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A capacidade do ferro, presente no corpo humano, em aceitar e doar elétrons o torna essencial para homeostase celular e várias reações biológicas. Contudo, o excesso deste metal no cérebro pode gerar efeitos deletérios através da produção de espécies reativas de oxigênio que causam o estresse oxidativo. Este estresse aparece como possível causa de doenças neurodegenerativas, caracterizadas por um aumento significativo da concentração de ferro em certas regiões do cérebro. Detectar e quantificar a deposição de ferro in vivo no cérebro torna-se de extrema relevância para entender diversas doenças neurodegenerativas. Neste estudo avaliamos a sensibilidade e a especificidade das principais técnicas de Ressonância Magnética in vivo para estimar o conteúdo de ferro depositado no cérebro. Foram estudados um grupo de 16 sujeitos saudáveis e outro de 14 pacientes com doença de Parkinson. Mapas de relaxometria (R2 e R2*) e susceptibilidade (QSM) foram estimados a partir de imagens adquiridas numa maquina de RM de 3.0T. Embora todos os mapas tenham apresentado correlação linear (r2 = 0; 7) com o acumulo de ferro reportado in vitro nas regiões do núcleo da base, apenas os mapas R2 e QSM apresentaram estatisticamente aumento significativo (p<0,05) para certas regiões do cérebro parkinsoniano (substância negra, núcleo rubro e globo pálido). O mapa QSM apresentou maior sensibilidade e especificidade para diferenciar pacientes com a doença quando comparados a sujeitos saudáveis por meio da análise da curva ROC. Concluímos que os mapas de relaxometria e susceptibilidade magnética podem estimar de forma indireta o conteúdo de ferro no cérebro, apesar de apresentarem dependências diferentes com a concentração deste metal. Observamos também que os valores de sususceptibilidade magnética obtidos com imagens de baixa resolução (1,0x1,0x2,0mm) não apresentaram mudanças significativas em relação aos obtidos com imagens de alta resolução (0,5x0,5x2,0mm). Logo, sugerimos a aquisição de imagens com baixa resolução para o processamento do mapa QSM. A analise de múltiplos valores de tempo de relaxação T2 determinou apenas um valor para cada região do núcleo da base para ambos os grupos, este resultado foi aparentemente afetado pela relação sinal ruído. / The capacity of the iron present in the human body to accept and donate electrons makes it essential for cellular homeostasis and various biological reactions. However, an excess of the metal in the brain can produce deleterious effects through the production of reactive oxygen species that cause oxidative stress. This stress can be the possible cause of neurodegenerative diseases which present a significant increase in iron concentration in certain brain regions. To detect and quantify iron deposition in the brain in vivo has high potential for understanding neurodegenerative diseases. In this study we evaluated the sensitivity and specificity of the main Magnetic Resonance technique in vivo to estimate the content of iron deposited in the brain. Were studied a group of 16 controls and 14 patient with Parkinson disease. Relaxometry map (R2 and R2*) and magnetic susceptibility map QSM were estimated by images obtained of scanner of Magnetic Resonance of 3T. Although all maps have presented linear correlation (r2=0.7) with the accumulation of iron reported in vitro regions of basal ganglia, only the R2 and QSM maps showed significant increase (p < 0.05) for certain regions of the parkinsonian brain (substantia nigra, red nucleus, and globus pallidus). The QSM map showed higher sensitivity and especificity for differentiate patients with the disease when compared with controls by the analysis of curve ROC. We conclude that magnetic susceptibility and relaxometry maps may estimate indirect the content of brain iron, although having different dependencies with the concentration of this metal. We also observed that the values of magnetic sususceptibility obtained with low resolution images (1,0 x1, 0x2, 0mm) showed no significant change compared to those obtained with high-resolution images (0,5 x0, 5x2,0mm). So, we suggest the acquisition of images with low resolution to process QSM map. The analysis of multiple relaxation time T2 determined just one value for basal ganglia in both groups, these results were apparently affected by rate noise signal.

