The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice.

Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control, veliparib (100 mg/kg diet), or olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine biomarkers, mice were fed with olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with veliparib or olaparib (200 mg/kg diet), the average age of the first detectable tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls. Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of olaparib delayed tumor development but were less effective than the highest dose. When fed intermittently, olaparib delayed the onset of the first palpable tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary, veliparib and olaparib are effective for delaying tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with olaparib was as effective as continuous dosing. These results suggest that the use of PARP inhibitors is a promising chemopreventive option.

Step-wise loss of bacterial flagellar torsion confers progressive phagocytic evasion.

Phagocytosis of bacteria by innate immune cells is a primary method of bacterial clearance during infection. However, the mechanisms by which the host cell recognizes bacteria and consequentially initiates phagocytosis are largely unclear. Previous studies of the bacterium Pseudomonas aeruginosa have indicated that bacterial flagella and flagellar motility play an important role in colonization of the host and, importantly, that loss of flagellar motility enables phagocytic evasion. Here we use molecular, cellular, and genetic methods to provide the first formal evidence that phagocytic cells recognize bacterial motility rather than flagella and initiate phagocytosis in response to this motility. We demonstrate that deletion of genes coding for the flagellar stator complex, which results in non-swimming bacteria that retain an initial flagellar structure, confers resistance to phagocytic binding and ingestion in several species of the gamma proteobacterial group of Gram-negative bacteria, indicative of a shared strategy for phagocytic evasion. Furthermore, we show for the first time that susceptibility to phagocytosis in swimming bacteria is proportional to mot gene function and, consequently, flagellar rotation since complementary genetically- and biochemically-modulated incremental decreases in flagellar motility result in corresponding and proportional phagocytic evasion. These findings identify that phagocytic cells respond to flagellar movement, which represents a novel mechanism for non-opsonized phagocytic recognition of pathogenic bacteria.

Uncoupling scavenger receptor A-mediated phagocytosis of bacteria from endotoxic shock resistance.

Unresolved infection by gram-negative bacteria can result in the potentially lethal condition known as endotoxic shock, whereby uncontrolled inflammation can lead to multiple organ failure and death of the infected host. Previous results have demonstrated that animals deficient in class A scavenger receptor (SRA), a trafficking receptor for bacteria and bacterium-derived molecules, are more susceptible to endotoxic shock. This has been proposed to be a result of impaired SRA-dependent phagocytic clearance of bacteria resulting in stronger proinflammatory stimuli. In this report, we test the hypothesis that there is an obligate reciprocal relationship between SRA-mediated phagocytosis of bacteria and susceptibility to endotoxic shock. Here, we demonstrate that both SRA-dependent and -independent gram-negative bacterial strains elicit SRA-dependent increased cytokine production in vitro and in vivo and increased susceptibility to endotoxic shock in SRA-deficient mice. This is the first evidence showing that SRA-mediated clearance of LPS is functionally distinct from the role of SRA in bacterial phagocytosis and is a formal demonstration that the SRA-dependent cytokine responses and the resultant endotoxic shock are not coupled to SRA-mediated clearance of bacteria.

Image integration using intracardiac ultrasound to guide catheter ablation of atrial fibrillation.

BACKGROUND: Three-dimensional (3D) reconstruction of the left atrium (LA) can be performed using real-time intracardiac echocardiography (ICE) to facilitate image integration during atrial fibrillation (AF) ablation. Current users of this technology generally image the LA indirectly from the right atrium (RA). OBJECTIVE: The purpose of this study was to assess the feasibility and accuracy of image integration with placement of the ICE catheter directly in the LA to visualize the LA. METHODS: Thirty consecutive patients undergoing an AF ablation with the CARTO-Sound system were enrolled. A 10-Fr phased-array ICE catheter was used to obtain two-dimensional echocardiographic images of the LA; in 15 patients the ICE probe was placed in the LA, and in 15 patients it was placed only in the RA. Sequential images were obtained and merged with a preacquired computed tomography/magnetic resonance image. The accuracy of image integration was assessed by the value of the average image integration error after surface registration. RESULTS: Thirty patients (60% paroxysmal AF, LA size = 42 +/- 7 mm, ejection fraction = 62% +/- 10%) were studied. There was no difference in the time required to create the LA anatomic map and perform image integration with imaging from the LA versus the RA (22 +/- 22 vs. 24 +/- 16 minutes; P = .8). The number of ultrasound contours obtained was also similar (LA = 26 +/- 17 vs. RA = 24 +/- 16; P = .7). The average integration error was less with direct LA imaging (LA = 1.83 +/- 0.32 vs. RA = 2.52 +/- 0.58 mm; P = .0004). CONCLUSION: Direct LA imaging with ICE is feasible and results in improved LA visualization and image integration.