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Overcoming tolerance to tumor-associated antigens remains a hurdle for cancer vaccine-based immunotherapy. A strategy to enhance the anti-tumor immune response is the inclusion of adjuvants to cancer vaccine protocols. In this report, we generated and systematically screened over twenty gene-based molecular adjuvants composed of cytokines, chemokines, and T cell co-stimulators for the ability to increase anti-tumor antigen T cell immunity. We identified several robust adjuvants whose addition to vaccine formulations resulted in enhanced T cell responses targeting the cancer antigens STEAP1 and TERT. We further characterized direct T cell stimulation through CD80-Fc and indirect T cell targeting via the dendritic cell activator Flt3L-Fc. Mechanistically, intramuscular delivery of Flt3L-Fc into mice was associated with a significant increase in infiltration of dendritic cells at the site of administration and trafficking of activated dendritic cells to the draining lymph node. Gene expression analysis of the muscle tissue confirmed a significant up-regulation in genes associated with dendritic cell signaling. Addition of CD80-Fc to STEAP1 vaccine formulation mimicked the engagement provided by DCs and increased T cell responses to STEAP1 by 8-fold, significantly increasing the frequency of antigen-specific cells expressing IFNγ, TNFα, and CD107a for both CD8+ and CD4+ T cells. CD80-Fc enhanced T cell responses to multiple tumor-associated antigens including Survivin and HPV, indicating its potential as a universal adjuvant for cancer vaccines. Together, the results of our study highlight the adjuvanting effect of T cell engagement either directly, CD80-Fc, or indirectly, Flt3L-Fc, for cancer vaccines.

In view of the integration of membrane resonators with more complex MEMS structures, we developed a general fabrication procedure for circular shape SiNx membranes using Deep Reactive Ion Etching (DRIE). Large area and high-stress SiNx membranes were fabricated and used as optomechanical resonators in a Michelson interferometer, where Q values up to 1.3 × 106 were measured at cryogenic temperatures, and in a Fabry-Pérot cavity, where an optical finesse up to 50000 has been observed.

Seafood elemental profiling (SEP) is the quantification of a range of elements in seafood products and may serve in addressing questions of seafood provenance and quality. Traditional methods for analyzing soft tissue present several limitations for the industry-level use of SEP. Portable handheld X-ray fluorescence (pXRF) analysis is a promising alternative to conventional methods; however, its application for biological analysis has not been fully established. Intact giant tiger prawn ( Penaeus monodon ) abdomens were analyzed with a Vanta M series XRF portable analyzer following a novel soft tissue protocol. Exploratory statistics (principal component analysis, nonmetric multidimensional scaling, and canonical discriminant analysis), as well as random forest models, have been implemented with pXRF profiles, yielding 81% accuracy when assigning the geographical origin of P. monodon . The results of this study highlight that SEP via pXRF is a viable industry-level analysis, and its application will depend on improved instrument calibration to account for fluctuating wetness factors that are influenced by cooking, storage, and other pre- and post-harvest treatments., Competing Interests: The authors declare that they have no known competing financial interests that could influence the work presented in this manuscript.

Background: The hypothesis of "cross-addiction" has never been validated, and numerous aspects speak against it., Objectives: To compare the differences between sleeve gastrectomy (SG) and gastric bypass (GB) procedures concerning cross-addiction., Setting: Center for maximum care in Germany., Methods: We performed a prospective analysis of patients undergoing SG or GB as the first surgical treatment for severe obesity. All patients completed validated questionnaires to evaluate food intake (Yale Food Addiction Scale, YFAS), alcohol intake (Alcohol Use Disorders Identification Test), nicotine use (Fagerstrom Test for Nicotine Dependence), exercise (Exercise Addiction Inventory), drug addiction (20-item Drug Abuse Screening Test), and Internet use disorder (Internet Addiction Test) before the operation (T0) and 6 (T6) and 24 (T24) months postoperatively (ClinicalTrials.gov identifier: NCT02757716)., Results: One hundred thirteen patients underwent SG (n = 68) or GB (n = 45). At the follow-up, 61% completed the questionnaires at T6 and 44% at T24. In the YFAS, the percentage of patients diagnosed with food addiction decreased from 69 to 10%, and the mean symptom count decreased from 3.52 ± 1.95 to 1.26 ± 0.99 at T24 (p < 0.0001); these values did not differ between the surgical groups (p = 0.784). No significant evidence of cross-addiction was observed for use of alcohol, nicotine, drugs, the Internet, or exercise in either surgical group. The percentage of patients with moderate nicotine dependence increased in the SG group (+8.9%) at T24, but this was not significant., Conclusion: In this single-center cohort study, surgery for obesity caused significant addiction remission regarding food but without inducing cross-addiction after 2 years. Importantly, no significant differences were seen between the SG and GB procedures., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Aortic arch curvature can be straightened by endograft placement. However, different measurement methods with dissimilar follow-up and endografts have been published. The aim of this study was to corroborate, for the first time, the pliability of the Conformable Gore TAG Thoracic Endoprosthesis (W.L. Gore and Associates, Flagstaff, AZ, USA) into the aortic arch, using different image vector analysis., Material and Methods: We, retrospectively, analyzed patients primarily treated for thoracic aortic aneurysms and blunt traumatic aortic injuries by means of a Conformable Gore TAG Thoracic Endoprosthesis endograft proximally sealed into the aortic arch (zones Z1-Z3) in five different Spanish centers, between 2010 and 2017. The preoperative, one-month and six-month postoperative, computed tomography angiographies (CTAs) were obtained, creating accurate 3D center lumen line and external lumen line from the aortic valve to the renal arteries. Three different image analysis methods were used to compare modifications of the aortic curvature: first, segment analysis (angulations of the center lumen line when divided into seven precise segments, examining anterior-posterior, right-left, and cranial-caudal displacement), second, center lumen line analysis (bending of the center lumen line itself in seven definite points), and third, expected behavior (length of the endograft in the external lumen line). Two independent observers performed a blind analysis of all CTAs. Changes between preoperative and postoperative CTAs at one and six months are compared, and differences are viewed between cases sealed proximally (Z1-Z2) and distally (Z3) into the aortic arch., Results: We analyzed 37 cases. At 1- and 6-month follow-ups, minimal changes occurred first in segment analysis (only a slight decrease of -2.0° in the XY plane at 10 cm from the brachiocephalic trunk at six-month follow-up was seen, P = 0.027). Second, center lumen line analysis again only showed negligible aortic curvature straightening (+3.5° at 10 cm from the brachiocephalic trunk at one month, P = 0.006, disappearing at six-month follow-up). Finally, good device length predictability was shown (interclass correlation coefficients: 0.995 and 0.994 at one and six months, P > 0.001). No differences were seen between cases proximally sealed into the proximal and distal aortic arch., Conclusions: Conformable Gore TAG Thoracic Endoprosthesis thoracic endograft showed a good pliability into the aortic arch and proximal thoracic aorta, with minimal changes in the aortic curvature after endograft placement in the short-term follow-up (up to six months). In addition, final endograft length into outer aortic curvature is highly predictable., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim of this work was to evaluate the incorporation of a freeze-dried probiotic strain ( Lactobacillus plantarum CIDCA 83114) into zeolites. The bacteria-zeolite mixture was added to poultry feed together with thyme, and the obtained product was stored for 60 days at 25 °C and 60-70% relative humidity. The ability of the obtained product to remove aflatoxin B1 (AFB1) was studied. The highest bacterial viability was observed when 50% w/w bacteria were added to zeolites. The bacterial:zeolite mixtures were then incorporated into poultry feed containing or not thyme. Initial counts of L. plantarum were in the range of 1-2 × 10 8 CFU/g for all samples. In all cases, bacterial viability decreased one logarithmic order after 20 days of storage, and three logarithmic orders after 60 days. No significant viability loss was observed after exposure of the poultry feed to gastro-intestinal conditions. Freeze-dried L. plantarum and zeolite were able to remove AFB1, with an average reduction of 20 and 80%, respectively. Moreover, the freeze-dried bacteria-zeolite mixture was capable to remove up to 90% AFB1. This work contributes to enhance the nutritional quality of poultry feed, with a strong impact in production.

The process of the health reform being experienced by Ecuador has had significant achievements because it occurs within the framework of a new Constitution of the Republic, which allowed the incorporation of historical social demands that arose from the criticism of neoliberalism in the restructure and modernization of the state. The backbone of the reform consists of three components: organization of a National Health System that overcomes the previous fragmentation and constitutes the Integral Public Health Network; development of policies to strengthen primary health care, articulating actions on the determinants of health, and finally, increasing funding to consolidate these changes. We conclude that challenges to the reform are related to the sustainability of the processes, financial sustainability of the system, greater activation of participatory mechanisms that enable citizen assessment of services and citizen empowerment regarding their right to health.

Background: Bexarotene was evaluated in treating advanced non small cell lung cancer (NSCLC) in two phase III trials. Although a significant survival benefit was not observed for the overall bexarotene-treated population (617 patients), a third of bexarotene-treated patients who developed high-grade hypertriglyceridemia exhibited significantly longer survival., Patients and Methods: In order to identify genomic polymorphisms that could serve as potential predictive biomarkers for response and improved survival in NSCLC patients, DNA samples extracted from plasma archived from 403 patients were genotyped using Affymetrix 500K whole genome SNP arrays and/or Sequenom iPLEX™ assays., Results: Fourteen SNPs were identified on nine loci that showed significant associations with high-grade hypertriglyceridemia induced by bexarotene. Four such single nucleotide polymorphisms (SNPs) reside on the region upstream of solute carrier family 10, member 2 (SLC10A2), and one SNP is located close to lymphocyte cytosolic protein 1 (LCP1), whose expression correlated with the activity of bexarotene in tumor cells., Conclusion: We identified novel polymorphisms exhibiting significant association with bexarotene induced hypertriglyceridemia, implicating their potential in predicting bexarotene-improved survival response.

Identification of active compounds in high-throughput screening (HTS) contexts can be substantially improved by applying classical experimental design and statistical inference principles to all phases of HTS studies. The authors present both experimental and simulated data to illustrate how true-positive rates can be maximized without increasing false-positive rates by the following analytical process. First, the use of robust data preprocessing methods reduces unwanted variation by removing row, column, and plate biases. Second, replicate measurements allow estimation of the magnitude of the remaining random error and the use of formal statistical models to benchmark putative hits relative to what is expected by chance. Receiver Operating Characteristic (ROC) analyses revealed superior power for data preprocessed by a trimmed-mean polish method combined with the RVM t-test, particularly for small- to moderate-sized biological hits.

Large-scale genetic-association studies that take advantage of an extremely dense set of genetic markers have begun to produce very compelling statistical associations between multiple makers exhibiting strong linkage disequilibrium (LD) in a single genomic region and a phenotype of interest. However, the ultimate biological or "functional" significance of these multiple associations has been difficult to discern. In fact, the LD relationships between not only the markers found to be associated with the phenotype but also potential functionally or causally relevant genetic variations that reside near those markers have been exploited in such studies. Unfortunately, LD, especially strong LD, between variations at neighboring loci can make it difficult to distinguish the functionally relevant variations from nonfunctional variations. Although there are (rare) situations in which it is impossible to determine the independent phenotypic effects of variations in LD, there are strategies for accommodating LD between variations at different loci, and they can be used to tease out their independent effects on a phenotype. These strategies make it possible to differentiate potentially causative from noncausative variations. We describe one such approach involving ridge regression. We showcase the method by using both simulated and real data. Our results suggest that ridge regression and related techniques have the potential to distinguish causative from noncausative variations in association studies.

