Orientador: Mary Rosa Rodrigues de Marchi / Banca: Christine Laure Marie Bourote / Banca: Annibal Duarte Pereira Netto / Banca: Nilva Ré Poppi / Banca: Roma Tauler / Resumo: No Brasil, a queima da cana de açúcar é utilizada para facilitar a colheita, mas este procedimento causa grande poluição ambiental devido a quantidade de fuligem lançada na atmosfera. O material particulado (MP) emitido contém inúmeros contaminantes, tais como: hidrocarbonetos policíclicos aromáticos (HPAs) e elementos. A cidade de Araraquara/SP possui cerca de 200.000 habitantes e é cercada por plantações de cana de açúcar, sendo que a prática de queimada é constante no período da safra (abril-novembro, todos os anos). Neste trabalho, determinou-se a concentração elementar e de HPAs em MP na cidade de Araraquara durante o período da safra (S) e da entre safra (E) da cana de açúcar. Foram coletadas 60 amostras (E) e 220 amostras (S) para a análise de HPAs, e 10 amostras (E) e 10 amostras (S) para a análise elementar. As amostras foram coletadas utilizando um amostrador dicotômico (vazão: 10 L min-1, 24 h) com filtros de PTFE (37 mm, 2 μm de tamanho de poro). Para a análise de HPAs, dez filtros de PTFE contendo o MP foram extraídos em banho de ultrassom com acetona/n-hexano (1:1 v/v), sendo que as análises foram efetuadas por HPLC/FLD. A análise elementar foi efetuada por fluorescência de raios X por energia dispersiva (EDXRF), sem tratamento prévio das amostras. A concentração mediana de HPAs totais foi de 1,9 ng m-3 (E) e 6,2 ng m-3 (S). A concentração mediana de benzo[a]pireno, HPA considerado carcinogênico, foi de 0,026 ng m-3 e 0,15 ng m-3 para os períodos de E e S, respectivamente. O risco potencial de câncer associado à exposição a HPAs por inalação, foi estimado com base na concentração de benzo[a]pireno equivalente (BaPeq), onde a toxicidade de uma mistura de HPAs é definida pela concentração de cada substância multiplicada pelo seu fator de equivalência de toxicidade relativa (FET). Os valores medianos encontrados para... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In Brazil, the sugar cane crops are burned to facilitate the harvesting, this procedure causes environmental pollution from the large amounts of soot that are released into the atmosphere. This particulate matter (MP) contains numerous contaminants such as polycyclic aromatic hydrocarbons (PAHs) and metals. The city of Araraquara, located at central area from São Paulo State, has around 200,000 inhabitants and is surrounded by sugarcane plantations (46,994 ha of total cultivated area, in the harvest 2008/2009). In this study, PAHs concentrations and elemental composition in the MP were determined in Araraquara city during the sugarcane harvesting (HV) and non-harvesting (NHV) seasons. 60 samples were collected during the NHV and 220 samples during the HV seasons for the analysis of PAHs. 10 samples were collected during the NHV and 10 samples during the HV season for the analysis of Si, K, Ca, Ti, V, Fe, Sr, Cr, Ni, Mn, Cu, Zn, As, Cd, Pb, Sb, Al, S and Cl. The samples were collected using a dichotomous sampler (10 L min-1, 24 h) with PTFE filters. Ten filters sets were extracted (ultrasonic bath with hexane/acetone (1:1 v/v)) and analyzed by HPLC/FLD for the analysis of PAHs. Information concerning the bulk elemental concentration was provided by energy-dispersive x-ray fluorescence (EDXRF). The median concentration for total PAHs was 1.9 ng m-3 (NHV) and 6.2 ng m-3 (HV). Benzo[a]pyrene median concentration was 0.026 ng m-3 and 0.15 ng m-3 for the NHV and HV seasons, respectively. The potential cancer risk associated to inhalation exposure was estimated based on the benzo[a]pyrene toxic equivalence (BaPeq), where the overall toxicity of a PAH mixture is defined by the concentration of each compound multiplied... (Complete abstract click electronic access below) / Doutor

5 à 10% des cancers du sein sont héréditaires mais parmi ceux-ci seulement la moitié est expliquée par une altération constitutionnelle d’un gène de prédisposition connu tels que les gènes BRCA1 et BRCA2. L’importante hétérogénéité génétique qui caractérise les famillesBRCAx rend difficile la réalisation d’études familiales groupées et ne permet pas l’identification de nouveaux gènes de prédisposition au cancer du sein selon les méthodes classiques de liaison génétique ou d’association. Les techniques de séquençage de nouvelle génération (NGS) à l’échelle de l’exome ou du génome entier, autorisent en revanche l’étude de familles individuelles à la recherche de mutations constitutionnelles privées mais le nombre considérable de variants génétiques identifiés impose leur tri sur des critères de pathogénicité ou de récurrence. Un autre critère de tri peut être représenté