From traumatic childhood to cocaine abuse: the critical function of the immune system

Background: Experiencing traumatic childhood is a risk factor for developing substance use disorder (SUD), but the mechanisms that underlie this relationship have not been determined. Adverse childhood experiences affect the immune system and the immune system mediates the effects of psychostimulants. However, whether this system is involved in the etiology of SUD in individuals who have experience early life stress is unknown. Methods:In this study, we performed a series of ex vivo and in vivo experiments in mice and humans to define the function of the immune system in the early-life stress-induced susceptibility to the neurobehavioral effects of cocaine. Results: We provide evidence that exposure to social-stress (S-S) at an early age permanently sensitizes the peripheral (splenocytes) and brain (microglia) immune responses to cocaine in mice. In the brain, microglial activation in the ventral tegmental area (VTA) of S-S mice was associated with functional alterations in dopaminergic neurotransmission, as measured by whole-cell voltage clamp recordings in dopamine (DA) neurons. Notably, preventing immune activation during the S-S exposure reverted the effects of DA in the VTA and the cocaine-induced behavioral phenotype to control levels. In humans, cocaine modulated Toll-like receptor 4-mediated innate immunity, an effect that was enhanced in cocaine addicts who had experienced a difficult childhood. Conclusions Collectively, our findings demonstrate that sensitization to cocaine in early-life-stressed individuals involves brain and peripheral immune responses and that this mechanism is shared between mice and humans

The Use of Sunn Hemp as Forage in Florida

Sunn hemp (Crotalaria juncea L.) is a warm-season annual legume that has been widely used as cover crop; however, there is potential to use sunn hemp as forage in subtropical regions. The objective of this study was to evaluate management practices to improve the efficiency of using sunn hemp as a forage crop. The study was conducted in Ona, Florida, USA from 2016 to 2018 and tested the factorial arrangement of five sunn hemp genotypes (Crescent Sunn, Ubon, Blue Leaf, and AU Golden) and two harvest times (60 d after seeding or flowering) with four replicates. There was a cultivar × harvest period effect on HA, crude protein (CP), and in vitro digestible organic matter (IVDOM) concentrations. Herbage accumulation was greater at flowering than 60 d harvest for all cultivars; however, the magnitude of increase was greater for Blue Leaf and Crescent Sun than AU Golden and Ubon. AU Golden and Ubon flowered at 83 and 92 d after seeding, while Blue Leaf and Crescent Sun flowered or were harvested at 166 d after seeding. AU Golden and Crescent Sunn had the greatest CP at 60 d harvest, and Blue Leaf and Ubon had the least CP concentrations. AU Golden and Crescent Sun had the greatest IVDOM at 60-d harvest; however, AU Golden and Ubon had greater IVDOM than Blue Leaf and Crescent Sun at flowering. Sunn hemp may be a feasible warm-season annual legume to be used in forage systems in Florida and harvest 60 d after seeding would results in forage with greater nutritive value

Learning Criteria and Evaluation Metrics for Textual Transfer between Non-Parallel Corpora

We consider the problem of automatically generating textual paraphrases with modified attributes or stylistic properties, focusing on the setting without parallel data (Hu et al., 2017; Shen et al., 2017). This setting poses challenges for learning and evaluation. We show that the metric of post-transfer classification accuracy is insufficient on its own, and propose additional metrics based on semantic content preservation and fluency. For reliable evaluation, all three metric categories must be taken into account. We contribute new loss functions and training strategies to address the new metrics. Semantic preservation is addressed by adding a cyclic consistency loss and a loss based on paraphrase pairs, while fluency is improved by integrating losses based on style-specific language models. Automatic and manual evaluation show large improvements over the baseline method of Shen et al. (2017). Our hope is that these losses and metrics can be general and useful tools for a range of textual transfer settings without parallel corpora

Effect of Lemon Waste Natural Dye and Essential Oil Loaded into Laminar Nanoclays on Thermomechanical and Color Properties of Polyester Based Bionanocomposites

[EN] In this work, polyester-based nanocomposites added with laminar nanoclays (calcined hydrotalcite, HT, and montmorillonite, MMT) loaded with lemon waste natural dye (LD) and essential oil (LEO) were prepared and characterized. The optimal conditions to synthetize the hybrid materials were obtained by using statistically designed experiments. The maximum LD adsorption with HT was found using 5 wt% of surfactant (sodium dodecyl sulfate), 5 wt% of mordant (aluminum potassium sulfate dodecahydrate) and 50% (v/v) ethanol. For MMT, 10 wt% of surfactant (cetylpyridinium bromide), 5 wt% of mordant, 1 wt% of (3-aminopropyl) triethoxysilane and 100% distilled water were used. LEO adsorption at 300 wt% was maximized with MMT, 10 wt% of surfactant and 50 degrees C following an evaporation/adsorption process. The obtained hybrid nanofillers were incorporated in a polyester-based matrix (INZEA) at different loadings (3, 5, and 7 wt%) and the obtained samples were characterized in terms of thermal stability, tensile behavior, and color properties. HT_LEM-based samples showed a bright yellow color compared to MMT_LEM ones. The presence of lemon hybrid pigments in INZEA-based systems produced a remarkable variation in CIELAB color space values, which was more visible with increasing the nanofillers ratio. A limited mechanical enhancement and reduced thermal stability was observed with the nanopigments addition, suggesting a limited extent of intercalation/exfoliation of MMT and HT in the polymer matrix. MMT_LEM pigments showed higher thermal stability than HT_LEM ones. A significant increase in Young's modulus of nanocomposites loaded with hybrid LEO was observed compared to the biopolymer matrix. The LEO inclusion into the nanoclays efficiently improved its thermal stability, especially for MMT.The authors express their gratitude to the Bio Based Industries Consortium and European Commission for the financial support to the project BARBARA: Biopolymers with advanced functionalities for building and automotive parts processed through additive manufacturing. This project has received funding from the Bio Based Industries Joint Undertaking under the European Union's Horizon 2020 research and innovation programme under grant agreement No 745578.Micó-Vicent, B.; Viqueira, V.; Ramos, M.; Luzi, F.; Dominici, F.; Torre, L.; Jiménez, A.... (2020). Effect of Lemon Waste Natural Dye and Essential Oil Loaded into Laminar Nanoclays on Thermomechanical and Color Properties of Polyester Based Bionanocomposites. Polymers. 12(7):1-22. https://doi.org/10.3390/polym12071451S12212

The dynamic use of EGFR mutation analysis in cell-free DNA as a follow-up biomarker during different treatment lines in non-small-cell lung cancer patients

Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9 5-13) to the best response (median = 0, IQR = 0-0, p < 0 01), followed by a significant increase at progression (median = 11, IQR = 11-15, p < 0 01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received

Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis

Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases

Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design

The diagnosis of myeloid neoplasms (MN) has significantly evolved through the last few decades. Next Generation Sequencing (NGS) is gradually becoming an essential tool to help clinicians with disease management. To this end, most specialized genetic laboratories have implemented NGS panels targeting a number of different genes relevant to MN. The aim of the present study is to evaluate the performance of four different targeted NGS gene panels based on their technical features and clinical utility. A total of 32 patient bone marrow samples were accrued and sequenced with 3 commercially available panels and 1 custom panel. Variants were classified by two geneticists based on their clinical relevance in MN. There was a difference in panel¿s depth of coverage. We found 11 discordant clinically relevant variants between panels, with a trend to miss long insertions. Our data show that there is a high risk of finding different mutations depending on the panel of choice, due both to the panel design and the data analysis method. Of note, CEBPA, CALR and FLT3 genes, remains challenging the use of NGS for diagnosis of MN in compliance with current guidelines. Therefore, conventional molecular testing might need to be kept in place for the correct diagnosis of MN for now

Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)

© The Author(s) 2018.Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative and the EuroFlow Consortium; Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER), numbers: CB16/12/00400, CB16/12/00369, CB16/12/00489 and CB16/12/00233; grant SA079U14 from the Consejería de Educación, Junta de Castilla y León, Valladolid, Spain and; grant DTS15/00119 from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain. Acuerdo de colaboración con Fundación de Hemoterapia y Hemodonación de Castilla y León, Valladolid, Spain. This study was also supported by the Qatar National Research Fund (QNRF) Award No. 7-916-3-237, the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV), ERA-NET TRANSCAN-2 (iMMunocell), by a 2017 Leonardo Grant (BZG10931) for Researchers and Cultural Creators, BBVA Foundation, and the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT)