Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis with 3 years of treatment: results from a long-term study.

Objective: To evaluate the long-term efficacy of once-daily baricitinib 4 mg in patients with active RA who were either naïve to DMARDs or who had inadequate response (IR) to MTX.

Methods: Analyses of data from two completed 52-week, phase III studies, RA-BEGIN (DMARD-naïve) and RA-BEAM (MTX-IR), and one ongoing long-term extension (LTE) study (RA-BEYOND) were performed (148 total weeks). At week 52, DMARD-naïve patients treated with MTX monotherapy or baricitinib 4 mg+MTX in RA-BEGIN were switched to open-label baricitinib 4 mg monotherapy; MTX-IR patients treated with adalimumab (+MTX) in RA-BEAM were switched to open-label baricitinib 4 mg (+MTX) in the LTE.

Serine 350 of human pregnane X receptor is crucial for its heterodimerization with retinoid X receptor alpha and transactivation of target genes in vitro and in vivo.

The human pregnane X receptor (hPXR), a member of the nuclear receptor superfamily, senses xenobiotics and controls the transcription of genes encoding drug-metabolizing enzymes and transporters. The regulation of hPXR's transcriptional activation of its target genes is important for xenobiotic detoxification and endobiotic metabolism, and hPXR dysregulation can cause various adverse drug effects. Studies have implicated the putative phosphorylation site serine 350 (Ser(350)) in regulating hPXR transcriptional activity, but the mechanism of regulation remains elusive.

Stability of the human pregnane X receptor is regulated by E3 ligase UBR5 and serine/threonine kinase DYRK2.

The hPXR (human pregnane X receptor), a major chemical toxin sensor, is a ligand-induced transcription factor activated by various xenobiotics and toxins, resulting in the transcriptional up-regulation of detoxifying enzymes. To date, little is known about the upstream regulation of hPXR. Using MS analysis and a kinome-wide siRNA screen, we report that the E3 ligase UBR5 (ubiquitin protein ligase E3 component n-recognin 5) and DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2) regulate hPXR stability.

Identification and characterization of phosphorylation sites within the pregnane X receptor protein.

Pregnane X receptor (PXR) is a xenobiotic sensor regulating the expression of genes involved in xenobiotic detoxification and elimination. Phosphorylation plays an important role in modulating PXR activity and several phosphorylation sites have been predicted and characterized in in vitro experiments. Although PXR has been shown to be a phosphoprotein in vivo, the exact residues that are phosphorylated remain elusive.

Tumor suppressor protein p53 negatively regulates human pregnane X receptor activity.

The human pregnane X receptor (PXR) regulates genes involved in drug metabolism and disposition. PXR associates with multiple corepressors that attenuate and coactivators that enhance its activity. PXR plays a vital role in the drug metabolism pathway, and a comprehensive examination of PXR-associated proteins will provide greater insight into the regulation of the receptor and possible therapeutic implications.

More sensitive and quantitative proteomic measurements using very low flow rate porous silica monolithic LC columns with electrospray ionization-mass spectrometry.

The sensitivity of proteomics measurements using liquid chromatography (LC) separations interfaced with electrospray ionization-mass spectrometry (ESI-MS) improves approximately inversely with liquid flow rate (for the columns having the same separation efficiency, linear velocity, and porosity), making attractive the use of smaller inner diameter LC columns. We report the development and initial application of 10 microm i.d.