Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis

Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined “CpG islands,” but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery

Oncoplastic breast consortium recommendations for mastectomy and whole breast reconstruction in the setting of post-mastectomy radiation therapy

Aim: Demand for nipple-and skin-sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario. Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology. Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recom-mendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR. Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BRPeer reviewe

RELATO DE VISITA TÉCNICA AO ASSENTAMENTO JOSÉ MARIA – PROBLEMATIZANDO A EDUCAÇÃO NO/DO CAMPO

O relato de Experiência a ser compartilhado com os participantes do II MEPEC será organizado no formato de “sessões de apresentação” com apoio de audiovisual. Os autores exporão aos visitantes a vivência ocorrida em setembro de 2016 durante visita técnica ao Campus Avançado do IFC em Abelardo Luz, situado no AssentamentoJosé Maria.Esta visita teve como objetivos:-Compreender o que representa a expressão “sem terra”, de modo a extrapolar a ideia de mera luta pela terra e entender que “sem terra” é uma identidade historicamente construída como afirmação de uma condição social (CALDART, 2001);-Conhecer o movimento pedagógico de uma escola que atua para a formação de sujeitos sociais e de seres humanos que têm a identidade de luta como elemento que os aproxima, a Escola de Ensino Médio Paulo Freire;-Olhar para o Movimento Sem Terra e sua trajetória, em especial, no que diz respeito à Pedagogia e à educação das crianças, jovens e adultos pertencentes ao Movimento, e pensar que em tempos de desumanidade crescente há que investir em processos de formação humana marcados pela alteridade, pelo reconhecimento do outro enquanto um outro diferente de mim;-Compreender a influência e a importância dos movimentos sociais na formação da consciência social do direito a Educação Básica, desde a Educação Infantil;-o direito à escola pública.-Aproximar as/os acadêmicas/os da realidade dos movimentos sociais, de modo que esta relação teoria-prática faça emergir sentidos que contribuam para problematizar conhecimentos produzidos no âmbito dos componentes curriculares do Curso de Pedagogia.A apresentação na II MEPEC está organizada em torno de quatro temas:-Vida de assentado: breve história, as lutas e conquistas, a situação atual…-O Campus avançado do IFC em Abelardo Luz;-Escola do/no campo: o ensino fundamental (as escolas municipais);-Escola do/no campo: o ensino médio (as escolas estaduais).No decorrer da apresentação dos temas serão utilizadas imagens (fotos) e entrevistas realizadas com pessoas do local, para o que se fará necessário contar com Datashow e computador e razão pela qual haverá mais de um expositor

Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models

The application of high-throughput genomic technologies has revealed that individual breast tumors display a variety of molecular features that require more personalized approaches to treatment. Several recent studies have demonstrated that a cross-species analytic approach provides a powerful means to filter through genetic complexity by identifying evolutionarily conserved genetic networks that are fundamental to the oncogenic process. Mouse-human tumor comparisons will provide insights into cellular origins of tumor subtypes, define interactive oncogenetic networks, identify potential novel therapeutic targets, and further validate as well as guide the selection of genetically engineered mouse models for preclinical testing

OFICINAS DO BRINCAR: UM RESGATE A INFÂNCIA POR MEIO DE JOGOS, BRINQUEDOS E BRINCADEIRAS. (relato de experiência)

A brincadeira e jogo são construções sociais e, portanto culturais. A criança ao nascer está impregnada de práticas estabelecidas nas relações com outros sujeitos, adultos e outras crianças que possibilitam o acesso aos códigos sociais estabelecidos na forma de aprendizagem social. É na brincadeira, na fantasia e posteriormente no jogo com a elaboração de regras mais complexas que a criança se apropria da organização social na qual está inserida. Como processo cultural, o acesso a brincadeira e ao jogo se dá fundamentalmente na relação com outro e com as condições de espaço, materiais e possibilidades de exploração desses elementos. Considerando a importância da brincadeira e do jogo em proposições criativas, de descobertas, elaborações ereelaborações, estamos realizando um projeto de pesquisa denominado “Oficinas do brincar: um resgate a infância por meio de jogos, brinquedos e brincadeiras”, desenvolvido com os acadêmicos da quarta fase do curso de Licenciatura em Pedagogia, do Instituto Federal Catarinense – campi Blumenau (SC), com a perspectiva de propiciar espaço de relacionamento significativo com a brincadeira, o jogo, o brinquedo e práticas corporais expressivas como elementos de acesso a cultura lúdica e, portanto de inserção num contexto social humanizador. A dinâmica do projeto compreende atividades sequenciais com os discentes, semanalmente, nos quais são utilizadas as dependências da própria instituição, que disponibiliza o espaço físico e conta com a colaboração dos estudantes ao trazerem os recursos - como brinquedos, jogos e materiais para práticas corporais e expressivas. O projeto está em fase inicial de desenvolvimento, mas vem confirmando a relevância de seus propósitos, haja visto que parte do princípio de propiciar resgate e vivências da infância, do brincar, através dos jogos, brinquedos e brincadeiras, tematizando discussões em torno da ludicidade, como processo histórico e social, capaz de proporcionar reflexão e colaborar com a formação humana pelo acesso e interação com essas formas de manifestação da cultura. Dessa forma, objetiva-se com esta oficina, propiciar espaço e oportunidades de autoconhecimento, vivências inclusivas, melhora da auto-estima, desenvolver habilidades de comunicação, expressão e interação social dos acadêmicos envolvidos no projeto com os sujeitos participantes, colaborando com a formação acadêmica dos alunos mediadores do projeto tanto no que se refere à prática pedagógica exercida sob a perspectiva de professor, intelectual-pesquisador, bem como para a comunidade envolvida, no sentido de poder recordar os jogos, brinquedos e brincadeiras de suas infâncias por meio de cantos temáticos (num estande ou sala de aula), contendo: mostra do acervo de brinquedos que fizeram parte da infância da turma; produção artesanal de brinquedos sustentáveis com matérias recicláveis; espaço do faz de conta, com oficineiros desenvolvendo atividades recreacionistas para o público visitante

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV