Objective. To identify a panel of protein and messenger RNA (mRNA) biomarkers in human whole saliva (WS) that may be used in the detection of primary Sjögren's syndrome (SS).Methods. Mass spectrometry and expression microarray profiling were used to identify candidate protein and mRNA biomarkers of primary SS in WS samples. Validation of the discovered mRNA and protein biomarkers was also demonstrated using real-time quantitative polymerase chain reaction and immunoblotting techniques.Results. Sixteen WS proteins were found to be down-regulated and 25 WS proteins were found to be up-regulated in primary SS patients compared with matched healthy control subjects. These proteins reflected the damage of glandular cells and inflammation of the oral cavity system in patients with primary SS. In addition, 16 WS peptides (10 up-regulated and 6 downregulated in primary SS) were found at significantly different levels (P < 0.05) in primary SS patients and controls. Using stringent criteria (3-fold change; P < 0.0005), 27 mRNA in saliva samples were found to be significantly up-regulated in the primary SS patients. Strikingly, 19 of 27 genes that were found to be overexpressed were interferon-inducible or were related to lymphocyte filtration and antigen presentation known to be involved in the pathogenesis of primary SS.Conclusion. Our preliminary study has indicated that WS from patients with primary SS contains molecular signatures that reflect damaged glandular cells and an activated immune response in this autoimmune disease. These candidate proteomic and genomic biomarkers may improve the clinical detection of primary SS once they have been further validated. We also found that WS contains more informative proteins, peptides, and mRNA, as compared with gland-specific saliva, that can be used in generating candidate biomarkers for the detection of primary SS.
Background Microneedle patches provide an alternative to conventional needle-and-syringe immunization, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability and safety. We describe safety, immunogenicity and acceptability of the first-in-human study on single, dissolvable microneedle patch vaccination against influenza. Methods The TIV-MNP 2015 study was a phase 1, partially blinded, placebo-controlled, randomized clinical trial conducted at Emory University that enrolled non-pregnant, immunocompetent adults (age 18–49 years) from Atlanta (USA) and naïve to 2014–2015 influenza vaccine. Participants were equally randomized among four groups and received a single dose of inactivated influenza vaccine 1) by microneedle patch or 2) by intramuscular injection, or received 3) placebo by microneedle patch, all administered by an unblinded healthcare worker; or received 4) inactivated influenza vaccine by microneedle patch self-administered by study participants. Primary safety outcomes were reactogenicity, grade 3 adverse events and serious adverse events within 8, 28 and 180 days and secondary safety outcomes were new-onset chronic illnesses within 180 days and unsolicited adverse events within 28 days all analyzed by intention to treat. Secondary immunogenicity outcomes were antibody titers at day 28 as well as seroconversion and seroprotection rates all determined by hemagglutination inhibition antibody. The trial is completed and registered with ClinicalTrials.gov, NCT02438423. Findings Twenty-five participants per group were enrolled between June 23 and September 25, 2015. There were no related serious adverse events, no related grade 3 or higher adverse events and no new-onset chronic illnesses. Overall incidence of solicited and unsolicited events was similar among vaccinated groups. Reactogenicity was mild, transient and most commonly reported as tenderness at 60% (95% CI, 39– 79%) and pain at 44% (95% CI, 24–65%) after intramuscular injection and tenderness at 66% (95% CI, 51–79%), erythema at 40% (95% CI, 26–55%) and pruritus at 82% (95% CI, 69–91%) after vaccination by microneedle patch application The geometric mean titers were comparable at day 28, between the microneedle patch administered by healthcare worker and the intramuscular route with values of 1197 (95% CI, 855– 1675) and 997 (95% CI, 703–1415) (p=0.5), respectively, for the H1N1 strain; 287 (95% CI, 192–430) and 223 (95% CI, 160–312) (p=0.4), respectively, for the H3N2 strain and 126 (95% CI, 86–184) and 94 (95% CI, 73–122) (p=0.06), respectively, for the B strain. Similar GMT titers were observed in participants who self-administered the microneedle patch. The seroconversion rates were significantly higher at day 28 after microneedle patch vaccination compared to placebo and were comparable to intramuscular injection. Interpretation Use of dissolvable microneedle patches for influenza vaccination was well-tolerated and generated robust antibody responses. Funding National Institutes of Health.
BackgroundDetection of low abundance metabolites is important for de novo mapping of metabolic pathways related to diet, microbiome or environmental exposures. Multiple algorithms are available to extract m/z features from liquid chromatography-mass spectral data in a conservative manner, which tends to preclude detection of low abundance chemicals and chemicals found in small subsets of samples. The present study provides software to enhance such algorithms for feature detection, quality assessment, and annotation.ResultsxMSanalyzer is a set of utilities for automated processing of metabolomics data. The utilites can be classified into four main modules to: 1) improve feature detection for replicate analyses by systematic re-extraction with multiple parameter settings and data merger to optimize the balance between sensitivity and reliability, 2) evaluate sample quality and feature consistency, 3) detect feature overlap between datasets, and 4) characterize high-resolution m/z matches to small molecule metabolites and biological pathways using multiple chemical databases. The package was tested with plasma samples and shown to more than double the number of features extracted while improving quantitative reliability of detection. MS/MS analysis of a random subset of peaks that were exclusively detected using xMSanalyzer confirmed that the optimization scheme improves detection of real metabolites.ConclusionsxMSanalyzer is a package of utilities for data extraction, quality control assessment, detection of overlapping and unique metabolites in multiple datasets, and batch annotation of metabolites. The program was designed to integrate with existing packages such as apLCMS and XCMS, but the framework can also be used to enhance data extraction for other LC/MS data software.
Supplementary data are available at Bioinformatics online.
SUMMARY Herpes Zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. While a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax®. Vaccination induces robust antigen-specific antibody, plasmablasts and CD4+ T cells, yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets such as transcriptomic and metabolomics signatures, cell populations and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity, and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
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