Unique pharmacological properties of etrasimod among S1P receptor modulators.

Etrasimod (ADP334) is an oral, once-daily, selective sphingosine 1-phosphate (S1P) receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of immune-mediated inflammatory diseases. Interaction between S1P and its five receptor subtypes (S1P-S1P) plays a role in several physiologic systems, including the cardiovascular and immune systems. Since differences in S1PR binding and downstream intracellular signaling could contribute to distinct profiles of drug efficacy and safety, we directly compared the S1P selectivity profile of etrasimod to three marketed S1PR modulators: fingolimod, ozanimod, and siponimod.

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms.

Discovery of 2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays.

Quantitative measurement of HER2 expression in breast cancers: comparison with 'real-world' routine HER2 testing in a multicenter Collaborative Biomarker Study and correlation with overall survival.

Introduction: Accurate assessment of HER2 status is critical in determining appropriate therapy for breast cancer patients but the best HER2 testing methodology has yet to be defined. In this study, we compared quantitative HER2 expression by the HERmark™ Breast Cancer Assay (HERmark) with routine HER2 testing by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and correlated HER2 results with overall survival (OS) of breast cancer patients in a multicenter Collaborative Biomarker Study (CBS).

Methods: Two hundred and thirty-two formalin-fixed, paraffin-embedded breast cancer tissues and local laboratory HER2 testing results were provided by 11 CBS sites.

Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.

The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.

Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer.

Introduction: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC).

Methods: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC- docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2-every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m × 1 and obatoclax 30 mg × 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose.

Lexical decision and the number of morphemes and affixes.

There has been a considerable amount of research looking at the effects of both syllable number and syllable frequency on lexical decision and word naming times. Recently, there has also been an increased interest in morphological variables, but there have been no large scale studies that have examined the role of the number of morphemes in lexical decision for nonwords. This is partly because of the difficulty of identifying morphemes in nonwords.

Bigram frequency, number of syllables and morphemes and their effects on lexical decision and word naming.

There has been an increasing volume of evidence supporting the role of the syllable in word processing tasks. Recently it has also been shown that orthographic redundancy, related to the pattern of bigram frequencies, could not explain the syllable number effect on lexical decision times. This was demonstrated on a large sample of words taken from the British Lexicon Project.

Inhibition of Mas G-protein signaling improves coronary blood flow, reduces myocardial infarct size, and provides long-term cardioprotection.

The Mas receptor is a class I G-protein-coupled receptor that is expressed in brain, testis, heart, and kidney. The intracellular signaling pathways activated downstream of Mas are still largely unknown. In the present study, we examined the expression pattern and signaling of Mas in the heart and assessed the participation of Mas in cardiac ischemia-reperfusion injury.

The role of syllables in anagram solution: a Rasch analysis.

Anagrams are frequently used by experimental psychologists interested in how the mental lexicon is organized. Until very recently, research has overlooked the importance of syllable structure in solving anagrams and assumed that solution difficulty was mainly due to frequency factors (e.g.

Relationship between cynicism and job satisfaction: exploration of mechanisms.

Personality traits related to evaluation of other people and the world are important to study in relation to job satisfaction, which itself is an evaluation of various facets of a job, including the social dimensions. Accordingly, the relationship between cynicism and job satisfaction was studied. Cynicism was expected to be negatively related to job satisfaction, employees' perceptions of job enrichment, quality of leader-member exchange, and support from coworkers.

Solubilized phenyl-pyrazole ureas as potent, selective 5-HT(2A) inverse-agonists and their application as antiplatelet agents.

Potent 5-HT(2A) inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation.

APD791, 3-methoxy-n-(3-(1-methyl-1h-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a novel 5-hydroxytryptamine 2A receptor antagonist: pharmacological profile, pharmacokinetics, platelet activity and vascular biology.

We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide] a novel 5-hydroxytryptamine 2A (5-HT(2A)) receptor antagonist. APD791 displayed high-affinity binding to membranes (K(i) = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC(50) = 5.

Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor.

G protein-coupled receptors (GPCRs) play an essential role in the regulation of cardiovascular function. Therapeutic modulation of GPCRs has proven to be beneficial in the treatment of human heart disease. Myocardial "orphan" GPCRs, for which the natural ligand is unknown, represent potential novel therapeutic targets for the treatment of heart disease.

Anti-thrombotic and vascular effects of AR246686, a novel 5-HT2A receptor antagonist.

We have evaluated the anti-platelet and vascular pharmacology of AR246686, a novel 5-hydroxytryptamine2A (5-HT2A) receptor antagonist. AR246686 displayed high affinity binding to membranes of HEK cells stably expressing recombinant human and rat 5-HT2A receptors (Ki=0.2 nM and 0.

Galphaq expression activates EGFR and induces Akt mediated cardiomyocyte survival: dissociation from Galphaq mediated hypertrophy.

Our laboratory has previously shown that adenoviral-mediated overexpression of Galphaq in neonatal rat ventricular cardiomyocytes increases the phosphorylation of Akt, a well-established anti-apoptotic effector. As demonstrated here, Galphaq expression protects cardiomyocytes against apoptosis induced by treatment with 2-deoxyglucose (2DOG) and this protection is lost when Akt activation is prevented by treatment with LY294002 (an inhibitor of PI3K). Galphaq-induced Akt phosphorylation is not caused by increased Gbetagamma signaling and does not appear to involve PKC activation.

Stimulus similarity decrements in children's working memory span.

Two experiments investigated the impact of the relationship between processing and storage stimuli on the working memory span task performance of children aged 7 and 9 years of age. In Experiment 1, two types of span task were administered (sentence span and operation span), and participants were required to recall either the products of the processing task (sentence-final word, arithmetic total) or a word or digit unrelated to the processing task. Experiment 2 contrasted sentence span and operation span combined with storage of either words or digits, in tasks in which the item to be remembered was not a direct product of the processing task in either condition.

Ca2+ dysregulation induces mitochondrial depolarization and apoptosis: role of Na+/Ca2+ exchanger and AKT.

We previously reported that constitutively activated Galpha(q) (Q209L) expression in cardiomyocytes induces apoptosis through opening of the mitochondrial permeability transition pore. We assessed the hypothesis that disturbances in Ca(2+) handling linked Galpha(q) activity to apoptosis because resting Ca(2+) levels were significantly increased prior to development of apoptosis. Treating cells with EGTA lowered Ca(2+) and blocked both loss of mitochondrial membrane potential (an indicator of permeability transition pore opening) and apoptosis (assessed by DNA fragmentation).

Children's working memory: investigating performance limitations in complex span tasks.

Three experiments investigated the roles of resource-sharing and intrinsic memory demands in complex working memory span performance in 7- and 9-year-olds. In Experiment 1, the processing complexity of arithmetic operations was varied under conditions in which processing times were equivalent. Memory span did not differ as a function of processing complexity.

Lysophosphatidic acid induces hypertrophy of neonatal cardiac myocytes via activation of Gi and Rho.

The effect of the lysophospholipid, lysophosphatidic acid (LPA), on signaling and hypertrophy of neonatal rat ventricular cardiomyocytes was examined. Myocytes express mRNA for all three G-protein-coupled LPA receptor subtypes (LPA(1)/Edg-2, LPA(2)/Edg-4, and LPA(3)/Edg-7) as indicated by RT-PCR analysis. LPA inhibits isoproterenol-stimulated cyclic AMP accumulation with an IC(50) approximately 40 nM and promotes phosphorylation of ERK-1/2.

Akt-mediated cardiomyocyte survival pathways are compromised by G alpha q-induced phosphoinositide 4,5-bisphosphate depletion.

Expression of the wild type alpha subunit of Gq (GqWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active G alpha q subunit (GqQ209L) induces apoptosis. Akt phosphorylation increases with GqWT expression but is markedly attenuated in cardiomyocytes expressing GqQ209L or in those expressing GqWT and treated with agonist. A membrane-targeted Akt rescues GqQ209L-expressing cardiomyocytes from apoptotic cell death.