Asymmetric Dimethylation of Ribosomal S6 Kinase 2 Regulates Its Cellular Localisation and Pro-Survival Function

Ribosomal S6 kinases (S6Ks) are critical regulators of cell growth, homeostasis, and survival, with dysregulation of these kinases found to be associated with various malignancies. While S6K1 has been extensively studied, S6K2 has been neglected despite its clear involvement in cancer progression. Protein arginine methylation is a widespread post-translational modification regulating many biological processes in mammalian cells. Here, we report that p54-S6K2 is asymmetrically dimethylated at Arg-475 and Arg-477, two residues conserved amongst mammalian S6K2s and several AT-hook-containing proteins. We demonstrate that this methylation event results from the association of S6K2 with the methyltransferases PRMT1, PRMT3, and PRMT6 in vitro and in vivo and leads to nuclear the localisation of S6K2 that is essential to the pro-survival effects of this kinase to starvation-induced cell death. Taken together, our findings highlight a novel post-translational modification regulating the function of p54-S6K2 that may be particularly relevant to cancer progression where general Arg-methylation is often elevated

Characterization of the “frequent exacerbator phenotype” in bronchiectasis

Rationale: Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described. Objectives: To establish if there is a \u201cfrequent exacerbator phenotype\u201d in bronchiectasis and the impact of exacerbations on long-term clinical outcomes. Methods: We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality. Measurements and Main Results: A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype.The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P, 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P, 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P, 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV1, radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during followup. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency. Conclusions: The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up

The economic burden of bronchiectasis - known and unknown:a systematic review

Abstract Background The increasing prevalence and recognition of bronchiectasis in clinical practice necessitates a better understanding of the economic disease burden to improve the management and achieve better clinical and economic outcomes. This study aimed to assess the economic burden of bronchiectasis based on a review of published literature. Methods A systematic literature review was conducted using MEDLINE, Embase, EconLit and Cochrane databases to identify publications (1 January 2001 to 31 December 2016) on the economic burden of bronchiectasis in adults. Results A total of 26 publications were identified that reported resource use and costs associated with management of bronchiectasis. Two US studies reported annual incremental costs of bronchiectasis versus matched controls of US$5681 and US$2319 per patient. Twenty-four studies reported on hospitalization rates or duration of hospitalization for patients with bronchiectasis. Mean annual hospitalization rates per patient, reported in six studies, ranged from 0.3–1.3, while mean annual age-adjusted hospitalization rates, reported in four studies, ranged from 1.8–25.7 per 100,000 population. The average duration of hospitalization, reported in 12 studies, ranged from 2 to 17 days. Eight publications reported management costs of bronchiectasis. Total annual management costs of €3515 and €4672 per patient were reported in two Spanish studies. Two US studies reported total costs of approximately US$26,000 in patients without exacerbations, increasing to US$36,00–37,000 in patients with exacerbations. Similarly, a Spanish study reported higher total annual costs for patients with > 2 exacerbations per year (€7520) compared with those without exacerbations (€3892). P. aeruginosa infection increased management costs by US$31,551 to US$56,499, as reported in two US studies, with hospitalization being the main cost driver. Conclusions The current literature suggests that the economic burden of bronchiectasis in society is significant. Hospitalization costs are the major driver behind these costs, especially in patients with frequent exacerbations. However, the true economic burden of bronchiectasis is likely to be underestimated because most studies were retrospective, used ICD-9-CM coding to identify patients, and often ignored outpatient burden and cost. We present a conceptual framework to facilitate a more comprehensive assessment of the true burden of bronchiectasis for individuals, healthcare systems and society

Übertragbarkeit der gesundheitsökonomischen Evaluationen : Methoden für die multinationalen Studien

Filonenko A. Generalizability of health economic evaluations : methods for multinational patient-level studies. Bielefeld (Germany): Bielefeld University; 2010.Background: Cost-effectiveness outcomes collected in multinational health economic studies may vary across countries and geographic areas due to numerous clinical and socioeconomic factors. The between-country variability poses the question of generalizability of the cost-effectiveness estimates, i.e. applicability of the trial-wide results for the decision-making in particular jurisdiction. Objectives: The purpose of this research is to illustrate how selected methods can improve generalizability of the results of patient-level health economic studies by a) exploring between-country variability in incremental costs, effectiveness and resource use, b) calculation of trial-wide and country-level incremental cost, effectiveness and resource use while accounting for patient- and country-level covariates, and c) assessing the potential of covariates to predict cost and effectiveness estimates for the settings outside the study. Methods: Review of published health-economic evidence and international HTA guidelines was conducted to evaluate applied or recommended methods and analytical strategies to improve generalizability of the health economic outcomes. In the case study, qualitative and quantitative homogeneity test by Simon and Gail is used to explore between-country heterogeneity of the treatment effects measured by incremental costs, effectiveness, resource use (length of hospitalization) and incremental net monetary benefit. Hierarchical modelling is applied to calculate trial-wide and country-level estimates, while accounting for clustering and incorporating country- and patient-level covariates. Results: Simon and Gail test indicated qualitative homogeneity for incremental effectiveness, costs, length of hospitalization and net monetary benefit between treatment and control arms. Trial-wide and country-level mean incremental costs and effectiveness were estimated using hierarchical models with and without covariates. Results of hierarchical modelling suggested, that new treatment was more efficacious, saved costs and resource use in majority of the countries. Conclusions: Homogeneity test and hierarchical models are complementary methods to explore heterogeneity and to estimate trial-wide and country-level parameters for cost-effectiveness analysis. Hierarchical models allow for country-level estimates and adjustment for covariates. In the case study the patient-level covariates showed effect on incremental cost and effectiveness; country-level covariates had very small impact on estimates. The use of country-level covariates as predictors for incremental cost and resource use to improve generalizability of health economic studies beyond the study setting merits further investigation

Effect of methyl jasmonate on production of 20- hydroxyecdysone and turkesterone in hairy roots of Silene linicola C.C.Gmelin

Methyl jasmonate (MeJ) affects the regulation of secondary metabolism, and it is considered to be a promising elicitor in the culture of cells, tissues and plant organs. High-performance liquid chromatography method was used to identify the composition of ecdysteroids in hairy roots of Silene linicola. MeJ was found to have a stimulating effect on ecdysteroid biosynthesis in this culture. Addition of MeJ at a concentration of 100 μM increased the biosynthesis of 20-hydroxyecdysone by 74% (day 3), and that of turkesterone by 35% (day 6). The share of turkesterone in total ecdysteroid content in the investigated samples was up to 60%, and the content of 20-hydroxyecdysone was up to 30%. The study shows that MeJ is a promising stimulator of ecdysteroid biosynthesis in hairy roots of S. linicola

Effect of methyl jasmonate on production of 20-hydroxyecdysone and turkesterone in hairy roots of Silene linicola C.C.Gmelin

Methyl jasmonate (MeJ) affects the regulation of secondary metabolism, and it is considered to be a promising elicitor in the culture of cells, tissues and plant organs. High-performance liquid chromatography method was used to identify the composition of ecdysteroids in hairy roots of Silene linicola. MeJ was found to have a stimulating effect on ecdysteroid biosynthesis in this culture. Addition of MeJ at a concentration of 100 μM increased the biosynthesis of 20-hydroxyecdysone by 74% (day 3), and that of turkesterone by 35% (day 6). The share of turkesterone in total ecdysteroid content in the investigated samples was up to 60%, and the content of 20-hydroxyecdysone was up to 30%. The study shows that MeJ is a promising stimulator of ecdysteroid biosynthesis in hairy roots of S. linicola

Cross design analysis of randomized and observational data – application to continuation rates for a contraceptive intra uterine device containing Levonorgestrel in adolescents and adults

Abstract Background To combine results from a randomized controlled study (RCT) and an observational study (OS) to evaluate discontinuation rate of a levonorgestrel-containing intrauterine contraceptive device (LNG IUD) in a real-life setting. Methods We included 253 parous and nulliparous women aged 21–40 years from our own phase II RCT. A total of 1607 women of all ages (including adolescents, < 20 years) were recruited from an OS. We applied the cross design synthesis (CDS) method recommended by the United States General Accounting Office. This method combines the different strengths of RCTs and OSs into one single estimate. Results Combined continuation rates for parous vs nulliparous women could be estimated more precisely as well as overall continuation rates after one (86.6%) and two years (78.5%), irrespective of age and parity. Conclusion Cross design synthesis allowed more precise estimation of continuation rates of an intrauterine device