As enfermidades virais sÃo as que causam maiores prejuÃzos registrados na carcinicultura. O surgimento do IMNV no Nordeste do Brasil em 2002 colocou os produtores de camarÃo frente a uma enfermidade desconhecida que causou perdas significativas para o setor, tornando imperativo buscar um maior conhecimento sobre a doenÃa e de como podem se comportar outras espÃcies de camarÃo ao vÃrus do IMN. O objetivo deste trabalho foi avaliar a susceptibilidade do camarÃo rosa Farfantepenaeus subtilis, nativo da costa brasileira, atravÃs de teste de desafio frente ao IMNV. Para realizaÃÃo do bioensaio foram utilizados 200 camarÃes jovens saudÃveis mantidos em tanques individuais de 4L durante 30 dias. No experimento os camarÃes foram separados em dois grupos: controle e desafiado; o grupo desafiado foi alimentado com mÃsculo de L. vannamei contaminado com IMNV e o controle alimentado com mÃsculo de L. vannamei livre do vÃrus em estudo, durante 3 dias via âper osâ. ApÃs o desafio foram realizadas coletas aleatÃrias de 40 animais, 20 camarÃes controle e 20 camarÃes desafiados, a cada cinco dias (5Â; 10Â; 15Â; 20 e 30Â) onde durante cada coleta, foram extraÃdas hemolinfa para contagem total de hemÃcitos (CTH), brÃnquias para anÃlise de RT/PCR e em seguida cada camarÃo foi fixado com soluÃÃo de Davidson para anÃlise histolÃgica. As anÃlises moleculares, utilizando a metodologia do Kit IQ2000, mostraram que dos 100 animais desafiados apenas dez (10 %) se mostraram positivos à infecÃÃo. Nas anÃlises histolÃgicas foi observado uma baixa infiltraÃÃo hemocÃtica nos mÃsculos; uma leve coagulaÃÃo e presenÃa de hemolinfa entre as fibras musculares caracterizando uma infecÃÃo leve. De acordo com o teste t de Student para dados independentes, houve diferenÃa estatisticamente significativa (p&#8805; 0,05) entre a contagem total de hemÃcitos do grupo desafiado e grupo controle na amostragem do 30 dia. O estudo demonstrou que a espÃcie nativa Farfantepenaeus subtilis à susceptÃvel ao vÃrus IMN. / Viral diseases are causing great damage in shrimp farming. With the IMN virus emergence in Northeastern Brazil in 2002, the shrimp producers faced an unknown disease that caused significant losses for the industry. Thus, a better knowledge about this disease and the investigation of how other species of shrimp are affected by the IMN virus will be an important contribution for the aquaculture industry. The objective of this study is to evaluate the susceptibility of Farfantepenaeus subtilis from the Brazilian coast, to the IMN virus. To conduct the bioassay it was used 200 healthy young shrimps kept in individual tanks of 4L for 30 days. The experimental design was composed by two separated groups: a control group and a challenged one which was exposed to the IMN virus. The challenged group was fed on L. vannamei muscle contaminated with IMNV and the control group was fed on muscle of L. vannamei free of the virus, for 3 days per os. After the challenge procedures, random samples of 40 animals, 20 control and 20 challenged were taken, every five days (5Â, 10Â, 15Â, 20 and 30Â). On each sampling hemolymph was drawn for the total count of hemocytes (THC), gills were taken for analysis by RT / PCR and then each animal was fixed with Davidson solution for histological analysis. The molecular analysis, using the methodology of Kit IQ2000, showed that among 100 animals challenged only ten (10%) were positive for infection. In histological analysis a low hemocyte infiltration was observed in muscles and a slight presence of hemolymph coagulation was detected between muscle fibers characterizing a mild infection. According to the Student t test for independent data, there was a statistically significant difference (p &#8805; 0.05) between the THC of challenged group and the control group sample of 30 days. The study showed wild specimens of F. subtilis to be susceptible to infection with IMNV.

Gliomas are a common type of brain tumour and for the treatment of a patient it is important to determine the tumour’s grade of malignancy. This is done today by a biopsy, a histopathological analysis of the tumourous tissue, that is classified by the World Health Organization on a malignancy scale from I to IV. Recent studies have shown that the local image variance (LIV) and the intratumoural susceptibility signal (ITSS) in susceptibility-weighted MR images correlate to the tumour grade. This thesis project aims to develop a software program as aid for the radiologists when grading a glioma. The software should by image analysis be able to separate the gliomas into low grade (I-II) and high grade (III-IV). The result is a graphical user interface written in Python 3.4.3. The user chooses an image, draws a region of interest and starts the analysis. The analyses implemented in the program are LIV and ITSS mentioned above, and the code can be extended to contain other types of analyses as research progresses. To validate the image analysis, 16 patients with glioma grades confirmed by biopsy are included in the study. Their susceptibility-weighted MR images were analysed with respect to LIV and ITSS, and the outcome of those image analyses was tested versus the known grades of the patients. No statistically significant difference could be seen between the high and the low grade group, in the case of LIV. This was probably due to hemorrhage and calcification, characteristic for some tumours and interpreted as blood vessels. Concerning ITSS a statistically significant difference could be seen between the high and the low grade group (p &lt; 0.02). The sensitivity and specificity was 80% and 100% respec- tively. Among these 16 gliomas, 11 were astrocytic tumours and between low and high grade astrocytomas a statistically significant difference was shown. The degree of LIV was significantly different between the two groups (p &lt; 0.03) and the sensitivity and specificity were 86% and 100% respectively. The degree of ITSS was significantly different between the two groups (p &lt; 0.04) and the sensitivity and specificity were 86% and 100% respectively. Spearman correlation showed a correlation between LIV and tumour grade (for all gliomas r = 0.53 and p &lt; 0.04, for astrocytomas r = 0.84 and p &lt; 0.01). A correlation was also found between ITSS and tumour grade (for all gliomas r = 0.69 and p &lt; 0.01, for astrocytomas r = 0.63 and p &lt; 0.04). The results indicate that SWI is useful for distinguishing between high and low grade astrocytoma with 1.5T imaging within this cohort. It also seems possible to distinguish between high and low grade glioma with ITSS.

O gÃnero Malassezia abrange leveduras lipofÃlicas e lipodependentes que, apÃs vÃrias mudanÃas em sua classificaÃÃo taxonÃmica, compreende na atualidade 13 espÃcies, incluindo M. pachydermatis, M. furfur, M. globosa, M. obtusa, M. sympodialis, M. slooffiae, M. restricta, M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae e M. eqÃina. Estas leveduras estÃo associadas a vÃrias enfermidades que incluem infecÃÃes, como a pitirÃase versicolor ou dermatoses, dermatite seborrÃica e dermatite atÃpica, entre outras. O objetivo geral deste trabalho foi contribuir para melhor entendimento sobre a identificaÃÃo fenotÃpica, manutenÃÃo em micoteca e sensibilidade a antifÃngicos in vitro de Malassezia spp.. A fenotipagem baseou-se nas caracterÃsticas macro e micromorfolÃgicas, bem como anÃlises em bioquÃmicas e nutricionais. Doze cepas de diferentes espÃcies de Malassezia spp. sofreram estocagem a -80ÂC sob Ãleos vegetais. A tÃcnica de microdiluiÃÃo foi realizada em caldo RPMI 1640, suplementado com bile, glicerol e Tween 20, sendo complementada com subcultivo em Ãgar Dixon, para determinaÃÃo da concentraÃÃo inibitÃria mÃnima (CIM) e da concentraÃÃo fungicida mÃnima (CFM). As drogas testadas foram Cetoconazol (CET), Itraconazol (ITR), Fluconazol (FLU), Voriconazol (VOR), Anfotericina B (ANB) e Caspofungina (CAS). Com a anÃlise fenotÃpica convencional das cepas (n=38), pode-se sugerir a presenÃa de M. furfur/ M. dermatis (n=17), M. sympodialis (n=8), M. slooffiae (n=5) e M. pachydermatis (n=8). O estoque realizado em Ãleos vegetais a -80ÂC demonstrou significativas taxas de recuperaÃÃo, no entanto caracterÃsticas fisiolÃgicas foram alteradas como _-glicosidase e assimilaÃÃo de Chremophor EL. A maioria das cepas estudadas (84,21%), M. pahydermatis e cepas lipodependentes, foram sensÃveis ao CET e ITR, obtendo valores de CIM &#61603;&#61472;0,03&#956;g/mL. Para o FLU, os valores de CIM variaram de 4 a 64&#956;g/mL e frente ao VOR as cepas de M. pachydermatis obtiveram CIMs que variaram de <0,03 a 2&#956;g/mL, enquanto as cepas lipodependentes de Malassezia spp. obtiveram resultados mais dispersos que variaram de <0,03 a >16&#956;g/mL. Perante ANB, o intervalo de CIM encontrado foi de 1 a >16&#956;g/mL. NÃo foi possÃvel determinar os valores de CIM e CFM frente à caspofungina. Os extratos oriundos das sementes do abacate foram ativos contra as cepas de M. pachydermatis. / The genus Malassezia enclose lipophylic and lipid-dependent yeast that after many changes in its taxonomic classification, comprises in the atuality 13 species, including M. pachydermatis, M. furfur, M. sympodialis, M. globosa, M. obtusa, M. restricta, M. slooffiae, M. dermatis, M. japonica, M. yamatoensis, M. nana, M. equine, and M. caprae. These yeasts are associated to several diseases including, such as pityriasis versicolor, or dermatoses, seborrheic dermatitis and atopic dermatitis, among others. The general aim of this study was to contribute to better knowledgement about the phenotypical identification, storage in fungal collection and in vitro antifungal susceptibility of Malassezia spp. The phenotiping was based on macro and micromorphologics characteristics, as well as biochemistry and nutritional analisys. Twenteen strains suffers storage at -80ÂC in vegetables oils. The microdilution technique was accomplished in RPMI 1640 broth, supplemented with ox bile, Tween 20 and glycerol, being complemented with subculture on Dixon agar, for determination of the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (CFM). The drugs tested were ketoconazole (KET), itraconazole (ITR), fluconazole (FLC), amphotericin B (AMB) and caspofungine (CAS). With the conventional phenotypical analysis of the strains (n=38), could suggest the presence of the M. furfur/ M. dermatis (n=17), M. sympodialis (n=8), M. slooffiae (n=5) and M. pachydermatis (n=8). The stored accomplished in vegetable oils at -80ÂC showed meaningful rate of recorver, but physiologic characteristics was modified, such as _-glicosidase activity and Chremophor EL assimilation. Most of the strains (84,21%) was sensitive for KET and ITR, obtaining values of MIC &#61603;&#61472;0.03&#956;g/mL. For FLC the MIC range was 4 to 64&#956;g/mL, against VOR the strains of M. pachydermatis obtained MIC range <0,03 a 2&#956;g/mL, therefore the lipid-dependents strains of Malassezia spp. obtained dispersive results from <0.03 to >16&#956;g/mL. Against ANB, the MIC range was 1 to >16&#956;g/mL. It was not possible determinate the MIC and MFC values for caspofungine. The extracts from avocado seeds were active against strains of M. pachydermatis.

