Evaluation of the Psoriasis Transcriptome across Different Studies by Gene Set Enrichment Analysis (GSEA)

Our objective was to develop a consistent molecular definition of psoriasis. There have been several published microarray studies of psoriasis, and we compared disease-related genes identified across these different studies of psoriasis with our own in order to establish a consensus.We present a psoriasis transcriptome from a group of 15 patients enrolled in a clinical study, and assessed its biological validity using a set of important pathways known to be involved in psoriasis. We also identified a key set of cytokines that are now strongly implicated in driving disease-related pathology, but which are not detected well on gene array platforms and require more sensitive methods to measure mRNA levels in skin tissues. Comparison of our transcriptome with three other published lists of psoriasis genes showed apparent inconsistencies based on the number of overlapping genes. We extended the well-established approach of Gene Set Enrichment Analysis (GSEA) to compare a new study with these other published list of differentially expressed genes (DEG) in a more comprehensive manner. We applied our method to these three published psoriasis transcriptomes and found them to be in good agreement with our study.Due to wide variability in clinical protocols, platform and sample handling, and subtle disease-related signals, intersection of published DEG lists was unable to establish consensus between studies. In order to leverage the power of multiple transcriptomes reported by several laboratories using different patients and protocols, more sophisticated methods like the extension of GSEA presented here, should be used in order to overcome the shortcomings of overlapping individual DEG approach

Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses

Biological agents have dramatically improved treatment options for patients with severe psoriasis. Etanercept (tumor necrosis factor [TNF] receptor–immunoglobulin fusion protein) is an effective treatment for many psoriasis patients, and blockade of TNF is considered to be its primary action. However, in this clinical trial, we show that etanercept has early inhibitory effects on a newly appreciated type of T cells: T helper type 17 (Th17) cells. Etanercept reduced the inflammatory dendritic cell products that drive Th17 cell proliferation (interleukin [IL] 23), as well as Th17 cell products and downstream effector molecules (IL-17, IL-22, CC chemokine ligand 20, and β-defensin 4). In contrast, Th1 cellular products and effector molecules (interferon γ, lymphotoxin α, and myxovirus resistance 1) were reduced late in disease resolution. This study suggests a role for Th17 in addition to Th1 cells in the pathogenesis of psoriasis. Th17 cells may be particularly important in driving epidermal activation in psoriatic plaques, whereas Th1 cells must also be eliminated for final disease resolution

Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis

Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell-cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis

Normatização da abertura de ligas acadêmicas: a experiência da Faculdade de Medicina de Botucatu

Student leagues have been created by medical students all across Brazil. Accepted as extracurricular university extension activities, the leagues have produced both benefits and risks for medical training. Student leagues thus need to be rationalized, with the aim of improving their activities. This report describes the regulation adopted by the Botucatu School of Medicine (Universidade Estadual Paulista, FMB/UNESP), framed within a discussion of the importance of such leagues as extracurricular activities and the potential harm they can cause to medical training. The regulation contains procedural guidelines and a set of criteria for the evaluation of proposals to create new leagues. The criteria assess the proposal’s relevance, objectives, planned management model, and training ideology. The use of these guidelines has allowed the development of projects for new leagues and triggered more in-depth reflection in the school on the role of student leagues.Acriação de ligas acadêmicas por estudantes de Medicina tem ocorrido em todo o Brasil. Aceitas como atividades extracurriculares de extensão universitária, as ligas trazem tanto benefícios como riscos à formação médica. Assim, a abertura de ligas deveria ser racionalizada, visando ao aperfeiçoamento de suas atividades. Neste relato, descrevemos a normatização adotada na Faculdade de Medicina de Botucatu – Universidade Estadual Paulista (FMB/Unesp), contextualizando-a numa discussão sobre a importância das ligas como atividades extracurriculares e os prejuí- zos que podem trazer à formação médica. A normatização contém orientações processuais e um conjunto de critérios para avaliação dos projetos de abertura de novas ligas. Os critérios avaliam a relevância da proposta, os objetivos, o modelo de gestão planejado e a ideologia da formação. A utilização destas diretrizes tem capacitado o desenvolvimento de projetos de novas ligas e desencadeado na escola o aprofundamento de reflexões sobre a função de ligas acadêmicas

Normatização da abertura de ligas acadêmicas: a experiência da Faculdade de Medicina de Botucatu

A criação de ligas acadêmicas por estudantes de Medicina tem ocorrido em todo o Brasil. Aceitas como atividades extracurriculares de extensão universitária, as ligas trazem tanto benefícios como riscos à formação médica. Assim, a abertura de ligas deveria ser racionalizada, visando ao aperfeiçoamento de suas atividades. Neste relato, descrevemos a normatização adotada na Faculdade de Medicina de Botucatu - Universidade Estadual Paulista (FMB/Unesp), contextualizando- a numa discussão sobre a importância das ligas como atividades extracurriculares e os prejuízos que podem trazer à formação médica. A normatização contém orientações processuais e um conjunto de critérios para avaliação dos projetos de abertura de novas ligas. Os critérios avaliam a relevância da proposta, os objetivos, o modelo de gestão planejado e a ideologia da formação. A utilização destas diretrizes tem capacitado o desenvolvimento de projetos de novas ligas e desencadeado na escola o aprofundamento de reflexões sobre a função de ligas acadêmicas