Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression

Background

Nasal gene expression profiling is a promising method to characterize COPD non-invasively. We aimed to identify a nasal gene expression profile to distinguish COPD patients from healthy controls. We investigated whether this COPD-associated gene expression profile in nasal epithelium is comparable with the profile observed in bronchial epithelium.

Methods

Genome wide gene expression analysis was performed on nasal epithelial brushes of 31 severe COPD patients and 22 controls, all current smokers, using Affymetrix Human Gene 1.0 ST Arrays. We repeated the gene expression analysis on bronchial epithelial brushes in 2 independent cohorts of mild-to-moderate COPD patients and controls.

Results

In nasal epithelium, 135 genes were significantly differentially expressed between severe COPD patients and controls, 21 being up- and 114 downregulated in COPD (false discovery rate?<?0.01). Gene Set Enrichment Analysis (GSEA) showed significant concordant enrichment of COPD-associated nasal and bronchial gene expression in both independent cohorts (FDR_GSEA <?0.001).

Conclusion

We identified a nasal gene expression profile that differentiates severe COPD patients from controls. Of interest, part of the nasal gene expression changes in COPD mimics differentially expressed genes in the bronchus. These findings indicate that nasal gene expression profiling is potentially useful as a non-invasive biomarker in COPD.

Trial registration

ClinicalTrials.gov registration number NCT01351792 (registration date May 10, 2011), ClinicalTrials.gov registration number NCT00848406 (registration date February 19, 2009), ClinicalTrials.gov registration number NCT00807469 (registration date December 11, 2008).

     

MiRNAs as regulators of the response to inhaled environmental toxins and airway carcinogenesis

miRNAs are a class of small, noncoding RNAs averaging 22 nucleotides in length that down-regulate gene expression by complimentary binding to the 3' UTR of target genes. A growing body of research suggests that these small RNA species play significant roles in modulating the cellular response to a variety of types of stress. In this review, we summarize the available literature regarding the general response of miRNA to cellular stress, and then specifically focus on the miRNA response to inhaled toxins. These miRNA responses to inhaled toxins appear to be recapitulated in lung carcinogenesis, opening the possibility that modulation of the miRNA response could be a novel strategy for chemoprevention.     

Increased free fat-graft survival with the long-term, local delivery of insulin, insulin-like growth factor-I, and basic fibroblast growth factor by PLGA/PEG microspheres

The present investigation evaluates the effects of long-term, local delivery of insulin, insulin-like growth factor-1 (IGF-1), and basic fibroblast growth factor (bFGF) on fat-graft survival using a poly (lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microsphere delivery system. Twelve-micrometer PLGA/PEG microspheres incorporated separately with insulin, IGF-1, and bFGF were manufactured using a double-emulsion solvent-extraction technique. Inguinal fat from Sprague Dawley rats was harvested, diced, washed, and mixed with (1) insulin microspheres, (2) insulin-like growth factor-1 microspheres, (3) basic fibroblast growth factor microspheres, (4) a combination of the insulin and IGF-1 microspheres, and (5) a combination of insulin, IGF-1, and bFGF microspheres. The treated fat grafts were implanted autologously into subdermal pockets in six animals for each group. Animals receiving untreated fat grafts and fat grafts treated with blank microspheres constituted two external control groups (six animals per external control group). At 12 weeks, all fat-graft groups were compared on the basis of weight maintenance and a histomorphometric analysis of adipocyte area percentage, indices of volume retention and cell composition, respectively. Weight maintenance was defined as the final graft weight as a percent of the implanted graft weight. All growth factor treatments significantly increased fat-graft weight maintenance objectively, and volume maintenance grossly, in comparison with the untreated and blank microsphere-treated controls. Treatment with insulin and IGF-1, alone or in combination, was found to increase the adipocyte area percentage in comparison with fat grafts treated with bFGF alone or in combination with other growth factors. In conclusion, the findings of this study indicate that long-term, local delivery of growth factors with PLGA/PEG microspheres has the potential to increase fat-graft survival rates. Further, the type of growth factor delivered may influence the cellular/stromal composition of the grafted tissue.     

Plasmodium vinckei: suppression of mouse infections with desferrioxamine B

Plasmodium vinckei kills NMRI mice within 6 days after infection. Treatment of infected animals with desferrioxamine B for 5 days was found to suppress the parasitemia in a dose-dependent manner. The desferrioxamine B-iron complex (DFO/Fe3+) was ineffective, which suggests that the iron-chelating capacity of free desferrioxamine B is the antimalarial principle. All mice survived when they were given 0.3 mg desferrioxamine B/g every 12 hr for 14 days after infection. In addition, they were resistant to reinfection for at least 8 weeks. Eight months after desferrioxamine B treatment, all mice had lost their induced immunity and were as susceptible to malaria as controls. These results illustrate the dependence of the malarial parasite on ionic iron and suggests new methods for the therapy of parasitic diseases.     