par l’identification de régions candidates définies en fonction de réarrangements génomiques tumoraux communs à plusieurs tumeurs au sein d’une même famille. Le génotypage tumoral par puces SNP (pour single nucleotide polymorphism) permet en effet la détection d’haplotypes conservés dans des régions récurrentes de LOH (pour loss of heterozygosity) communes à plusieurs tumeurs familiales et donc l’identification de régions candidates suspectes d’abriter des mutations germinales dans des gènes de prédisposition au cancer. La combinaison de ces deux approches, génotypage tumoral puis NGS, a été appliquée à une série de 17 familles avec agrégation de cancers du sein pour lesquelles au moins deux échantillons tumoraux étaient disponibles. Aucun nouveau gène de prédisposition au cancer du sein n’a été identifié mais une mutation délétère constitutionnelle du gène ATM a ainsi été retrouvée, associée à une perte de l’allèle sauvage dans les 2 tumeurs d’une famille BRCAx. L’analyse de 17 tumeurs du sein supplémentaires provenant de 10 familles avec agrégation de cancers du sein et mutation constitutionnelle du gène ATM identifiée chez le cas index, a révélé que l’allèle sauvage d’ATM était fréquemment perdu dans ces tumeurs (>80% contre 20% attendu en situation sporadique ; p<0.001). Ce résultat plaide fortement en faveur de l’implication d’ATM dans la carcinogénèse de ces cancers du sein tel un gène suppresseur de tumeur et suggère que les mutations constitutionnelles d’ATM sont impliquées dans des formes familiales de cancer du sein. / Hereditary breast cancers (BCs) account for 5-10% of all diagnosed BCs, yet only 50% of such tumors arise in the context of a germline mutation in known tumor suppressor genes such as BRCA1 or BRCA2. The vast genetic heterogeneity which characterizes BRCAx families makes grouped studies impossible to perform. Next generation sequencing (NGS) techniques, however, allow individual families to be studied in order to identify private mutations. Single nucleotide polymorphism (SNP) arrays allow the detection of conserved haplotypes within recurrent regions of loss of heterozygosity, common to several familial tumors, therefore identifying genomic loci likely to harbor a germline mutation in cancer predisposition genes. The combination of both exome sequencing and SNP arrays for a series of 17 familial BC did not allow the identification of a novel BC predisposition gene, but revealed a germline ATM mutation associated with a loss of the wild-type allele in a BRCAx family. The analysis of 17 additional breast tumors from ten BC families in which a germline ATM mutation had been identified revealed a high frequency of wild-type allele loss in these tumors (>80% compared to the 20% expected in sporadic BC; p <0.001). This result argues strongly in favor of the involvement of ATM in the carcinogenesis of these tumors as a tumor suppressor gene and suggests that germline ATM mutations are involved in a subset of familial BC.

There is growing evidence that patients with type 2 diabetes mellitus have increased cancer risk. We examined the association between diabetes, cancer, and cancer-related mortality and hypothesized that insulin sensitizers lower cancer-related mortality. Participants in the Diabetes Cardiovascular Risk and Evaluation: Targets and Essential Data for Commitment of Treatment study, a nationwide cross-sectional and prospective epidemiological study, were recruited from German primary care practices. In the cross-sectional study, subjects with type 2 diabetes mellitus had a higher prevalence of malignancies (66/1308, 5.1%) compared to nondiabetic subjects (185/6211, 3.0%) (odds ratio, 1.64; 95% confidence interval, 1.12-2.41) before and after adjustment for age, sex, hemoglobin A1c, smoking status, and body mass index. Patients on metformin had a lower prevalence of malignancies, comparable with that among nondiabetic patients, whereas those on any other oral combination treatment had a 2-fold higher risk for malignancies even after adjusting for possible confounders; inclusion of metformin in these regimens decreased the prevalence of malignancies. In the prospective analyses, diabetic patients in general and diabetic patients treated with insulin (either as monotherapy or in combination with other treatments) had a 2- and 4-fold, respectively, higher mortality rate than nondiabetic patients, even after adjustment for potential confounders (incidence of cancer deaths in patients with type 2 diabetes mellitus [2.6%] vs the incidence of cancer deaths in patients without type 2 diabetes mellitus [1.2%]). Our results suggest that diabetes and medications for diabetes, with the exception of the insulin sensitizer metformin, increase cancer risk and mortality.

Secular trends in breast cancer incidence in younger women suggest environmental factors, like exposure to environmental chemicals, may play a role in rising incidence. One of the strongest risk factors for developing breast cancer, next to family history, is high mammographic breast density, which is defined as the proportion of fibroglandular breast tissue relative to fat as seen on a mammogram. Phthalates, a ubiquitous endocrine disrupting chemical, have the potential to interfere with endogenous hormones like estrogen and androgens. There is growing evidence from animal and epidemiologic studies indicating distinct periods of heightened susceptibility to endocrine disrupting chemicals throughout the life course, particularly during critical windows of breast development. Exposure to hormonally active environmental chemicals like phthalates may be a modifiable risk factor for breast cancer, therefore reducing or eliminating exposure could have substantial public health benefits. The overarching goal of this dissertation was to assess the relationship between exposure to phthalates during two critical windows of susceptibility, the prenatal and pregnancy periods, and its effect on breast tissue composition in adolescence and adulthood. First, a comprehensive review of epidemiologic studies summarized the body of evidence for the association between phthalate exposure and intermediate markers known to be in the causal pathway of breast cancer risk (age at breast development, menarche, and breast tissue composition). This systematic review of the literature aimed to identify potential patterns of evidence by outcome and timing of exposure. Evidence from this review suggested that phthalate exposure during the prenatal and childhood periods may play a role in altering menarche. Findings for phthalate exposure and age at breast development were inconclusive. There was a considerable lack of epidemiologic data on phthalate exposure and breast tissue composition throughout the life course. Based on one study, there is a potential association between phthalate exposure during pre-puberty and altered breast tissue density in adolescent girls. No study assessed the relationship between phthalate exposure during the prenatal or pregnancy period and subsequent breast tissue composition. Second, an examination for the association between prenatal phthalate exposure and breast tissue composition measured in adolescence (Chapter 3) and the association between phthalate exposure during pregnancy and breast tissue composition measured during or after the postpartum transient period (Chapter 4) aimed to address this major gap identified from the comprehensive review. The empirical chapters of this dissertation used data from an ongoing longitudinal birth cohort study of mothers and their children conducted by the New York City Columbia Center for Children's Environmental Health and the Breast Cancer and the Environment Research Project (CCCEH-BCERP). The CCCEH-BCERP study cohort has prospective data on nine phthalate metabolite concentrations measured during the third trimester of pregnancy and breast tissue composition measured in a subsample of mother-daughter dyads. Notably, we used novel non-invasive methods (optical breast spectroscopy) in this younger cohort of mothers and daughters to objectively measure specific components of the bulk breast composition before mammography screening age. There was significant evidence of altered breast tissue composition in both mothers and daughters. For daughters (n=127, mean age 15.2 ± 1.9 years), prenatal exposures to select low molecular weight (LMW) and high molecular weight (HMW) phthalate metabolites altered overall breast density in opposing directions, which appears to be driven by significant altered percent breast water. There was a significant association between higher prenatal levels of a LMW phthalate metabolite (monobutyl phthalate) and lower levels of overall breast density (adjusted β = -0.32; 95% CI: -0.51, -0.13) and significant association between sum of di(2-ethylhexyl) phthalate (∑DEHP), a HMW phthalate metabolite, and higher levels of overall breast density in girls (adjusted β = 0.20; 95% CI: 0.05, 0.34). For mothers (n=133, mean age 41 ± 5.3 years at follow-up), there was a significant association between two LMW phthalate metabolites and lower levels of percent breast collagen. Additionally, there was a significant inverse relationship between levels of mono-(3-carboxypropyl), a HMW phthalate metabolite, and percent total hemoglobin of the breast (adjusted β =-0.03; 95% CI: -0.06, 0.00, p=0.05). Overall, this dissertation increased our understanding of the impact that exposure to phthalates during critical windows of susceptibility may have on specific components of the breast. Reducing exposure to both HMW and LMW phthalates may have an impact in reducing breast cancer risk, particularly for girls prenatally exposed, as there was stronger evidence of higher overall breast density and percent water from exposure to select HMW phthalates. Future prospective studies should confirm these results as findings might provide an opportunity for modifying potential breast cancer risk.

Breast cancer is the most common form of cancer among women, with around 9000 new diagnoses in Sweden yearly. Detecting and localizing risk of breast cancer could give the opportunity for individualized examination programs and preventative measures if necessary, and potentially be lifesaving. In this study, two deep learning methods have been designed, trained and evaluated on mammograms from healthy patients whom were later diagnosed with breast cancer, to examine how well deep learning models can localize suspicious areas in mammograms. The first proposed model is a ResNet-18 regression model which predicts the pixel coordinates of the annotated target pixel in the prior mammograms. The regression model produces predictions with an average of 44.25mm between the predictions and targets on the test set, which for average sized breasts correspond to a general area of the breast, and not a specific location. The regression network is hence not able to accurately localize suspicious areas in mammograms. The second model is a U-net segmentation model that segments out a risk area in the mammograms. The segmentation model had a 25% IoU, meaning that there is on average a 25% overlap between the target area and the prediction area. 57% of the predictions of the segmentation network had some overlap with the target mask, and predictions that did not overlap with the target often marked high density areas that are traditionally associated with high risk. Overall, the segmentation model did better than the regression model, but needs further improvement before it can be considered adequate to merge with a risk value model and used in practice. However, it is evident that there is sufficient information present in many of the mammogram images to localize the risk, and the research area holds potential for future improvements. / Bröstcancer är den vanligaste cancerformen bland kvinnor, med cirka 9000 nya diagnoser i Sverige årligen. Att upptäcka och lokalisera risken för bröstcancer kan möjliggöra individualiserade undersökningsprogram och förebyggande åtgärder vid behov och kan vara livräddande. I denna studie har två djupinlärningsmodeller designats, tränats och utvärderats på mammogram från friska patienter som senare diagnostiserades med bröstcancer, för att undersöka hur väl djupinlärningsmodeller kan lokalisera misstänkta områden i mammogram. Den första föreslagna modellen är en ResNet-baserad regressionsmodell som förutsäger pixelkoordinaterna för den utmarkerade målpixeln i de friska mammogrammen. Regressionsmodellen producerar förutsägelser med ett genomsnitt på 44,25 mm mellan förutsägelserna och målpunkterna för testbilderna, vilket för medelstora bröst motsvarar ett allmänt bröstområde och inte en specifik plats i bröstet. Regressionsnätverket kan därför inte med precision lokalisera misstänkta områden i mammogram. Den andra modellen är en U-net segmenteringsmodell som segmenterar ut ett riskområde ur mammogrammen. Segmenteringsmodellen hade ett IoU på 25%, vilket innebär att det i genomsnitt fanns en 25-procentig överlappning mellan målområdet och förutsägelsen. 57% av förutsägelserna från segmenteringsnätverket hade viss överlappning med målområdet, och förutsägelser som inte överlappade med målet markerade ofta områden med hög täthet som traditionellt är förknippade med hög risk. Sammantaget presterade segmenteringsmodellen bättre än regressionsmodellen, men behöver ytterligare förbättring innan den kan anses vara adekvat nog att sammanfogas med en riskvärdesmodell och användas i praktiken. Det är dock uppenbart att det finns tillräcklig information i många av mammogrambilderna för att lokalisera risken, och att forskningsområdet har potential för framtida förbättringar.

