Chronic urticaria in the real‐life clinical practice setting in the UK: results from the non‐interventional multicentre AWARE study

Abstract Background Chronic urticaria (CU) is a skin condition characterised by repeated occurrence of itchy wheals and/or angioedema for >6 weeks. Aim To provide data demonstrating the real‐life burden of CU in the UK. Methods This UK subset of the worldwide, prospective, non‐interventional AWARE study included patients aged 18–75 years diagnosed with H1‐antihistamine (H1‐AH)‐refractory chronic spontaneous urticaria (CSU) for >2 months. Baseline characteristics, disease activity, treatments, comorbidities and healthcare resource use were documented. Quality of life, work productivity and activity impairment were assessed. Results Baseline analysis included 252 UK patients. Mean age and body mass index were 45.0 years and 29.0 kg/m2, respectively. Most patients were female (77.8%) and had moderate/severe disease activity (mean Urticaria Activity Score over 7 days, 18.4) and a ‘spontaneous’ component to their CU (73.4% CSU; 24.6% CSU and chronic inducible urticaria). Common comorbidities included depression/anxiety (24.6%), asthma (23.8%) and allergic rhinitis (12.7%). A previous treatment was recorded for 57.9% of patients. Mean Dermatology Life Quality Index score was 9.5 and patients reported impairments in work productivity and activity. Healthcare resource use was high. Severity of CSU was associated with gender, obesity, anxiety and diagnosis. Only 28.5% of patients completed all nine study visits, limiting analysis of long‐term treatment patterns and disease impact. Conclusions Adult H1‐AH‐refractory CU patients in the UK reported high rates of healthcare resource use and impairment in quality of life, work productivity and activity at baseline. The differing structures of UK healthcare may explain the high study discontinuation rates versus other countries

14-3-3 zeta is a molecular target in guggulsterone induced apoptosis in Head and Neck cancer cells

<p>Abstract</p> <p>Background</p> <p>The five-year survival rates for head and neck squamous cell carcinoma (HNSCC) patients are less than 50%, and the prognosis has not improved, despite advancements in standard multi-modality therapies. Hence major emphasis is being laid on identification of novel molecular targets and development of multi-targeted therapies. 14-3-3 zeta, a multifunctional phospho-serine/phospho-threonine binding protein, is emerging as an effector of pro-survival signaling by binding to several proteins involved in apoptosis (Bad, FKHRL1 and ASK1) and may serve as an appropriate target for head and neck cancer therapy. Herein, we determined effect of guggulsterone (GS), a farnesoid X receptor antagonist, on 14-3-3 zeta associated molecular pathways for abrogation of apoptosis in head and neck cancer cells.</p> <p>Methods</p> <p>Head and neck cancer cells were treated with guggulsterone (GS). Effect of GS-treatment was evaluated using cell viability (MTT) assay and apoptosis was verified by annexin V, DNA fragmentation and M30 CytoDeath antibody assay. Mechanism of GS-induced apoptosis was determined by western blotting and co-IP assays using specific antibodies.</p> <p>Results</p> <p>Using in vitro models of head and neck cancer, we showed 14-3-3 zeta as a key player regulating apoptosis in GS treated SCC4 cells. Treatment with GS releases BAD from the inhibitory action of 14-3-3 zeta in proliferating HNSCC cells by activating protein phosphatase 2A (PP2A). These events initiate the intrinsic mitochondrial pathway of apoptosis, as revealed by increased levels of cytochrome c in cytoplasmic extracts of GS-treated SCC4 cells. In addition, GS treatment significantly reduced the expression of anti-apoptotic proteins, Bcl-2, xIAP, Mcl1, survivin, cyclin D1 and c-myc, thus committing cells to apoptosis. These events were followed by activation of caspase 9, caspase 8 and caspase 3 leading to cleavage of its downstream target, poly-ADP-ribose phosphate (PARP).</p> <p>Conclusion</p> <p>GS targets 14-3-3 zeta associated cellular pathways for reducing proliferation and inducing apoptosis in head and neck cancer cells, warranting its investigation for use in treatment of head and neck cancer.</p

