Individualized Household Allergen Intervention Lowers Allergen Level But Not Asthma Medication Use: A Randomized Controlled Trial.

Background: Environmental exposures to indoor allergens are major contributors to asthma symptoms, particularly in inner cities. The effectiveness of household allergen reduction as an adjunct to National Asthma Education Prevention Program guideline-based pharmacologic therapy in asthma has not been prospectively studied.

Objective: To study the effect of individualized allergen reduction on ability to reduce asthma pharmacologic therapy over 40 weeks.

DNA methylation of the allergy regulatory gene interferon gamma varies by age, sex, and tissue type in asthmatics.

Background: Asthma is associated with allergic sensitization in about half of all cases, and asthma phenotypes can vary by age and sex. DNA methylation in the promoter of the allergy regulatory gene interferon gamma (IFNγ) has been linked to the maintenance of allergic immune function in human cell and mouse models. We hypothesized that IFNγ promoter methylation at two well-studied, key cytosine phosphate guanine (CpG) sites (-186 and -54), may differ by age, sex, and airway versus systemic tissue in a cohort of 74 allergic asthmatics.

Analysis of multiple ethyl methanesulfonate-mutagenized Caenorhabditis elegans strains by whole-genome sequencing.

Whole-genome sequencing (WGS) of organisms displaying a specific mutant phenotype is a powerful approach to identify the genetic determinants of a plethora of biological processes. We have previously validated the feasibility of this approach by identifying a point-mutated locus responsible for a specific phenotype, observed in an ethyl methanesulfonate (EMS)-mutagenized Caenorhabditis elegans strain. Here we describe the genome-wide mutational profile of 17 EMS-mutagenized genomes as assessed with a bioinformatic pipeline, called MAQGene.

Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity.

Rationale: Silent gastroesophageal reflux (GER) is common in patients with asthma, but it is unclear whether GER is associated with worse asthma symptoms or reduced lung function.

Objectives: To determine in patients with poorly controlled asthma, whether proximal or distal esophageal reflux is associated with asthma severity, symptoms, physiology, or functional status.

Methods: Baseline asthma characteristics were measured in patients with asthma enrolled in a multicenter trial assessing the effectiveness of esomeprazole on asthma control.

SAR of carbon-linked, 2-substituted purines: synthesis and characterization of AP23451 as a novel bone-targeted inhibitor of Src tyrosine kinase with in vivo anti-resorptive activity.

Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Here, we describe structure activity relationships of a novel series of carbon-linked, 2-substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone-targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface.

Genetic screens for Caenorhabditis elegans mutants defective in left/right asymmetric neuronal fate specification.

We describe here the results of genetic screens for Caenorhabditis elegans mutants in which a single neuronal fate decision is inappropriately executed. In wild-type animals, the two morphologically bilaterally symmetric gustatory neurons ASE left (ASEL) and ASE right (ASER) undergo a left/right asymmetric diversification in cell fate, manifested by the differential expression of a class of putative chemoreceptors and neuropeptides. Using single cell-specific gfp reporters and screening through a total of almost 120,000 haploid genomes, we isolated 161 mutants that define at least six different classes of mutant phenotypes in which ASEL/R fate is disrupted.

Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds.

The tyrosine kinase pp60src (Src) is the prototypical member of a family of proteins that participate in a broad array of cellular signal transduction processes, including cell growth, differentiation, survival, adhesion, and migration. Abnormal Src family kinase (SFK) signaling has been linked to several disease states, including osteoporosis and cancer metastases. Src has thus emerged as a molecular target for the discovery of small-molecule inhibitors that regulate Src kinase activity by binding to the ATP pocket within the catalytic domain.

Structure-based design of novel nonpeptide inhibitors of the Src SH2 domain:phosphotyrosine mimetics exploiting multifunctional group replacement chemistry.

A series of novel nonpeptide inhibitors of the pp60(c-Src) (Src) SH2 domain is described that exploit multifunctional group replacement of the phenylphosphate moiety of phosphotyrosine (pTyr). Relative to an x-ray structure of citrate complexed to the pTyr binding site of the Src SH2 domain, these nonpeptide ligands illustrate the systematic replacement of the phosphate group by multiple nonhydrolyzable, mono- or dianionic functionalities. Specifically, several phenylalanine (Phe) analogs incorporating key 4' and 3' substituents were synthesized and incorporated into a bicyclic benzamide template previously reported (W.

Bone-targeted pyrido[2,3-d]pyrimidin-7-ones: potent inhibitors of Src tyrosine kinase as novel antiresorptive agents.

The design of bone-targeted pyrido[2,3-d]pyrimidin-7-ones as Src tyrosine kinase inhibitors is described. Leveraging SAR from known compounds and using structure-based methods, we were able to rapidly incorporate bone binding components, which maintained, and even increased potency against the target enzyme. Compound 4 displayed a high affinity for hydroxyapatite, a major constituent of bone, and demonstrated antiresoprtive activity in our cell-based assay.

Bone-targeted 2,6,9-trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases.

Novel bone-targeted 2,6,9-trisubstituted purine template-based inhibitors of Src tyrosine kinase are described. Drug design studies of known purine compounds revealed that both positions-2 and -6 were suitable for incorporating bone-seeking moieties. A variety of bone-targeting groups with different affinity to hydroxyapatite were utilized in the study.

Bone-targeted Src kinase inhibitors: novel pyrrolo- and pyrazolopyrimidine analogues.

Src tyrosine kinase is a therapeutic target for bone diseases that has been validated by gene knockout studies. Furthermore, in vitro cellular studies implicate that Src has a positive regulatory role in osteoclasts and a negative regulatory role in osteoblasts. The potential use of Src inhibitors for osteoporosis therapy has been previously shown by novel bone-targeted ligands of the Src SH2 (e.