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Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) is the most common hereditary syndrome predisposing to colorectal cancer, accounting for 1-3% of all colorectal cancer. This multi-organ cancer predisposition syndrome is caused by mutations in the mismatch repair (MMR) genes, especially MLH1 and MSH2, and to lesser extents MSH6 and PMS2, which lead to widespread genetic instability and thus microsatellite instability (MSI). Hereditary cancer often manifests in two or more tumours in a single individual; 35-40% of Lynch syndrome patients have synchronous or metachronous tumours of the two major Lynch syndrome-related cancers: colorectal and endometrial. The main purposes of the work underlying this thesis were to identify persons at risk of Lynch syndrome or other types of hereditary colorectal cancer, to estimate the cancer risks associated with these predispositions and to identify the underlying genetic causes. A population-based cohort of 78 persons with double primary colorectal or colorectal and endometrial cancer was identified. Cancer risks in their 649 first-degree relatives were estimated in relation to tumour MSI status (positive or negative) and age at diagnosis (before or after 50 years of age) in the probands. The overall standardised incidence ratio was 1.69 (95% CI; 1.39-2.03). The highest risks for Lynch syndrome-associated cancers: (colorectal, endometrial, ovarian and gastric) were found in families with young MSI-positive probands, likely representing Lynch syndrome families. Importantly, no overall risk was found in families with old probands, irrespective of MSI status. Blood samples were available from 24 MSI-positive patients for mutation screening of MLH1, MSH2 and MSH6. Sequence variants or rearrangements predicted to affect protein function were found in 16 patients. Six novel variants were found: two large rearrangements, two truncating and two missense mutations. The missense mutations were found to segregate in the families. Studies of allele frequencies, MSI and loss of immunostaning in tumours from family members further supports the hypothesis that these missense changes play a role in Lynch syndrome, as do the non-conservative nature and evolutionary conservation of the amino acid exchanges. Five families had mutations in MLH1, five in MSH2, and six in MSH6. The unexpectedly large impact of MSH6 was in genealogical studies shown to be due to a founder effect. Cumulative risk studies showed that the MSH6 families, despite their late age of onset, have a high lifetime risk for all Lynch syndrome-related cancers, significantly higher in women (89% by age 80 years) than in men (69%). The gender differences are in part due to high endometrial (70%) and ovarian cancer risk (33%) in addition to the high colorectal cancer risk (60%). These findings are of great importance for counselling and surveillance of families with MSH6 mutations. Finally, in a large family with MSI-negative hereditary colorectal cancer for which the MMR genes and APC had been excluded as possible causes, a genome-wide linkage analysis was performed, resulting in a suggested linkage to chromosome 7. Conclusions: Relatives of probands with MSI-positive, double primary colorectal and endometrial cancer diagnosed before the age of 50 years have significantly increased risks of Lynch syndrome-related cancers. MSH6 mutations, which have unusually high impact in this study population due to a founder effect, confer high cumulative risks of cancer despite the generally late age of onset.

Made available in DSpace on 2016-12-23T13:56:11Z (GMT). No. of bitstreams: 1 Neide Aparecida Tosato Boldrini.pdf: 1554664 bytes, checksum: f1a0fa6f6e19b3d6ef0434edfba4dd67 (MD5) Previous issue date: 2012-04-04 / Introduction: The squamous cell cervical cancer develops from precancerous lesions well defined which can progress to invasive disease if not earlier diagnosed and treated. Objectives: To determine the prevalence and factors associated with high-grade lesions and cervical cancer among women treated at University Hospital in Vitoria, ES. Methods: A cross-section conducted in women 18-59 years who were referred for outpatient cervical pathology in 2011. Women were invited to participate and were interviewed for collecting demographics, epidemiological and clinical data. After the interview, they were submitted to gynecological examination to collect specimens for cervical cytology, Chlamydia trachomatis and HPV Hybrid Capture tests, and HPV DNA detection by PCR and