Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases.

Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases.

BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma.

Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM.

Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an Efficacious TLR7/8 Antagonist.

Inappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8, starting from a co-crystal structure of a small screening hit. Further optimization of the physicochemical properties for cellular potency and expansion of the structure-activity relationship for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated efficacy after oral dosing.

US cost-effectiveness and budget impact of point-of-care NAAT for streptococcus.

Objectives: In the United States, approximately 12 million individuals seek medical care for pharyngitis each year, accounting for about 2% of ambulatory care visits. Although the gold standard for diagnosing group A streptococcus (GAS) is culture, it is time intensive. Rapid antigen detection tests (RADT) with or without culture confirmation are commonly used instead.

BET bromodomain inhibitors regulate keratinocyte plasticity.

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing.

Development of autotaxin inhibitors: A series of tetrazole cinnamides.

A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments.

Target-Based Identification and Optimization of 5-Indazol-5-yl Pyridones as Toll-like Receptor 7 and 8 Antagonists Using a Biochemical TLR8 Antagonist Competition Assay.

Inappropriate activation of endosomal TLR7 and TLR8 occurs in several autoimmune diseases, in particular systemic lupus erythematosus (SLE). Herein, the development of a TLR8 antagonist competition assay and its application for hit generation of dual TLR7/8 antagonists are reported. The structure-guided optimization of the pyridone hit using this biochemical assay in combination with cellular and TLR8 cocrystal structural data resulted in the identification of a highly potent and selective TLR7/8 antagonist () with efficacy.

Budget impact of intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency in France.

Aims: This analysis aims to evaluate the budget impact of intravenous iron therapy with ferric carboxymaltose for patients with systolic chronic heart failure and iron deficiency, from the perspective of the French public health insurance.

Methods And Results: A budget impact model was adapted to forecast the budget impact over 5 years, according to two scenarios: one where patients receive ferric carboxymaltose according to market share forecast and another where patients are not treated for iron deficiency. Clinical data were extrapolated from pooled data from four randomized controlled trials.

Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM.

Human antigen R (HuR) is a key regulator of cellular mRNAs containing adenylate/uridylate-rich elements (AU-rich elements; AREs). These are a major class of elements within 3' untranslated regions, targeting these mRNAs for rapid degradation. HuR contains three RNA recognition motifs (RRMs): a tandem RRM1 and 2, followed by a flexible linker and a C-terminal RRM3.

Development of autotaxin inhibitors: A series of zinc binding triazoles.

A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF-8380, as a template. Replacement of the benzoxazolone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 - a selective, high affinity, orally-bioavailable inhibitor of ATX.

Molecular detection of Borrelia burgdorferi sensu lato - An analytical comparison of real-time PCR protocols from five different Scandinavian laboratories.

Introduction: Lyme borreliosis (LB) is the most common tick transmitted disease in Europe. The diagnosis of LB today is based on the patient´s medical history, clinical presentation and laboratory findings. The laboratory diagnostics are mainly based on antibody detection, but in certain conditions molecular detection by polymerase chain reaction (PCR) may serve as a complement.

ICP Materials Trends in Corrosion, Soiling and Air Pollution (1987-2014).

Results from the international cooperative programme on effects on materials including historic and cultural monuments are presented from the period 1987-2014 and include pollution data (SO₂, NO₂, O₃, HNO₃ and PM), corrosion data (carbon steel, weathering steel, zinc, copper, aluminium and limestone) and data on the soiling of modern glass for nineteen industrial, urban and rural test sites in Europe. Both one-year and four-year corrosion data are presented. Corrosion and pollution have decreased significantly and a shift in the magnitude is generally observed around 1997: from a sharp decrease to a more modest decrease or to a constant level without any decrease.

Assessment of Hypertension Management and Outcomes at an Indianapolis Student-Run Free Clinic.

Purpose: To characterize the quality of health care at student-run free clinics (SRFCs) by analyzing hypertension management and outcomes at the Indiana University Student Outreach Clinic (IUSOC).

Methods: A retrospective review of medical records was conducted for hypertensive patients managed at IUSOC over 15 months (N = 64). Indiana University Student Outreach Clinic's hypertension control rate was compared with National Health and Nutrition Examination Survey (NHANES) data.

The Status of Biofilms in Penile Implants.

Erectile dysfunction is prevalent among men and will continue to become more so with the aging population. Of the available treatment options, implantable prosthetic devices are typically thought of as a third line treatment even though they have the highest satisfaction rate and continually improving success rates. Infection and mechanical failure are the most common reasons for implant revision in the past.

Health Care Evolution Is Driving Staffing Industry Transformation.

The powerful transformation in the health care industry is reshaping not only patient care delivery and the business of health care but also demanding new strategies from vendors who support the health care system. These new strategies may be most evident in workforce solutions and health care staffing services. Consolidation of the health care industry has created increased demand for these types of services.

Retrospective characterisation of solitary cutaneous histiocytoma with lymph node metastasis in eight dogs.

Objectives: To describe a small subset of canine solitary cutaneous histiocytoma in which lymph node metastasis has been documented.

Methods: Cases of dogs with solitary cutaneous histiocytoma lesions and regional lymph node metastasis diagnosed via histopathology were found through a retrospective search of the databases of IDEXX Laboratories and the University of California, Davis Veterinary Medical Teaching Hospital Clinical Diagnostic Laboratories. Information on signalment, history and clinical follow-up was obtained from the submittal form and/or via a questionnaire to the submitting veterinarian.

Global Health in Family Medicine Residency Programs: A Nationwide Survey of US Residency Directors: A CERA Study.

Background And Objectives: Interest in global health (GH) has increased significantly among medical trainees in the past 3 decades. Despite the potential for family medicine to be a major contributor to GH, there are no recent, large-scale studies of GH education and experiences in family medicine training. This study was designed to assess current opportunities, educational activities, resident interest, perceived program benefits, and barriers to international and domestic GH training in US family medicine residencies.

River bank burrowing by invasive crayfish: Spatial distribution, biophysical controls and biogeomorphic significance.

Invasive species generate significant global environmental and economic costs and represent a particularly potent threat to freshwater systems. The biogeomorphic impacts of invasive aquatic and riparian species on river processes and landforms remain largely unquantified, but have the potential to generate significant sediment management issues within invaded catchments. Several species of invasive (non-native) crayfish are known to burrow into river banks and visual evidence of river bank damage is generating public concern and media attention.

Ovarian stimulation with GnRH analogues.

Objective: Analysis and compare data between two induction protocols (long agonist and flexible antagonist) in patients submitted an assisted reproduction technique in Porto Alegre.

Methods: Cross-sectional study comparing the intermediate results with the use of two different ovarian stimulation protocols with gonadotropin-releasing hormone agonist versus antagonist to assisted reproductive techniques. The statistical analysis of the retrieved data (age, body mass index, number of oocytes recovered, number of fertilized oocytes, number of oocytes cleaved, total dose of FSH used and ovarian hyperstimulation syndrome) was performed by Student's t-test for parametric data and analysis of covariance for the dependent variables.

Release and environmental impact of silver nanoparticles and conventional organic biocides from coated wooden façades.

This study represents for the first time a comprehensive assessment of functionality and environmental impacts of metallic silver nanoparticles (Ag-NP) compared to conventional organic biocides. Four different transparent, hydrophobic coatings of wooden outdoor façades were tested during one year outdoor weathering. The total silver release from products with Ag-NP was proportional to the overall erosion of the coating.

Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project--part 2).

Background: Epidermal growth factor and v-Ki-ras2 Kirsten ras sarcoma (KRAS) mutation status, although associated with EGFR- tyrosine kinase inhibitor (TKI) efficacy, has not been used in clinical practice until recently. The prospective Evaluation of the EGFR Mutation status for the administration of EGFR-TKIs in non small cell lung Carcinoma (ERMETIC) study aimed to implement these biomarkers in France.

Methods: Between March 2007 and April 2008, EGFR and KRAS were studied by sequencing DNA tumor specimens from 522 consecutive advanced non-small-cell lung cancer patients treated with EGFR-TKI, mostly in second- or third-line settings.

Caspases cleave and inhibit the microRNA processing protein DiGeorge Critical Region 8.

DGCR8 (DiGeorge Critical Region 8) is an essential microRNA (miRNA) processing protein that recognizes primary transcripts of miRNAs (pri-miRNAs) and triggers their cleavage by the Drosha nuclease. We previously found that Fe(III) heme binds and activates DGCR8. Here we report that in HeLa cells, DGCR8 undergoes two proteolytic events that produce two C-terminal fragments called DGCR8(C1) and DGCR8(C2) , respectively.

Ultrathin, flexible, and transparent polymer multilayer composites for the protection of silver surfaces.

Silver coatings at the nanoscale became of high interest for the integration of electronic functionalities on all kinds of objects for daily use. In these thin coatings, corrosion is a big problem as it destroys these thin layers and leads to a loss of conductivity due to missing bulk material. For protection of thin silver coatings against H(2)S induced corrosion, we developed nanocoatings based on the covalent layer-by-layer technique.