Chronic musculoskeletal impairment is associated with alterations in brain regions responsible for the production and perception of movement.

Key Points: Massive irreparable rotator cuff tear was used as a model to study the impact of chronic pain and motor impairment on the motor systems of the human brain using magnetic resonance imaging. Patients show markers of lower grey/white matter integrity and lower functional connectivity compared with control participants in regions responsible for movement and the perception of visual movement and body shape. An independent cohort of patients showed relative deficits in the perception of visual motion and hand laterality compared with an age-matched control group.

PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis.

Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases.

In-plane and out-of-plane rotational motion of individual chain molecules in steady shear flow of polymer melts and solutions.

Recent nonequilibrium molecular dynamics (NEMD) simulations of mildly entangled CH and moderately entangled CH linear polyethylene melts undergoing steady shear flow have revealed that several inconsistencies between theory and experiment could be rectified by consideration of the rotational motion of individual polymer chains that occurs at moderate to high flow strengths. In this study, we investigated the configurational dynamics of the individual molecular chains that allow these once-entangled, long-chain molecules to execute retraction/extension semi-periodic cycles in response to the imposed shear via NEMD simulations. Brownian dynamics simulations were also performed to extract dynamical and configurational information about the similar cycles of polymer chain behavior that occur in dilute solutions of macromolecular chain liquids dissolved in low molecular weight solvents.

Amino Acid Block Copolymers with Broad Antimicrobial Activity and Barrier Properties.

Antimicrobial properties of a long-chain, synthetic, cationic, and hydrophobic amino acid block copolymer are reported. In 5 and 60 min time-kill assays, solutions of K L block copolymers (poly(l-lysine·hydrochloride) -b-poly(l-leucine) ) at concentrations of 10-100 µg mL show multi-log reductions in colony forming units of Gram-positive and Gram-negative bacteria, as well as yeast, including multidrug-resistant strains. Driven by association of hydrophobic segments, K L copolymers form viscous solutions and self-supporting hydrogels in water at concentrations of 1 and 2 wt%, respectively.

Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity.

Regulatory T cells (Tregs) expand in peripheral lymphoid organs and can produce immunosuppressive cytokines to support tumor growth. IL-10 abrogation efficiently induces Treg formation but dampens tumoral neuropilin-1 (Nrp-1) Treg signaling, which simultaneously augments Th1 and Th17 immunity. These effects are associated with the plasticity and stability of Tregs and effector T cell functions that can limit tumorigenesis.

The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature.

CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions.

Recent development of poly(ethylene glycol)-cholesterol conjugates as drug delivery systems.

Poly(ethylene glycol)-cholesterol (PEG-Chol) conjugates are composed of "hydrophilically-flexible" PEG and "hydrophobically-rigid" Chol molecules. PEG-Chol conjugates are capable of forming micelles through molecular self-assembly and they are also used extensively for the PEGylation of drug delivery systems (DDS). The PEGylated DDS have been shown to display optimized physical stability properties in vitro and longer half-lives in vivo when compared with non-PEGylated DDS.

IL-37 ameliorates the inflammatory process in psoriasis by suppressing proinflammatory cytokine production.

IL-37 is a potent inhibitor of innate immunity by shifting the cytokine equilibrium away from excessive inflammation. Psoriasis is thought to be initiated by abnormal interactions between the cutaneous keratinocytes and systemic immune cells, triggering keratinocyte hyperproliferation. In the current study, we assessed IL-37 in two well-known psoriasis models: a human keratinocyte cell line (HaCaT) and the keratin 14 VEGF-A-transgenic mouse model.

Pyrvinium targets autophagy addiction to promote cancer cell death.

Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity.

Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone.

Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA) may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs) or anti-TNF-α therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active ("unstable") RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a disease-modifying anti-rheumatoid drug (DMARD) and an anti-TNF-α agent (infliximab or etanercept) to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N = 122), unstable DMARD patients (N = 18), stable DMARD patients (N = 26), and stable patients on combination therapy (N = 20).

Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma.

Background: Developing analytical methodologies to identify biomarkers in easily accessible body fluids is highly valuable for the early diagnosis and management of cancer patients. Peripheral whole blood is a "nucleic acid-rich" and "inflammatory cell-rich" information reservoir and represents systemic processes altered by the presence of cancer cells.

Methodology/principal Findings: We conducted transcriptome profiling of whole blood cells from melanoma patients.

Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.

The objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-κβ ligand (RANKL) and osteoprotegerin (OPG) as biomarkers of disease activity, progressive joint damage, and therapeutic response, during cytokine blockade in rheumatoid arthritis (RA). Patients with active RA entered a randomized open-label 12-month study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 μg/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline, at 4 weeks and at the final time point.

Generation of a prophylactic melanoma vaccine using whole recombinant yeast expressing MART-1.

Malignant melanoma is a potentially deadly form of skin cancer and people at high-risk of developing melanoma will benefit from effective preventive intervention. Yeast can be used as an efficient vehicle of antigen loading and immunostimulation. Saccharomyces cerevisiae is not pathogenic to humans and can be easily engineered to express specific antigens.

Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2.

Tumor necrosis factor (TNF) is a multifunctional cytokine that has a role in induction and regulation of host innate and adaptive immune responses. The importance of TNF antiviral mechanisms is reflected by the diverse strategies adopted by different viruses, particularly members of the herpesvirus family, to block TNF responses. TNF binds and signals through two receptors, Tnfrsf1a (TNF receptor 1 [TNFR1], or p55) and Tnfrsf1b (TNFR2, or p75).

Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor alpha.

Objective: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha.

Mechanism of action differences in the antitumor effects of transmembrane and secretory tumor necrosis factor-alpha in vitro and in vivo.

The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) exists naturally in two forms, a 26 kDa transmembrane form (TM-TNFalpha), and a 17 kDa secretory form (S-TNFalpha). The biological roles for each of these forms of TNFalpha in tumor killing have not been completely elucidated. Therefore, in this study, three different recombinant retroviral vectors, wild-type TNFalpha, solely secretable TNFalpha mutant, and uncleavable transmembrane TNFalpha mutant, were constructed by molecular techniques and stably transfected into a murine hepatic carcinoma cell line (H22).

A phase 2 dose-finding study of PEGylated recombinant methionyl human soluble tumor necrosis factor type I in patients with rheumatoid arthritis.

Objective: In a phase 2 study, to assess the efficacy and safety of pegsunercept, a soluble tumor necrosis factor receptor type I, for the treatment of rheumatoid arthritis (RA).

Methods: Patients were randomized to receive weekly subcutaneous injections of placebo (n = 61) or active drug [400 microg/kg (n = 67) or 800 microg/kg (n = 66)] for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12.

Differential maturation of murine bone-marrow derived dendritic cells with lipopolysaccharide and tumor necrosis factor-alpha.

Dendritic cells (DCs) play a key role in the interface between the innate and acquired immune systems. In response to both exogenous as well as endogenous signals, DCs undergo a programmed maturation to become an efficient, antigen-presenting cell. Yet little is known regarding the differential responses by endogenous versus exogenous stimuli on DC maturation.

Mouse splenic B lymphocyte activation using different activation stimuli induces in vitro splicing of tumor necrosis factor-alpha nuclear pre-mRNA.

The pleiotropic functions of tumor necrosis factor-alpha (TNFalpha) have brought considerable attention in the past decade to its physiological and pathological roles in inflammatory and autoimmune diseases. However, little is known about how the production of TNFalpha is regulated at the transcriptional and translational levels in immune cells such as T and B lymphocytes. Our previous study demonstrated that unspliced "pre-mRNA" of TNFalpha is present in resting T cells.

Drug discovery and development for inflammatory diseases.

Numerous recent investigations have pointed to a key role of the pro-inflammatory, pleotropic cytokines TNF-alpha and IL-1 in host defence and inflammatory disease processes. TNF and IL-1 overexpression has been found in disease target tissue and in the circulation of patients with acute and chronic inflammatory diseases, and it was suggested early on in this field of basic medical research that TNF-alpha and IL-1 were crucial in these diseases. Over the last 10 years, several approaches to inhibit TNF-alpha and, in one case, IL-1 activity, have been developed by the biotechnology and pharmaceutical industries.

Biology of tumor necrosis factor-alpha- implications for psoriasis.

Numerous recent investigations have pointed to a key role of the proinflammatory, pleiotropic cytokine tumor necrosis factor-alpha (TNF-alpha) in host defense and inflammatory processes. TNF overexpression has been found in lesional skin and in the circulation of psoriatic patients, and it was suggested that TNF-alpha is crucial in this and other immune diseases. Several approaches to inhibit TNF-alpha activity have been developed.

Interleukin-1 receptor antagonist transiently impairs antibacterial defense but not survival in murine pneumococcal pneumonia.

The inhibition of the biological activity of IL-1 by recombinant human IL-1 receptor antagonist (IL-1ra) has been investigated in several, controlled clinical trials. Encouraging results have been reported, in particular in patients with rheumatoid arthritis. In the present study, we investigated the influence of treatment of wild type mice with IL-1ra, which resulted in an incomplete and transient inhibition of IL-1 activity.

A locus on mouse chromosome 6 that determines resistance to herpes simplex virus also influences reactivation, while an unlinked locus augments resistance of female mice.

During studies to determine a role for tumor necrosis factor (TNF) in herpes simplex virus type 1 (HSV-1) infection using TNF receptor null mutant mice, we discovered a genetic locus, closely linked to the TNF p55 receptor (Tnfrsf1a) gene on mouse chromosome 6 (c6), that determines resistance or susceptibility to HSV-1. We named this locus the herpes resistance locus, Hrl, and showed that it also mediates resistance to HSV-2. Hrl has at least two alleles, Hrl(r), expressed by resistant strains like C57BL/6 (B6), and Hrl(s), expressed by susceptible strains like 129S6 (129) and BALB/c.

Design of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) for chronic inflammatory diseases.

A recombinant C-terminal truncated form of the human soluble tumor necrosis factor receptor type I (sTNF-RI) was produced in E. coli. This soluble receptor contains the first 2.

Autoimmune thyroid disease induced by thyroglobulin and lipopolysaccharide is inhibited by soluble TNF receptor type I.

Experimental autoimmune thyroiditis (EAT) is inducible in mice by immunization with thyroglobulin and adjuvant. Previous studies have shown that EAT is an autoimmune Th1-mediated disease but its characteristics differ with the adjuvant. Granulomatous lesions with marked follicular disruption develop following administration of thyroglobulin (Tg) and complete Freund's adjuvant (CFA) whereas when lipopolysaccharide (LPS) is used as the adjuvant only focal infiltrates of mononuclear cells are observed.