Generalized Read-Across (GenRA): A workflow implemented into the EPA CompTox Chemicals Dashboard.

Generalized Read-Across (GenRA) is a data driven approach which makes read-across predictions on the basis of a similarity weighted activity of source analogues (nearest neighbors). GenRA has been described in more detail in the literature (Shah et al., 2016; Helman et al.

Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol.

Background: Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self-administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons.

The CompTox Chemistry Dashboard: a community data resource for environmental chemistry.

Despite an abundance of online databases providing access to chemical data, there is increasing demand for high-quality, structure-curated, open data to meet the various needs of the environmental sciences and computational toxicology communities. The U.S.

In Vitro and In Vivo Evaluation of Cysteine Rebridged Trastuzumab-MMAE Antibody Drug Conjugates with Defined Drug-to-Antibody Ratios.

The conjugation of monomethyl auristatin E (MMAE) to trastuzumab using a reduction bis-alkylation approach that is capable of rebridging reduced (native) antibody interchain disulfide bonds has been previously shown to produce a homogeneous and stable conjugate with a drug-to-antibody ratio (DAR) of 4 as the major product. Here, we further investigate the potency of the DAR 4 conjugates prepared by bis-alkylation by comparing to lower drug loaded variants to maleimide linker based conjugates possessing typical mixed DAR profiles. Serum stability, HER2 receptor binding, internalization, in vitro potency, and in vivo efficacy were all evaluated.

Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor.

Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists.

S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties.

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor.

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

Bridging disulfides for stable and defined antibody drug conjugates.

To improve both the homogeneity and the stability of ADCs, we have developed site-specific drug-conjugating reagents that covalently rebridge reduced disulfide bonds. The new reagents comprise a drug, a linker, and a bis-reactive conjugating moiety that is capable of undergoing reaction with both sulfur atoms derived from a reduced disulfide bond in antibodies and antibody fragments. A disulfide rebridging reagent comprising monomethyl auristatin E (MMAE) was prepared and conjugated to trastuzumab (TRA).

Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease.

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.

Site-specific PEGylation at histidine tags.

The efficacy of protein-based medicines can be compromised by their rapid clearance from the blood circulatory system. Achieving optimal pharmacokinetics is a key requirement for the successful development of safe protein-based medicines. Protein PEGylation is a clinically proven strategy to increase the circulation half-life of protein-based medicines.

Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P₁ agonists.

S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.

Nutritional bioactive components of wheat straw as affected by genotype and environment.

Policosanol (PC) and phytosterol (PS) enriched dietary supplements and functional foods are marketed for their low density lipoprotein lowering properties. The presence of PC and PS in wheat straw has been reported previously. Wheat straw can be a potential source for recovery of high value components.

Normoxia vs. hyperoxia: impact of oxygen tension strategies on outcomes for patients receiving cardiopulmonary bypass for routine cardiac surgical repair.

Oxygen pressure field theory (OPFT) was originally described in the early 1900s by Danish physiologist, Dr. August Krogh. This revolutionary theory described microcirculation of blood gases at the capillary level using a theoretical cylindrical tissue model commonly referred to as the Krogh cylinder.

Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions.

Background: The mechanism(s) by which pulmonary veins (PVs) become ectopically active and subsequently initiate and sustain atrial fibrillation (AF) remains poorly understood.

Objectives: The purpose of this study was to produce an acute canine model of paroxysmal AF arising from the PVs.

Methods: In 11 dogs, a thoracotomy was performed and a 26-gauge needle with a polyethylene tube attached was inserted into a fat pad containing autonomic ganglia at the base of the PV.

A versatile extracorporeal circuit for use during repair of descending and thoracoabdominal aortic aneurysms in high-risk patients with cardiac and/or pulmonary dysfunction: a novel approach to a significant perfusion management dilemma.

The incidence of ischemic complications associated with repair of descending and thoracoabdominal aortic aneurysms has been significantly reduced by the use of distal aortic perfusion with moderate hypothermia, cerebral spinal fluid drainage, and segmental sequential clamping techniques. However, because the maintenance of proximal perfusion, the adequacy of left heart bypass (LHB), and the ability to ventilate patients on only one lung are all dependent on ventricular and pulmonary function, high-risk patients with descending and/or thoracoabdominal aortic aneurysms in the presence of cardiopulmonary insufficiency or instability present a difficult challenge for the surgical team. Traditional closed LHB circuits become nonfunctional in the event of cardiac arrest or refractory arrhythmias that create hemodynamic instability and are unable to provide necessary pulmonary support if the patient fails to ventilate adequately on one lung during thoracotomy.

Successful use of Argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient.

Whereas heparin is the most widely used intravenous anticoagulant in the US for the treatment of thromboembolic disease and is a seminal adjunct to many clinical procedures, its use can cause serious adverse events. Heparin-induced thrombocytopenia (HIT) has emerged as one of the most frequently seen complications of heparin therapy and can be a life-threatening immunohematological challenge for patients requiring cardiopulmonary bypass (CPB) with obligatory heparin exposure. Unfortunately, lack of convenient monitoring techniques and the presence of HIT and other comorbidities in the complex patient frequently limits or precludes the use of most alternatives to heparin anticoagulation during CPB.