that the structure of such species is a determining factor of both biological activities. Experiments at the interactions of these complexes with the biomolecule DNA and human serum albumim, were also conducted by UV/Vis and circular dichroism spectroscopies, respectively, and complemented the previous studies. Nuclease activity was also assessed, in the presence of hydrogen peroxide, monitored by cleavage assays in agarose gel, in order to contribute to the elucidation of the mechanisms of action of these complexes

Compostos de cobre(II) dinucleares, contendo ligantes nitrogenados, foram preparados, caracterizados por diversas técnicas espectroscópicas (UV/Vis, IV e EPR) e tiveram sua reatividade frente a células melanomas (B16F10 e TM1) verificada. Estes compostos são miméticos da tirosinase, enzima contendo em seu sítio ativo dois íons de cobre, presente em bactérias, plantas, animais e humanos, sendo responsável pela oxidação de fenóis a catecóis e destes às correspondentes quinonas. São enzimas relacionadas também à melanogênese, isto é, síntese de melanina, com formação de polímeros eumelanina e feomelanina, responsáveis pela pigmentação de nossa pele, olhos e cabelos. Os compostos mononucleares correspondentes foram também preparados e estudados, para efeito de comparação. Os resultados indicaram que os complexos dinucleares são mais ativos, tanto como miméticos da tirosinase, quanto em relação à citotoxicidade frente a melanomas, que os análogos mononucleares, mostrando que a estrutura é um fator determinante de ambas as atividades biológicas aqui estudadas. Ensaios de interação com as biomoléculas DNA e albumina humana (HSA) através de espectroscopia de UV/Vis e dicroísmo circular (CD) respectivamente, também foram realizados e complementaram os estudos. Atividade nuclease significativa foi observada para os complexos dinucleares, em presença de peróxido de hidrogênio, através de ensaios de clivagem em gel de agarose, buscando uma possível elucidação dos mecanismos de ação dos complexos em estudo. / Dinuclear copper(II) complexes with nitrogenated ligands were prepared, characterized by spectroscopic techniques (UV/Vis, IR and EPR) and had their reactivity verified towards melanoma cells (B16F10 and TM1). These compounds are tyrosinase mimics, an enzyme present in bacteria, fungi, animals and humans, capable of catalyzing the oxidation of phenols to catechols, and catechols to the corresponding quinines, and containing two copper ions in its active site. Tyrosinases are also enzymes related to melanogenesis, assisting the formation of eumelanin and pheomelanin polymers, responsible for the colour of our eyes, skin and hair. The corresponding mononuclear copper(II) complexes were also prepared and comparative studies were performed. The results indicated that the dinuclear species are more reactive than the mononuclear ones, both as tyrosinase mimics as in cytotoxicity damage to melanoma cells, showing that the structure of such species is a determining factor of both biological activities. Experiments at the interactions of these complexes with the biomolecule DNA and human serum albumim, were also conducted by UV/Vis and circular dichroism spectroscopies, respectively, and complemented the previous studies. Nuclease activity was also assessed, in the presence of hydrogen peroxide, monitored by cleavage assays in agarose gel, in order to contribute to the elucidation of the mechanisms of action of these complexes

Purpose: The objective of this study was to examine the timing of the age and the magnitude of peak lean tissue mass accrual (peak lean tissue velocity, PLTV) as it relates to the age and magnitude of peak cross sectional area velocity (PCSAV) and section modulus velocity (PZV) of proximal femur in both males and females during adolescence. We hypothesized that the age of PLTV would precede the age of PCSAV and PZV and that there be a positive relationship between the magnitude of PLTV and both PCSAV and PZV in both genders. <p>Methods: 41 males and 42 females aged 8-18 years were selected from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2005). Participants total body lean tissue mass was assessed annually for 6 consecutive years using DXA. Narrow neck, intertrochanteric and femoral shaft cross sectional areas (CSA) and section modulus (Z) were determined annually using the hip structural analysis (HSA) program. Participants were aligned by maturational age (years from peak height velocity). Lean tissue mass, CSA, and Z were converted into whole year velocities and the maturational age of peak tissue velocities was determined using a cubic spline curve fitting procedure. A 2x3 (gender x tissue) factorial MANOVA with repeated measures was used to test for differences between age of PLTV and both, the age of PCSAV and PZV between males and females. Multiple regression analyses were used to determine the relationship between PLTV and both PCSAV and PZV.<p>Results: There were no sex differences in the ages at which tissue peaks occurred when aligned by maturational age. There were significant differences between the age of PLTV and both PCSAV and PZV at the narrow neck (p=0.001) and femoral shaft (p=0.03), where the age of PLTV preceded both PCSAV and PZV when pooled by gender. There were no significant differences at the intertrochanteric site (p=0.814). PLTV was a significant predictor of the magnitude of both PCSAV and PZV at all sites (p<0.05). <p> Conclusions: These findings support the hypothesis that the age of PLTV precedes the age of PCSA and PZV at the proximal femur and provides further evidence to support the muscle-bone relationship, suggesting that lean tissue mass accrual influences bone strength development at proximal femur during pubertal growth.

Purpose: The objective of this study was to examine the timing of the age and the magnitude of peak lean tissue mass accrual (peak lean tissue velocity, PLTV) as it relates to the age and magnitude of peak cross sectional area velocity (PCSAV) and section modulus velocity (PZV) of proximal femur in both males and females during adolescence. We hypothesized that the age of PLTV would precede the age of PCSAV and PZV and that there be a positive relationship between the magnitude of PLTV and both PCSAV and PZV in both genders. <p>Methods: 41 males and 42 females aged 8-18 years were selected from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2005). Participants total body lean tissue mass was assessed annually for 6 consecutive years using DXA. Narrow neck, intertrochanteric and femoral shaft cross sectional areas (CSA) and section modulus (Z) were determined annually using the hip structural analysis (HSA) program. Participants were aligned by maturational age (years from peak height velocity). Lean tissue mass, CSA, and Z were converted into whole year velocities and the maturational age of peak tissue velocities was determined using a cubic spline curve fitting procedure. A 2x3 (gender x tissue) factorial MANOVA with repeated measures was used to test for differences between age of PLTV and both, the age of PCSAV and PZV between males and females. Multiple regression analyses were used to determine the relationship between PLTV and both PCSAV and PZV.<p>Results: There were no sex differences in the ages at which tissue peaks occurred when aligned by maturational age. There were significant differences between the age of PLTV and both PCSAV and PZV at the narrow neck (p=0.001) and femoral shaft (p=0.03), where the age of PLTV preceded both PCSAV and PZV when pooled by gender. There were no significant differences at the intertrochanteric site (p=0.814). PLTV was a significant predictor of the magnitude of both PCSAV and PZV at all sites (p<0.05). <p> Conclusions: These findings support the hypothesis that the age of PLTV precedes the age of PCSA and PZV at the proximal femur and provides further evidence to support the muscle-bone relationship, suggesting that lean tissue mass accrual influences bone strength development at proximal femur during pubertal growth.