1,720,967 research outputs found
VEO-IBD AS MODELS FOR PATHOGENIC STUDIES AND DEVELOPMENT OF PRECISION THERAPIES
No full textMultiple monogenic disorders present as very early onset inflammatory bowel disease (VEOIBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients’ management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. Monogenic VEOIBD diagnostic approach changed over time, especially after the advent of next generation sequencing (NGS) techniques. NGS should be preferred in patients with nonspecific phenotypes. Nevertheless, Sanger sequencing is still effective in patients with suggestive clinical and immunological findings. In a multicentric collaboration with Bambino Gesù Children’s hospital, we developed a target gene panel sequencing (TGPS) including the most common monogenic diseases presenting with IBD symptoms, as first line of genetic approach for patient with non-specific phenotypes and negativity to this panel, we performed WES with an in silico analysis of 400 genes responsible for primary immunodeficiencies. 94 patients were included, and 13 (14%) reached a genetic diagnosis. Candidate sequencing was performed in 47 patients (50%), and NGS was performed in 85 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. Although we identified 14% of monogenic disease in our cohort, the majority of cases remains without a genetic diagnosis. We hypothesized that transcriptome analysis by RNA sequencing (RNAseq) could help grouping multifactorial cases and correlating profiles with those found in distinct monogenic forms. We proposed a disease-similarity method for patients’ stratification and the detection of possible biomarkers. 13 out of 94 patients, depending on RNA availability (4 monogenic and 9 nonmonogenic) described in the previous genetic workup, performed gene expression analysis by RNAseq of peripheral blood cells. We compared gene expression profile of the 4 monogenic IBD (XIAP, TTC37, DKC1, and LRBA) with nonmonogenic IBD and performed cluster analysis. The most evident impact on peripheral blood cells came
from XIAP and DKC1. TTC37 and LRBA did not show enriched pathway probably due to wrong sampling. Few nonmonogenic patients that presented extraintestinal manifestations (feature suggestive of monogenic defect) had a hybrid expression profile between monogenic and nonmonogenic IBD. Cluster and machine learning analyses might be applied to group patients by gene expression patterns in an unbiased manner. We performed an unsupervised analysis including our monogenic IBD, the nonmonogenic IBD from the cohort of Trieste and the first 13 genetically undefined VEOIBD and EOIBD enrolled within the collaborative project with University of Brescia, whose clinical collection data and genetic investigations are in progress. However, this data should be complemented by clinical reports and therapeutic management at the time of sampling to get more precise results and evaluate the obtained functional subgroups. Nevertheless, the characterization of more monogenic forms is a crucial point to expand this analysis and obtain more reliable results. The implementation of this knowledge may allow the use of monogenic disorders as prototypical diseases for the stratification and the therapeutic management of likely multifactorial cases towards a tailored therapy
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Vasculitis, Autoimmunity, and Cytokines: How the Immune System Can Harm the Brain
Full text linkMore and more findings suggest that neurological disorders could have an immunopathological cause. Thus, immune-targeted therapies are increasingly proposed in neurology (even if often controversial), as anakinra, inhibiting IL-1 for febrile inflammatory illnesses, and JAK inhibitors for anti-interferons treatment. Precision medicine in neurology could be fostered by a better understanding of the disease machinery, to develop a rational use of immuno-modulators in clinical trials. In this review, we focus on monogenic disorders with neurological hyper-inflammation/autoimmunity as simplified “models” to correlate immune pathology and targeted treatments. The study of monogenic models yields great advantages for the elucidation of the pathogenic mechanisms that can be reproduced in cellular/animal models, overcoming the limitations of biological samples to study. Moreover, monogenic disorders provide a unique tool to study the mechanisms of neuroinflammatory and autoimmune brain damage, in all their manifestations. The insight of clinical, pathological, and therapeutic aspects of the considered monogenic models can impact knowledge about brain inflammation and can provide useful hints to better understand and cure some neurologic multifactorial disorders
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Effect of the Janus kinase inhibitor tofacitinib in the treatment of juvenile scleroderma: A single-center experience
No full textJuvenile scleroderma (JS) is a group of diseases characterized byincreased skin thickness and fibrosis. It is the third-most commonrheumatic condition in childhood. There are two major forms of thedisease: juvenile localized scleroderma (JLS) and juvenile systemicsclerosis (JSSc), both classified into different subtypes depending onthe extent of the disease and the depth of the lesions.1 JLS, alsoknown as morphea, affects only the skin and subdermal tissues,while JSSc also includes fibrous changes in internal organs such asthe esophagus, intestines, heart, lungs, and kidney
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Study on mupirocin treatment in cutaneous lupus erythematosus: comment on the article by Abernathy-Close et al
No full textAbernathy-Close et al1 provide a valuable contribution to theunderstanding of therapy for cutaneous lupus erythematosus(CLE) through their proof-of-concept study examining the effectsof mupirocin, a topical antibiotic, on inflammatory pathways withinCLE lesions. Their data indicate a correlation between reducedStaphylococcus aureus bacterial load and a subsequent declinein local inflammation, as well as decreased expression of inflam-matory genes, .particularly those related to type I interferon (IFN)signaling. These findings highlight the pivotal role of the skinmicrobiome in influencing immune responses and advancingtreatment options for lupus-associated skin lesion
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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