Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study

Background: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes. Methods: All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests. Results: The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001. Conclusions: The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway

Prevalence of asthma, aspirin sensitivity and allergy in chronic rhinosinusitis: data from the UK National Chronic Rhinosinusitis Epidemiology Study

Background: Chronic rhinosinusitis (CRS) is a common disorder associated with other respiratory tract diseases such as asthma and inhalant allergy. However, the prevalence of these co-morbidities varies considerably in the existing medical literature and by phenotype of CRS studied. The study objective was to identify the prevalence of asthma, inhalant allergy and aspirin sensitivity in CRS patients referred to secondary care and establish any differences between CRS phenotypes. Methods: All participants were diagnosed in secondary care according to international guidelines and invited to complete a questionnaire including details of co-morbidities and allergies. Data were analysed for differences between controls and CRS participants and between phenotypes using chi-squared tests. Results: The final analysis included 1470 study participants: 221 controls, 553 CRS without nasal polyps (CRSsNPs), 651 CRS with nasal polyps (CRSwNPs) and 45 allergic fungal rhinosinusitis (AFRS). The prevalence of asthma was 9.95, 21.16, 46.9 and 73.3% respectively. The prevalence of self-reported confirmed inhalant allergy was 13.1, 20.3, 31.0 and 33.3% respectively; house dust mite allergy was significantly higher in CRSwNPs (16%) compared to CRSsNPs (9%, p < 0.001). The prevalence of self- reported aspirin sensitivity was 2.26, 3.25, 9.61 and 40% respectively. The odds ratio for aspirin sensitivity amongst those with AFRS was 28.8 (CIs 9.9, 83.8) p < 0.001. Conclusions: The prevalence of asthma and allergy in CRS varies by phenoytype, with CRSwNPs and AFRS having a stronger association with both. Aspirin sensitivity has a highly significant association with AFRS. All of these comorbidities are significantly more prevalent than in non-CRS controls and strengthen the need for a more individualised approach to the combined airway

A function blocking anti-mouse integrin α5β1 antibody inhibits angiogenesis and impedes tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Integrins are important adhesion molecules that regulate tumor and endothelial cell survival, proliferation and migration. The integrin α5β1 has been shown to play a critical role during angiogenesis. An inhibitor of this integrin, volociximab (M200), inhibits endothelial cell growth and movement <it>in vitro</it>, independent of the growth factor milieu, and inhibits tumor growth <it>in vivo </it>in the rabbit VX2 carcinoma model. Although volociximab has already been tested in open label, pilot phase II clinical trials in melanoma, pancreatic and renal cell cancer, evaluation of the mechanism of action of volociximab has been limited because this antibody does not cross-react with murine α5β1, precluding its use in standard mouse xenograft models.</p> <p>Methods</p> <p>We generated a panel of rat-anti-mouse α5β1 antibodies, with the intent of identifying an antibody that recapitulated the properties of volociximab. Hybridoma clones were screened for analogous function to volociximab, including specificity for α5β1 heterodimer and blocking of integrin binding to fibronectin. A subset of antibodies that met these criteria were further characterized for their capacities to bind to mouse endothelial cells, inhibit cell migration and block angiogenesis <it>in vitro</it>. One antibody that encompassed all of these attributes, 339.1, was selected from this panel and tested in xenograft models.</p> <p>Results</p> <p>A panel of antibodies was characterized for specificity and potency. The affinity of antibody 339.1 for mouse integrin α5β1 was determined to be 0.59 nM, as measured by BIAcore. This antibody does not significantly cross-react with human integrin, however 339.1 inhibits murine endothelial cell migration and tube formation and elicits cell death in these cells (EC₅₀= 5.3 nM). In multiple xenograft models, 339.1 inhibited the growth of established tumors by 40–60% (<it>p </it>< 0.05) and this inhibition correlates with a concomitant decrease in vessel density.</p> <p>Conclusion</p> <p>The results herein demonstrate that 339.1, like volociximab, exhibits potent anti-α5β1 activity and confirms that inhibition of integrin α5β1 impedes angiogenesis and slows tumor growth <it>in vivo</it>.</p

The pairwise disconnectivity index as a new metric for the topological analysis of regulatory networks

<p>Abstract</p> <p>Background</p> <p>Currently, there is a gap between purely theoretical studies of the topology of large bioregulatory networks and the practical traditions and interests of experimentalists. While the theoretical approaches emphasize the global characterization of regulatory systems, the practical approaches focus on the role of distinct molecules and genes in regulation. To bridge the gap between these opposite approaches, one needs to combine 'general' with 'particular' properties and translate abstract topological features of large systems into testable functional characteristics of individual components. Here, we propose a new topological parameter – the pairwise disconnectivity index of a network's element – that is capable of such bridging.</p> <p>Results</p> <p>The pairwise disconnectivity index quantifies how crucial an individual element is for sustaining the communication ability between connected pairs of vertices in a network that is displayed as a directed graph. Such an element might be a vertex (i.e., molecules, genes), an edge (i.e., reactions, interactions), as well as a group of vertices and/or edges. The index can be viewed as a measure of topological redundancy of regulatory paths which connect different parts of a given network and as a measure of sensitivity (robustness) of this network to the presence (absence) of each individual element. Accordingly, we introduce the notion of a path-degree of a vertex in terms of its corresponding incoming, outgoing and mediated paths, respectively. The pairwise disconnectivity index has been applied to the analysis of several regulatory networks from various organisms. The importance of an individual vertex or edge for the coherence of the network is determined by the particular position of the given element in the whole network.</p> <p>Conclusion</p> <p>Our approach enables to evaluate the effect of removing each element (i.e., vertex, edge, or their combinations) from a network. The greatest potential value of this approach is its ability to systematically analyze the role of every element, as well as groups of elements, in a regulatory network.</p

Beyond word frequency: Bursts, lulls, and scaling in the temporal distributions of words

Background: Zipf's discovery that word frequency distributions obey a power law established parallels between biological and physical processes, and language, laying the groundwork for a complex systems perspective on human communication. More recent research has also identified scaling regularities in the dynamics underlying the successive occurrences of events, suggesting the possibility of similar findings for language as well. Methodology/Principal Findings: By considering frequent words in USENET discussion groups and in disparate databases where the language has different levels of formality, here we show that the distributions of distances between successive occurrences of the same word display bursty deviations from a Poisson process and are well characterized by a stretched exponential (Weibull) scaling. The extent of this deviation depends strongly on semantic type -- a measure of the logicality of each word -- and less strongly on frequency. We develop a generative model of this behavior that fully determines the dynamics of word usage. Conclusions/Significance: Recurrence patterns of words are well described by a stretched exponential distribution of recurrence times, an empirical scaling that cannot be anticipated from Zipf's law. Because the use of words provides a uniquely precise and powerful lens on human thought and activity, our findings also have implications for other overt manifestations of collective human dynamics

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations

Predicting survival of de novo metastatic breast cancer in Asian women: Systematic review and validation study

10.1371/journal.pone.0093755PLoS ONE94-POLN

Anti-Malarial Drug Artesunate Attenuates Experimental Allergic Asthma via Inhibition of the Phosphoinositide 3-Kinase/Akt Pathway

, and has been shown to inhibit PI3K/Akt activity. We hypothesized that artesunate may attenuate allergic asthma via inhibition of the PI3K/Akt signaling pathway.Female BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E-binding protein 1, and transactivation of NF-κB. Similarly, artesunate blocked the phosphorylation of Akt and its downstream substrates in lung tissues from OVA-challenged mice. Anti-inflammatory effect of artesunate was further confirmed in a house dust mite mouse asthma model.Artesunate ameliorates experimental allergic airway inflammation probably via negative regulation of PI3K/Akt pathway and the downstream NF-κB activity. These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma