Alteration of ribosome function upon 5-fluorouracil treatment favors cancer cell drug-tolerance.

Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes

Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults

BACKGROUND: Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults. METHODS: 10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria. RESULTS: No clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation. CONCLUSION: Although the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45828668

Early-onset airway damage in early-career elite athletes: A risk factor for exercise-induced bronchoconstriction

Exercise-induced bronchoconstriction is present in 24.5% of 12-13 years old early-career elite athletes. Epithelial damage might be an early phase hallmark in the development of EIB, in the absence of overt cellular inflammation.status: publishe

Damage-associated molecular pattern and innate cytokine release in the airways of competitive swimmers

Daily intensive exercise by elite athletes can result in exercise-induced asthma especially in elite swimmers and this may be linked to epithelial damage.status: publishe

AQUA((c)) Questionnaire as prediction tool for atopy in young elite athletes

Several studies have already identified atopy as a risk factor for the development of exercise-induced bronchoconstriction (EIB) in adult elite athletes (1-3). Skin prick test or serum specific IgE to common aero-allergens is used to determine the patient's atopy status (4). In 2009, Bonini M et al. introduced a screening tool to predict atopy in elite adult athletes, namely the Allergy Questionnaire for Athletes or short the AQUA© questionnaire (5). This article is protected by copyright. All rights reserved.status: publishe

The Antarctic Planet Interferometer

The Antarctic Planet Interferometer is an instrument concept designed to detect and characterize extrasolar planets by exploiting the unique potential of the best accessible site on earth for thermal infrared interferometry. High-precision interferometric techniques under development for extrasolar planet detection and characterization (differential phase, nulling and astrometry) all benefit substantially from the slow, low-altitude turbulence, low water vapor content, and low temperature found on the Antarctic plateau. At the best of these locations, such as the Concordia base being developed at Dome C, an interferometer with two-meter diameter class apertures has the potential to deliver unique science for a variety of topics, including extrasolar planets, active galactic nuclei, young stellar objects, and protoplanetary disks