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work.Y.L. was supported by the National Natural Science Foundation of China (Grant No. 31600929) and the Fundamental Research Funds for the Central Universities (010914380002). G.S. was supported by a Veni grant from the Netherlands Organization for Scientific Research (Grant No. 016.155.218). J.J. was supported by the Academy of Finland (Grant No. 295580), the Finnish Medical Foundation, and the Finnish Foundation for Alcohol Studies. V.K. was supported by the Academy of Finland (Grant No. 256836) and the Finnish Foundation for Alcohol Studies. S.G. and H.R.S. were supported by the Danish Council for Independent Research in Social Sciences through a grant to Thomas Ramsøy (“Decision Neuroscience Project”; Grant No. 0601-01361B) and by the Lundbeck Foundation through a Grant of Excellence (“ContAct”; Grant No. R59 A5399). A.G. was supported by Deutsche Forschungsgemeinschaft (DFG) HE2597/15–1, HE2597/15–2, and DFG Graduiertenkolleg 1589/2 “Sensory Computation in Neural Systems”. N.R.-S. was supported by a research grant by the Senatsverwaltung für Gesundheit und Soziales, Berlin, Germany (Grant No. 002–2008/I B 35). C.M.R.d.L. and J.C.P. were supported by a grant from the Spanish Government (Ministerio de Economía y Competitividad, Secretaría de Estado de Investigación, Desarrollo e Innovación; Convocatoria 2017 de Proyectos I+D de Excelencia, Spain; co-funded by the Fondo Europeo de Desarrollo Regional, FEDER, European Union; Grant No. PSI2017–85488-P). J.-C. D. was supported by “LABEX ANR-11-LABEX-0042” of Université de Lyon within the program Investissements d’Avenir (ANR-11-IDEX-007) operated by the French National Research Agency and by a grant from the Fondation pour la Recherche Médicale (Grant No. DPA20140629796)

The role of impulsivity in the aetiology of drug dependence: reward sensitivity versus automaticity

Journal ArticleResearch Support, Non-U.S. Gov'tCopyright © The Author(s) 2011.RATIONALE: Impulsivity has long been known as a risk factor for drug dependence, but the mechanisms underpinning this association are unclear. Impulsivity may confer hypersensitivity to drug reinforcement which establishes higher rates of instrumental drug-seeking and drug-taking behaviour, or may confer a propensity for automatic (non-intentional) control over drug-seeking/taking and thus intransigence to clinical intervention. METHOD: The current study sought to distinguish these two accounts by measuring Barratt Impulsivity and craving to smoke in 100 smokers prior to their completion of an instrumental concurrent choice task for tobacco (to measure the rate of drug-seeking) and an ad libitum smoking test (to measure the rate of drug-taking-number of puffs consumed). RESULTS: The results showed that impulsivity was not associated with higher rates of drug-seeking/taking, but individual differences in smoking uptake and craving were. Rather, nonplanning impulsivity moderated (decreased) the relationship between craving and drug-taking, but not drug-seeking. CONCLUSIONS: These data suggest that whereas the uptake of drug use is mediated by hypervaluation of the drug as an instrumental goal, the orthogonal trait nonplanning impulsivity confers a propensity for automatic control over well-practiced drug-taking behaviour.MR

Suppression of BCL6 Function by HDAC Inhibitor Mediated Acetylation and Chromatin Modification Enhances BET Inhibitor Effects in B-cell Lymphoma Cells

Multiple genetic aberrations in the regulation of BCL6, including in acetyltransferase genes, occur in clinically aggressive B-cell lymphomas and lead to higher expression levels and activity of this transcriptional repressor. BCL6 is, therefore, an attractive target for therapy in aggressive lymphomas. In this study romidepsin, a potent histone deacetylase inhibitor (HDACi), induced apoptosis and cell cycle arrest in Burkitt and diffuse large B-cell lymphoma cell lines, which are model cells for studying the mechanism of action of BCL6. Romidepsin caused BCL6 acetylation at early timepoints inhibiting its function, while at later timepoints BCL6 expression was reduced and target gene expression increased due to chromatin modification. MYC contributes to poor prognosis in aggressive lymphoma. MYC function is reduced by inhibition of chromatin readers of the bromodomain and extra-terminal repeat (BET) family, which includes BRD4. The novel combination of romidepsin and JQ1, a BRD4 inhibitor was investigated and showed synergy. Collectively we suggest that the combination of HDACi and BRD4i should be pursued in further pre-clinical testing.Funding: The work was supported by grants SAF2014-53526-R and SAF2017-88026-R from MINECO, Spanish Government, to M.D.D. and J.L. (partially funded by FEDER program from European Union). M.G.C. was recipient of a “Marcos Fernández” fellowship from Leukemia and Lymphoma foundation. L.G.G. was recipient of a FPI fellowship from Spanish Government