s-ICAM-1 and s-VCAM-1 in healthy men are strongly associated with traits of the metabolic syndrome, becoming evident in the postprandial response to a lipid-rich meal

<p>Abstract</p> <p>Background</p> <p>The importance of the postprandial state for the early stages of atherogenesis is increasingly acknowledged. We conducted assessment of association between postprandial triglycerides, insulin and glucose after ingestion of a standardized lipid-rich test meal, and soluble cellular adhesion molecules (sCAM) in young healthy subjects.</p> <p>Methods</p> <p>Metabolic parameters and sICAM-1, sVCAM-1 and E-selectin were measured before and hourly until 6 hours after ingestion of a lipid-rich meal in 30 healthy young men with fasting triglycerides <150 mg/dl and normal fasting glucose levels. Subjects were classified as either normal responders (NR) (postprandial triglyceride maxima < 260 mg/dl) or high responders (HR) (postprandial triglyceride maxima > 260 mg/dl). Levels of CAM were compared in HR and NR, and correlation with postprandial triglyceride, insulin and glucose response was assessed.</p> <p>Results</p> <p>Fasting sICAM-1 and sVCAM-1 levels were significantly higher in HR as compared to NR (p = 0.046, p = 0.03). For sE-selectin there was such a trend (p = 0.05). There was a strong positive and independent correlation between sICAM-1 and postprandial insulin maxima (r = 0.70, p < 0.001). sVCAM-1 showed significant correlation with postprandial triglycerides (AUC) (r = 0.37, p = 0.047). We found no correlation between sCAMs and fasting insulin or triglyceride concentrations.</p> <p>Conclusion</p> <p>This independent association of postprandial triglycerides with sICAM-1 may indicate a particular impact of postprandial lipid metabolism on endothelial reaction.</p

Participation in an innovative patient support program reduces prescription abandonment for adalimumab-treated patients in a commercial population.

Purpose: Nonadherence to indicated therapy reduces treatment effectiveness and may increase cost of care. HUMIRA Complete, a Patient Support Program (PSP), aims to reduce nonadherence in patients prescribed adalimumab (ADA). The objective of this study was to assess the relationship between participation in the PSP and prescription abandonment rates among ADA-treated patients. Patients and methods: This longitudinal study using patient-level data from AbbVie\u27s PSP linked with medical and pharmacy claims data included patients ≥18 years with an ADA-approved indication, ≥1 pharmacy claim for ADA, and available data ≥3 months before and ≥6 months after the index date (defined as the initial ADA claim [01/2015 to 02/2017]). Abandonment was defined as reversal of initial ADA prescription with no paid claim during 3-month follow-up. Abandonment rates were compared between PSP and non-PSP cohorts using multivariable logistic regression controlling for potentially confounding baseline characteristics. Results: In 17,371 patients (9,851 PSP; 7,520 non-PSP), the overall abandonment rate was 10.8-16.8% across indications. The odds of ADA abandonment were 70% less for PSP vs non-PSP patients (5.6% vs 20.4%, odds ratio [OR]=0.30, [95% confidence interval (CI)=0.27-0.33] Conclusion: Participation in the PSP, higher income, and using a specialty pharmacy were associated with lower odds of abandoning ADA therapy, whereas increased copayments were associated with greater abandonment. PSPs should be considered to improve initiation of ADA therapy

Centimeter to decimeter hollow concretions and voids in Gale Crater sediments, Mars

Voids and hollow spheroids between ∼1 and 23 cm in diameter occur at several locations along the traverse of the Curiosity rover in Gale crater, Mars. These hollow spherical features are significantly different from anything observed in previous landed missions. The voids appear in dark-toned, rough-textured outcrops, most notably at Point Lake (sols 302-305) and Twin Cairns Island (sol 343). Point Lake displays both voids and cemented spheroids in close proximity; other locations show one or the other form. The spheroids have 1-4 mm thick walls and appear relatively dark-toned in all cases, some with a reddish hue. Only one hollow spheroid (Winnipesaukee, sol 653) was analyzed for composition, appearing mafic (Fe-rich), in contrast to the relatively felsic host rock. The interior surface of the spheroid appears to have a similar composition to the exterior with the possible exceptions of being more hydrated and slightly depleted in Fe and K. Origins of the spheroids as Martian tektites or volcanic bombs appear unlikely due to their hollow and relatively fragile nature and the absence of in-place clearly igneous rocks. A more likely explanation to both the voids and the hollow spheroids is reaction of reduced iron with oxidizing groundwater followed by some re-precipitation as cemented rind concretions at a chemical reaction front. Although some terrestrial concretion analogs are produced from a precursor siderite or pyrite, diagenetic minerals could also be direct precipitates for other terrestrial concretions. The Gale sediments differ from terrestrial sandstones in their high initial iron content, perhaps facilitating a higher occurrence of such diagenetic reactions

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis.MethodsGWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes.ResultsMIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility

Local RNA structure alignment with incomplete sequence

Motivation: Accuracy of automated structural RNA alignment is improved by using models that consider not only primary sequence but also secondary structure information. However, current RNA structural alignment approaches tend to perform poorly on incomplete sequence fragments, such as single reads from metagenomic environmental surveys, because nucleotides that are expected to be base paired are missing

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Work-family life courses and markers of stress and inflammation in mid-life: evidence from the National Child Development Study.

Background This study investigated associations between work-family life courses and biomarkers of inflammation and stress in mid-life among British men and women. Gender differences in these associations were also explored. Methods A novel statistical method-multi-channel sequence analysis-defined work-family life courses between the ages of 16 and 42 years, combining annual information on work, partnership and parenthood. Associations between work-family life courses and inflammation [C-reactive protein (CRP), fibrinogen and von Willebrand factor] and cortisol at age 44/45 years were tested using multivariate linear regression using multiply-imputed data on almost 6500 participants from the National Child Development Study 1958 British birth cohort. Results Compared with those who combined strong ties to paid work with later transitions to stable family lives ('Work, later family' group), 'Teen parents' had higher CRP [40.6% higher, 95% confidence interval (CI): 5.6, 87.0] and fibrinogen (7.8% higher, 95% CI: 2.3, 13.5) levels, and homemakers ('No paid work, early family') had raised fibrinogen levels (4.7% higher, 95% CI: 0.7, 9.0), independent of childhood health and socioeconomic position, adult socioeconomic position, health behaviours and body mass index (BMI). Those who combined later transitions to stable family ties with a career break for childrearing had higher post-waking cortisol than the 'Work, later family' group; however, no associations were seen for other work-family types, therefore suggesting a null finding with cortisol. No statistically significant gender interactions in associations between work-family types and inflammatory or cortisol outcomes were found. Conclusions Work-family life courses characterised by early parenthood or weak work ties were associated with a raised risk profile in relation to chronic inflammation

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts