Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure.

Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N-acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.

The influence of psychosocial factors in veteran adjustment to civilian life.

AIM: Although most veterans have a successful transition to civilian life when they leave the military, some struggle to cope and adjust to the demands and challenges of civilian life. This study explores how a variety of psychosocial factors influence veteran adjustment to civilian life in Scotland, UK, and which of these factors predict a poor adjustment. METHODS: One hundred and fifty-four veterans across Scotland completed a set of questionnaires that measured veteran adjustment difficulty, quality of life, mental health, stigma, self-stigma, attitude towards help-seeking, likelihood of help-seeking, experiential avoidance, reappraisal and suppression. RESULTS: Veteran adjustment difficulty and quality of life were significantly correlated to a number of psychosocial factors. Mental health, experiential avoidance and cognitive reappraisal were found to be predictors of veteran adjustment difficulty, and experiential avoidance and cognitive reappraisal partially mediated the relationship between mental health and veteran adjustment, with experiential avoidance being the stronger mediator. DISCUSSION: Our findings suggest that early assessment of experiential avoidance and cognitive reappraisal and the provision of relevant emotion regulation skills training could potentially reduce the veteran's need for more complex (and costly) psychological interventions in the future. Implications for veterans, as well as the services and professionals involved with veteran transition and health care are discussed.

Development of a platform process for adenovirus purification that removes human SET and nucleolin and provides high purity vector for gene delivery.

The manufacturing of virus occurs at a modest scale in comparison to many therapeutic proteins mainly because a gene therapy dose is typically only µg of vector. Although modest in scale the generation of high purity virus is challenging due to low viral expression levels and the difficulties in adequately characterizing such a large and complex molecule. A 100 L bioreactor might produce only 100 mg of virus that must be separated from host and process impurities that are typically greater by several orders of magnitude. Furthermore, in the later purification stages the main milieu component is often virus at low concentration (µg/mL) which may non-specifically adsorb to purification surfaces resulting in a lowered virus recovery. This study describes our approach to develop a scalable, manufacturable robust process for an Adenovirus (Ad) gene therapy vector. A number of analytical tools were developed to guide the purification design. During process development, two human proteins, SET and nucleolin, were identified in viral preparations. To our knowledge, this is the first time that SET and nucleolin have been described in Ad. In this report we detail a process for their removal and the robust removal of all process, product and host cell impurities.