Clinical application of next-generation sequencing of plasma cell-free DNA for genotyping untreated advanced non-small cell lung cancer

Simple Summary Plasma ctDNA is a material source for molecular analysis particularly useful when tissue is not available or sufficient. NGS-based plasma genotyping should be integrated into the clinical workup of newly diagnosed advanced NSCLC. Background: Analysis of circulating tumor DNA (ctDNA) has remarkable potential as a non-invasive lung cancer molecular diagnostic method. This prospective study addressed the clinical value of a targeted-gene amplicon-based plasma next-generation sequencing (NGS) assay to detect actionable mutations in ctDNA in patients with newly diagnosed advanced lung adenocarcinoma. Methods: ctDNA test performance and concordance with tissue NGS were determined, and the correlation between ctDNA findings, clinical features, and clinical outcomes was evaluated in 115 patients with paired plasma and tissue samples. Results: Targeted-gene NGS-based ctDNA and NGS-based tissue analysis detected 54 and 63 genomic alterations, respectively; 11 patients presented co-mutations, totalizing 66 hotspot mutations detected, 51 on both tissue and plasma, 12 exclusively on tissue, and 3 exclusively on plasma. NGS-based ctDNA revealed a diagnostic performance with 81.0% sensitivity, 95.3% specificity, 94.4% PPV, 83.6% NPV, test accuracy of 88.2%, and Cohen's Kappa 0.764. PFS and OS assessed by both assays did not significantly differ. Detection of ctDNA alterations was statistically associated with metastatic disease (p = 0.013), extra-thoracic metastasis (p = 0.004) and the number of organs involved (p = 0.010). Conclusions: This study highlights the potential use of ctDNA for mutation detection in newly diagnosed NSCLC patients due to its high accuracy and correlation with clinical outcomes

A motivação para estudar química: Interdisciplinaridade na utilização do livro didático de Química

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A comprehensive assessment of the transcriptome of cork oak (Quercus suber) through EST sequencing

Background: Cork oak (Quercus suber) is one of the rare trees with the ability to produce cork, a material widely used to make wine bottle stoppers, flooring and insulation materials, among many other uses. The molecular mechanisms of cork formation are still poorly understood, in great part due to the difficulty in studying a species with a long life-cycle and for which there is scarce molecular/genomic information. Cork oak forests are of great ecological importance and represent a major economic and social resource in Southern Europe and Northern Africa. However, global warming is threatening the cork oak forests by imposing thermal, hydric and many types of novel biotic stresses. Despite the economic and social value of the Q. suber species, few genomic resources have been developed, useful for biotechnological applications and improved forest management. Results: We generated in excess of 7 million sequence reads, by pyrosequencing 21 normalized cDNA libraries derived from multiple Q. suber tissues and organs, developmental stages and physiological conditions. We deployed a stringent sequence processing and assembly pipeline that resulted in the identification of ~159,000 unigenes. These were annotated according to their similarity to known plant genes, to known Interpro domains, GO classes and E.C. numbers. The phylogenetic extent of this ESTs set was investigated, and we found that cork oak revealed a significant new gene space that is not covered by other model species or EST sequencing projects. The raw data, as well as the full annotated assembly, are now available to the community in a dedicated web portal at http://www.corkoakdb.org. Conclusions: This genomic resource represents the first trancriptome study in a cork producing species. It can be explored to develop new tools and approaches to understand stress responses and developmental processes in forest trees, as well as the molecular cascades underlying cork differentiation and disease response.Peer Reviewe

Risk of mortality for small newborns in Brazil, 2011-2018: A national birth cohort study of 17.6 million records from routine register-based linked data.

BACKGROUND: Preterm birth (25 times higher for LBW (HR=25.8; (95% CI:25.5-26.1) compared to normal birth weight (NBW). 18% of all live births were included in one of the small vulnerable newborn phenotypes. Of those 8.2% were term-SGA (4.7%NBW, 3.5%LBW), 0.6% were term-AGA-LBW, 8.3% preterm-AGA (3.8%NBW, 4.5%LBW) and 1.0% preterm-SGA-LBW. Compared to term-AGA-NBW, the highest mortality risk was for preterm-LBW phenotypes (HR=36.2(95%CI 35.6-36.8) preterm-AGA-LBW, HR=62.0(95%CI 60.8-63.2) preterm-SGA-LBW). The increased mortality risk associated with vulnerable newborn phenotypes was highest in the first month of life, with attenuated but continued high risk in the post-neonatal period and 1-4 years of age. INTERPRETATION: Our findings support the value of using more detailed phenotypes to identify those at highest risk. More granular data can inform care at the individual level, advance research, especially for prevention, and accelerate progress towards global targets such as the Sustainable Development Goals. FUNDING: Wellcome Trust

A genome-wide association study of asthma symptoms in Latin American children

Abstract\ud \ud Background\ud Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated genetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies have been carried out in recent years, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the Brazilian population.\ud \ud \ud Methods\ud 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were identified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Following quality control, 1 877 526 autosomal SNPs were tested for association with childhood asthma symptoms by logistic regression using an additive genetic model. We complemented the analysis with an estimate of the phenotypic variance explained by common genetic variants. Replications were investigated in independent Mexican and US Latino samples.\ud \ud \ud Results\ud Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the 14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95 % CI 1.45–2.18, p-value 2.83 × 10−8) and 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95 % CI 2.02–4.49, p-value 6.68 × 10−8 and rs8029377, MAF 0.03, OR 2.49, 95 % CI 1.76–3.53, p-value 2.45 × 10−7). eQTL analysis suggests that rs1999071 regulates the expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples.\ud \ud \ud Conclusions\ud We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood.This work was supported by the Department of Science and Technology\ud (DECIT, Ministry of Health), National Fund for Scientific and Technological\ud Development (FNDCT, Ministry of Science and Technology), Funding of\ud Studies and Projects (FINEP, Ministry of Science and Technology, Brazil), the\ud Brazilian National Research Council (CNPq) and the Wellcome Trust UK, Ref\ud 072405/Z/03/Z.\ud E.G.B. was funded by grants from National Institutes of Health (HL088133,\ud HL078885, HL004464, HL104608, HL117004, ES015794 and MD006902) and\ud by the American Asthma Foundation, the Sandler Foundation and the RWJF\ud Amos Medical Faculty Development Award.\ud Supported in part by the Intramural Research Program of the NIH, National\ud Institute of Environmental Health Sciences, USA