Investigação de Hiperplasia Endometrial em mulheres obesas na pré e pós menopausa: Uma Revisão Sistemática / Investigation of Endometrial Hyperplasia in obese pre and postmenopausal women: A Systematic Review

INTRODUÇÃO A obesidade é um dos principais fatores de risco de câncer de endométrio (CE) e este, por sua vez, apresenta-se como uma possível evolução fisiopatológica da hiperplasia endometrial (HE). O objetivo deste estudo consiste em analisar se a obesidade isoladamente teria o poder de indicar uma investigação complementar para HE e CE em mulheres na pré e pós menopausa, sintomáticas ou não. METODOLOGIA: Foi realizada uma Revisão Sistemática da Literatura a partir de 21 artigos selecionados para responder a questão de pesquisa levantada. As bases de dados selecionadas foram PubMed, Scielo, LILACS, Cochrane, Scopus e Embase. RESULTADOS E DISCUSSÃO: Mulheres obesas possuem de 2.7 a 17 vezes mais chances de desenvolver HE e CE em relação às não obesas. O ultrassom transvaginal (USTV) apresenta acurácia diminuída em obesas, sendo a videohisteroscopia (VH) seguida de biópsia o exame mais recomendado neste grupo, porém de acesso limitado. Não há consenso sobre quando iniciar propedêutica com estes exames complementares. Atualmente, a investigação não é recomendada em pacientes assintomáticas, independentemente do fator de risco. CONCLUSÃO: Apesar da forte associação entre obesidade e HE, não há evidências suficientes para estabelecer o momento ideal de se investigar ou rastrear a doença e a forma de se fazer essa investigação

Interações linfócitos/células nervosas, in vitro, na infecção experimental pelo Trypanosoma cruzi possível participação da matriz extracelular

Made available in DSpace on 2014-12-05T18:40:16Z (GMT). No. of bitstreams: 2 fernanda_mariz_ioc_mest_2002.pdf: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 1_fernanda_mariz_ioc_mest_2002.pdf: 397710 bytes, checksum: c5806b803bc46b6c3532cd3281026b69 (MD5) Previous issue date: 2014-11-18Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, BrasilA doença de Chagas, cujo agente etiológico é o Trypanosoma cruzi, é considerada uma parasitose endêmica que acomete mais de 18 milhões de indivíduos na América Latina. Uma parte destes apresenta acometimento do sistema nervoso central e periférico. Vem sendo descrito, durante a fase aguda da doença, um intenso infiltrado inflamatório em regiões do tecido nervoso. Entretanto, os mecanismos envolvidos no aporte de células T e nas interações celulares neste tecido permanecem pouco esclarecidos. Assim, utilizamos neste trabalho um modelo in vitro visando estudar as interações entre células T de camundongos na fase aguda de infecção e células neuronais, exemplificadas por uma linhagem de neuroblastoma murino (N2a), e por neurônios do córtex cerebral oriundos de cultivo primário. Em particular, procuramos avaliar as interações mediadas por elementos de matriz extracelular (ECM), os quais sabidamente são capazes de interferir com os eventos de migração celular Inicialmente, observamos que células N2a e neurônios de cultivo primário expressam constitutivamente proteínas de ECM (laminina, fibronectina e colágeno tipo IV), cuja presença é aumentada na vigência de infecção in vitro pelo T. cruzi. Também pudemos notar aumento na adesão de células T às células N2a quando estas são infectadas in vitro e/ou quando os linfócitos T são oriundos de animais infectados. Este fenômeno é mediado, pelo menos em parte, por elementos de ECM, visto que pôde ser bloqueado por anticorpos antifibronectina, antilaminina e anticolágeno tipo IV. Nossos resultados indicam que ligantes e receptores de ECM encontram-se envolvidos na interação células T/células neuronais, a qual pode ocorrer após a infecção experimental pelo T. cruziChagas disease, caused by the protozoan Trypanosoma cruzi , is an endemic parasitic disease affecting more than 18 million individuals in Latin America. Part of these patients develop symptoms related to the disorders in the pe ripheral and central nervous system. It has been described, during the acute phase of the d isease, an intense inflammatory infiltrate in the nervous tissue, but the mechanism (s) driving T cells to this tissue remain(s) to be clarified. We used an in vitro model to study the interactions between T cells derived T. cruzi -infected mice and neurons, herein exemplified by t he N2a murine neuroblastoma cell line, as well as by a brain cort ex-derived primary culture of murine neurons. In particular, we looked for extracellular matrix (ECM)- mediated interactions, known to affect T cell migration. We first showed that N2a cells and the primary cult ures of neurons constitutively express the ECM proteins, laminin, fibronectin and collagen type IV and that such an expression is upregulated upon T. cruzi infection in vitro . Moreover, adhesion of peripheral T cells was enhanc ed (as compared to non- infected conditions) when N2a cells were infected in vitro , or when T cells were derived from T. cruzi infected mice. This likely represents an ECM- medi ated event since it could be partially inhibited with anti-ECM antibodies. In conclusion, our results indicate that ECM ligand s and receptors are involved in the T cell/neuronal interactions that may occur following T. cruzi infectio

Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy

Made available in DSpace on 2015-06-08T14:01:46Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) fernanda_marizetal_IOC_2014.pdf: 928634 bytes, checksum: bea5c3f8ed6d81901b351d7c4243f0b8 (MD5) Previous issue date: 2014Université Paris-Est. Ecole Nationale Vétérinaire d’Alfort. UPR de Neurobiologie. Paris, France.Université Pierre et Marie Curie-Paris. Institut de Myologie. Paris, France/ Universidade Federal do Rio de Janeiro. Instituto de Pediatria. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Université Pierre et Marie Curie-Paris . Institut de Myologie. Paris, France.Université Paris-Est. Ecole Nationale Vétérinaire d’Alfort. Unité D’Épidémiologie clinique et de Biostatistique. Paris, France / CNRS UMR 7179, MNHN, Brunoy 91800, France.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Câncer (INCA). Departamento de Pesquisa Clínica. Rio de Janeiro, RJ, Brasil.Université Pierre et Marie Curie-Paris . Institut de Myologie. Paris, France.Université Pierre et Marie Curie-Paris . Institut de Myologie. Paris, France.Université Paris-Est. Ecole Nationale Vétérinaire d’Alfort. UPR de Neurobiologie. Paris, France.Université Pierre et Marie Curie-Paris . Institut de Myologie. Paris, France.In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4+CD49dhi T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease

Genetic screening in a Brazilian cohort with inborn errors of immunity

Abstract Background Inherited genetic defects in immune system-related genes can result in Inborn Errors of Immunity (IEI), also known as Primary Immunodeficiencies (PID). Diagnosis of IEI disorders is challenging due to overlapping clinical manifestations. Accurate identification of disease-causing germline variants is crucial for appropriate treatment, prognosis, and genetic counseling. However, genetic sequencing is challenging in low-income countries like Brazil. This study aimed to perform genetic screening on patients treated within Brazil's public Unified Health System to identify candidate genetic variants associated with the patient’s phenotype. Methods Thirteen singleton unrelated patients from three hospitals in Rio de Janeiro were enrolled in this study. Genomic DNA was extracted from the peripheral blood lymphocytes of each patient, and whole exome sequencing (WES) analyses were conducted using Illumina NextSeq. Germline genetic variants in IEI-related genes were prioritized using a computational framework considering their molecular consequence in coding regions; minor allele frequency ≤ 0.01; pathogenicity classification based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines gathered from the VarSome clinical database; and IEI-related phenotype using the Franklin tool. The genes classification into IEI categories follows internationally recognized guidelines informed by the International Union of Immunological Societies Expert Committee. Additional methods for confirmation of the variant included Sanger sequencing, phasing analysis, and splice site prediction. Results A total of 16 disease-causing variants in nine genes, encompassing six different IEI categories, were identified. X-Linked Agammaglobulinemia, caused by BTK variations, emerged as the most prevalent IEI disorder in the cohort. However, pathogenic and likely pathogenic variants were also reported in other known IEI-related genes, namely CD40LG, CARD11, WAS, CYBB, C6, and LRBA. Interestingly, two patients with suspected IEI exhibited pathogenic variants in non-IEI-related genes, ABCA12 and SLC25A13, potentially explaining their phenotypes. Conclusions Genetic screening through WES enabled the detection of potentially harmful variants associated with IEI disorders. These findings contribute to a better understanding of patients' clinical manifestations by elucidating the genetic basis underlying their phenotypes

Data table 3 - Detailed information of the rare and Pathogenic/Likely pathogenic variants found in the cohort

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

Data table 2 - Overview of the sequencing metrics

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

CD49d is a disease progression biomarker and a potential target for immunotherapy in Duchenne muscular dystrophy

International audienceBackground: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. The immune inflammatory response also contributes to disease progression in DMD patients. In a previous study, we demonstrated higher levels of circulating CD49dhi and CD49ehi T cells in DMD patients compared to healthy control. DMD patients are clinically heterogeneous and the functional defect cannot be correlated with genotype. Therefore, it is important to be able to define reliable noninvasive biomarkers to better define the disease progression at the beginning of clinical trials. Results: We studied 75 DMD patients at different stages of their disease and observed that increased percentages of circulating CD4+CD49dhi and CD8+CD49dhi T lymphocytes were correlated with both severity and a more rapid progression of the disease. Moreover, T+CD49d+ cells were also found in muscular inflammatory infiltrates. Functionally, T cells from severely affected patients exhibited higher transendothelial and fibronectin-driven migratory responses and increased adhesion to myotubes, when compared to control individuals. These responses could be blocked with an anti-CD49d monoclonal antibody.Conclusion : CD49d can be used as a novel biomarker to stratify DMD patients by predicting disease progression for clinical trials. Moreover, anti-CD49d peptides or antibodies can be used as a therapeutic approach to decrease inflammation-mediated tissue damage in DMD

Data file 1 - Flowchart of the pipeline used to prioritize genetic variants

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

Data table 1 - Demographic characteristics of the cohort

This work aims (i) to make available genomic data generated from the whole-exome sequencing (WES) of Brazilian patients' suspicion of inborn error of immunity (IEI) without genetic diagnosis; (ii) to improve the diagnostic yield of monogenic disorders by providing a clinically relevant dataset; and (iii) to provide high-throughput data with exploitable potential to gain insights about the genomic population structure of the Brazilians.  We sequenced genomic DNA from twenty unrelated patients treated at four different hospitals in the state of Rio de Janeiro, Brazil. Half of the patients were male with mean ages of 9±3 while females were 12±10  years old. WES were conducted through Illumina NextSeq platform and achieved 90% of the genetic basis coverage by >30 reads. More than 80% of the sequencing reads were uniquely mapped to the reference genome. Each sample had an average of 20,274 variants, being 114 classified as rare pathogenic or likely pathogenic according to ACMG guidelines. Overall, the access to clinical exome sequencing data is limited, challenging exploratory analyses and the understanding of genetic mechanisms underlying disorders. Thus, by making these data available, we foresee increasing the number of WES data from Brazilians despite contributing to the study of  monogenic IEI-disorders. </p

Additional file 1: Table S1. of CD49d is a disease progression biomarker and a potential target for immunotherapy in Duchenne muscular dystrophy

General characteristics of the DMD patients enrolled in the study of blood samples. (DOC 35 kb