Doença de Paget do mamilo em paciente octogenária: um achado incomum

A Doença de Paget do mamilo é uma manifestação incomum do câncer de mama, sendo mais prevalente em mulheres na 6ª década de vida, no período da pós-menopausa. Geralmente, tal patologia pode estar associada ao carcinoma intraductal mamário. Sua principal manifestação clínica é a presença de lesão eczematosa e pruriginosa mamilar, de longa data e que não apresenta melhora, apesar de terapias tópicas dermatológicas. Relatamos o caso de uma paciente feminina, de 88 anos, encaminhada para consulta ginecológica, oriunda do ambulatório de dermatologia com quadro de lesão escamosa, eczematosa e exuberante em mamilo direito, associada a descamação e prurido, sem dor ou tumoração local e sem melhora com tratamento tópico, há aproximadamente um ano. Foi submetida a biópsia incisional do mamilo que mostrou epiderme fragmentada e espongiótica, inconclusiva. Somente após o resultado da imuno-histoquímica a qual mostrou positividade para expressão de citoqueratina 7, HER-2 positivo 3+/3+, receptor de estrogênio negativo e marcador de histogênese melanocítico não-reagente, que se confirmou tratar-se de Doença de Paget do Mamilo. Portanto, destacamos a importância da anamnese detalhada para qualquer paciente com eczema ou rash mamilar, independe da idade, devendo sempre ser aventado a possibilidade de Doença de Paget, tendo-se em vista que o atraso no diagnóstico pode impactar na terapêutica específica, aumentando assim a possibilidade de disseminações metastáticas e comprometendo seu prognóstico

GADGET: A code for collisionless and gasdynamical cosmological simulations

We describe the newly written code GADGET which is suitable both for cosmological simulations of structure formation and for the simulation of interacting galaxies. GADGET evolves self-gravitating collisionless fluids with the traditional N-body approach, and a collisional gas by smoothed particle hydrodynamics. Along with the serial version of the code, we discuss a parallel version that has been designed to run on massively parallel supercomputers with distributed memory. While both versions use a tree algorithm to compute gravitational forces, the serial version of GADGET can optionally employ the special-purpose hardware GRAPE instead of the tree. Periodic boundary conditions are supported by means of an Ewald summation technique. The code uses individual and adaptive timesteps for all particles, and it combines this with a scheme for dynamic tree updates. Due to its Lagrangian nature, GADGET thus allows a very large dynamic range to be bridged, both in space and time. So far, GADGET has been successfully used to run simulations with up to 7.5e7 particles, including cosmological studies of large-scale structure formation, high-resolution simulations of the formation of clusters of galaxies, as well as workstation-sized problems of interacting galaxies. In this study, we detail the numerical algorithms employed, and show various tests of the code. We publically release both the serial and the massively parallel version of the code.Comment: 32 pages, 14 figures, replaced to match published version in New Astronomy. For download of the code, see http://www.mpa-garching.mpg.de/gadget (new version 1.1 available

Orla. Experimentações em narrativa sequencial

ORLA é uma exposição e uma publicação online que resultam de alguns trabalhos propostos pelos alunos, em consequência de exercícios e reflexões realizados no contexto da UC Ilustração e Narrativa Visual, do 1 ° semestre do 1 ° ano da Licenciatura em Artes Plásticas.Uma orla, como uma cercadura envolvendo explorações realizadas num contexto de procura, momentos de descoberta de possibilidades e caminhos próprios, inserindo-se como um pequeno passo (entre tantos outros) a favor de processos de reflexão, de criação de direções próprias de cada aluno. O que é criado, como é criado e o que daí é visualizado. Entre visões e processos ligados à comunicação e/ou à exploração direcionada. Reflexões e experimentações em ilustração e narrativa sequencial com diferentes grafismos e materialidades. a favor de narrativa e/ou poética em objetos. Relacionar imagens e sub-imagens, ilustrações e vinhetas, pistas e direções. Relacionar o que acontece na vinheta e o que acontece fora da vinheta, o que surge no enquadramento, o todo , e os elementos que o compõem. Criar foco. Tentativas e erros como parte de percursos que estão no seu início.info:eu-repo/semantics/publishedVersio

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Pathogen-sugar interactions revealed by universal saturation transfer analysis

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor