Associations between evaporative cooling and dust-mite allergens, endotoxins, and ß-(1 → 3)-d-glucans in house dust: A study of low-income homes.

Recent work suggests that evaporative coolers increase the level and diversity of bioaerosols, but this association remains understudied in low-income homes. We conducted a cross-sectional study of metropolitan, low-income homes in Utah with evaporative coolers (n = 20) and central air conditioners (n = 28). Dust samples (N = 147) were collected from four locations in each home and analyzed for dust-mite allergens Der p1 and Der f1, endotoxins, and ß-(1 â†’ 3)-d-glucans. In all sample locations combined, Der p1 or Der f1 was significantly higher in evaporative cooler versus central air conditioning homes (OR = 2.29, 95% CI = 1.05-4.98). Endotoxin concentration was significantly higher in evaporative cooler versus central air conditioning homes in furniture (geometric mean (GM) = 8.05 vs 2.85 EU/mg, P < .01) and all samples combined (GM = 3.60 vs 1.29 EU/mg, P = .03). ß-(1 â†’ 3)-d-glucan concentration and surface loads were significantly higher in evaporative cooler versus central air conditioning homes in all four sample locations and all samples combined (P < .01). Our study suggests that low-income, evaporative cooled homes have higher levels of immunologically important bioaerosols than central air-conditioned homes in dry climates, warranting studies on health implications and other exposed populations.

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.

Coordinated regulation of synthesis and stability of RNA during the acute TNF-induced proinflammatory response.

Steady-state gene expression is a coordination of synthesis and decay of RNA through epigenetic regulation, transcription factors, micro RNAs (miRNAs), and RNA-binding proteins. Here, we present bromouride labeling and sequencing (Bru-Seq) and bromouridine pulse-chase and sequencing (BruChase-Seq) to assess genome-wide changes to RNA synthesis and stability in human fibroblasts at homeostasis and after exposure to the proinflammatory tumor necrosis factor (TNF). The inflammatory response in human cells involves rapid and dramatic changes in gene expression, and the Bru-Seq and BruChase-Seq techniques revealed a coordinated and complex regulation of gene expression both at the transcriptional and posttranscriptional levels. The combinatory analysis of both RNA synthesis and stability using Bru-Seq and BruChase-Seq allows for a much deeper understanding of mechanisms of gene regulation than afforded by the analysis of steady-state total RNA and should be useful in many biological settings.

Inactivation of Apc in the mouse prostate causes prostate carcinoma.

Alterations of the Wnt/beta-catenin signaling pathway are positively associated with the development and progression of human cancer, including carcinoma of the prostate. To determine the role of activated Wnt/beta-catenin signaling in mouse prostate carcinogenesis, we created a mouse prostate tumor model using probasin-Cre-mediated deletion of Apc. Prostate tumors induced by the deletion of Apc have elevated levels of beta-catenin protein and are highly proliferative. Tumor formation is fully penetrant and follows a consistent pattern of progression. Hyperplasia is observed as early as 4.5 weeks of age, and adenocarcinoma is observed by 7 months. Continued tumor growth usually necessitated sacrifice between 12 and 15 months of age. Despite the high proliferation rate, we have not observed metastasis of these tumors to the lymph nodes or other organs. Surgical castration of 6-week-old mice inhibited tumor formation, and castration of mice with more advanced tumors resulted in the partial regression of specific prostate glands. However, significant areas of carcinoma remained 2 months postcastration, suggesting that tumors induced by Apc loss of function are capable of growth under conditions of androgen depletion. We conclude that the prostate-specific deletion of Apc and the increased expression of beta-catenin associated with prostate carcinoma suggests a role for beta-catenin in prostate cancer and offers an appropriate animal model to investigate the interaction of Wnt signaling with other genetic and epigenetic signals in prostate carcinogenesis.

Personal exposure to fine particulate air pollution while commuting: An examination of six transport modes on an urban arterial roadway.

Traffic-related air pollution in urban areas contributes significantly to commuters' daily PM2.5 exposures, but varies widely depending on mode of commuting. To date, studies show conflicting results for PM2.5 exposures based on mode of commuting, and few studies compare multiple modes of transportation simultaneously along a common route, making inter-modal comparisons difficult. In this study, we examined breathing zone PM2.5 exposures for six different modes of commuting (bicycle, walking, driving with windows open and closed, bus, and light-rail train) simultaneously on a single 2.7 km (1.68 mile) arterial urban route in Salt Lake City, Utah (USA) during peak "rush hour" times. Using previously published minute ventilation rates, we estimated the inhaled dose and exposure rate for each mode of commuting. Mean PM2.5 concentrations ranged from 5.20 µg/m3 for driving with windows closed to 15.21 µg/m3 for driving with windows open. The estimated inhaled doses over the 2.7 km route were 6.83 µg for walking, 2.78 µg for cycling, 1.28 µg for light-rail train, 1.24 µg for driving with windows open, 1.23 µg for bus, and 0.32 µg for driving with windows closed. Similarly, the exposure rates were highest for cycling (18.0 µg/hr) and walking (16.8 µg/hr), and lowest for driving with windows closed (3.7 µg/hr). Our findings support previous studies showing that active commuters receive a greater PM2.5 dose and have higher rates of exposure than commuters using automobiles or public transportation. Our findings also support previous studies showing that driving with windows closed is protective against traffic-related PM2.5 exposure.

Lrp5 functions in bone to regulate bone mass.

The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.

Wnt signaling and prostate cancer.

Canonical Wnt signaling has emerged as an important pathway that underlies the initia nottion of prostate cancer. Both human cancers and mouse models have confirmed that mutations or altered expression of components of this pathway are associated with prostate tumors. Additionally, several reports suggest that this pathway plays a key role in the establishment of skeletal metastasis. This review discusses our current knowledge of the Wnt signaling pathway in the development of prostate cancer. First, we will overview the Wnt signaling pathway to provide background for the rest of the discussion. We will then review the literature on the role of this pathway and the down notstream effector, beta-catenin, in the development and progression of prostate cancer and skeletal metastasis. We will also discuss reports that suggest that beta-catenin can directly interact with the androgen receptor to modulate its activity. These recent developments may provide insight into how tumor growth can be achieved under androgen deprivation. Finally, we speculate on how the pathway may be targeted for therapeutic treatment and what agents may be available to achieve this goal.