The availability of cost-effective, high-throughput genotyping technologies has generated a tremendous amount of interest in genetic association studies. This interest has led to the belief that one could possibly test thousands to millions of representative polymorphic sites on the genome for association with a trait or disease in order to identify the few sites that may be of relevance to the expression of that trait or disease. The choice of which polymorphic sites are "representative" and to be interrogated in such studies is problematic and has involved considerations of the putative functional significance of the sites as well as the linkage disequilibrium relationships between variations at those sites and other neighboring sites. We consider an obvious alternative to genotyping-based strategies and settings for association studies for which decisions about which variations to interrogate are obviated. Essentially, we anticipate a time when cost-effective, high-throughput DNA sequencing technologies are available and researchers will have actual sequence information on the individuals under study rather than information about what variations they possess at a few well-chosen polymorphic genomic sites. We consider Multivariate Distance Matrix Regression analysis to evaluate associations between DNA sequence information and quantitative traits such as blood pressure and cholesterol level. We evaluate the potential of the method in a few (albeit contrived) settings via simulation studies. Ultimately, we show that the procedure has promise and argue that consideration of DNA sequence-based association data should usher in a new era in genetic association study designs and methodologies.

Motivation: High-throughput screening (HTS) is an early-stage process in drug discovery which allows thousands of chemical compounds to be tested in a single study. We report a method for correcting HTS data prior to the hit selection process (i.e. selection of active compounds). The proposed correction minimizes the impact of systematic errors which may affect the hit selection in HTS. The introduced method, called a well correction, proceeds by correcting the distribution of measurements within wells of a given HTS assay. We use simulated and experimental data to illustrate the advantages of the new method compared to other widely-used methods of data correction and hit selection in HTS., Supplementary Information: Supplementary data are available at Bioinformatics online.

Motivation: High-throughput screening (HTS) plays a central role in modern drug discovery, allowing for testing of >100,000 compounds per screen. The aim of our work was to develop and implement methods for minimizing the impact of systematic error in the analysis of HTS data. To the best of our knowledge, two new data correction methods included in HTS-Corrector are not available in any existing commercial software or freeware., Results: This paper describes HTS-Corrector, a software application for the analysis of HTS data, detection and visualization of systematic error, and corresponding correction of HTS signals. Three new methods for the statistical analysis and correction of raw HTS data are included in HTS-Corrector: background evaluation, well correction and hit-sigma distribution procedures intended to minimize the impact of systematic errors. We discuss the main features of HTS-Corrector and demonstrate the benefits of the algorithms.

High-throughput screening is an early critical step in drug discovery. Its aim is to screen a large number of diverse chemical compounds to identify candidate 'hits' rapidly and accurately. Few statistical tools are currently available, however, to detect quality hits with a high degree of confidence. We examine statistical aspects of data preprocessing and hit identification for primary screens. We focus on concerns related to positional effects of wells within plates, choice of hit threshold and the importance of minimizing false-positive and false-negative rates. We argue that replicate measurements are needed to verify assumptions of current methods and to suggest data analysis strategies when assumptions are not met. The integration of replicates with robust statistical methods in primary screens will facilitate the discovery of reliable hits, ultimately improving the sensitivity and specificity of the screening process.

Forty-eight strains of listeria isolated from sick animals (27 goats, 19 sheep, 2 cows) from 33 farms, and 40 isolated from the silage eaten by these animals were studied. Listeria were isolated more frequently from poor quality silages than from those of good quality, although they were found in 11 out of 31 excellent silages with a pH value comprised between 3.6 and 4. The 88 strains were characterized by biochemical and serological examinations, phage typing and measurement of their virulence. They showed a wide variety of characteristics and in only one case, three strains with the same characteristics were isolated one from a dead ewe with symptoms of encephalitis and the two others from the silage it had eaten. In four flocks, identical strains were found in several animals from each farm, but in five other flocks, strains isolated from animals were different. The listeria of the silage may be the direct cause of the disease, but the isolation of strain with different characteristics from animals of the same flock led us to think that other causes might favour the infection. So, it seems difficult to control the disease only by enhancement of the quality of the silage.