Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer.

Toll-like receptors (TLRs), which serve as a bridge between innate and adaptive immunity, may be viable treatment targets. TLRs are the first line of defense against microbes and activate signaling cascades that induce immune and inflammatory responses. Patients with "hot" versus "cold" tumors may respond more favorably to immune checkpoint inhibition, and through their downstream effects, TLR agonists have the potential to convert "cold tumors" into "hot tumors" making TLRs in combination with immune checkpoint inhibitors, potential targets for cancer therapies.

Impact of apremilast on quality of life in Behçet's syndrome: analysis of the phase 3 RELIEF study.

Objective: To assess apremilast's impact on patient quality of life (QoL) in active Behçet's syndrome and correlations between improvement in patients' QoL and efficacy measures in the phase 3 RELIEF study.

Methods: QoL measures included Behçet's Disease QoL (BDQoL), 36-Item Short-Form Health Survey V.2 (SF-36v2) Physical/Mental Component Summary (PCS/MCS) and eight subscale scores, focusing on Physical Functioning (PF).

Apremilast in a Japanese subgroup with Behçet's syndrome: Results from a Phase 3, randomised, double-blind, placebo-controlled study.

Objectives: Apremilast efficacy and safety was assessed in a prespecified subgroup of Japanese patients with oral ulcers associated with Behçet's syndrome from a Phase 3 randomized, placebo-controlled, double-blind study of apremilast (RELIEF).

Methods: The primary end point was area under the curve for number of oral ulcers during the 12-week placebo-controlled phase (AUCWk0-12). Key secondary end points were change from baseline in oral ulcer pain, complete oral ulcer resolution, and measures of disease activity and quality of life (QoL).

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical trial.

Objectives: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks.

Methods: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course.

A Phase III Randomized Study of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, for Active Ankylosing Spondylitis.

Objective: To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with active ankylosing spondylitis (AS).

Methods: This phase III, multicenter, double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01583374) randomized patients with active AS (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily for 24 weeks, followed by a long-term extension phase (up to 5 yrs).

Trial of Apremilast for Oral Ulcers in Behçet's Syndrome.

Background: The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited.

Non-clinical pharmacology, pharmacokinetics, and safety findings for the antihistamine bepotastine besilate.

Scope: The purpose of this review is to examine published non-clinical literature on the antihistamine bepotastine besilate, including pharmacokinetic and pharmacologic properties.

Methods: Standard literature searches using diverse databases were used to find articles on bepotastine besilate published between 1997 and 2009. Articles primarily described non-clinical data utilized for the development of an oral formulation of bepotastine besilate and were published in Japanese.

Shear stress regulates forward and reverse planar cell polarity of vascular endothelium in vivo and in vitro.

Cultured vascular endothelium displays profound morphological adaptations to shear stress that include planar cell polarity (PCP) that is directed downstream. Endothelial cells in blood vessels are also polarized; however, the direction of polarity is vessel specific, and shear-independent mechanisms have been inferred. The regulation of endothelial PCP is therefore controversial.

Shear-induced reorganization of endothelial cell cytoskeleton and adhesion complexes.

Endothelial cells undergo profound morphologic changes in response to alterations in shear stresses that are imposed on them by blood flow, and these responses have important implications for physiologic and pathophysiologic function of blood vessels. Shear-induced changes in cell morphology represent a unique mode of cell motility: elongation of the cells in the direction of shear stress is achieved by a reorientation and assembly of F-actin stress fibers at the basal cell surface that ultimately protrudes the upstream and downstream limits of the plasma membrane. Shape change is also accommodated by dramatic reorganization of cell-substrate and cell-cell junctional complexes.

Assembly and reorientation of stress fibers drives morphological changes to endothelial cells exposed to shear stress.

Fluid shear stress greatly influences the biology of vascular endothelial cells and the pathogenesis of atherosclerosis. Endothelial cells undergo profound shape change and reorientation in response to physiological levels of fluid shear stress. These morphological changes influence cell function; however, the processes that produce them are poorly understood.