Epidemiologic and animal studies have shown that exposure to particulate matter air pollution (PM) is a risk factor for the development of atherosclerosis. Whether PM-induced lung and systemic inflammation is involved in this process is not clear. We hypothesized that PM exposure causes lung and systemic inflammation, which in turn leads to vascular endothelial dysfunction, a key step in the initiation and progression of atherosclerosis. New Zealand White rabbits were exposed for 5 days (acute, total dose 8 mg) and 4 wk (chronic, total dose 16 mg) to either PM smaller than 10 mum (PM(10)) or saline intratracheally. Lung inflammation was quantified by morphometry; systemic inflammation was assessed by white blood cell and platelet counts and serum interleukin (IL)-6, nitric oxide, and endothelin levels. Endothelial dysfunction was assessed by vascular response to acetylcholine (ACh) and sodium nitroprusside (SNP). PM(10) exposure increased lung macrophages (P<0.02), macrophages containing particles (P<0.001), and activated macrophages (P<0.006). PM(10) increased serum IL-6 levels in the first 2 wk of exposure (P<0.05) but not in weeks 3 or 4. PM(10) exposure reduced ACh-related relaxation of the carotid artery with both acute and chronic exposure, with no effect on SNP-induced vasodilatation. Serum IL-6 levels correlated with macrophages containing particles (P=0.043) and ACh-induced vasodilatation (P=0.014 at week 1, P=0.021 at week 2). Exposure to PM(10) caused lung and systemic inflammation that were both associated with vascular endothelial dysfunction. This suggests that PM-induced lung and systemic inflammatory responses contribute to the adverse vascular events associated with exposure to air pollution.
Under continuous, glucose-limited conditions, budding yeast exhibit robust metabolic cycles associated with major oscillations of gene expression. How such fluctuations are linked to changes in chromatin status is not well understood. Here we examine the correlated genome-wide transcription and chromatin states across the yeast metabolic cycle at unprecedented temporal resolution, revealing a “just-in-time supply chain” by which components from specific cellular processes such as ribosome biogenesis become available in a highly coordinated manner. We identify distinct chromatin and splicing patterns associated with different gene categories and determine the relative timing of chromatin modifications to maximal transcription. There is unexpected variation in the chromatin modification and expression relationship, with histone acetylation peaks occurring with varying timing and “sharpness” relative to RNA expression both within and between cycle phases. Chromatin modifier occupancy reveals subtly distinct spatial and temporal patterns compared to the modifications themselves.
Rationale: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activationregulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum. Objectives: To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality. Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study. Measurements and Main Results: Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P , 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort. Conclusions: Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
Background: Interleukin-6 (IL6) is a pleiotropic proinflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/ C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Methods: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV 1 ) over 5 years and baseline FEV 1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). Results: In the LHS, three IL6 SNPs were associated with decline in FEV 1 (0.023(p(0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01(p(0.04 in additive genetic models). Conclusion:The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV 1 and susceptibility to COPD in smokers.Interleukin 6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine secreted by airway epithelial cells, alveolar macrophages, adipocytes and myocytes as well as other tissues and cells.1 2 The potential importance of IL6 in the pathogenesis of chronic obstructive pulmonary disease (COPD) is suggested by studies showing that high levels of serum or sputum IL6 are associated with impaired lung function or a faster decline in lung function.1 2 IL6 has been related to skeletal muscle weakness in COPD, 3 as well as to exacerbations 4 and pulmonary infections 5 in patients with COPD. In addition, overexpression of IL6 in the murine lung resulted in airway inflammation and emphysema-like airspace enlargement. 6 Furthermore, IL6 is an important mediator of the acute phase response and can upregulate C-reactive protein (CRP) at the transcriptional level.7 CRP has been associated with lung function levels in healthy individuals and/or lung function decline in smoking-induced COPD. Taken together, these data support IL6 as an appealing candidate gene for smoking-induced lung function impairment and COPD.The IL6 gene is located on chromosome 7p21. Previous studies have identified a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6.10 Before initiation of the current study, a small study reported no association of an IL6 SNP with COPD.11 Recently, another group showed that the IL6_-572C allele was associated with COPD.12 Large well-designed stu...
Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a doseescalation phase performed in a 3þ3 design (Part A; n ¼ 54), two dose-confirmation phases [Part B at 420 mg (n ¼ 18) and Part C at 300 mg (n ¼ 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor-positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n ¼ 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.
Aims/hypothesis The paucity of information on the epigenetic barriers that are blocking reprogramming protocols, and on what makes a beta cell unique, has hampered efforts to develop novel beta cell sources. Here, we aimed to identify enhancers in pancreatic islets, to understand their developmental ontologies, and to identify enhancers unique to islets to increase our understanding of islet-specific gene expression. Methods We combined H3K4me1-based nucleosome predictions with pancreatic and duodenal homeobox 1 (PDX1), neurogenic differentiation 1 (NEUROD1), v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA) and forkhead box A2 (FOXA2) occupancy data to identify enhancers in mouse islets. Results We identified 22,223 putative enhancer loci in in vivo mouse islets. Our validation experiments suggest that nearly half of these loci are active in regulating islet gene expression, with the remaining regions probably poised for activity. We showed that these loci have at least nine developmental ontologies, and that islet enhancers predominately acquire H3K4me1 during differentiation. We next discriminated 1,799 enhancers unique to islets and showed that these islet-specific enhancers have reduced association with annotated genes, and identified a subset that are instead associated with novel islet-specific long non-coding RNAs (lncRNAs). Conclusions/interpretations Our results indicate that genes with islet-specific expression and function tend to have enhancers devoid of histone methylation marks or, less often, that are bivalent or repressed, in embryonic stem cells and liver. Further, we identify a subset of enhancers unique to islets that are associated with novel islet-specific genes and lncRNAs. We anticipate that these data will facilitate the development of novel sources of functional beta cell mass.
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