Comparing GIS-Based Measures in Access to Mammography and Their Validity in Predicting Neighborhood Risk of Late-Stage Breast Cancer

Background

Assessing neighborhood environment in access to mammography remains a challenge when investigating its contextual effect on breast cancer-related outcomes. Studies using different Geographic Information Systems (GIS)-based measures reported inconsistent findings.

Methods

We compared GIS-based measures (travel time, service density, and a two-Step Floating Catchment Area method [2SFCA]) of access to FDA-accredited mammography facilities in terms of their Spearman correlation, agreement (Kappa) and spatial patterns. As an indicator of predictive validity, we examined their association with the odds of late-stage breast cancer using cancer registry data.

Results

The accessibility measures indicated considerable variation in correlation, Kappa and spatial pattern. Measures using shortest travel time (or average) and service density showed low correlations, no agreement, and different spatial patterns. Both types of measures showed low correlations and little agreement with the 2SFCA measures. Of all measures, only the two measures using 6-timezone-weighted 2SFCA method were associated with increased odds of late-stage breast cancer (quick-distance-decay: odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.01–1.32; slow-distance-decay: OR = 1.19, 95% CI = 1.03–1.37) after controlling for demographics and neighborhood socioeconomic deprivation.

Conclusions

Various GIS-based measures of access to mammography facilities exist and are not identical in principle and their association with late-stage breast cancer risk. Only the two measures using the 2SFCA method with 6-timezone weighting were associated with increased odds of late-stage breast cancer. These measures incorporate both travel barriers and service competition. Studies may observe different results depending on the measure of accessibility used.     

A twist in the tail: SHAPE mapping of long-range interactions and structural rearrangements of RNA elements involved in HCV replication

The RNA structure and long-range interactions of the SL9266 cis-acting replication element located within the NS5B coding region of hepatitis C virus (HCV) were determined using selective 2'-hydroxyl acylation analysed by primer extension. Marked differences were found in the long-range interactions of SL9266 when the two widely used genotype 2a JFH-1 (HCVcc) and genotype 1b Con1b sub-genomic replicon systems were compared. In both genomes, there was evidence for interaction of the sub-terminal bulge loop of SL9266 and sequences around nucleotide 9110, though the replication phenotype of genomes bearing mutations that disrupted this interaction was fundamentally different. In contrast, a 'kissing loop' interaction between the terminal loop of SL9266 and sequences in the 3'-untranslated X-tail was only detectable in JFH-1-based genomes. In the latter, where both long-range interactions are present, they were independent, implying that SL9266 forms the core of an extended pseudoknot. The presence of the 'kissing loop' interaction inhibited the formation of SL9571 in the 3'-X-tail, an RNA structure implicated in genome replication. We propose that, SL9266 may contribute a switch function that modulates the mutually incompatible translation and replication events that must occur for replication of the positive-strand RNA genome of HCV.     

Investigation of piperazine benzamides as human β3 adrenergic receptor agonists for the treatment of overactive bladder

The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human β₃-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established β₃ potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.     

Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension

We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.     

Inducible cytochrome P450 activities in renal glomerular mesangial cells: biochemical basis for antagonistic interactions among nephrocarcinogenic polycyclic aromatic hydrocarbons

BACKGROUND: Benzo(a)pyrene (BaP), anthracene (ANTH) and chrysene (CHRY) are polynuclear aromatic hydrocarbons (PAHs) implicated in renal toxicity and carcinogenesis. These PAHs elicit cell type-specific effects that help predict toxicity outcomes in vitro and in vivo. While BaP and ANTH selectively injure glomerular mesangial cells, and CHRY targets cortico-tubular epithelial cells, binary or ternary mixtures of these hydrocarbons markedly reduce the overall cytotoxic potential of individual hydrocarbons. METHODS: To study the biochemical basis of these antagonistic interactions, renal glomerular mesangial cells were challenged with BaP alone (0.03 - 30 microM) or in the presence of ANTH (3 microM) or CHRY (3 microM) for 24 hr. Total RNA and protein will be harvested for Northern analysis and measurements of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin-O-deethylase (EROD) activity, respectively, to evaluate cytochrome P450 mRNA and protein inducibility. Cellular hydrocarbon uptake and metabolic profiles of PAHs were analyzed by high performance liquid chromatography (HPLC). RESULTS: Combined hydrocarbon treatments did not influence the cellular uptake of individual hydrocarbons. ANTH or CHRY strongly repressed BaP-inducible cytochrome P450 mRNA and protein expression, and markedly inhibited oxidative BaP metabolism. CONCLUSION: These findings indicate that antagonistic interactions among nephrocarcinogenic PAHs involve altered expression of cytochrome P450s that modulate bioactivation profiles and nephrotoxic/ nephrocarcinogenic potential.     

Design,synthesis and structure-activity relationships of novel imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists

SAR studies of lead GnRH receptor antagonists 2a and 2b reported earlier resulted in the discovery of compound 10b which showed much higher potency (K(i)=4.6 nM, compared with 2b, K(i)=230 nM) in which the 7-position of the imidazolo[1,2-a]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group.