Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells

Inflammatory Rheumatic Disorders and Bone

Inflammatory joint diseases such as rheumatoid arthritis, as well as other rheumatic conditions, such as systemic lupus erythematosus (SLE) and ankylosing spondylitis, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone loss and fractures. The concept of osteoimmunology is based on growing insights into the links between the immune system and bone. The pathogenesis of osteoporosis in these patients is multifactorial. We have, more or less as an example, described this extensively for patients with SLE. High disease activity (inflammation) and immobility are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on, among other factors, age, body mass index, and gender. Although no fracture reduction has been shown in intervention studies in patients with inflammatory rheumatic diseases, we present treatment options that might be useful for clinicians who are treating these patients

Obesity in total hip arthroplasty—does it really matter?: A meta-analysis

Discussion persists as to whether obesity negatively influences the outcome of hip arthroplasty. We performed a meta-analysis with the primary research question of whether obesity has a negative effect on short- and long-term outcome of total hip arthroplasty. We searched the literature and included studies comparing the outcome of hip arthroplasty in different weight groups. The methodology of the studies included was scored according to the Cochrane guidelines. We extracted and pooled the data. For continuous data, we calculated a weighted mean difference and for dichotomous variables we calculated a weighted odds ratio (OR). Heterogeneity was calculated using I(2) statistics. 15 studies were eligible for data extraction. In obese patients, dislocation of the hip (OR = 0.54, 95% CI: 0.38-0.75) (10 studies, n = 8,634), aseptic loosening (OR = 0.64, CI: 0.43-0.96) (6 studies, n = 5,137), infection (OR = 0.3, CI: 0.19-0.49) (10 studies, n = 7,500), and venous thromboembolism (OR = 0.56, CI: 0.32-0.98) (7 studies, n = 3,716) occurred more often. Concerning septic loosening and intraoperative fractures, no statistically significant differences were found, possibly due to low power. Subjective outcome measurements did not allow pooling because of high heterogeneity (I(2) = 68%). Obesity appears to have a negative influence on the outcome of total hip replacemen

Transcendental-Phenomenological Proof and Descriptive Metaphysics

Following P.F. Strawson's reading of Kant, the majority of the literature on transcendental arguments seeks to divorce such arguments from their original Kantian context. This thesis is concerned with Mark Sacks's recent defence of transcendental arguments, which takes a different approach. A critique is given of Sacks's work and extensions and modifications of his approach are recommended. It is proposed that certain difficulties encountered by Kant's transcendentally-ideal approach can be overcome with Hegelian solutions

Children’s Participation in the Justice System

The rights of children in youth justice and civil court proceedings, and in particular the right of children to be heard or to “participate” in such systems, is an area in which there has been much interest in recent years, particularly sparked by Article 12 of the UN Convention on the Rights of the Child. There are a wide variety of proceedings in which children’s interests are decided, for example, where they are accused of a crime, where their parents are in dispute on family breakdown and where there are child protection concerns. This chapter examines recent developments in standards at international level concerning children’s participation in proceedings, such as the drafting of General Comment No. 12 of the UN Committee on the Rights of the Child on the right to be heard and the Guidelines on Child-friendly Justice of the Council of Europe. It draws on recent international research in order to provide analysis of the extent to which such standards have affected practice and made a difference for children. It concludes that although the development of such standards is to be welcomed, and although these standards have achieved some improvements at domestic level, the more extensive modifications required for genuine participation of children in the justice system has not occurred.Effective Protection of Fundamental Rights in a pluralist worl

The impact of biologics and tofacitinib on cardiovascular risk factors and outcomes in patients with rheumatic disease: a systematic literature review

Introduction Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. Methods A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. Results Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Conclusions Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients