B1 but not B2 bradykinin receptor agonists promote DU145 prostate cancer cell proliferation and migration

Background

The kallikrein-kinin system (KKS) is an endogenous pathway involved in angiogenesis and tumourigenesis, both vital for cancer growth and progression.

Objectives

To investigate the effect of two bradykinin receptor (B1R and B2R) agonists on growth and motility of prostate tumour (DU145) and micro-vascular endothelial cells (dMVECs).

Methods

Increasing concentrations of selective B1R and B2R agonists were added to cultured cells. Cell proliferation and migration were assessed using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and modified Boyden Chamber assays, respectively. Where significant stimulation was found, the influence of an antagonist was also investigated.

Results

Neither growth nor motility of endothelial cells was affected by either agonist. In DU145 cells, while the B2R agonist was without any significant effect, the B1R agonist stimulated proliferation and migration at concentrations of 10nM and 50nM respectively. Further, this effect was abrogated when cells were pre-incubated with a B1R antagonist.

Conclusions

Unlike the physiologically-active B2R, the pathologically-inducible B1R may be implicated in prostate tumourigenic events. The involvement of the KKS in malignant prostate pathology supports on-going exploration of bradykinin receptor antagonists as target candidates in the development of alternate approaches to cancer therapy.     

The insulin‐like growth factor system and sarcomas

Sarcomas are a diverse group of malignant mesenchymal tumours arising from bone and soft tissues. The identification of critical cellular signalling pathways in sarcomas is an important issue for the development of new targeted therapies. This review highlights the experimental and clinical evidence supporting the role of the insulin‐like growth factor (IGF) signalling system in the cellular transformation and progression of several types of sarcoma, including rhabdomyosarcoma, synovial sarcoma, leiomyosarcoma, Ewing's sarcoma and osteosarcoma. Preclinical data suggest that the IGF system could be a promising target for therapy in these sarcomas. Currently, therapies interrupting IGF signalling have been or are being developed. In recent phase 1 clinical studies with humanized monoclonal antibodies directed against IGF receptor type 1 (IGF‐1R), objective tumour responses were observed in several patients with Ewing's sarcoma, encouraging further clinical testing in Ewing's sarcoma and other sarcoma (sub)types. Moreover, the occasional occurrence of paraneoplastic hypoglycaemia as a result of the secretion of incompletely processed forms of pro‐IGF‐II by sarcomas is discussed. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Retrospective reports of college students' childhood problems

College students and a subsample of their mothers and fathers participated in a study examining their retrospective reports of childhood emotional and behavioral problems experienced by college students. College students and their mothers and fathers exhibited moderate correspondence in their recollection of internalizing and externalizing problems that college students experienced during their childhood. In contrast, college students tended to endorse significantly greater levels of both internalizing and externalizing problems relative to their mothers and fathers. Current psychological symptoms predicted the greater endorsement of childhood internalizing and externalizing problems by college students and the greater endorsement of college students' childhood internalizing problems by their mothers. Further, college students' current perceptions of their parents predicted their endorsement of childhood internalizing problems, and college students' current masculinity and femininity predicted their endorsement of childhood externalizing problems. Results of this study emphasized the importance of noting factors that may be related to retrospective reports.     

Hyperspectral and multispectral bioluminescence optical tomography for small animal imaging

