Toward the Discovery of a Novel Class of YAP⁻TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP⁻TEAD Protein⁻Protein Interface.

Intrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP-hTEAD1 complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD.

De-escalation of antifungal treatment in critically ill patients with suspected invasive Candida infection: incidence, associated factors, and safety.

Background: Antifungal treatment is common in critically ill patients, but only a small proportion of patients receiving antifungals have a proven fungal infection. However, antifungal treatment has side effects such as toxicity, emergence of resistance, and high cost. Moreover, empirical antifungal treatment is still a matter for debate in these patients.

Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review.

Objective: To describe safety and efficacy of rituximab in patients with systemic sclerosis.

Methods: We included 13 patients with systemic sclerosis treated with rituximab and pooled with 40 additional patients from the literature. SSc rituximab untreated patients were matched to rituximab treated ones.

Immunoglobulin G (IgG) and IgG subclass reference intervals in children, using Optilite® reagents.

Background: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite® reagents from The Binding Site Group Ltd.

Supercritical fluid chromatography versus high performance liquid chromatography for enantiomeric and diastereoisomeric separations on coated polysaccharides-based stationary phases: Application to dihydropyridone derivatives.

For analytical applications, SFC has always remained in the shadow of LC. Analytical enantioseparation of eight dihydropyridone derivatives, was run in both High Performance Liquid Chromatography and Supercritical Fluid Chromatography. Four polysaccharide based chiral stationary phases namely amylose and cellulose tris(3, 5-dimethylphenylcarbamate), amylose tris((S)-α-phenylethylcarbamate) and cellulose tris(4-methylbenzoate) with four mobile phases consisted of either n-hexane/ethanol or propan-2-ol (80:20 v:v) or carbon dioxide/ethanol or propan-2-ol (80:20 v:v) mixtures were investigated under same operatory conditions (temperature and flow-rate).

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism.

The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease.

Association between Rheumatoid Arthritis and Pulmonary Hypertension: Data from the French Pulmonary Hypertension Registry.

Background: Precapillary pulmonary hypertension (PH), and particularly pulmonary arterial hypertension (PAH), is a life-threatening complication of connective tissue diseases (systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease). The relationship between PH and rheumatoid arthritis (RA) has not been clearly established.

Objectives: The aim of the study was to evaluate the relationship between precapillary PH and RA.

Development of novel oxazolo[5,4-d]pyrimidines as competitive CB neutral antagonists based on scaffold hopping.

A series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB/CB cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB ligands with K values less than 1 μM.

Value of the Overall Pneumococcal Polysaccharide Response in the Diagnosis of Primary Humoral Immunodeficiencies.

Background: An overall response assay [OVA, based on a 23-valent pneumococcal polysaccharide vaccine (PPV23)] is widely used to screen for anti-pneumococcal antibodies. Given the heterogeneity of response from one polysaccharide (PS) to another, a World Health Organization-standardized serotype-specific enzyme-linked immunosorbent assay (SSA) is considered to be the only reliable method for testing anti-PS antibody responses in individuals with suspected primary immunodeficiencies (PIDs).

Objective: To evaluate the OVA relative to the reference SSA.

A standardized flow cytometry procedure for the monitoring of regulatory T cells in clinical trials.

Background: Quantification of regulatory T cells (Tregs) is crucial in immunomonitoring in clinical trials as this cell population has been shown to be involved in a wide range of diseases, including cancers, autoimmune diseases, infections, and allergies. Human Tregs are defined as CD4 CD25 CD127 FoxP3 cells, and the standardization of their staining by flow cytometry is a challenge, especially in multicenter clinical trials, notably because of the intracellular location of FoxP3.

Method: A flow cytometry staining procedure was settled and standardized to measure human Tregs in peripheral whole blood using precoated dried antibodies in ready-to-use tubes.

The next generation of rapid point-of-care testing identification tools for ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is a frequent issue in intensive care units (ICU), with a major impact on morbidity, mortality and cost of care. VAP diagnosis remains challenging: traditional culture-based microbiological techniques are still the gold-standard, but are too slow to enable clinicians to improve prognosis with timely antimicrobial therapy adjustment. Prolonged exposure to inappropriate antibiotics has also been shown to increase the incidence of multi-drug-resistant organisms (MDROs).

(A Critical Appraisal of) Classification of Hypereosinophilic Disorders.

Hypereosinophilia (HE) is a heterogeneous condition that can be reported in various (namely inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. In 1975, Chusid et al. published the first diagnostic criteria of hypereosinophilic syndromes (HES).

Association Between Low Plasma Level of Citrulline Before Allogeneic Hematopoietic Cell Transplantation and Severe Gastrointestinal Graft vs Host Disease.

Background & Aims: The gastrointestinal form of acute graft vs host disease increases morbidity and mortality following allogeneic hematopoietic cell transplantation. Plasma levels of citrulline, a non-proteinogenic amino acid, indicate functional enterocyte mass. We measured citrulline in patients before allogeneic hematopoietic cell transplantation and investigated its association with incidence and severity of gastrointestinal graft vs host disease.

One- or Two-Step Synthesis of C-8 and N-9 Substituted Purines.

A novel and original strategy to obtain rapidly a large diversity of C-8 and N-9 substituted purines was developed. The present procedure describes annulation reactions in one or two steps starting from 5-aminoimidazole-4-carbonitriles 1-8 in moderate to good yields. 8,9-Disubstituted-6,9-dihydro-1H-purin-6-ones 9-14, 6-amino-8,9-disubstituted-3,9-dihydro-2H-purin-2-ones 15-20, 8,9-disubstituted-3,9-dihydro-2H-purin-2,6-diamines 21-24 and 6-imino-1-phenyl-8,9-disubstituted-6,9-dihydro-1H-purin-2-(3H)-ones 25-26 were synthesized in one step using formic acid, urea, guanidine carbonate, and phenylisocyanate, respectively, whereas 8,9-disubstituted-9H-purin-6-amines 27-31 and 6-imino-8,9-disubstituted-6,9-dihydro-1H-purin-1-amines 32-33 were obtained in two steps using formamide and hydrazine, respectively.

Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon.

Background: Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection.

Better early outcome with enteral rather than parenteral nutrition in children undergoing MAC allo-SCT.

There is no consensus on the type of nutritional support to introduce in children undergoing allogeneic stem cell transplantation (allo-SCT) after myeloablative conditioning (MAC). This retrospective, multicenter, observational study compared the early administration of enteral nutrition (EN group, n = 97) versus parenteral nutrition (PN group, n = 97) in such patients with matching for important covariates. The primary endpoint was the study of day 100 overall mortality.

Factors associated with the variability of calcineurin inhibitor blood levels in kidney recipients grafted for more than 1 year.

The study of calcineurin inhibitor (CNI) blood level variability to evaluate adherence in transplantation has improved over the years. The aim of our study was to assess factors associated with this variability using the coefficient of variation (CV). A cross-sectional sample of kidney recipients grafted for more than 1 year was recruited.

Peroxisome proliferator-activated receptor gamma (PPARγ) regulates lactase expression and activity in the gut.

Lactase (LCT) deficiency affects approximately 75% of the world's adult population and may lead to lactose malabsorption and intolerance. Currently, the regulation of LCT gene expression remains poorly known. Peroxisome proliferator activator receptorγ (PPARγ) is a key player in carbohydrate metabolism.

Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial.

Purpose: The aim of this study was to determine the impact of a biomarker-based strategy on early discontinuation of empirical antifungal treatment.

Methods: Prospective randomized controlled single-center unblinded study, performed in a mixed ICU. A total of 110 patients were randomly assigned to a strategy in which empirical antifungal treatment duration was determined by (1,3)-β-D-glucan, mannan, and anti-mannan serum assays, performed on day 0 and day 4; or to a routine care strategy, based on international guidelines, which recommend 14 days of treatment.

Factors Generating Glucose Degradation Products In Sterile Glucose Solutions For Infusion: Statistical Relevance Determination Of Their Impacts.

Sterilising glucose solutions by heat promotes the generation of a large number of glucose degradation products (GDPs). It has been shown that high levels of GDPs may result in Advanced Glycation End products that have an impact on cellular homeostasis and health in general. If data is available for peritoneal dialysis solutions, little has been published for glucose infusion fluids.

The Expression of the Short Isoform of Thymic Stromal Lymphopoietin in the Colon Is Regulated by the Nuclear Receptor Peroxisome Proliferator Activated Receptor-Gamma and Is Impaired during Ulcerative Colitis.

The etiology of inflammatory bowel diseases remains largely unknown. We previously demonstrated that the expression of the peroxisome proliferator activated receptor-gamma (PPARγ) is downregulated in colonic epithelial cells of patients with ulcerative colitis (UC). PPARγ is a nuclear receptor that modulates inflammation.