Gene Expression Patterns in Peripheral Blood Correlate with the Extent of Coronary Artery Disease

Systemic and local inflammation plays a prominent role in the pathogenesis of atherosclerotic coronary artery disease, but the relationship of whole blood gene expression changes with coronary disease remains unclear. We have investigated whether gene expression patterns in peripheral blood correlate with the severity of coronary disease and whether these patterns correlate with the extent of atherosclerosis in the vascular wall

Virus-host interactomics: new insights and opportunities for antiviral drug discovery

International audienceThe current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. Our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. Towards this goal, the construction of virus-host interactomes is instrumental, mainly relying on the assumption that a viral infection at the cellular level can be viewed as a number of perturbations introduced into the host protein network when viral proteins make new connections and disrupt existing ones. Here, we review advances in interactomic approaches for viral infections, focusing on high-throughput screening (HTS) technologies and on the generation of high-quality datasets. We show how these are already beginning to offer intriguing perspectives in terms of virus-host cell biology and the control of cellular functions, and we conclude by offering a summary of the current situation regarding the potential development of host-oriented antiviral therapeutics

A systematic approach to preclinical and clinical safety biomarker qualification incorporating Bradford Hill’s principles of causality association

A number of pharmaceutical companies have become involved in exploring novel safety biomarkers based on the premise that improved predictors or earlier reporters of toxicity events will reduce the rate of drug attrition and repurpose resources to other improvements in R&D. Until recently, advances in safety biomarker research have lagged behind advances in efficacy-based biomarkers used in drug discovery and development. There are currently a number of pharmaceutical-academic-regulatory collaborations e.g. the C-Path Institute’s Predictive Safety Testing Consortium (PSTC), the Health and Environmental Sciences Institute (HESI-US), The International Life Sciences Institute (ILSI-worldwide) and Innovative Medicine Inititative’s Safer And Faster Evidence-based Translation consortium (IMI SAFE-T) aim to foster collective knowledge in the qualification of novel safety biomarkers to reduce new chemical entity attrition rates. While this is a laudable goal, scientific processes and appropriate standards for ‘prioritising’, ‘validating’ and ‘qualifying’ or candidate biomarkers are not clearly established and recognised. The recent FDA/EMEA guidelines on qualification of biomarkers are an important step in the regulatory processes of biomarker qualification1. Still, there are a number of unanswered concerns regarding what constitutes a useful biomarker with added value to historical biomarkers and what are the optimal ways of collecting and evaluating scientific evidence for the clinical qualification of a biomarker. The focus of this publication is to provide clarity on what is meant by the prioritisation and qualification of biomarker candidates. It is proposed that the well-known concept of Bradford Hill’s causality association criteria could be applied as a general framework for this purpose. Sir Austin Bradford Hill established the following nine criteria for causation (does factor A cause disorder B) to separate the causal and non-causal mechanisms of the observed associations. Although developed for use in the field of occupational medicine, these criteria (strength of association, consistency, temporality, biological gradient, plausibility, coherence, specificity, experimental evidence and analogy) can be used in many situations to establish causal relationships and we are proposing that Hill’s criteria offer a useful approach to aid the qualification of safety biomarkers

Discovery of proteins related to coronary artery disease using industrial-scale proteomics analysis of pooled plasma

Background Relating a disease state to an entire population of proteins provides an opportunity to gain new insights into a disease. Methods Male populations of 53 patients with angiographic coronary artery disease and 53 control subjects without coronary disease from the Duke Databank for Cardiovascular Disease were established and matched for age and race as well as extremes of risk factors. Major plasma protein abnormalities were excluded. Plasma samples of each group were pooled to make large volumes (6 L each) to identify low-abundance proteins. After removal of albumin as well as immunoglobulins and enrichment of smaller proteins (<20-40 kDa), samples were separated into 12 960 fractions by cation exchange and 2 reversed-phase chromatography steps. Proteins were analyzed by liquid chromatography–electrospray ionization tandem mass spectrometry. Results There were 731 plasma proteins or fragments identified. Of these proteins, 95 were differentially displayed in the case versus control populations. These represent broad categories of proteins involved with natural defenses, inflammation, growth, and coagulation

Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-α2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%–67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (–0.1 log 10 IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-α2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials

An anti-diabetic drug targets NEET (CISD) proteins through destabilization of their [2Fe-2S] clusters

Elevated levels of mitochondrial iron and reactive oxygen species (ROS) accompany the progression of diabetes, negatively impacting insulin production and secretion from pancreatic cells. In search for a tool to reduce mitochondrial iron and ROS levels, we arrived at a molecule that destabilizes the [2Fe-2S] clusters of NEET proteins (M1). Treatment of db/db diabetic mice with M1 improved hyperglycemia, without the weight gain observed with alternative treatments such as rosiglitazone. The molecular interactions of M1 with the NEET proteins mNT and NAF-1 were determined by X-crystallography. The possibility of controlling diabetes by molecules that destabilize the [2Fe–2S] clusters of NEET proteins, thereby reducing iron-mediated oxidative stress, opens a new route for managing metabolic aberration such as in diabetes