A capacidade do ferro, presente no corpo humano, em aceitar e doar elétrons o torna essencial para homeostase celular e várias reações biológicas. Contudo, o excesso deste metal no cérebro pode gerar efeitos deletérios através da produção de espécies reativas de oxigênio que causam o estresse oxidativo. Este estresse aparece como possível causa de doenças neurodegenerativas, caracterizadas por um aumento significativo da concentração de ferro em certas regiões do cérebro. Detectar e quantificar a deposição de ferro in vivo no cérebro torna-se de extrema relevância para entender diversas doenças neurodegenerativas. Neste estudo avaliamos a sensibilidade e a especificidade das principais técnicas de Ressonância Magnética in vivo para estimar o conteúdo de ferro depositado no cérebro. Foram estudados um grupo de 16 sujeitos saudáveis e outro de 14 pacientes com doença de Parkinson. Mapas de relaxometria (R2 e R2*) e susceptibilidade (QSM) foram estimados a partir de imagens adquiridas numa maquina de RM de 3.0T. Embora todos os mapas tenham apresentado correlação linear (r2 = 0; 7) com o acumulo de ferro reportado in vitro nas regiões do núcleo da base, apenas os mapas R2 e QSM apresentaram estatisticamente aumento significativo (p<0,05) para certas regiões do cérebro parkinsoniano (substância negra, núcleo rubro e globo pálido). O mapa QSM apresentou maior sensibilidade e especificidade para diferenciar pacientes com a doença quando comparados a sujeitos saudáveis por meio da análise da curva ROC. Concluímos que os mapas de relaxometria e susceptibilidade magnética podem estimar de forma indireta o conteúdo de ferro no cérebro, apesar de apresentarem dependências diferentes com a concentração deste metal. Observamos também que os valores de sususceptibilidade magnética obtidos com imagens de baixa resolução (1,0x1,0x2,0mm) não apresentaram mudanças significativas em relação aos obtidos com imagens de alta resolução (0,5x0,5x2,0mm). Logo, sugerimos a aquisição de imagens com baixa resolução para o processamento do mapa QSM. A analise de múltiplos valores de tempo de relaxação T2 determinou apenas um valor para cada região do núcleo da base para ambos os grupos, este resultado foi aparentemente afetado pela relação sinal ruído. / The capacity of the iron present in the human body to accept and donate electrons makes it essential for cellular homeostasis and various biological reactions. However, an excess of the metal in the brain can produce deleterious effects through the production of reactive oxygen species that cause oxidative stress. This stress can be the possible cause of neurodegenerative diseases which present a significant increase in iron concentration in certain brain regions. To detect and quantify iron deposition in the brain in vivo has high potential for understanding neurodegenerative diseases. In this study we evaluated the sensitivity and specificity of the main Magnetic Resonance technique in vivo to estimate the content of iron deposited in the brain. Were studied a group of 16 controls and 14 patient with Parkinson disease. Relaxometry map (R2 and R2*) and magnetic susceptibility map QSM were estimated by images obtained of scanner of Magnetic Resonance of 3T. Although all maps have presented linear correlation (r2=0.7) with the accumulation of iron reported in vitro regions of basal ganglia, only the R2 and QSM maps showed significant increase (p < 0.05) for certain regions of the parkinsonian brain (substantia nigra, red nucleus, and globus pallidus). The QSM map showed higher sensitivity and especificity for differentiate patients with the disease when compared with controls by the analysis of curve ROC. We conclude that magnetic susceptibility and relaxometry maps may estimate indirect the content of brain iron, although having different dependencies with the concentration of this metal. We also observed that the values of magnetic sususceptibility obtained with low resolution images (1,0 x1, 0x2, 0mm) showed no significant change compared to those obtained with high-resolution images (0,5 x0, 5x2,0mm). So, we suggest the acquisition of images with low resolution to process QSM map. The analysis of multiple relaxation time T2 determined just one value for basal ganglia in both groups, these results were apparently affected by rate noise signal.

