Uniformity of cardiac I-MIBG uptake on SPECT images in older adults with normal cognition and patients with dementia.

Introduction: Some studies report that assessing regional I-cardiac MIBG uptake can aid in the diagnosis of Lewy body disease, but others report heterogeneity in healthy controls. We aimed to evaluate regional cardiac MIBG uptake patterns in healthy older adults and patients with dementia.

Methods: 31 older adults with normal cognition, 15 Alzheimer's disease (AD), and 17 Dementia with Lewy bodies (DLB) patients were recruited.

Assessment of normal reference values for thyroid uptake of technetium-99m pertechnetate in a single centre UK population.

Objective: This study aims to explore the normal reference values for thyroid uptake of technetium-99m (Tc) pertechnetate in a UK population.

Patients And Methods: A retrospective review of 60 euthyroid patients who underwent thyroid imaging with Tc pertechnetate between January 2012 to April 2014 as part of dual-tracer subtraction parathyroid scintigraphy. Tc pertechnetate thyroid uptake values were determined for each patient.

The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study.

Abnormal methylation in gene promoters is a hallmark of the cancer genome; however, factors that may influence promoter methylation have not been well elucidated. As the one-carbon metabolism pathway provides the universal methyl donor for methylation reactions, perturbation of this pathway might influence DNA methylation and, ultimately, affect gene functions. Utilizing approximately 800 breast cancer tumor tissues from a large population-based study, we investigated the relationships between dietary and genetic factors involved in the one-carbon metabolism pathway and promoter methylation of a panel of 13 breast cancer-related genes.

Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors.

Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with approximately 1-10mM binding affinity (K(D)) were iteratively optimized to give leads with approximately 200nM biochemical activity and low microM cellular activity in a Replicon assay.

SAR by MS: discovery of a new class of RNA-binding small molecules for the hepatitis C virus: internal ribosome entry site IIA subdomain.

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole 'hit' 1 with a KD approximately 100 microM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure-activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct.

Aryl urea analogs with broad-spectrum antibacterial activity.

The preparation and evaluation of novel aryl urea analogs as broad-spectrum antibacterial agents is described. Numerous compounds showed low micromolar minimum inhibitory concentrations (MIC) against both Gram-positive and Gram-negative bacteria. Selected analogs also exhibited in vivo efficacy in a lethal murine model of bacterial septicemia.

Optimizing the antibacterial activity of a lead structure discovered by "SAR by MS" technology.

We report on lead optimization of a compound that was originally discovered to bind bacterial 23S rRNA near the L11 binding site and inhibit translation in vitro, but lacked detectable antibacterial activity. In this study, we were able to generate compounds with antibacterial activity against Gram-negative and Gram-positive pathogens, including a methicillin-resistant S. aureus strain.

Biaryl guanidine inhibitors of in vitro HCV-IRES activity.

A structure-activity relationship analysis was carried out on a high-throughput small molecule screening lead for HCV-IRES translation inhibition. The study led to the identification of a guanidine-based structure with low microM inhibitory activity.

Identification of 2-aminobenzimidazole dimers as antibacterial agents.

The preparation and evaluation of 2-aminobenzimidazole dimers as antibacterial agents is described. Biological screening of the dimers indicated that compounds with multiple chloro substituents possessed optimal antibacterial activity.

Antibacterial activity of quinolone-macrocycle conjugates.

Novel quinolone-macrocycle conjugates displayed submicromolar antibacterial activity against Escherichia coli and Staphylococcus aureus bacterial strains. An analogous open-chain structure was not active at 100 microM against the same pathogenic strains.

SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets.

A technique for lead discovery vs RNA targets utilizing mass spectrometry (MS) screening methods is described. The structure-activity relationships (SAR) derived from assaying weak binding motifs allows the pharmacophores discovered to be elaborated via "SAR by MS" to higher affinity ligands. Application of this strategy to a subdomain of the 23S rRNA afforded a new class of compounds with functional activity.

New inhibitors of bacterial protein synthesis from a combinatorial library of macrocycles.

A mixture-based combinatorial library of 14-membered macrocycles was synthesized to target ribosomal RNA and uncover a new class of antibacterial agents. High-throughput screening identified a macrocyclic mixture that inhibited cell-free-coupled transcription/translation in Escherichia coli-derived extracts, with an IC(50) value in the 25-50 microM range. In a follow-up library of 64 single macrocycles, 8 gave IC(50) values ranging from 12 to 50 microM in the cell-free protein synthesis inhibition assay.