Safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral allosteric TYK2 inhibitor ESK-001 using a randomized, double-blind, placebo-controlled study design.

ESK-001 is a highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2), which plays an essential role in mediating cytokine signaling in multiple immune-mediated diseases. In 2 phase I studies, a first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study and a multiple-dose (MD) study, we evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of orally administered ESK-001 in healthy participants using a randomized, double-blind, placebo-controlled study design. ESK-001 was rapidly absorbed with systemic exposures generally increasing dose-proportionally across all cohorts.

The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.

Objective: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting.

Methods: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs.

Distinct clinical phenotypes for Crohn's disease derived from patient surveys.

Background: Defining clinical phenotypes provides opportunities for new diagnostics and may provide insights into early intervention and disease prevention. There is increasing evidence that patient-derived health data may contain information that complements traditional methods of clinical phenotyping. The utility of these data for defining meaningful phenotypic groups is of great interest because social media and online resources make it possible to query large cohorts of patients with health conditions.

GWAS of self-reported mosquito bite size, itch intensity and attractiveness to mosquitoes implicates immune-related predisposition loci.

Understanding the interaction between humans and mosquitoes is a critical area of study due to the phenomenal burdens on public health from mosquito-transmitted diseases. In this study, we conducted the first genome-wide association studies (GWAS) of self-reported mosquito bite reaction size (n = 84,724), itchiness caused by bites (n = 69,057), and perceived attractiveness to mosquitoes (n = 16,576). In total, 15 independent significant (P < 5×10-8) associations were identified.

A Chromosome 13 locus is associated with male-specific mortality in mice.

Background And Aim: Mortality is a highly complex trait influenced by a wide array of genetic factors.

Methods: We examined a population of 1200 mice that were F2 generation offspring of a 4-way reciprocal cross between C57BL6/J and DBA2/J strains. Animals were sacrificed at age 200, 500, or 800 days and genotyped at 96 markers.

CHD7 gene polymorphisms and familial idiopathic scoliosis.

Study Design: Model-independent linkage analysis and tests of association were performed for 22 single nucleotide polymorphisms in the CHD7 gene in 244 families of European descent with familial idiopathic scoliosis (FIS).

Objective: To replicate an association between FIS and the CHD7 gene on 8q12.2 in an independent sample of families of European descent.