), which mediate 3 defined steps of the inflammatory response; namely, leukocyte rolling, firm adhesion, and transmigration. In this study, we have investigated the role of p75 in TNF-␣-induced leukocyte adhesion molecules using cultured ECs derived from wildtype (WT), p75-null (p75 ؊/؊ ), or p55-null (p55 ؊/؊ ) mice. We observed that p75 was essential for TNF-␣-induced E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) expression. We also investigated the putative role of p75 in inflammation in vivo using an intravital microscopic approach with a mouse cremaster muscle model. TNF-␣-stimulated leukocyte rolling, firm adhesion to ECs, and transmigration were dramatically reduced in p75 ؊/؊ mice. Transplanted WT cremaster in p75 ؊/؊ mice showed a robust leukocyte rolling and firm adhesion upon TNF-␣ activation, suggesting that the impairment in EC-leukocyte interaction in p75 ؊/؊ mice is due to EC dysfunction. These results demonstrate, for the first time, that endothelial p75 is essential for TNF-␣-induced leukocyte-endothelial-cell interaction. Our findings may contribute to the identification of novel p75-targeted therapeutic approaches for inflammatory diseases. IntroductionTumor necrosis factor ␣ (TNF-␣) and its 2 receptors, p55 and p75, are expressed in a variety of cell types. p55 is noninducible, whereas p75 is inducible at the transcriptional level by various external stimuli. 1 The receptors contain a conserved N-terminal extracellular TNF-␣ binding domain, a small transmembrane region, and a nonconserved cytoplasmic domain. 1 Due to the lack of homology in the cytoplasmic region, it has been postulated that these receptors may trigger distinct signaling cascades upon TNF-␣ ligation. Experiments in cultured cells have demonstrated that the 2 TNF-␣ receptors are able to induce both common and distinct signaling pathways. For example, although p55 showed a stronger response, both receptors, upon TNF-␣ activation, were shown to be capable of translocating nuclear factor (NF) B from the cytosol to the nucleus and to induce the transcription of NFB-responsive genes. 2,3 Also, both receptors use TRAF-2 (TNFR-associated protein), a common signaling intermediate that along with other adaptor proteins form signaling complexes and activate several signaling cascades. 4 On the other hand, caspase activation and subsequent induction of apoptosis by TNF-␣ is an exclusive feature of p55 activation by virtue of a well-defined death domain, which is absent in p75. Recently, Pan et al 5 determined that Etk/Bmx (endothelial/epithelial tyrosine kinase) binds constitutively to p75, and implicated it in TNF-␣-induced endothelial-cell (EC) migration and angiogenesis.Activation of ECs by TNF-␣ induces the expression of multiple leukocyte adhesion molecules, such as E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Regulated expression of these adhesion molecules and their interactions with specific leukocyte r...

BackgroundTo the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications.Methods and findingsFor commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004–2013) and (2) Truven MarketScan (years: 2003–2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88–0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84–0.99] and 0.84 [0.76–0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01–1.10] and 1.07 [1.01–1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98–1.13] and 1.11 [1.05–1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by ...

ObjectivesTo compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients.DesignObservational cohort study.SettingPrivate (a large commercial health plan) and public (Medicaid) insurance programs in the US.ParticipantsBeneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort).Main outcome measuresPatients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products.ResultsA total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort.ConclusionSwitching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products.

Whole genome sequencing (WGS) studies are uncovering disease-associated variants in both rare and non-rare diseases. Utilizing the next-generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline –gNOME – to prioritize phenotype-associated variants while minimizing false positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype associated variants, and the result summaries are provided at variant-, gene-, and genome-levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared to population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss of function variants in known cancer pathways. gNOME web-server and source codes are freely available to the academic community.