Association of CYP1A1 gene polymorphisms (A4889G and T6235C) with clinical and epidemiological features of breast cancer

Orientadores: Luis Otavio Zanatta Sarian, Maria Salete Costa Gurgel, Carmem Silvia Passos LimaTese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: A terapêutica sistêmica para o câncer de mama envolve o uso do agente antiestrogênico tamoxifeno, fármaco metabolizado pelo fígado no sistema do citocromo P-450 (CYP). Este, por sua vez, é parcialmente codificado pelo gene CYP1A1, e alguns polimorfismos deste gene têm sido associados com interferências na sua eficácia metabólica. Além disso, diferenças interindividuais no CYP explicam parte das variações na resistência ao tamoxifeno e metabolismo dos estrogênios. Dentre esses polimorfismos, o A4889G (M2) e o T6235C (M1) são conhecidos por afetar a ativação da estrona e do estradiol, e por provocar a redução da concentração de metabólitos altamente ativos do tamoxifeno, reduzindo teoricamente o efeito antiestrogênico desta modalidade de hormonioterapia no tecido mamário. Embora plausíveis do ponto de vista biológico, as implicações clínicas dos polimorfismos do CYP1A1, ou seja, as características patológicas dos tumores e um pior prognóstico decorrente do aumento dos estrógenos circulantes e redução dos metabólitos ativos do tamoxifeno, não foram ainda avaliadas. Objetivo: Avaliar a associação entre os polimorfismos M1 e M2 do gene CYP1A1 e as características patológicas e clínicas de mulheres com câncer de mama esporádico, em duas abordagens: 1) determinar as associações entre estes polimorfismos e as características patológicas, clínicas e o padrão de sobrevida global em mulheres com câncer de mama esporádico e 2) determinar as associações entre estespolimorfismos e as caracteríasticas patológicas e o comportamento clínico de tumores de mama com receptores hormonais positivos na vigência do uso de tamoxifeno. Métodos: foram incluídas 741 mulheres com câncer de mama esporádico, 405 das quais com tumores positivos para receptores esteroides e que usaram tamoxifeno como terapia antiestrogênica primária, para as quais os dados referentes a cinco anos de seguimento estavam disponíveis. Foram avaliadas as associações de informações-chave patológicas e clínicas, incluindo a sobrevida geral em cinco anos, com as diferentes combinações de polimorfismos do gene CYP1A1. Resultados: Em mulheres portadoras de ambos os polimorfismos M1 e M2 do CYP1A1, a proporção de tumores grau histológico III (80,3%) foi significativamente menor que nas não-portadoras (89,6%); p ajustado <0,01. O mesmo ocorreu na análise restrita às mulheres com tumores RE+ usando tamoxifeno (76,1% vs. 85,9%; p ajustado= 0,02). Após 60 meses de seguimento, cerca de 75% das mulheres estavam vivas. Não houve diferença significativa na sobrevivência relacionada com o estado do gene CYP1A1. Conclusões: embora associados a tumores de menor grau histológico, não há nenhuma evidência da associação dos polimorfismos do CYP1A1 com prognóstico do câncer da mamaAbstract: Introduction: systemic therapy for breast cancer involves the use of the anti-estrogen agent tamoxifen, which is metabolized by the liver cytochrome P-450 (CYP). This, in turn, is partially encoded by CYP1A1, and some polymorphisms of this gene have been associated with metabolic disturbance at their effectiveness. Moreover, interindividual differences in efficiency of CYP explain part of the variations in resistance to tamoxifen and estrogen metabolism. Among these polymorphisms, the A4889G (M2) and T6235C (M1) are known to affect the activation of estrone and estradiol, and cause the reduction of the concentration of highly active metabolites of tamoxifen, theoretically reducing the anti-estrogenic effect of this form of endocrine therapy in breast tissue. Although plausible from the biological point of view, the clinical implications of polymorphisms of CYP1A1, ie, the pathologic features of tumors and a worse prognosis due to increased circulating estrogens and reduction of active metabolites of tamoxifen have not yet been evaluated. Objectives: To evaluate the association between CYP1A1 A4889G and T6235C gene polymorphisms and clinical and pathological characteristics of women with sporadic breast cancer in two approaches: 1) determine the associations between CYP1A1 A4889G and T6235C gene polymorphisms and the pathological characteristics of the tumors, and the clinical features, including overall survival, of women with sporadic breast cancer and 2) determine the associations between CYP1A1 A4889G and T6235C gene polymorphisms and the pathological characteristics and clinical behavior of estrogen receptor-positive breast tumors in patients using tamoxifen. Methods: We included 741 women with sporadic breast cancer, 405 of whom had tumors positive for steroid receptors and using tamoxifen as primary antiestrogen therapy, for which data on five years of follow-up were available. We evaluated the associations of key pathological and clinical features, including overall survival at five years, with different combinations of the CYP1A1 gene polymorphisms. Results: In women with both polymorphisms of the CYP1A1 gene, the proportion of grade III tumors (80.3%) was significantly lower than in non-carriers (89.6%), adjusted p <0.01. The same was true for women with ER + tumors using tamoxifen (76.1% vs. 85.9%; adjusted p = 0.02). After 60 months of follow up, 75% of the women were alive. There was no significant difference in survival related to the state of the CYP1A1 gene. Conclusions: Although associated with tumors of lower grade, there is no evidence of an association of CYP1A1 polymorphisms with breast cancer prognosisDoutoradoOncologia Ginecológica e MamáriaDoutor em Ciências Médica

Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in brazilian women

We examined the influence of CYP1A1 A4889G and T6235C polymorphisms on the risk of sporadic breast cancer. DNA from 742 sporadic breast cancer patients and 742 controls was analyzed using the polymerase chain reaction, followed by the restriction fragment length polymorphism technique. RESULTS: More patients had the CYP1A1 4889AG + GG genotype compared to controls (29.0% versus 23.2%, p=0.004). The G allele carriers had a 1.50-fold increased risk (95% CI: 1.14-1.97) of sporadic breast cancer compared to the other study participants. The frequency of the 4889AG + GG genotype among the Caucasian patients was higher than in the non-Caucasian patients (30.4% versus 20.2%, p=0.03) and controls (30.4% versus 23.2%, p=0.002). Caucasians and G allele carriers had a 1.61-fold increased risk (95% CI: 1.20-2.15) of sporadic breast cancer compared to other subjects. The CYP1A1 4889AG + GG genotype was more common among patients with a younger median age at first full-term pregnancy than among controls (33.8% versus 23.2%, p=0.001) and subjects whose first full-term pregnancies occurred at an older age (33.8% versus 26.1%, p=0.03). Women with the CYP1A1 4889AG + GG genotype and earlier first full-term pregnancies had a 1.87-fold (95% CI: 1.32-2.67) increased risk of sporadic breast cancer compared to the other study participants. Excess CYP1A1 4889AG + GG (39.8% versus 27.1%, p=0.01) and 6235TC + CC (48.4% versus 35.9%, p=0.02) genotypes were also observed in patients with grade I and II tumors compared to patients with grade III tumors and controls (39.8% versus 23.2%, p=0.04; 48.4% versus 38.6%, p=0.04). The G and C allele carriers had a 2.44-fold (95% CI: 1.48-4.02) and 1.67-fold (95% CI: 1.03-2.69) increased risk, respectively, of developing grade I and II tumors compared to other subjects. The CYP1A1 A4889G and T6235C polymorphisms may alter the risk of sporadic breast cancer in Brazilian women.7010680685FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPES

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Influencia dos polimorfismos dosalelos Mu 1 (GSTM1) e Theta 1 (GSTT1) do sistema da glutatina S-transferase na susceptibilidade ao cander de mama esporadico

Orientador: Maria Salete Costa GurgelDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Introdução: As deleções dos genes GSTM1 e GSTT1 têm sido associadas ao aumento do risco de várias neoplasias, porém não há consenso sobre suas influências no câncer de mama. Objetivo: Avaliar a ocorrência das deleções homozigóticas dos GSTM1 e GSTT1 em mulheres com câncer de mama esporádico (CME) ¿ casos - e em mulheres sem câncer ¿ controles - e comparar as características clínicas e biológicas dos CME entre mulheres portadoras e não-portadoras das referidas deleções. Casuística e Método: Foram avaliados 177 casos e 169 controles, com determinação das freqüências das referidas deleções pelo PCR. Estas foram correlacionadas às características clínicas e biológicas através do cálculo de odds ratio com seus respectivos intervalos de confiança de 95%. Resultados: Dos casos e controles, respectivamente, 46% e 45% não apresentaram qualquer deleção, 37% e 35% apenas do GSTM1, 11% e 10% apenas do GSTT1, 6% e 9% apresentaram ambos os genes deletados. Observou-se freqüência menor da deleção do GSTM1 em mulheres pardas (p=0,1128), OR=0,48 (0,24 ¿ 0,98). O risco foi menor de ocorrência de tumores grau nuclear 3 em pacientes com deleção do GSTT1 (p=0,04), OR=0,37 (0,15 - 0,90). A deleção homozigótica de pelo menos um dos genes associou-se com mulheres que não amamentaram (p=0,0202), OR=0,41 (0,19 ¿ 0,88), e com a ausência de expressão dos receptores hormonais (p=0,0300), ORadj=2,25 (1,03 ¿ 4,90). Já a deleção de ambos os genes associou-se ao aumento de risco da ocorrência de tipos histológicos diferentes do carcinoma ductal invasivo clássico (p=0,0571), ORadj=12,09 (1,03 ¿ 142,03). Conclusões: mulheres com CME e antecedente de miscigenação com etnia negra tiveram menor freqüência da deleção do GSTM1, enquanto os tumores com grau de diferenciação nuclear mais favorável relacionaram-se à deleção do GSTT1. Já as pacientes com pelo menos um dos genes deletados apresentaram maior risco de tumores que não expressam receptores hormonais, e a deleção combinada de ambos os genes associou-se ao aumento de risco para tipo histológico não ductal clássicoAbstract: Introduction: The GSTM1 and GSTT1 gene deletions have been associated with an increased risk of various neoplasms, although there is a lack of consensus about their influence on breast cancer. Objective: To evaluate the occurrence of homozygous deletions of the GSTM1 and GSTT1 genes in women with sporadic breast cancer (SBC) ¿ cases ¿ and in women without cancer ¿ controls ¿ and compare the clinical and biological characteristics of SBC among women with and without the referred deletions. Case Study and Method: The study evaluated 177 cases and 169 controls, determining the frequency of the abovementioned deletions by PCR. These were correlated with the clinical and biological characteristics by calculating the odds ratios and their 95% confidence intervals. Results: Of the cases and controls, 46% and 45% did not present any deletion, 37% and 35% had only GSTM1 deletion, 11% and 10% had only GSTT1 deletion, 6% and 9% had both genes deleted, respectively. A lower frequency of GSTM1 deletion was observed in mulatto women (p=0.1128), OR=0.48 (0.24 ¿ 0.98). The risk of occurring nuclear grade 3 tumors was lower in patients with GSTT1 deletion (p=0.04), OR=0.37 (0.15 ¿ 0.90). Homozygous deletion of at least one gene was associated with women who had not breastfed (p=0.0202), OR=0.41 (0.19 ¿ 0.88), and with absence of hormone receptor expression (p=0.0300), ORadj=2.25 (1.03 ¿ 4.90). The deletion of both genes was associated with an increased risk of occurring histologic types different from classic invasive ductal carcinoma (p=0.0571), ORadj=12.09 (1.03 ¿ 142.03). Conclusions: women with SBC and a history of miscegination with the black race had a lower frequency of GSTM1 deletion, while tumors with a more favorable degree of nuclear differentiation were related to GSTT1 deletion. Patients with at least one gene deleted had a higher risk for tumors that did not express hormone receptors, and the combined deletion of both genes was associtated with a greater risk for the non-classic ductal histologic typeMestradoTocoginecologiaMestre em Tocoginecologi

Brief history of Musical Theatre in Brazil, and compilation of their titles

Musical Theater is nowadays one of the leading entertainment performances between the cities of Rio de Janeiro and Sao Paulo, in Brazil. Its growing popularity, together with the technical and commercial improvements, has contributed decisively to this art form. Objective: List of the major titles of Musical Theatre works produced since the 1950s, and place them in the cultural context to which they belonged. Methods: Systematic Data search through internet and literature of Musical Theater titles produced in Brazil. Key findings: the number of Musical Theatre productions has grown, with a change from the 1990s, leaning towards more stagings of versions of the main titles from Broadway, with an increase in audience and funding. It is important to highlight the positive pressure on the singers-actors, who pursue better technical and artistic training in order to increase their qualifications for performing in Musical Theater.Introdução: O teatro musical no Brasil se revela hoje um dos principais elementos de entretenimento no ei-xo Rio-São Paulo. O grande aquecimento desse mercado, aliado ao crescimento técnico e comercial, tem contribuído decisivamente para este mercado de f1612944sem informaçãosem informaçãoMusical Theater is nowadays one of the leading entertainment performances between the cities of Rio de Janeiro and Sao Paulo, in Brazil. Its growing popularity, together with the technical and commercial improvements, has contributed decisively to this a

Breast cancer survival after mammography dissemination in Brazil: a population-based analysis of 2,715 cases

Abstract Background This study aims to assess breast cancer survival rates after one decade of mammography in a large urban area of Brazil. Methods It is a population-based retrospective cohort of women with breast cancer in Campinas, São Paulo, from 2010 to 2014. Age, vital status and stage were accessed through the cancer and mortality registry, and patients records. Statistics used Kaplan–Meier, log-rank and Cox's regression. Results Out of the 2,715 cases, 665 deaths (24.5%) were confirmed until early 2020. The mean age at diagnosis was 58.6 years. Women 50–69 years were 48.0%, and stage I the most frequent (25.0%). The overall mean survival was 8.4 years (8.2–8.5). The 5-year survival (5yOS) for overall, 40–49, 50–59, 60–69, 70–79 years was respectively 80.5%, 87.7%, 83.7%, 83.8% and 75.5%. The 5yOS for stages 0, I, II, III and IV was 95.2%, 92.6%, 89.4%, 71.1% and 47.1%. There was no significant difference in survival in stage I or II (p = 0.058). Compared to women 50–59 years, death's risk was 2.3 times higher for women 70–79 years and 26% lower for women 40–49 years. Concerning stage I, the risk of death was 1.5, 4.1 and 8.6 times higher, and 34% lower, respectively, for stage II, III, IV and 0. Conclusions In Brazil, breast cancers are currently diagnosed in the early stages, although advanced cases persist. Survival rates may reflect improvements in screening, early detection and treatment. The results can reflect the current status of other regions or countries with similar health care conditions