A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.

Unlabelled: Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.

Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor alpha in immature bovine and adult human articular cartilage.

Objective: Traumatic joint injury can damage cartilage and release inflammatory cytokines from adjacent joint tissue. The present study was undertaken to study the combined effects of compression injury, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) and its soluble receptor (sIL-6R) on immature bovine and adult human knee and ankle cartilage, using an in vitro model, and to test the hypothesis that endogenous IL-6 plays a role in proteoglycan loss caused by a combination of injury and TNFalpha.

Methods: Injured or uninjured cartilage disks were incubated with or without TNFalpha and/or IL-6/sIL-6R.

Mechanical injury of cartilage explants causes specific time-dependent changes in chondrocyte gene expression.

Objective: Joint injury in young adults leads to an increased risk of developing osteoarthritis (OA) later in life. This study was undertaken to determine if injurious mechanical compression of cartilage explants results in changes at the level of gene transcription that may lead to subsequent degradation of the cartilage.

Methods: Cartilage was explanted from the femoropatellar groove of newborn calves.

Evaluation of medium supplemented with insulin-transferrin-selenium for culture of primary bovine calf chondrocytes in three-dimensional hydrogel scaffolds.

Insulin-transferrin-selenium (ITS) was investigated as a complete or partial replacement for fetal bovine serum (FBS) during in vitro culture of bovine calf chondrocytes in hydrogel scaffolds. Chondrocyte-seeded agarose and self-assembling peptide hydrogels were maintained in Dulbecco's modified Eagle's medium plus 10% FBS, 1% ITS plus 0.2% FBS, or 1% ITS and evaluated for biosynthesis, cell division, and surface outgrowth of fibroblastic-like cells and fibrous capsule formation over several weeks of culture.

Effects of dynamic compressive loading on chondrocyte biosynthesis in self-assembling peptide scaffolds.

Dynamic mechanical loading has been reported to affect chondrocyte biosynthesis in both cartilage explant and chondrocyte-seeded constructs. In this study, the effects of dynamic compression on chondrocyte-seeded peptide hydrogels were analyzed for extracellular matrix synthesis and retention over long-term culture. Initial studies were conducted with chondrocyte-seeded agarose hydrogels to explore the effects of various non-continuous loading protocols on chondrocyte biosynthesis.

Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury.

Objective: Acute joint injury leads to increased risk for osteoarthritis (OA). Although the mechanisms underlying this progression are unclear, early structural, metabolic, and compositional indicators of OA have been reproduced using in vitro models of cartilage injury. This study was undertaken to determine whether glycosaminoglycan (GAG) loss following in vitro cartilage injury is mediated by cellular biosynthesis, activation of enzymatic activity, or mechanical disruption of the cartilage extracellular matrix.

Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: interaction with exogenous cytokines.

Objective: Traumatic joint injury leads to an increased risk of osteoarthritis (OA), but the progression to OA is not well understood. We undertook this study to measure aspects of proteoglycan (PG) degradation after in vitro injurious mechanical compression, including up-regulation of enzymatic degradative expression and cytokine-stimulated degradation.

Methods: Articular cartilage tissue explants were obtained from newborn bovine femoropatellar groove and from adult normal human donor knee and ankle tissue.

Development-associated differences in integrative cartilage repair: roles of biosynthesis and matrix.

A recurring problem in tissue transplantation therapies for articular cartilage defects is the lack of integration between the implant and the host cartilage. Previous studies have shown that in vitro integration between explants of calf cartilage is markedly higher than that between fetal cartilage, despite similarly high levels of deposition of newly synthesized collagen. The aim of this study was to determine if cellular biosynthesis and extracellular matrix each contribute to these development-associated differences in integrative repair in vitro.