Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab

Background Treatment response, remission rates and compliance in patients with polyarticular juvenile idiopathic arthritis (polyJIA) treated with adalimumab, etanercept, or tocilizumab were analyzed in clinical practice. Methods Data collected in the German BIKER registry were analyzed in patients with polyJIA who started treatment with approved biologics, adalimumab, etanercept or tocilizumab, from 2011 to 2015. Baseline patient characteristics, treatment response, safety and drug survival were compared. Results Two hundred thirty- six patient started adalimumab, 419 etanercept and 74 tocilizumab, with differences in baseline patient characteristics. Baseline Juvenile Disease Activity Score (JADAS)10 (mean ± SD) in the adalimumab/etanercept/tocilizumab cohorts was 12.1+/−7.6, 13.8 ± 7.1 and 15.1 ± 7.4, respectively (adalimumab vs etanercept, p = 0.01), and Childhood Health Assessment Questionnaire (CHAQ)-disability index scores was 0.43 ± 0.58, 0.59 ± 0.6 and 0.63 ± 0.55, respectively (adalimumab vs etanercept, p < 0.001). Uveitis history was more frequent in the adalimumab cohort (OR 5.73; p < 0.001). Balanced patients’ samples were obtained by a generalized propensity score to adjust for baseline differences. Pediatric ACR30/50/70/90 criterion improvement after 3 months treatment was achieved by 68%/60%/42%/24% in the etanercept cohort, 67%/59%/43%/27% in the adalimumab cohort and 61%/52%/35%/26% in the tocilizumab cohort. At 24 months, JADAS minimal disease activity was achieved in 52.4%/61.3%/52.4% and JADAS remission in 27.9%/34.8%/27.9% patients in the adalimumab/etanercept/tocilizumab cohorts, respectively. Etanercept was used in 95.5% of patients as a first biologic, adalimumab in 50.8% and tocilizumab in 20.2%. There were no important differences in efficacy between first-line and second-line use of biologics. In total 60.4%/49.4%/31.1% patients discontinued adalimumab/etanercept/tocilizumab, respectively (HR for adalimumab 1.67; p < 0.001; HR for tocilizumab 0.35; p = 0.001). Drug survival rates did not differ significantly in patients on biologic monotherapy compared with combination therapy with methotrexate. Over 4 years observation under etanercept/adalimumab/tocilizumab, 996/386/103 adverse events, and 148/119/26 serious adverse events, respectively, were reported. Conclusions In clinical practice, etanercept is most frequently used as first-line biologic. Adalimumab/etanercept/tocilizumab showed comparable efficacy toward polyJIA. Overall, tolerance was acceptable. Interestingly, compliance was highest with tocilizumab and lowest with adalimumab. This study provides the first indication for the comparison of different biologic agents in polyarticular JIA based on observational study data with all their weaknesses and demonstrates the need for well-controlled head-to-head studies for confirmation

Sex differences in cancer mechanisms

We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients

Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile

Farnesyl diphosphate synthase is involved in the resistance to zoledronic acid of osteosarcoma cells.

We recently demonstrated original anti-tumor effects of zoledronic acid (Zol) on osteosarcoma cell lines independently of their p53 and Rb status. The present study investigated the potential Zol-resistance acquired by osteosarcoma cells after prolonged treatment. After 12 weeks of culture in the presence of 1 microm Zol, the effects of high doses of Zol (10-100 microm) were compared between the untreated rat (OSRGA, ROS) and human (MG63, SAOS2) osteosarcoma cells and Zol-pretreated cells in terms of cell proliferation, cell cycle analysis, migration assay and cytoskeleton organization. Long-term treatment with 1 microm Zol reduced the sensitivity of osteosarcoma cells to high concentrations of Zol. Furthermore, the Zol-resistant cells were sensitive to conventional anti-cancer agents demonstrating that this resistance process is independent of the multidrug resistance phenotype. However, as similar experiments performed in the presence of clodronate and pamidronate evidenced that this drug resistance was restricted to the nitrogen-containing bisphosphonates, we then hypothesized that this resistance could be associated with a differential expression of farnesyl diphos-phate synthase (FPPS) also observed in human osteosarcoma samples. The transfection of Zol-resistant cells with FPPS siRNA strongly increased their sensitivity to Zol. This study demonstrates for the first time the induction of metabolic resistance after prolonged Zol treatment of osteosarcoma cells confirming the therapeutic potential of Zol for the treatment of bone malignant pathologies, but points out the importance of the treatment regimen may be important in terms of duration and dose to avoid the development of drug metabolic resistance

Do-It-Yourself Preoperative High-Resolution Ultrasound-Guided Flap Design of the Superficial Circumflex Iliac Artery Perforator Flap (SCIP)

The superficial circumflex iliac artery perforator (SCIP) flap is a well-documented, thin, free tissue flap with a minimal donor site morbidity, and has the potential to become the new method for resurfacing moderate-size skin defects. The aim of this study is to describe an easy, reliable, systematic, and standardized approach for preoperative SCIP flap design and perforator characterization, using color-coded duplex sonography (CCDS). A list of customized settings and a straightforward algorithm are presented, which are easily applied by an operator with minimal experience. Specific settings for SCIP flap perforator evaluation were investigated and tested on 12 patients. Deep and superficial superficial circumflex iliac artery (SCIA) branches, along with their corresponding perforators and cutaneous veins, were marked individually with a permanent marker and the anatomy was verified intraoperatively. From this, a simplified procedure for preoperative flap design of the SCIP flap was developed. Branches could be localized and evaluated in all patients. A preoperative structured procedure for ultrasonically guided flap design of the SCIP flap is described. A 100% correlation between the number and emergence points of the branches detected by preoperative CCDS mapping and the intraoperative anatomy was found

Lassie: HOL4 Tactics by Example

Proof engineering efforts using interactive theorem proving have yielded several impressive projects in software systems and mathematics. A key obstacle to such efforts is the requirement that the domain expert is also an expert in the low-level details in constructing the proof in a theorem prover. In particular, the user needs to select a sequence of tactics that lead to a successful proof, a task that in general requires knowledge of the exact names and use of a large set of tactics. We present Lassie, a tactic framework for the HOL4 theorem prover that allows individual users to define their own tactic language by example and give frequently used tactics or tactic combinations easier-to-remember names. The core of Lassie is an extensible semantic parser, which allows the user to interactively extend the tactic language through a process of definitional generalization. Defining tactics in Lassie thus does not require any knowledge in implementing custom tactics, while proofs written in Lassie retain the correctness guarantees provided by the HOL4 system. We show through case studies how Lassie can be used in small and larger proofs by novice and more experienced interactive theorem prover users, and how we envision it to ease the learning curve in a HOL4 tutorial

Viel gelernt, doch nichts verändert? Eine Beobachtungsstudie zur geschlechtsspezifischen Interaktion in politischen Basisgruppen

Im Rahmen eines Lehrforschungsprojektes (Integrierter Methodenkurs über vier Semester im Grundstudium des Soziologie-Diplomstudiengangs) wurden im Themenfeld "Geschlechtsspezifische Interaktionsstrukturen" fünf Studien, von denen hier eine vorgestellt wird, mit einmaliger, hypothesenprüfender, standardisierter Beobachtung im Feld mittels SYMLOG durchgeführt. Die Projektgruppe hatte sich eine Themenstellung im Bereich der politischen Arbeit gewählt und dafür die Interaktion in 18 parteiunabhängigen Basisgruppen aus dem Spektrum der 'Neuen sozialen Bewegungen', gemischt- wie gleichgeschlechtlichtlichen, während der Gruppensitzungen untersucht. Nach der Entwicklung von vier Hypothesen wurde die Feldbeobachtung (offen, nicht teilnehmend) mit dem Adjektiv-Ratingbogen des standardisierten Beobachtungssystems SYMLOG (Bales & Cohen 1982) durchgeführt und ausgewertet. Die Befunde bestätigen die Erwartungen, dass in gemischtgeschlechtlichen Gruppen die Frauen eher kooperativ und die Männer eher konkurrent agieren, während in gleichgeschlechtlichen Arbeitsgruppen von Frauen wie von Männern ein breiteres Rollenspektrum wahrgenommen wird