Mapping of the c-myc, pvt-1 and immunoglobulin kappa genes in relation to the mouse plasmacytoma-associated variant (6;15) translocation breakpoint.

A variant mouse plasmacytoma (MPC)-associated translocation chromosome has arisen by pericentric inversion and exchange of the distal segments of a Robertsonian 6;15 fusion chromosome in the CAK TEPC 1198 mouse plasmacytoma, as described earlier. In situ hybridization was performed on the normal and the inverted Rb chromosomes, using myc and kappa probes. On the normal Rb chromosome, myc was in the 15 D2/3 region, whereas kappa hybridized in the 6 C2 area, as expected. On the inverted Rb chromosome, myc remains on the centrometric side of the translocation breakpoint on the chromosome 15-derived portion, whereas kappa has moved to the chromosome 6-derived segment that joined the same breakpoint on the telomeric side. Taken together with our recent demonstration that the murine c-myc locus is oriented 'head up' on chromosome 15, and with the results of Cory and co-workers concerning the relationship between the kappa gene and the associated pvt-1 region in the CAK TEPC 1198 tumor, the following conclusions can be drawn: (i) in the variant translocation of the CAK TEPC 1198 MPC, the breakage occurs 3' of the c-myc gene, as in the human Burkitt lymphoma-associated variant translocations; (ii) the pvt-1 gene on chromosome 15 is distal to the myc gene; (iii) the kappa light chain locus is oriented 'head up' on mouse chromosome 6 and faces pvt-1 and, beyond it, c-myc, in a head-to-tail configuration.     

Mechanisms of human immunodeficiency virus Type 1 (HIV-1) neutralization: irreversible inactivation of infectivity by anti-HIV-1 antibody.

An assay for the neutralization of human immunodeficiency virus type 1 (HIV-1) is described in which the reduction in infectious titer of HIV-1 after preincubation at 37 degrees C with antibody-positive serum is the measure of neutralization. The assay format and its controls allow several experimental manipulations that, taken together, indicate an effect of antibody on HIV-1 infectivity that occurs before or independently of HIV-1 attachment. The direct inactivation of HIV-1 infectivity by antibody is irreversible and temperature dependent, requires a bivalent antibody directed against accessible envelope determinants, and does not require a heat-labile or (Ca2+)- or (Mg2+)-dependent cofactor. The mechanism of inactivation cannot be explained by agglutination of virus, nor is it associated with disruption or dissociation of envelope protein from virions. Rather, the antibody is likely to perturb some metastable property of the envelope that is required for entry. Laboratory-adapted HIV-1 isolates were more sensitive to the inactivating effects of sera than were primary patient isolates. The latter were particularly resistant to inactivation by contemporary autologous sera, a feature not explained by blocking antibodies. Additional studies showed a weak relationship between disease course and serum inactivation of the reference LAI laboratory strain of HIV-1. Heteroduplex analysis and autologous inactivation assays of sequential specimens from individual patients indicate that over time, the viral quasispecies that emerge and dominate are resistant to the inactivating effects of earlier sera.     

Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility

The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway‐based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome‐sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high‐risk women was also identified by pathway‐based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high‐risk and control women, using cell‐based functional assays, drug‐response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell‐based experiments indicate that cell–cell and cell–extracellular matrix adhesion processes seem to be disrupted in non‐malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development.     

Ichthyophthiriasis in the mirror carp Cyprinus carpio (L.) IV. Physiological dysfunction*

Changes in blood ion concentration, oxygen absorption, blood haemoglobin concentration and blood urea-ammonia nitrogen level were measured in a group of mirror carp, Cyprinus carpio (L.) infected with measured numbers of Ichthyophthirius multifiliis under standardized conditions. The disease was characterized by a drop in serum sodium and magnesium and increase in serum potassium. The ability of infected fish to absorb oxygen was reduced as was their ability to tolerate dissolved oxygen concentrations under 5 ppm. Blood ureaammonia level was elevated during the disease but blood haemoglobin level remained unchanged.     

Bacillus cereus-Induced Fluid Accumulation in Rabbit Ileal Loops

The usefulness of the ligated rabbit ileal loop as an experimental model of Bacillus cereus food poisoning was investigated. Positive responses, as measured by fluid accumulation in the loop, were obtained from 19 of 22 strains of B. cereus. Four of six strains of B. thuringiensis also elicited fluid accumulation, but eight strains of other Bacillus spp. failed to evoke a response. The growth medium employed markedly affected the ability of a given strain of B. cereus to provoke a response. Brain heart infusion broth (BHI) (Difco) proved to be best for this purpose. Loop fluid-inducing activity was produced by exponentially growing cells and was present in cell-free culture filtrates and associated with washed vegetative cells. Intraluminal growth of B. cereus did not elicit fluid accumulation. Cultures grown at temperatures in the range of 18 C to 43 C were loop active. When BHI cultures of selected loop positive strains were injected intraluminally into the normal ileum of rabbits, they failed to elicit diarrhea.