Orientadores: Mariangela Ribeiro Resende, Maria Luiza Moretti / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T01:04:19Z (GMT). No. of bitstreams: 1 Ferrari_MichelaDeLuca_D.pdf: 2448021 bytes, checksum: 102166bb9666827fb2f7de549ded2752 (MD5) Previous issue date: 2013 / Resumo: O resumo poderá ser visualizado no texto completo da tese digital / Abstract: The complete abstract is available with the full electronic document / Doutorado / Clinica Medica / Doutora em Clínica Médica

The thermodynamics of disorder have been studied for hundreds of years, with physicists using entropy to quantitatively connect the macroscopic properties of a system to its microscopic multiplicity (disorder). Here, we consider the effect of disorder in magnetic materials. The pyrochlore oxides (A2B2O7), comprised of a bipartite lattice of corner-sharing tetrahedra, have been central to the study of geometric frustration for the past several decades. Pyrochlores, in which the A-site is occupied by the magnetic cation dysprosium, tend to exhibit spin ice ordering down to low temperatures, in spite of chemical perturbations to the B-site lattice. With the motivation of this study being the investigation of how adding B-site disorder to the traditional Dy2ScNbO7 form of Dy-pyrochlores, a stoichiometric mixture of Sc-3+ and Nb-5+ was used to synthesize Dy2ScNbO7, the pyrochlore material that is central to this thesis work. We show using magnetometry, heat capacity, muon spin relaxation, and inelastic neutron scattering that the mixed B-site pyrochlore Dy2ScNbO7, does not adopt the spin ice ground state. The low temperature spin dynamics are much faster than other analogous dysprosium pyrochlores, the residual entropy is significantly smaller than that predicted for a spin ice and there are low-lying crystal field excitations. These results all indicate that the B-site disorder appears to destroy the predicted Ising anisotropy of dysprosium. / Thesis / Master of Science (MSc)

Avoir une apparentée atteinte d’un cancer du sein (CS) multiplie par 2 le risque de développer un CS. Environ 20 % du risque familial de CS est attribué à une mutation fortement pénétrante dans les gènes BRCA1 ou BRCA2. D’autres gènes connus, comme ATM ou TP53, ainsi que des variants génétiques fréquents (SNP) identifiés dans des études pangénomiques (GWAS) réalisées en population générale, expliqueraient 30 % supplémentaires des cas familiaux. La majorité des formes familiales de CS restent donc inexpliquées. Par ailleurs, il existe de fortes variations du risque parmi les porteurs d’une mutation BRCA1/2. Il a été montré que certains SNP identifiés dans les GWAS modifient leur risque. Cependant, l'effet propre de ces SNP n'a pu être estimé puisque ces études ont été réalisées chez les porteurs de mutation BRCA1/2. Dans une première partie de ma thèse, j’ai développé une stratégie intégrant aux analyses sur les facteurs génétiques des facteurs « environnementaux ». Cette stratégie a été utilisées pour analyser les données de l'étude GENESIS qui inclut des paires de sœurs atteintes de CS et sans mutation BRCA1/2 et des témoins de population générale. Elle regroupe 5 000 cas de CS et témoins génotypés pour les 200 000 SNP de la puce iCOGS. Les femmes de GENESIS ont été réparties dans des groupes selon leur profil d’expositions aux radiations ou aux facteurs gynéco-obstétriques. Alors que l’analyse stratifiée sur les groupes construits à partir des expositions aux facteurs gynéco-obstétriques ne nous permet pas de mettre en évidence de potentiels SNPs spécifiques, l’analyse stratifiée sur les groupes construits à partir des expositions aux radiations a permis de mettre en évidence des SNPs spécifiques potentiels aux femmes non exposées, dans les gènes XRCC4 et MAGI1, et à celle fortement exposées aux radiations, dans le gène FGFR2, déjà trouvés en population générale.Le deuxième objectif de ma thèse visait à optimiser la caractérisation des gènes BRCA1/2 en étudiant leurs interactions avec des SNPs modificateurs à partir des données des consortia