Differential expression and function of breast regression protein 39 (BRP-39) in murine models of subacute cigarette smoke exposure and allergic airway inflammation

Background

While the presence of the chitinase-like molecule YKL40 has been reported in COPD and asthma, its relevance to inflammatory processes elicited by cigarette smoke and common environmental allergens, such as house dust mite (HDM), is not well understood. The objective of the current study was to assess expression and function of BRP-39, the murine equivalent of YKL40 in a murine model of cigarette smoke-induced inflammation and contrast expression and function to a model of HDM-induced allergic airway inflammation.

Methods

CD1, C57BL/6, and BALB/c mice were room air- or cigarette smoke-exposed for 4 days in a whole-body exposure system. In separate experiments, BALB/c mice were challenged with HDM extract once a day for 10 days. BRP-39 was assessed by ELISA and immunohistochemistry. IL-13, IL-1R1, IL-18, and BRP-39 knock out (KO) mice were utilized to assess the mechanism and relevance of BRP-39 in cigarette smoke- and HDM-induced airway inflammation.

Results

Cigarette smoke exposure elicited a robust induction of BRP-39 but not the catalytically active chitinase, AMCase, in lung epithelial cells and alveolar macrophages of all mouse strains tested. Both BRP-39 and AMCase were increased in lung tissue after HDM exposure. Examining smoke-exposed IL-1R1, IL-18, and IL-13 deficient mice, BRP-39 induction was found to be IL-1 and not IL-18 or IL-13 dependent, while induction of BRP-39 by HDM was independent of IL-1 and IL-13. Despite the importance of BRP-39 in cellular inflammation in HDM-induced airway inflammation, BRP-39 was found to be redundant for cigarette smoke-induced airway inflammation and the adjuvant properties of cigarette smoke.

Conclusions

These data highlight the contrast between the importance of BRP-39 in HDM- and cigarette smoke-induced inflammation. While functionally important in HDM-induced inflammation, BRP-39 is a biomarker of cigarette smoke induced inflammation which is the byproduct of an IL-1 inflammatory pathway.     

Chromosome-breakage genomic instability and chromothripsis in breast cancer

Background

Chromosomal breakage followed by faulty DNA repair leads to gene amplifications and deletions in cancers. However, the mere assessment of the extent of genomic changes, amplifications and deletions may reduce the complexity of genomic data observed by array comparative genomic hybridization (array CGH). We present here a novel approach to array CGH data analysis, which focuses on putative breakpoints responsible for rearrangements within the genome.

Results

We performed array comparative genomic hybridization in 29 primary tumors from high risk patients with breast cancer. The specimens were flow sorted according to ploidy to increase tumor cell purity prior to array CGH. We describe the number of chromosomal breaks as well as the patterns of breaks on individual chromosomes in each tumor. There were differences in chromosomal breakage patterns between the 3 clinical subtypes of breast cancers, although the highest density of breaks occurred at chromosome 17 in all subtypes, suggesting a particular proclivity of this chromosome for breaks. We also observed chromothripsis affecting various chromosomes in 41% of high risk breast cancers.

Conclusions

Our results provide a new insight into the genomic complexity of breast cancer. Genomic instability dependent on chromosomal breakage events is not stochastic, targeting some chromosomes clearly more than others. We report a much higher percentage of chromothripsis than described previously in other cancers and this suggests that massive genomic rearrangements occurring in a single catastrophic event may shape many breast cancer genomes.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-579) contains supplementary material, which is available to authorized users.     

Development and characterization of highly polymorphic long TC repeat microsatellite markers for genetic analysis of peanut

Background

The immune system has paradoxical roles during cancer development and the prognostic significance of immune modulating factors is controversial. The aim of this study was to determine the expression of cyclooxygenase 2 (COX-2), transforming growth factor-beta (TGF- beta), interleukin-10 (IL-10) and their prognostic significance in breast cancers. Ki67 was included as a measure of growth fraction of tumor cells.

Methods

On immunohistochemical stained slides from 38 breast cancer patients, we performed digital video analysis of tumor cell areas and adjacent tumor stromal areas from the primary tumors and their corresponding lymph node metastases. COX-2 was recorded as graded staining intensity.

Results

The expression of TGF-beta, IL-10 and Ki67 were recorded in tumor cell areas and adjacent tumor stromal areas. In both primary tumors and metastases, the expression of COX-2 was higher in the tumor stromal areas than in the tumor cell areas (both P < 0.001). High stromal staining intensity in the primary tumors was associated with a 3.9 (95% CI 1.1-14.2) times higher risk of death compared to the low staining group (P = 0.036). The expression of TGF-beta was highest in the tumor cell areas of both primary tumors and metastases (both P < 0.001). High stromal expression of TGF-beta was associated with increased mortality. For IL-10, the stromal expression was highest in the primary tumors (P < 0.001), whereas in the metastases the expression was highest in tumor cell areas (P < 0.001). High IL-10 expression in tumor- and stromal cell areas of primary tumors predicted mortality. Ki67 was higher expressed in tumor stromal areas of the metastases, and in tumor cell areas of the primary tumors (P < 0.001). Ki67 expression in tumor cell areas and stromal areas of the metastases was independently associated with breast cancer mortality.

Conclusions

Stromal expression of COX-2, TGF-beta and Ki67 may facilitate tumor progression in breast cancer.     

The first record of gynodioecy in a species of Gnidia (Thymelaeaceae) from South Africa

Sexual polymorphism was studied in the shrub Gnidia wikstroemiana (Thunb.) Meisn. from the semiarid Nama Karoo Biome, South Africa. The populations comprised plants bearing either female flowers, or hermaphrodite flowers with variable female function. In two populations, female plants accounted for 36–37% of the flowering plants. Female flowers were smaller and their stamens were reduced to staminodes, but their styles were significantly longer than those of hermaphrodite flowers. Energy investment in flowers and fruits for females and hermaphrodites was measured using bomb calorimetry. Females produce a greater number of less costly flowers than hermaphrodites, and invest less energy per unit in production of flowers and inflorescences. In contrast, females invest more energy per unit in production of fruits and infructescences than hermaphrodites. Females overall invest 7.3% more energy in reproduction than hermaphrodites. Female flowers were obligate out-crossers (xenogamous), with 35% of nonmanipulated, open-pollinated flowers setting fruit, comparable with fruit set among selfed hermaphrodite flowers. The breeding strategy of G. wikstroemiana most closely resembles gynodioecy. This is the first report of sexual dimorphism in Gnidia L. and sub-Saharan Thymelaeaceae.  © 2006 The Linnean Society of London, Botanical Journal of the Linnean Society , 2006, 152 , 219–233.     

Ribosomal RNA secondary structure: compensatory mutations and implications for phylogenetic analysis

Using sequence data from the 28S ribosomal RNA (rRNA) genes of selected vertebrates, we investigated the effects that constraints imposed by secondary structure have on the phylogenetic analysis of rRNA sequence data. Our analysis indicates that characters from both base-pairing regions (stems) and non-base-pairing regions (loops) contain phylogenetic information, as judged by the level of support of the phylogenetic results compared with a well-established tree based on both morphological and molecular data. The best results (the greatest level of support of well-accepted nodes) were obtained when the complete data set was used. However, some previously supported nodes were resolved using either the stem or loop bases alone. Stem bases sustain a greater number of compensatory mutations than would be expected at random, but the number is < 40% of that expected under a hypothesis of perfect compensation to maintain secondary structure. Therefore, we suggest that in phylogenetic analyses, the weighting of stem characters be reduced by no more than 20%, relative to that of loop characters. In contrast to previous suggestions, we do not recommend weighting of stem positions by one-half, compared with that of loop positions, because this overcompensates for the constraints that selection imposes on the secondary structure of rRNA.      

Spatial Organization and Mineralization of the Basal Plate of Elasmoid Scales in Osteichthyans

In Sarcopterygii (Latimeria, Neoceratodus, Protopterus, Leptdosiren)and Amiidae (Amia) collagen fibrils of the basal plate are packedin bundles whereas they remain isolated in Teleostei. The basalplate looks like plywood, a system of superimposed layers ofparallel fibers or fibrils the directions of which rotate witha regular angle in two successive layers. The double twistedplywood is constituted of two imbricate systems, the odd andthe even, where the rotation of the fibrillar directions isright-handed in Sarcopterygii and lefthanded in Amiidae andnumerous primitive Teleostei. The orthogonal plywood, with itstwo main orthogonal fibrillar directions, characterizes theevolved Teleostei and some more primitive ones. In most teleosteanspecies, as in Amia and Protopterus, mineralization of the basalplate in elasmoid scales involves Mandl's corpuscles that mineralizewithout contact with a pre-existing calcified tissue; they growand coalesce with the neighbouring ones and fuse to the mineralizingfront. Their shape is directly influenced by the local arrangementof the collagenous fibrils. In two teleostean families (Osteoglossidaeand Mormyridae) Mandl's corpuscles are completely lacking butspreading of mineralization in the basal plate has a peculiaraspect. Whatever that may be, the various characteristic organizationsof the skeletal tissues or isopedine that constitute the basalplate of osteichthyan elasmoid scales, all are varieties ofbone tissue that have undergone more or less important specializationlinked to the general regression of dermal ossifications andto functional adaptations.     

Origins of Laboratory Mice Deduced from Restriction Patterns of Mitochondrial DNA

To determine the origins of laboratory mice, the restriction patterns of mitochondrial DNAs (mtDNAs) from various strains were compared with those of relevant subspecies and/or races of mus musculus . In most strains and substrains of laboratory mice examined (50/55), the cleavage patterns were identical to those of the European subspecies M. m. domesticus . Those that varied include two sublines of NZB, the strain NZC, and the Japanese strain RR. The NZB and NZC patterns were identical to that of the European subspecies M. m. brevirostris , which itself has restriction patterns similar to M. m. domesticus . On the other hand, the RR pattern was identical to M. m. molossinus -like mice trapped in Western China and slightly different from Japanese M. m. molossinus . These findings suggest that the strains NZB and NZC stemmed from a European founder stock which differed from the ancestral stocks of other laboratory strains and that the ancestral mice of the RR strain had been transported from China to Japan. Therefore, most laboratory strains of mice are derived from the European subspecies M. m. domesticus while M. m. brevirostris and M. m. molossinus have made minor contributions. M. m. musculus does not appear to have made any contribution.     

Integrative analysis of multiple gene expression profiles with quality-adjusted effect size models

Background  

With the explosion of microarray studies, an enormous amount of data is being produced. Systematic integration of gene expression data from different sources increases statistical power of detecting differentially expressed genes and allows assessment of heterogeneity. The challenge, however, is in designing and implementing efficient analytic methodologies for combination of data generated by different research groups.