Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.

We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.

Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.

Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in preclinical studies and clinical trials for MDS and AML.

Characterization of Oligomer Formation of Surfactant Protein-D (SP-D) Using AF4-MALLS.

Background: Surfactant protein-S (SP-D) is a naturally occurring lung protein with the potential to treat pulmonary infections. A recombinant surfactant protein-D (SP-D) has been produced and was previously found to exist in multiple oligomeric states.

Introduction: Separation and characterization of interconverting oligomeric states of a protein can be difficult using chromatographic methods, so an alternative separation technique was employed for SPD to characterize the different association states that exist.

The Emergent Yo-yo Movement of Nuclei Driven by Cytoskeletal Remodeling in Pseudo-synchronous Mitotic Cycles.

Many aspects in tissue morphogenesis are attributed to a collective behavior of the participating cells. Yet, the mechanism for emergence of dynamic tissue behavior is not well understood. Here, we report that the "yo-yo"-like nuclear movement in the Drosophila syncytial embryo displays emergent features indicative of collective behavior.

Structure and activity of human surfactant protein D from different natural sources.

Surfactant protein D (SP-D) is a C-type lectin that participates in the innate immune defense of lungs. It binds pathogens through its carbohydrate recognition domain in a calcium-dependent manner. Human surfactant protein D (hSP-D) has been routinely obtained from bronchoalveolar lavage of patients suffering from pulmonary alveolar proteinosis (PAP) and from amniotic fluid (AF).

Mechanical Model of Nuclei Ordering in Drosophila Embryos Reveals Dilution of Stochastic Forces.

During the initial development of syncytial embryos, nuclei go through cycles of nuclear division and spatial rearrangement. The arising spatial pattern of nuclei is important for subsequent cellularization and morphing of the embryo. Although nuclei are contained within a common cytoplasm, cytoskeletal proteins are nonuniformly packaged into regions around every nucleus.

A 'molecular guillotine' reveals the interphase function of Kinesin-5.

Motor proteins are important for transport and force generation in a variety of cellular processes and in morphogenesis. Here, we describe a general strategy for conditional motor mutants by inserting a protease cleavage site into the 'neck' between the head domain and the stalk of the motor protein, making the protein susceptible to proteolytic cleavage at the neck by the corresponding protease. To demonstrate the feasibility of this approach, we inserted the cleavage site of the tobacco etch virus (TEV) protease into the neck of the tetrameric motor Kinesin-5.

Cannabinor, a selective cannabinoid-2 receptor agonist, improves bladder emptying in rats with partial urethral obstruction.

Purpose: We studied the effects of chronic treatment with the novel selective cannabinoid 2 receptor agonist cannabinor (Procter & Gamble Pharmaceuticals, Cincinnati, Ohio) on bladder function in conscious rats with partial urethral obstruction and on the functional properties of isolated detrusor muscle.

Materials And Methods: A total of 24 female Sprague-Dawley® rats with surgically created partial urethral obstruction received daily intraperitoneal injections of 3 mg/kg cannabinor (12) or saline as controls (12) for 2 weeks. Cystometry was done, the rats were sacrificed and the bladders were prepared for in vitro studies.

Urothelial beta-3 adrenergic receptors in the rat bladder.

Aims: To investigate the distribution of beta-3 adrenergic receptors (β(3)ARs) in the rat bladder and to examine the contribution of urothelial β(3)ARs to agonist-induced suppression of bladder reflexes and relaxation of smooth muscle.

Methods: Bladder tissue was collected from 8- to 10-month old female SD rats. In some samples, the urothelium was surgically separated from the smooth muscle.

β-Adrenergic receptor subtype expression in myocyte and non-myocyte cells in human female bladder.

β(3)-Adrenergic receptor agonists are currently under clinical development for the treatment of overactive bladder, a condition that is prevalent in postmenopausal women. These agents purportedly relax bladder smooth muscle through a direct action at the myocyte β(3)-receptor. The aim of this study was to examine the expression of the individual beta-adrenergic receptors in full thickness sections from ageing human female bladder.

Comparison of the effects of oestrogen deficiency and old age on primary bladder afferent activity and voiding behaviour in the ageing female rat.

Objective: To determine if a decrease in oestrogen (E) levels increases activity in bladder afferent nerves, by investigating the effects of E loss on afferent nerve activity in ovariectomized (OVX) rats, and making comparisons with findings in ageing female rats.

Materials And Methods: Female Sprague-Dawley rats were divided into four groups: ageing; OVX+ E; OVX+ vehicle (V); and sham-operated (SHAM) + V. The E (250 µg/kg) or V (cottonseed oil) was injected s.

Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats.

Background: Cannabinoid (CB) receptors may be involved in the control of bladder function; the role of CB receptor subtypes in micturition has not been established.

Objectives: Our aim was to evaluate the effects of cannabinor, a novel CB2 receptor agonist, on rat bladder function.

Design, Setting, And Participants: Sprague Dawley rats were used.

Effects of beta3-adrenergic receptor activation on rat urinary bladder hyperactivity induced by ovariectomy.

Voiding dysfunctions, including increased voiding frequency, urgency, or incontinence, are prevalent in the postmenopausal population. Beta(3)-adrenergic receptor (beta(3)AR) agonists, which relax bladder smooth muscle, are being developed to treat these conditions. We utilized the rat ovariectomy (OVX) model to investigate the effect of ovarian hormone depletion on bladder function and the potential for beta(3)AR agonists to treat bladder hyperactivity in this setting.

AMD3100 is a CXCR7 ligand with allosteric agonist properties.

The bicyclam AMD3100 is known as a small synthetic inhibitor of the CXCL12-binding chemokine receptor CXCR4. Here, we show that AMD3100 also binds to the alternative CXCL12 receptor CXCR7. CXCL12 or AMD3100 alone activate beta-arrestin recruitment to CXCR7, which we identify as a previously unreported signaling pathway of CXCR7.

GPR30 contributes to estrogen-induced thymic atrophy.

The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta), in 17beta-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ERalpha and ERbeta gene-deficient mice. Our study shows that whereas ERalpha mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that preferentially occurs in T cell receptor beta chain(-/low) double-positive thymocytes.

The Y2 receptor mediates increases in collateral-dependent blood flow in a model of peripheral arterial insufficiency.

We have utilized a rat model of peripheral artery disease (PAD) to examine whether the known angiogenic activity of the Y(2) receptor would translate into a meaningful increase in collateral blood flow. The maximal increase in collateral blood flow capacity of approximately 60% (p<0.001) was obtained with a 10microg/kgday (IA infusion, 14 days) of either PYY or PYY(3-36) and did not differ from that obtained with a maximally angiogenic dose of VEGF(165).

Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165.

Neuropilin-1 (Npn-1) is a receptor for both semaphorin 3A (Sema3A) and vascular endothelial growth factor 165 (VEGF(165)). To understand the role Npn-1 plays as a receptor for these structurally and functionally unrelated ligands, we set out to identify structural features of Npn-1 that confer binding to Sema3A or VEGF(165). We constructed Npn-1 variants containing deletions within the "a" and "b" domains of Npn-1.