colposcopic examination. The patients with cervical lesions at cytology and colposcopy were confirmed by histopathology. Results: A total of 291 women participated in the study. The median age was 38 years (DIQ: 30 - 48 years), 74 (25.4%) had completed four years of schooling; 178 (61.2%) were married and 83 (28.5%) had monthly family income up to three minimum wages. When considering histopathological results, the prevalence of high-grade lesions/cervical cancer was 18.2% (95% CI: 13.8% -22.6%), being 48 (16.5%) cases of high-grade lesions (CIN II, CIN IIIca in situ) and 5 (1.7%) cases of invasive carcinoma. One hundred and eight women (37.1%) were smokers; 11 (3.8%) reported using illicit drugs;38 (13.1%) reported their first sexual intercourse before age 15;221 (75 9%) had more than one partner in life; 20 (6.9%) had more than one partner in the last 12 months;220 (75.6%) reported not using condoms;90 (30.2%) reported anal sex practice;46 (15.8%) reported previous STD. In the final logistic regression model, age between 30-49 years [OR = 4.4 (95%:1.01-19.04), history of smoking [OR = 2.43 (95% CI 1.14 to 5 , 18)], practice of anal intercourse [OR = 2.35 (95% CI 1.10 to 5.03)] and have a positive hybrid capture test for high risk HPV positive [OR = 11.23 (95% 4 0.79 to 26, 36)] remained independently associated with high-grade lesion/cervical cancer. Conclusions: The results show high prevalence of precursor lesions of cervical cancer and high prevalence of high risk HPV. The most prevalent HPV was HPV 16 followed by HPV 31. Associated risk factors for HSIL/carcinoma were age between 30-49 years, history of smoking, practice of anal sex and have a positive hybrid capture test for high risk HPV positive. The study emphasizes the importance of prevention and care strategies for the control of cervical cancer. / Introdução: O câncer cervical de células escamosas se desenvolve a partir de lesões pré-cancerosas bem definidas, que podem progredir para doença invasiva, se não forem precocemente diagnosticadas e tratadas. Objetivos: Determinar a prevalência e os fatores associados para lesões de alto grau (HSIL) e câncer de colo uterino em mulheres atendidas em Hospital Universitário de Vitória, ES. Métodos: Estudo de corte-transversal conduzido em mulheres de 18 a 59 anos que foram referenciadas para o ambulatório de patologia cervical em 2011. As mulheres foram convidadas a participar do estudo e responderam a uma entrevista contendo dados demográficos, epidemiológicos e clínicos. Após a entrevista foram submetidas ao exame ginecológico para coleta de espécime para citologia cervical, para detecção de HPV e Chlamydia trachomatis por teste de Captura Híbrida, pesquisa de DNA de HPV pela técnica de PCR e exame colposcópico. Os casos que apresentaram lesões cervicais na citologia e colposcopia foram confirmados pelo exame histopatológico. Resultados: um total de 291 mulheres participaram do estudo. A mediana de idade foi de 38 anos (DIQ: 30- 48 anos); 74 (25,4%) tinham até quatro anos de estudo, 178 (61,2%) eram casadas e em 83 (28,5%) a renda familiar era de até três salários mínimos. Quando se considerou o resultado histopatológico, a prevalência de HSIL/câncer cervical foi de 18,2% (IC95%:13,8%-22,6%), sendo 48 (16,5%) casos de lesão de alto grau (NIC II,NIC IIIca in situ) e 5 (1,7%) casos de carcinoma invasor. Cento e oito mulheres (37,1%) eram fumantes, 11 (3,8%) informaram usar drogas ilícitas; 38 (13,1%) tiveram o primeiro coito antes dos 15 anos; 221 (75,9%) tiveram mais de um parceiro na vida; 20 (6,9%) tiveram mais de um parceiro nos últimos 12 meses; 220 (75,6%) relataram não usar preservativos; 90 (30,2%) referiram ter pratica de sexual anal; 46 (15,8%) DST prévia. No modelo final de regressão logística, ter idade entre 30-49 anos [OR=4,4 (IC95%:1,01-19,04); história de tabagismo [OR=2,43 (IC95% 1,14-5,18)]; a prática de coito anal [OR=2,35 (IC95% 1,10-5,03)] e ter teste de captura híbrida para HPV de alto risco positivo [OR=11,23 (IC95% 4,79-26,36)] permaneceram independentemente associados à lesão de alto grau/câncer cervical. Conclusões: Os resultados mostram alta prevalência de lesões precursoras de carcinoma cervical e alta prevalência de HPV de alto risco. O HPV mais prevalente foi o HPV 16, seguido do HPV 31. Os fatores de risco associados à HSIL/carcinoma foram ter idade entre 30 e 49 anos, ser tabagista, relatar prática de coito anal e ter resultado positivo para HPV de alto risco. O estudo enfatiza a importância das estratégias de prevenção e assistência para o controle do câncer cervical.