A pathological hallmark of Alzheimer's disease is the senile plaque, containing beta-amyloid fibrils, microglia and astrocytes. Beta-amyloid fibrils exert a cytotoxic effect on neurons, and stimulate microglia to produce neurotoxins, such as reactive oxygen species. Mononuclear phagocytes, including microglia, express scavenger receptors that mediate endocytosis of oxidized low-density lipoproteins, and adhesion to glucose-modified extra-cellular matrix proteins. Here we report that class A scavenger receptors mediate adhesion of rodent microglia and human monocytes to beta-amyloid fibril-coated surfaces leading to secretion of reactive oxygen species and cell immobilization. Thus, class A scavenger receptors are potential therapeutic targets in Alzheimer's disease.

Fibrinogen and fibrin serve as adhesive substrates for a variety ofcells including platelets, endothelial cells, and leukocytes. Previously, we identified the C terminus of the y chain of fibrinogen as the region of the fibrinogen molecule that contains a ligand for CD11b/CD18 (complement receptor 3) on phorbol ester-stimulated polymorphonuclear leukocytes.

We have studied the interactions of phosphodiester and phosphorothioate oligodeoxynucleotides with Mac-1 (CD11b/CD18; alpha M beta 2), a heparin-binding integrin found predominantly on the surface of polymorphonuclear leukocytes (PMNs), macrophages and natural killer cells. Binding of a homopolymer of thymidine occurred on both the alpha M and beta 2 subunits. Soluble fibrinogen, a natural ligand for Mac-1, was an excellent competitor of the binding of a phosphorothioate oligodeoxynucleotide to both TNF-alpha-activated and nonactivated PMNs. Upregulation of cell-surface Mac-1 expression increased cell-surface binding of oligodeoxynucleotides. Binding was inhibited by anti-Mac-1 monoclonal antibodies, and the increase in cell-surface binding was correlated with a three- to fourfold increase in internalization by PMNs. An oligodeoxynucleotide inhibited beta 2-dependent migration through Matrigel, but the production of reactive oxygen species in PMNs adherent to fibrinogen dramatically increased. Thus, our data demonstrate that Mac-1 is a cell-surface receptor for oligodeoxynucleotides that can mediate their internalization and that this binding may have important functional consequences.

Background Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors. Objective To study the role of transmembrane protease, serine 2 (TMPRSS2)–v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA. Design, setting, and participants The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials. Intervention Patients received AA 1000 mg daily and continuously. Measurements TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria. Results and limitations Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7–103 cells per 7.5 ml). A PSA decline ≥50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes. Conclusions Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer–specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.

Background: Use of ultrasound-guided techniques to facilitate central venous cannulation (CVC) may reduce the risk of misplacement and complications. A meta-analysis was conducted to compare real-time two-dimensional ultrasound (RTUS) guidance technique with anatomical landmark technique for CVC to determine whether RTUS has any advantages. Methods: Randomized studies comparing outcomes in patients undergoing CVC with either RTUS or landmark technique were retrieved from PubMed, ISI Web of Knowledge, EMBASE, and OVID EBM Reviews from their inception to March 2012. Results: Twenty-six studies involving 4,185 CVC procedures met the inclusion criteria. Compared with landmark technique, patients with RTUS had a pooled relative risk (RR) of 0.18 (95% CI: 0.10-0.32) for cannulation failure, 0.25 (95% CI: 0.15-0.42) for arterial puncture, 0.30 (95% CI: 0.19-0.46) for hematoma, 0.21 (95% CI: 0.06-0.73) for pneumothorax, and 0.10 (95% CI: 0.02-0.54) for hemothorax from random-effects models. However, RTUS did not show a reduction in the risk of cannulation failure (RR = 0.26, 95% CI: 0.03-2.55), arterial puncture (RR = 0.34, 95% CI: 0.05-2.60), hematoma (RR = 0.13, 95% CI: 0.01-2.42), pneumothorax (RR = 0.40, 95% CI: 0.02-9.61), and hemothorax (RR = 0.40, 95% CI: 0.02-9.61) in children or infants when the limited data were analyzed. Conclusions: Among adults receiving CVC, RTUS was associated with decreased risks of cannulation failure, arterial puncture, hematoma, and hemothorax. Additional data of randomized studies are necessary to evaluate these outcomes in pediatric patients.