Salivary biomarker development using genomic, proteomic and metabolomic approaches.

The use of saliva as a diagnostic sample provides a non-invasive, cost-efficient method of sample collection for disease screening without the need for highly trained professionals. Saliva collection is far more practical and safe compared with invasive methods of sample collection, because of the infection risk from contaminated needles during, for example, blood sampling. Furthermore, the use of saliva could increase the availability of accurate diagnostics for remote and impoverished regions. However, the development of salivary diagnostics has required technical innovation to allow stabilization and detection of analytes in the complex molecular mixture that is saliva. The recent development of cost-effective room temperature analyte stabilization methods, nucleic acid pre-amplification techniques and direct saliva transcriptomic analysis have allowed accurate detection and quantification of transcripts found in saliva. Novel protein stabilization methods have also facilitated improved proteomic analyses. Although candidate biomarkers have been discovered using epigenetic, transcriptomic, proteomic and metabolomic approaches, transcriptomic analyses have so far achieved the most progress in terms of sensitivity and specificity, and progress towards clinical implementation. Here, we review recent developments in salivary diagnostics that have been accomplished using genomic, transcriptomic, proteomic and metabolomic approaches

Modeling of subharmonics and chaos in DC motor drives

In this paper, the nonlinear dynamics of both voltage-mode and current-mode controlled dc motor drive systems are presented. The investigation is based on the derivation of the discrete mappings that describe their system subharmonics and chaos in the continuous conduction mode of operation. It illustrates that different bifurcation diagrams can be obtained by using different modes of control while varying the same system parameters. A unified modeling approach for the period-1 and hence the period-p orbits as well as their stability analysis during both voltage-mode and current-mode of control is proposed and verified.published_or_final_versio

Differential Proteomic Analysis of Human Saliva using Tandem Mass Tags Quantification for Gastric Cancer Detection.

Novel biomarkers and non-invasive diagnostic methods are urgently needed for the screening of gastric cancer to reduce its high mortality. We employed quantitative proteomics approach to develop discriminatory biomarker signatures from human saliva for the detection of gastric cancer. Salivary proteins were analyzed and compared between gastric cancer patients and matched control subjects by using tandem mass tags (TMT) technology. More than 500 proteins were identified with quantification, and 48 of them showed significant difference expression (p < 0.05) between normal controls and gastric cancer patients, including 7 up-regulated proteins and 41 down-regulated proteins. Five proteins were selected for initial verification by ELISA and three were successfully verified, namely cystatin B (CSTB), triosephosphate isomerase (TPI1), and deleted in malignant brain tumors 1 protein (DMBT1). All three proteins could differentiate gastric cancer patients from normal control subjects, dramatically (p < 0.05). The combination of these three biomarkers could reach 85% sensitivity and 80% specificity for the detection of gastric cancer with accuracy of 0.93. This study provides the proof of concept of salivary biomarkers for the non-invasive detection of gastric cancer. It is highly encouraging to turn these biomarkers into an applicable clinical test after large scale validation

Evaluation of a novel saliva-based epidermal growth factor receptor mutation detection for lung cancer: A pilot study.

BackgroundThis article describes a pilot study evaluating a novel liquid biopsy system for non-small cell lung cancer (NSCLC) patients. The electric field-induced release and measurement (EFIRM) method utilizes an electrochemical biosensor for detecting oncogenic mutations in biofluids.MethodsSaliva and plasma of 17 patients were collected from three cancer centers prior to and after surgical resection. The EFIRM method was then applied to the collected samples to assay for exon 19 deletion and p.L858 mutations. EFIRM results were compared with cobas results of exon 19 deletion and p.L858 mutation detection in cancer tissues.ResultsThe EFIRM method was found to detect exon 19 deletion with an area under the curve (AUC) of 1.0 in both saliva and plasma samples in lung cancer patients. For L858R mutation detection, the AUC of saliva was 1.0, while the AUC of plasma was 0.98. Strong correlations were also found between presurgery and post-surgery samples for both saliva (0.86 for exon 19 and 0.98 for L858R) and plasma (0.73 for exon 19 and 0.94 for L858R).ConclusionOur study demonstrates the feasibility of utilizing EFIRM to rapidly, non-invasively, and conveniently detect epidermal growth factor receptor mutations in the saliva of patients with NSCLC, with results corresponding perfectly with the results of cobas tissue genotyping

Bioinformatics advances in saliva diagnostics

There is a need recognized by the National Institute of Dental & Craniofacial Research and the National Cancer Institute to advance basic, translational and clinical saliva research. The goal of the Salivaomics Knowledge Base (SKB) is to create a data management system and web resource constructed to support human salivaomics research. To maximize the utility of the SKB for retrieval, integration and analysis of data, we have developed the Saliva Ontology and SDxMart. This article reviews the informatics advances in saliva diagnostics made possible by the Saliva Ontology and SDxMart

Association between pain and sexual health in older people: results from the English Longitudinal Study of Ageing

There is little information on the impact of pain on sexual health in later life. The aim of this analysis was to determine the association between self-reported pain and sexual health in older men and women. Data were collected for the nationally representative English Longitudinal Study of Ageing. Community-dwelling adults aged 50 years and older completed the Sexual Relationships and Activities questionnaire in wave 6 (2012/2013). Participants were asked (waves 1 to 6 [2002- 2013]) if they were "often troubled with pain" and, how severe was their pain; mild, moderate or severe. The association between pain and sexual health was assessed using logistic regression. Analyses were stratified by gender, with adjustments made for age followed by adjustments for health and lifestyle factors, depressive symptoms and socioeconomic status. Of the 3,916 participants who reported having sexual activity in the past year, 28% of women and 23% of men reported experiencing moderate or severe pain often at wave 6. After adjusting for age, compared to men experiencing no pain, men with moderate or severe pain reported less frequent intercourse and masturbation, more erectile difficulties, and more concerns about their sexual health. After age adjustment there were no associations between pain severity and sexual health among women. Of the 1,872 participants with a cumulative pain score, there were significant associations between reporting pain and concerns about sexual health in both men and women. Pain was associated with impairment in sexual health in men and women though the effect was more marked in men

F-Theory and the Mordell-Weil Group of Elliptically-Fibered Calabi-Yau Threefolds

The Mordell-Weil group of an elliptically fibered Calabi-Yau threefold X contains information about the abelian sector of the six-dimensional theory obtained by compactifying F-theory on X. After examining features of the abelian anomaly coefficient matrix and U(1) charge quantization conditions of general F-theory vacua, we study Calabi-Yau threefolds with Mordell-Weil rank-one as a first step towards understanding the features of the Mordell-Weil group of threefolds in more detail. In particular, we generate an interesting class of F-theory models with U(1) gauge symmetry that have matter with both charges 1 and 2. The anomaly equations --- which relate the Neron-Tate height of a section to intersection numbers between the section and fibral rational curves of the manifold --- serve as an important tool in our analysis.Comment: 29 pages + appendices, 5 figures; v2: minor correction

Study protocol: a randomised controlled trial investigating the effect of exercise training on peripheral blood gene expression in patients with stable angina

Background: Exercise training has been shown to reduce angina and promote collateral vessel development in patients with coronary artery disease. However, the mechanism whereby exercise exerts these beneficial effects is unclear. There has been increasing interest in the use of whole genome peripheral blood gene expression in a wide range of conditions to attempt to identify both novel mechanisms of disease and transcriptional biomarkers. This protocol describes a study in which we will assess the effect of a structured exercise programme on peripheral blood gene expression in patients with stable angina, and correlate this with changes in angina level, anxiety, depression, and exercise capacity. Methods/Design: Sixty patients with stable angina will be recruited and randomised 1: 1 to exercise training or conventional care. Patients randomised to exercise training will attend an exercise physiology laboratory up to three times weekly for supervised aerobic interval training sessions of one hour in total duration. Patients will undergo assessments of angina, anxiety, depression, and peripheral blood gene expression at baseline, after six and twelve weeks of training, and twelve weeks after formal exercise training ceases. Discussion: This study will provide comprehensive data on the effect of exercise training on peripheral blood gene expression in patients with angina. By correlating this with improvement in angina status we will identify candidate peripheral blood transcriptional markers predictive of improvements in angina level in response to exercise training

Switching Virally Suppressed, Treatment-Experienced Patients to a Raltegravir-Containing Regimen Does Not Alter Levels of HIV-1 DNA

Background: Current HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group. Methods: 14 ART experienced individuals with a suppressed viral load (,50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at $2 timepoints up to 4866 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays. Results: There was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95 % CI: 211.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/10 6 PBMCs at baseline and the other had 34 copies/10 6 PBMCs at week 51. Conclusions: The switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravi