No abstract

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

No abstract

The c subunit is an inner mitochondrial membrane (IMM) protein encoded by three nuclear genes. Best known as an integral part of the F0 complex of the ATP synthase, the c subunit is also present in other cytoplasmic compartments in ceroid lipofuscinoses. Under physiological conditions, this 75 residue-long peptide folds into an α-helical hairpin and forms oligomers spanning the lipid bilayer. In addition to its physiological role, the c subunit has been proposed as a key participant in stress-induced IMM permeabilization by the mechanism of calcium-induced permeability transition. However, the molecular mechanism of the c subunit participation in IMM permeabilization is not completely understood. Here we used fluorescence spectroscopy, atomic force microscopy and black lipid membrane methods to gain insights into the structural and functional properties of unmodified c subunit protein that might make it relevant to mitochondrial toxicity. We discovered that c subunit is an amyloidogenic peptide that can spontaneously fold into β-sheets and self-assemble into fibrils and oligomers in a Ca2+-dependent manner. C subunit oligomers exhibited ion channel activity in lipid membranes. We propose that the toxic effects of c subunit might be linked to its amyloidogenic properties and are driven by mechanisms similar to those of neurodegenerative polypeptides such as Aβ and α-synuclein.

The investigations of the platelet-derived biologic agents in osteoarthritis treatment had shown promising but often controversial Abstracts / Osteoarthritis and Cartilage 25 (2017) S76eS444 S438