A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon

Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP). Previous analyses found no significant differences between the distributions of CTLA-4 polymorphisms in the melanoma population vs. controls, no significant difference in relapse free and overall survivals among patients and no correlation between autoimmunity and specific alleles. We report new analysis of these CTLA-4 genetic profiles, using Network Phenotyping Strategy (NPS). It is graph-theory based method, analyzing the SNP patterns. Application of NPS on CTLA-4 polymorphism captures allele relationship pattern for every patient into 6-partite mathematical graph P. Graphs P are combined into weighted 6-partite graph S, which subsequently decomposed into reference relationship profiles (RRP). Finally, every individual CTLA-4 genotype pattern is characterized by the graph distances of P from eight identified RRP's. RRP's are subgraphs of S, collecting equally frequent binary allele co-occurrences in all studied loci. If S topology represents the genetic "dominant model", the RRP's and their characteristic frequencies are identical to expectation-maximization derived haplotypes and maximal likelihood estimates of their frequencies. The graphrepresentation allows showing that patient CTLA-4 haplotypes are uniquely different from the controls by absence of specific SNP combinations. New function-related insight is derived when the 6-partite graph reflects allelic state of CTLA-4. We found that we can use differences between individual P and specific RRPs to identify patient subpopulations with clearly different polymorphic patterns relatively to controls as well as to identify patients with significantly different survival. © 2014 Pancoska et al

Validation of food store environment secondary data source and the role of neighborhood deprivation in Appalachia, Kentucky

Background Based on the need for better measurement of the retail food environment in rural settings and to examine how deprivation may be unique in rural settings, the aims of this study were: 1) to validate one commercially available data source with direct field observations of food retailers; and 2) to examine the association between modified neighborhood deprivation and the modified retail food environment score (mRFEI). Methods Secondary data were obtained from a commercial database, InfoUSA in 2011, on all retail food outlets for each census tract. In 2011, direct observation identifying all listed food retailers was conducted in 14 counties in Kentucky. Sensitivity and positive predictive values (PPV) were compared. Neighborhood deprivation index was derived from American Community Survey data. Multinomial regression was used to examine associations between neighborhood deprivation and the mRFEI score (indicator of retailers selling healthy foods such as low-fat foods and fruits and vegetables relative to retailers selling more energy dense foods). Results The sensitivity of the commercial database was high for traditional food retailers (grocery stores, supermarkets, convenience stores), with a range of 0.96-1.00, but lower for non-traditional food retailers; dollar stores (0.20) and Farmer’s Markets (0.50). For traditional food outlets, the PPV for smaller non-chain grocery stores was 38%, and large chain supermarkets was 87%. Compared to those with no stores in their neighborhoods, those with a supercenter [OR 0.50 (95% CI 0.27. 0.97)] or convenience store [OR 0.67 (95% CI 0.51, 0.89)] in their neighborhood have lower odds of living in a low deprivation neighborhood relative to a high deprivation neighborhood. Conclusion The secondary commercial database used in this study was insufficient to characterize the rural retail food environment. Our findings suggest that neighborhoods with high neighborhood deprivation are associated with having certain store types that may promote less healthy food options

Secondary structures comparison of aquaporin-1 and bacteriorhodopsin: a Fourier transform infrared spectroscopy study of two-dimensional membrane crystals.

Aquaporins are integral membrane proteins found in diverse animal and plant tissues that mediate the permeability of plasma membranes to water molecules. Projection maps of two-dimensional crystals of aquaporin-1 (AQP1) reconstituted in lipid membranes suggested the presence of six to eight transmembrane helices in the protein. However, data from other sequence and spectroscopic analyses indicate that this protein may adopt a porin-like beta-barrel fold. In this paper, we use Fourier transform infrared spectroscopy to characterize the secondary structure of highly purified native and proteolyzed AQP1 reconstituted in membrane crystalline arrays and compare it to bacteriorhodopsin. For this analysis the fractional secondary structure contents have been determined by using several different algorithms. In addition, a neural network-based evaluation of the Fourier transform infrared spectra in terms of numbers of secondary structure segments and their interconnections [sij] has been performed. The following conclusions were reached: 1) AQP1 is a highly helical protein (42-48% alpha-helix) with little or no beta-sheet content. 2) The alpha-helices have a transmembrane orientation, but are more tilted (21 degrees or 27 degrees, depending on the considered refractive index) than the bacteriorhodopsin helices. 3) The helices in AQP1 undergo limited hydrogen/deuterium exchange and thus are not readily accessible to solvent. Our data support the AQP1 structural model derived from sequence prediction and epitope insertion experiments: AQP1 is a protein with at least six closely associated alpha-helices that span the lipid membrane