Lysophosphatidylcholine in phospholipase A(2)-modified LDL triggers secretion of angiopoietin 2

Background and aims: Secretory phospholipase A(2) (PLA(2)) hydrolyzes LDL phospholipids generating modified LDL particles (PLA(2)-LDL) with increased atherogenic properties. Exocytosis of Weibel-Palade bodies (WPB) releases angiopoietin 2 (Ang2) and externalizes P-selectin, which both play important roles in vascular inflammation. Here, we investigated the effects of PLA(2)-LDL on exocytosis of WPBs. Methods: Human coronary artery endothelial cells (HCAECs) were stimulated with PLA(2)-LDL, and its uptake and effect on Ang2 release, leukocyte adhesion, and intracellular calcium levels were measured. The effects of PLA(2)-LDL on Ang2 release and WPB exocytosis were measured in and ex vivo in mice. Results: Exposure of HCAECs to PLA(2)-LDL triggered Ang2 secretion and promoted leukocyte-HCAEC interaction. Lysophosphatidylcholine was identified as a critical component of PLA(2)-LDL regulating the WPB exocytosis, which was mediated by cell-surface proteoglycans, phospholipase C, intracellular calcium, and cytoskeletal remodeling. PLA(2)-LDL also induced murine endothelial WPB exocytosis in blood vessels in and ex vivo, as evidenced by secretion of Ang2 in vivo, P-selectin translocation to plasma membrane in intact endothelial cells in thoracic artery and tracheal vessels, and reduced Ang2 staining in tracheal endothelial cells. Finally, in contrast to normal human coronary arteries, in which Ang2 was present only in the endothelial layer, at sites of advanced atherosclerotic lesions, Ang2 was detected also in the intima, media, and adventitia. Conclusions: Our studies reveal PLA(2)-LDL as a potent agonist of endothelial WPB exocytosis, resulting in increased secretion of Ang2 and translocation of P-selectin. The results provide mechanistic insight into PLA(2)-LDL-dependent promotion of vascular inflammation and atherosclerosis.Peer reviewe

Genetic Dissection of an Exogenously Induced Biofilm in Laboratory and Clinical Isolates of E. coli

Microbial biofilms are a dominant feature of many human infections. However, developing effective strategies for controlling biofilms requires an understanding of the underlying biology well beyond what currently exists. Using a novel strategy, we have induced formation of a robust biofilm in Escherichia coli by utilizing an exogenous source of poly-N-acetylglucosamine (PNAG) polymer, a major virulence factor of many pathogens. Through microarray profiling of competitive selections, carried out in both transposon insertion and over-expression libraries, we have revealed the genetic basis of PNAG-based biofilm formation. Our observations reveal the dominance of electrostatic interactions between PNAG and surface structures such as lipopolysaccharides. We show that regulatory modulation of these surface structures has significant impact on biofilm formation behavior of the cell. Furthermore, the majority of clinical isolates which produced PNAG also showed the capacity to respond to the exogenously produced version of the polymer

Lack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction

Androgen receptor (AR) is regulated by SUMOylation at its transactivation domain. In vitro, the SUMOylation is linked to transcriptional repression and/or target gene-selective regulation. Here, we generated a mouse model (ArKl) in which the conserved SUMO acceptor lysines of AR are permanently abolished (Ar-K381R, (K500R)) ArKl males develop normally, without apparent defects in their systemic androgen action in reproductive tissues. However, the ArKl males are infertile. Their spermatogenesis appears unaffected, but their epididymal sperm maturation is defective, shown by severely compromised motility and fertilization capacity of the sperm. Fittingly, their epididymal AR chromatin-binding and gene expression associated with sperm maturation and function are misregulated. AR is SUMOylated in the wild-type epididymis but not in the testis, which could explain the tissue-specific response to the lack of AR SUMOylation. Our studies thus indicate that epididymal AR SUMOylation is essential for the post-testicular sperm maturation and normal reproductive capability of male mice

BICEPP: an example-based statistical text mining method for predicting the binary characteristics of drugs

