NMR And Biophysical Studies Of G-Quadruplex DNA Within The KRAS Proto-Oncogene Promoter Region

The role of G-quadruplexes (G4) which can coexist with canonical duplex DNA in the human genome is still largely unknown. Although G4s are found throughout the entire genome, much of the attention have been invested in promotor regions of disease-related genes. The human KRAS proto-oncogene contains a nuclease hypersensitive element (4) located upstream of the major transcription start site. This region regulates transcription of KRAS and it was proposed as a new target for drug development. The knowledge of the detailed structure of this target is crucial for the development of new effective drugs. In this study, we report a high-resolution NMR structure of the G-rich element within the KRAS NHE, and their interaction with small ligands. The G-rich elements forms a parallel structure with three G-quartets connected by a four-nucleotide loop, two one-nucleotide double-chain-reversal loops and a thymine bulge. The loops of different lengths and the presence of a bulge between G-quartets are structural elements that can potentially be targeted by small ligands that would further stabilize the structure. In addition, we explore the polymorphism of G-quadruplexes structures within the promotor region. Consequently, our work suggests an alternative route for the development of anticancer agents that could regulate KRAS expression

Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis

Abstract BACKGROUND: Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis. METHODS: We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks. RESULTS: Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI). Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels ( 651 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred. CONCLUSIONS: Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo. (Funded by Sanofi-Aventis; TEMSO ClinicalTrials.gov number, NCT00134563.)

Randomized trial of oral teriflunomide for relapsing multiple sclerosis

Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis