Search

Introduction: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE)., Methods: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed., Results: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects., Conclusions: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases., Trial Registration: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Background: Integrins and enzymes of the eicosanoid pathway are both well-established contributors to cancer. However, this is the first report of the interdependence of the two signaling systems. In a screen for proteins that interacted with, and thereby potentially regulated, the human platelet-type 12-lipoxygenase (12-LOX, ALOX12), we identified the integrin β4 (ITGB4)., Methods: Using a cultured mammalian cell model, we have demonstrated that ITGB4 stimulation leads to recruitment of 12-LOX from the cytosol to the membrane where it physically interacts with the integrin to become enzymatically active to produce 12(S)-HETE, a known bioactive lipid metabolite that regulates numerous cancer phenotypes., Results: The net effect of the interaction was the prevention of cell death in response to starvation. Additionally, regulation of β4-mediated, EGF-stimulated invasion was shown to be dependent on 12-LOX, and downstream Erk signaling in response to ITGB4 activation also required 12-LOX., Conclusions: This is the first report of an enzyme of the eicosanoid pathway being recruited to and regulated by activated β4 integrin. Integrin β4 has recently been shown to induce expansion of prostate tumor progenitors and there is a strong correlation between stage/grade of prostate cancer and 12-LOX expression. The 12-LOX enzymatic product, 12(S)-HETE, regulates angiogenesis and cell migration in many cancer types. Therefore, disruption of integrin β4-12LOX interaction could reduce the pro-inflammatory oncogenic activity of 12-LOX. This report on the consequences of 12-LOX and ITGB4 interaction sets a precedent for the linkage of integrin and eicosanoid biology through direct protein-protein association.

Background: Anthracnose (Colletotrichum gloeosporioides) is a major limiting factor in the production of yam (Dioscorea spp.) worldwide. Availability of high quality sequence information is necessary for designing molecular markers associated with resistance. However, very limited sequence information pertaining to yam is available at public genome databases. Therefore, this collaborative project was developed for genetic improvement and germplasm characterization of yams using molecular markers. The current investigation is focused on studying gene expression, by large scale generation of ESTs, from one susceptible (TDa 95-0310) and two resistant yam genotypes (TDa 87-01091, TDa 95-0328) challenged with the fungus. Total RNA was isolated from young leaves of resistant and susceptible genotypes and cDNA libraries were sequenced using Roche 454 technology., Results: A total of 44,757 EST sequences were generated from the cDNA libraries of the resistant and susceptible genotypes. Greater than 56% of ESTs were annotated using MapMan Mercator tool and Blast2GO search tools. Gene annotations were used to characterize the transcriptome in yam and also perform a differential gene expression analysis between the resistant and susceptible EST datasets. Mining for SSRs in the ESTs revealed 1702 unique sequences containing SSRs and 1705 SSR markers were designed using those sequences., Conclusion: We have developed a comprehensive annotated transcriptome data set in yam to enrich the EST information in public databases. cDNA libraries were constructed from anthracnose fungus challenged leaf tissues for transcriptome characterization, and differential gene expression analysis. Thus, it helped in identifying unique transcripts in each library for disease resistance. These EST resources provide the basis for future microarray development, marker validation, genetic linkage mapping and QTL analysis in Dioscorea species.

Rheumatoid arthritis (RA) is a complex, chronic inflammatory disease implicated to have several plausible candidate loci; however, these may not account for all the genetic variations underlying RA. Common disorders are hypothesized to be highly complex with interaction among genes and other risk factors playing a major role in the disease process. This complexity is further magnified because such interactions may be with or without a strong independent effect and are thus difficult to detect using traditional statistical methodologies. The main challenge to analyze such gene x gene and gene x environment interaction is attributed to a phenomenon referred to as the "curse of dimensionality." Several combinatorial methodologies have been proposed to tackle this analytical challenge. Because quantitative traits underlie complex phenotypes and contain more information on the trait variation within genotypes than qualitative dichotomy, analyzing quantitative traits correlated with the affection status is a more powerful tool for mapping such trait genes. Recently, a generalized multifactor dimensionality reduction method was proposed that allows for adjustment for discrete and quantitative traits and can be used to analyze qualitative and quantitative phenotypes in a population based study design.In this report, we evaluate the efficiency of the generalized multifactor dimensionality reduction statistical suite to decipher small interacting factors that contribute to RA disease pathogenesis.

Genetic association of population-based quantitative trait data has traditionally been analyzed using analysis of variance (ANOVA). However, violations of certain statistical assumptions may lead to false-positive association results. In this study, we have explored model-free alternatives to ANOVA using correlations between allele frequencies in the different quantile intervals of the quantitative trait and the quantile values. We performed genome-wide association scans on anti-cyclic citrullinated peptide and rheumatoid factor-immunoglobulin M, two quantitative traits correlated with rheumatoid arthritis, using the data provided in Genetic Analysis Workshop 16. Both the quantitative traits exhibited significant evidence of association on Chromosome 6, although not in the human leukocyte antigen region which is known to harbor a major gene predisposing to rheumatoid arthritis. We found that while a majority of the significant findings using the asymptotic thresholds of ANOVA was not validated using permutations, a relatively higher proportion of the significant findings using the asymptotic cut-offs of the correlation statistic were validated using permutations.

Background: Transcriptome expression analysis in peanut to date has been limited to a relatively small set of genes and only recently has a significant number of ESTs been released into the public domain. Utilization of these ESTs for oligonucleotide microarrays provides a means to investigate large-scale transcript responses to a variety of developmental and environmental signals, ultimately improving our understanding of plant biology., Results: We have developed a high-density oligonucleotide microarray for peanut using 49,205 publicly available ESTs and tested the utility of this array for expression profiling in a variety of peanut tissues. To identify putatively tissue-specific genes and demonstrate the utility of this array for expression profiling in a variety of peanut tissues, we compared transcript levels in pod, peg, leaf, stem, and root tissues. Results from this experiment showed 108 putatively pod-specific/abundant genes, as well as transcripts whose expression was low or undetected in pod compared to peg, leaf, stem, or root. The transcripts significantly over-represented in pod include genes responsible for seed storage proteins and desiccation (e.g., late-embryogenesis abundant proteins, aquaporins, legumin B), oil production, and cellular defense. Additionally, almost half of the pod-abundant genes represent unknown genes allowing for the possibility of associating putative function to these previously uncharacterized genes., Conclusion: The peanut oligonucleotide array represents the majority of publicly available peanut ESTs and can be used as a tool for expression profiling studies in diverse tissues.

Background: There are several known factors that cause ischemic heart disease. However, the part played by air pollution still remains something of a mystery. Recent attention has focused on the chronic effect of particulate matter on heart disease. Satellite-derived aerosol optical depth (AOD) was found to be correlated with PM2.5 in the eastern US. The objective of this study was to examine if there is an association between aerosol air pollution as indicated by AOD and chronic ischemic heart disease (CIHD) in the eastern US., Methods: An ecological geographic study method was employed. Race and age standardized mortality rate (SMR) of CIHD was computed for each of the 2306 counties for the time period 2003-2004. A mean AOD raster grid for the same period was derived from Moderate Resolution Imaging Spectrometer (MODIS) aerosol data and the average AOD was calculated for each county. A bivariate Moran's I scatter plot, a map of local indicator of spatial association (LISA) clusters, and three regression models (ordinary least square, spatial lag, and spatial error) were used to analyze the relationship between AOD and CIHD SMR., Results: The global Moran's I value is 0.2673 (p = 0.001), indicating an overall positive spatial correlation of CIHD SMR and AOD. The entire study area is dominated by spatial clusters of AOD against SMR (high AOD and high SMR in the east, and low AOD and low SMR in the west) (permutations = 999, p = 0.05). Of the three regression models, the spatial error model achieved the best fit (R2 = 0.28). The effect of AOD is positive and significant (beta = 0.7774, p = 0.01)., Conclusion: Aerosol particle pollution has adverse effect on CIHD mortality risk in the eastern US. High risk of CIHD mortality was found in areas with elevated levels of outdoor aerosol air pollution as indicated by satellite derived AOD. The evidence of the association would support targeting of policy interventions on such areas to reduce air pollution levels. Remote sensing AOD data could be used as an alternative health-related indictor of air quality.

Background: Relatively few studies have examined the association between air pollution and stroke mortality. Inconsistent and inclusive results from existing studies on air pollution and stroke justify the need to continue to investigate the linkage between stroke and air pollution. No studies have been done to investigate the association between stroke and greenness. The objective of this study was to examine if there is association of stroke with air pollution, income and greenness in northwest Florida., Results: Our study used an ecological geographical approach and dasymetric mapping technique. We adopted a Bayesian hierarchical model with a convolution prior considering five census tract specific covariates. A 95% credible set which defines an interval having a 0.95 posterior probability of containing the parameter for each covariate was calculated from Markov Chain Monte Carlo simulations. The 95% credible sets are (-0.286, -0.097) for household income, (0.034, 0.144) for traffic air pollution effect, (0.419, 1.495) for emission density of monitored point source polluters, (0.413, 1.522) for simple point density of point source polluters without emission data, and (-0.289,-0.031) for greenness. Household income and greenness show negative effects (the posterior densities primarily cover negative values). Air pollution covariates have positive effects (the 95% credible sets cover positive values)., Conclusion: High risk of stroke mortality was found in areas with low income level, high air pollution level, and low level of exposure to green space.

Background: Terminalia chebula (Combretaceae) has been widely used in Ayurveda for the treatment of diabetes. In the present investigation, the chloroform extract of T. chebula seed powder was investigated for its antidiabetic activity in streptozotocin-induced diabetic rats using short term and long term study protocols. The efficacy of the extract was also evaluated for protection of renal functions in diabetic rats., Methods: The blood glucose lowering activity of the chloroform extract was determined in streptozotocin-induced (75 mg/kg, i.p.; dissolved in 0.1 M acetate buffer; pH 4.5) diabetic rats, after oral administration at the doses of 100, 200 and 300 mg/kg in short term study. Blood samples were collected from the eye retro-orbital plexus of rats before and also at 0.5, 1, 2, 4, 6, 8 and 12 h after drug administration and the samples were analyzed for blood glucose by using glucose-oxidase/peroxidase method using a visible spectrophotometer. In long term study, the extract (300 mg/kg) was administered to streptozotocin-induced diabetic rats, daily for 8 weeks. Blood glucose was measured at weekly intervals for 4 weeks. Urine samples were collected before the induction of diabetes and at the end of 8 weeks of treatments and analyzed for urinary protein, albumin and creatinine levels. The data was compared statistically using one-way ANOVA with post-hoc Dunnet's t-test., Results: The chloroform extract of T. chebula seeds produced dose-dependent reduction in blood glucose of diabetic rats and comparable with that of standard drug, glibenclamide in short term study. It also produced significant reduction in blood glucose in long term study. Significant renoprotective activity is observed in T. chebula treated rats. The results indicate a prolonged action in reduction of blood glucose by T. chebula and is probably mediated through enhanced secretion of insulin from the beta-cells of Langerhans or through extra pancreatic mechanism. The probable mechanism of potent renoprotective actions of T. chebula has to be evaluated., Conclusion: The present studies clearly indicated a significant antidiabetic and renoprotective effects with the chloroform extract of T. chebula and lend support for its traditional usage. Further investigations on identification of the active principles and their mode of action are needed to unravel the molecular mechanisms involved in the observed effects.

Background: Investigation of two independent outbreaks of post cataract surgery endophthalmitis identified the reservoir of epidemic strains of P. aeruginosa., Methods: Patient isolates cultured from vitreous fluid of all the nine cases and from the peripheral devices of phacoemulsification machine were subjected to high-resolution Fluorescent Amplified Fragment Length Polymorphism (FAFLP) analysis., Results: FAFLP based genotyping of the isolates confirmed nosocomial transmission. Although biochemical characterization and antibiotic susceptibility profiles grouped all the isolates together, FAFLP based genotyping revealed that, all the outbreak isolates were derived from 2 different strains, with independent origins. One group of isolates was traced to phacoprobe and the second one to the internal tubing system of the phacoemulsification machine used in cataract surgery. In silico analysis indicated possible evolution in both the clusters of P. aeruginosa isolates due to genetic polymorphisms. The polymorphisms were mapped to gene products (cell envelope, outer membrane proteins) possibly having significant role in pathogenesis., Conclusion: The present study is probably the first one to apply FAFLP typing successfully to investigate outbreaks of postoperative endophthalmitis (POE) in an ophthalmic setting, which was able to identify the source, and helped to make rational decisions on sterilization procedures that halted more cases of infection in these hospitals.

Background: Genomic diversity of H. pylori from many different human populations is largely unknown. We compared genomes of 65 H. pylori strains from Nottingham, England. Molecular analysis was carried out to identify rearrangements within and outside the cag-pathogenicity-island (cag PAI) and DNA sequence divergence in candidate genes. Phylogenetic analysis was carried out based on various high-resolution genotyping techniques., Results: Analyses of virulence genes (cagT, cagE, cagA, vacA, iceA, oipA and babB) revealed that H. pylori strains from England are genetically distinct from strains obtained from other countries. The toxigenic vacA s1m1 genotype was found to be less common and the plasticity region cluster was found to be disrupted in all the isolates. English isolates showed a predominance of iceA1 alleles and a functional proinflammatory oipA gene. The English H. pylori gene pool revealed several Asian/oriental features. This included the predominance of cagA - glr (cagA right junction) motif types III and II (up to 42%), presence of vacA m1c alleles and phylogenetic affinity towards East Asian / Amerindian gene pools based on fluorescent amplified fragment length polymorphism (FAFLP) analysis and glmM sequence analysis., Conclusion: Overall, our results demonstrated genetic affinities of H. pylori in England with both European and the Asian gene pools and some distinctive genetic features of virulence genes that may have evolved in this important European population.