internationaux CIMBA (Consortium of Investigators of Modifiers of BRCA1/2) et BCAC (Breast Cancer Association Consortium). J’ai développé une stratégie d’analyse GWAS case-only, comparant la fréquence de 60 212 cas de cancer du sein de la population générale (BCAC) et 13,007 cas porteurs d’une mutation BRCA1/2 (CIMBA). J’ai identifié 4 nouvelles régions associés au CS chez les femmes porteuses d’une mutation BRCA1 et 4 autres chez les femmes porteuses d’une mutation BRCA2. Les gènes MADD, SPI1 et EIF1, déjà associées à la biologie du cancer du sein dans d’autres études, ont été prédits par l’outil INQUISIT comme étant des gènes cibles des potentiels variants causaux se trouvant dans la région 11p11.2 associée au statut BRCA1.Ces nouveaux SNPs mis en évidence pourraient être utilisés pour améliorer les prédictions de risque des PRS (Polygénic Risk Score). Les analyses prenant en compte des profils d’exposition devraient être poursuivies sur des études de grande dimension. Les modèles pourraient alors évoluer vers une adaptation des PRS en fonction des profils d’expositions des femmes et cela tout au long de leur vie. / One of the most important risk factors for breast cancer (BC) is having a family history of BC. Around 20% of the familial BC risk is explained by rare mutations in the genes BRCA1 and BRCA2 (BRCA1/2). An additional 30% of the risk is accounted for mutations in other known genes, like ATM or TP53, and by common genetic variants, called single nucleotide polymorphism (SNPs), identified in population-based GWAS. Therefore, the majority of the familial forms of BC remains unexplained. Furthermore, there are large variations in the estimation of the BC lifetime risk for BRCA1/2 mutation carriers. It has been shown that some SNPs identified in the general population by GWAS (Genome Wide Association Studies) modified BC risk for BRCA1/2 mutation carriers. Therefore, little is known on how these SNPs interact with BRCA1/2 mutations since association studies have been performed within the population of BRCA1/2 mutation carriers so far.In the first part of this PhD project, I developed a novel strategy to analyze genetic factors by integrating simultaneously environmental and lifestyle factors. This strategy was used to analyze the data of GENESIS study composed of pairs of sisters affected by BC without BRCA1/2 mutation and controls from the general population. 5,000 BC cases and controls were genotyped for the 200,000 SNPs targeted by the iCOGS array. Groups of subjects was created according to their exposition profile reflecting expositions to radiation or reproductive factors. Analyses stratified on groups built according to their reproduction factors exposures did not highlighted specific variants. However, analyses stratified on groups reflecting the chest X—ray exposures showed potential specific SNPs for women who had never been exposed to chest X—ray, in genes XRCC4 and MAGI1, and for women highly exposed to X-ray exposures, in gene FGFR2, already known in the general population.The second aim was to identify and characterize genetic modifiers of BC risk for BRCA1/2 mutation carriers using data from the international consortia CIMBA (Consortium of Investigators of Modifiers of BRCA1/2) and BCAC (Breast Cancer Association Consortium). I developed a case-only GWAS analysis where we compare genotype frequencies between 60,212 unselected BC cases from the BCAC and 13,007 BC cases from CIMBA. We identified 4 novel variants associated with BC for BRCA1 mutation carriers and 4 for BRCA2 mutation carriers at P<10-8. MADD, SPI1 and EIF1 genes, already associated with BC biology, was predicted by the tool INQUISIT, to be target genes of the potential causal variants located in the locus 11p11.2 associated with BRCA1 status.These new SNPs could be used to improve polygenic risk scores (PRS). Studies considering the exposure profile should be implemented in larger population. The models could then evolve towards an adaptation of the PRS according to women’s exposure profiles and that throughout their life.