<p>Abstract</p> <p>Background</p> <p>The identification of drug characteristics is a clinically important task, but it requires much expert knowledge and consumes substantial resources. We have developed a statistical text-mining approach (BInary Characteristics Extractor and biomedical Properties Predictor: BICEPP) to help experts screen drugs that may have important clinical characteristics of interest.</p> <p>Results</p> <p>BICEPP first retrieves MEDLINE abstracts containing drug names, then selects tokens that best predict the list of drugs which represents the characteristic of interest. Machine learning is then used to classify drugs using a document frequency-based measure. Evaluation experiments were performed to validate BICEPP's performance on 484 characteristics of 857 drugs, identified from the Australian Medicines Handbook (AMH) and the PharmacoKinetic Interaction Screening (PKIS) database. Stratified cross-validations revealed that BICEPP was able to classify drugs into all 20 major therapeutic classes (100%) and 157 (of 197) minor drug classes (80%) with areas under the receiver operating characteristic curve (AUC) > 0.80. Similarly, AUC > 0.80 could be obtained in the classification of 173 (of 238) adverse events (73%), up to 12 (of 15) groups of clinically significant cytochrome P450 enzyme (CYP) inducers or inhibitors (80%), and up to 11 (of 14) groups of narrow therapeutic index drugs (79%). Interestingly, it was observed that the keywords used to describe a drug characteristic were not necessarily the most predictive ones for the classification task.</p> <p>Conclusions</p> <p>BICEPP has sufficient classification power to automatically distinguish a wide range of clinical properties of drugs. This may be used in pharmacovigilance applications to assist with rapid screening of large drug databases to identify important characteristics for further evaluation.</p

Serum 25-Hydroxyvitamin D and Risk of Lung Cancer in Male Smokers: A Nested Case-Control Study

A role for vitamin D in cancer risk reduction has been hypothesized, but few data exist for lung cancer. We investigated the relationship between vitamin D status, using circulating 25-hydroxyvitamin D [25(OH)D], and lung cancer risk in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers.Lung cancer cases (n = 500) were randomly selected based on month of blood collection, and 500 controls were matched to them based on age and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariate-adjusted conditional logistic regression. To account for seasonal variation in 25(OH)D concentrations, season-specific and season-standardized quintiles of 25(OH)D were examined, and models were also stratified on season of blood collection (darker season = November-April and sunnier season = May-October). Pre-determined, clinically-defined cutpoints for 25(OH)D and 25(OH)D as a continuous measure were also examined.Overall, 25(OH)D was not associated with lung cancer. Risks were 1.08 (95% CI 0.67-1.75) and 0.83 (95% CI 0.53-1.31) in the highest vs. lowest season-specific and season-standardized quintiles of 25(OH)D, respectively, and 0.91 (95% CI 0.48-1.72) for the ≥75 vs. <25 nmol/L clinical categories. Inverse associations were, however, suggested for subjects with blood collections from November-April, with ORs of 0.77 (95% CI 0.41-1.45, p-trend = 0.05) and 0.65 (95% CI 0.37-1.14, p-trend = 0.07) in the highest vs. lowest season-specific and season-standardized quintiles of 25(OH)D, respectively, and 0.61 (95% CI 0.24-1.52, p-trend = 0.01) for ≥75 vs. <25 nmol/L. We also found 11% lower risk for a 10 nmol/L increase in 25(OH)D in the darker season based on the continuous measure (OR = 0.89, 95% CI 0.81-0.98, p = 0.02).In this prospective study of male smokers, circulating 25(OH)D was not associated with lung cancer risk overall, although inverse associations were suggested among those whose blood was drawn during darker months

Androgen receptor expression predicts breast cancer survival: the role of genetic and epigenetic events

Background: Breast cancer outcome, including response to therapy, risk of metastasis and survival, is difficult to predict using currently available methods, highlighting the urgent need for more informative biomarkers. Androgen receptor (AR) has been implicated in breast carcinogenesis however its potential to be an informative biomarker has yet to be fully explored. In this study, AR protein levels were determined in a cohort of 73 Grade III invasive breast ductal adenocarcinomas

Helicobacter pylori Seropositivity and Risk of Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide. Helicobacter pylori (H. pylori) is a risk factor for distal stomach cancer, and a few small studies have suggested that H. pylori may be a potential risk factor for lung cancer. To test this hypothesis, we conducted a study of 350 lung adenocarcinoma cases, 350 squamous cell carcinoma cases, and 700 controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) cohort of male Finnish smokers. Controls were one-to-one matched by age and date of baseline serum draw. Using enzyme-linked immunosorbent assays to detect immunoglobulin G antibodies against H. pylori whole-cell and cytotoxin-associated gene (CagA) antigens, we calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between H. pylori seropositivity and lung cancer risk using conditional logistic regression. H. pylori seropositivity was detected in 79.7% of cases and 78.5% of controls. After adjusting for pack-years and cigarettes smoked per day, H. pylori seropositivity was not associated with either adenocarcinoma (OR: 1.1, 95% CI: 0.75–1.6) or squamous cell carcinoma (OR: 1.1, 95% CI: 0.77–1.7). Results were similar for CagA-negative and CagA-positive H. pylori seropositivity. Despite earlier small studies suggesting that H. pylori may contribute to lung carcinogenesis, H. pylori seropositivity does not appear to be associated with lung cancer