For bioluminescence imaging studies in small animals, it is important to be able to accurately localize the three-dimensional (3D) distribution of the underlying bioluminescent source. The spectrum of light produced by the source that escapes the subject varies with the depth of the emission source because of the wavelength-dependence of the optical properties of tissue. Consequently, multispectral or hyperspectral data acquisition should help in the 3D localization of deep sources. In this paper, we describe a framework for fully 3D bioluminescence tomographic image acquisition and reconstruction that exploits spectral information. We describe regularized tomographic reconstruction techniques that use semi-infinite slab or FEM-based diffusion approximations of photon transport through turbid media. Singular value decomposition analysis was used for data dimensionality reduction and to illustrate the advantage of using hyperspectral rather than achromatic data. Simulation studies in an atlas-mouse geometry indicated that sub-millimeter resolution may be attainable given accurate knowledge of the optical properties of the animal. A fixed arrangement of mirrors and a single CCD camera were used for simultaneous acquisition of multispectral imaging data over most of the surface of the animal. Phantom studies conducted using this system demonstrated our ability to accurately localize deep point-like sources and show that a resolution of 1.5 to 2.2 mm for depths up to 6 mm can be achieved. We also include an in vivo study of a mouse with a brain tumour expressing firefly luciferase. Co-registration of the reconstructed 3D bioluminescent image with magnetic resonance images indicated good anatomical localization of the tumour.     

Collaborative study of antibiotic medium 3 and flow cytometry for identification of amphotericin B-resistant Candida isolates

Center 1 used the National Committee for Clinical Laboratory Standards M27-A2 method and antibiotic medium 3 (AM3) test to determine amphotericin B resistance in 5 of 30 Candida isolates. These isolates were tested at center 2 by AM3 test and flow cytometry (FC). The agreements (C1-C2) were 90% for AM3 test and FC and 73% for the AM3 tests.     

Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints

The CLSI Antifungal Subcommittee followed the M23-A2 “blueprint” to develop interpretive MIC breakpoints for anidulafungin, caspofungin, and micafungin against Candida species. MICs of ≤2 μg/ml for all three echinocandins encompass 98.8 to 100% of all clinical isolates of Candida spp. without bisecting any species group and represent a concentration that is easily maintained throughout the dosing period. Data from phase III clinical trials demonstrate that the standard dosing regimens for each of these agents may be used to treat infections due to Candida spp. for which MICs are as high as 2 μg/ml. An MIC predictive of resistance to these agents cannot be defined based on the data from clinical trials due to the paucity of isolates for which MICs exceed 2 μg/ml. The clinical data set included only three isolates from patients treated with an echinocandin (caspofungin) for which the MICs were >2 μg/ml (two C. parapsilosis isolates at 4 μg/ml and one C. rugosa isolate at 8 μg/ml). Based on these data, the CLSI subcommittee has decided to recommend a “susceptible only” breakpoint MIC of ≤2 μg/ml due to the lack of echinocandin resistance in the population of Candida isolates thus far. Isolates for which MICs exceed 2 μg/ml should be designated “nonsusceptible” (NS). For strains yielding results suggestive of an NS category, the organism identification and antimicrobial-susceptibility test results should be confirmed. Subsequently, the isolates should be submitted to a reference laboratory that will confirm the results by using a CLSI reference dilution method.     

Reliability of quantitative EEG (qEEG) measures and LORETA current source density at 30 days

There is a growing interest for using quantitative EEG and LORETA current source density in clinical and research settings. Importantly, if these indices are to be employed in clinical settings then the reliability of these measures is of great concern. Neuroguide (Applied Neurosciences) is sophisticated software developed for the analyses of power, and connectivity measures of the EEG as well as LORETA current source density. To date there are relatively few data evaluating topographical EEG reliability contrasts for all 19 channels and no studies have evaluated reliability for LORETA calculations. We obtained 4 min eyes-closed and eyes-opened EEG recordings at 30-day intervals. The EEG was analyzed in Neuroguide and FFT power, coherence and phase was computed for traditional frequency bands (delta, theta, alpha and beta) and LORETA current source density was calculated in 1 Hz increments and summed for total power in eight regions of interest (ROI). In order to obtain a robust measure of reliability we utilized a random effects model with an absolute agreement definition. The results show very good reproducibility for total absolute power and coherence. Phase shows lower reliability coefficients. LORETA current source density shows very good reliability with an average 0.81 for ECB and 0.82 for EOB. Similarly, the eight regions of interest show good to very good agreement across time. Implications for future directions and use of qEEG and LORETA in clinical populations are discussed.