Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours

Lysozyme-induced transcriptional regulation of tnf-\u3b1 pathway genes in cells of the monocyte lineage

Lysozyme is one of the most important anti-bacterial effectors in the innate immune system of animals. Besides its direct antibacterial enzymatic activity, lysozyme displays other biological properties, pointing toward a significant anti-inflammatory effect, many aspects of which are still elusive. Here we investigate the perturbation of gene expression profiles induced by lysozyme in a monocyte cell line in vitro considering a perspective as broad as the whole transcriptome profiling. The results of the RNA-seq experiment show that lysozyme induces transcriptional modulation of the TNF-\u3b1/IL-1\u3b2 pathway genes in U937 monocytes. The analysis of transcriptomic profiles with IPA\uae identified a simple but robust molecular network of genes, in which the regulation trends are fully consistent with the anti-inflammatory activity of lysozyme. This study provides the first evidence in support of the anti-inflammatory action of lysozyme on the basis of transcriptomic regulation data resulting from the broad perspective of a whole-transcriptome profiling. Such important effects can be achieved with the supplementation of relatively low concentrations of lysozyme, for a short time of exposure. These new insights allow the potential of lysozyme in pharmacological applications to be better exploited

Central nervous system metastases from castration-resistant prostate cancer in the docetaxel era.

Central nervous system (brain or leptomeningeal) metastases (BLm) are considered rare in castration-resistant prostate cancer (CRPC) patients. Now that docetaxel has become the reference drug for first-line treatment of CRPC, patients whose disease is not controlled by hormonal manipulations may live much longer than before and have higher risk of developing BLm. We retrospectively reviewed the records of all patients with CRPC attending our centres from 2002 to 2010, and identified all of those who were diagnosed as having BLm and received (or were considered to have been eligible to receive) docetaxel-based treatment. We identified 31 cases of BLm (22 brain metastases and 9 leptomeningeal metastases) with an incidence of 3.3%. BLm-free survival was 43.5 months, and survival after BLm discovery was 4 months. With six patients surviving for more than 1 year after developing BLm, the projected 1-year BL-S rate was 25.8%. The findings of our study may be relevant in clinical practice as they indicate that incidence of BLm in CRPC patients in the docetaxel era seems to be higher than in historical reports, meaning that special attention should be paid to the appearance of neurological symptoms in long-term CRPC survivors because they may be related to BLm

In-beam fast-timing measurements in 103,105,107Cd

Fast-timing measurements were performed recently in the region of the medium-mass 103,105,107Cd isotopes, produced in fusion evaporation reactions. Emitted gamma-rays were detected by eight HPGe and five LaBr3:Ce detectors working in coincidence. Results on new and re-evaluated half-lives are discussed within a systematic of transition rates. The $7/2_1^+$ states in 103,105,107Cd are interpreted as arising from a single-particle excitation. The half-life analysis of the $11/2_1^-$ states in 103,105,107Cd shows no change in the single-particle transition strength as a function of the neutron number

Effect of Contour Shape of Nervous System Electromagnetic Stimulation Coils on the Induced Electrical Field Distribution

BACKGROUND: Electromagnetic stimulation of the nervous system has the advantage of reduced discomfort in activating nerves. For brain structures stimulation, it has become a clinically accepted modality. Coil designs usually consider factors such as optimization of induced power, focussing, field shape etc. In this study we are attempting to find the effect of the coil contour shape on the electrical field distribution for magnetic stimulation. METHOD AND RESULTS: We use the maximum of the induced electric field stimulation in the region of interest as the optimization criterion. This choice required the application of the calculus of variation, with the contour perimeter taken as a pre-set condition. Four types of coils are studied and compared: circular, square, triangular and an 'optimally' shaped contour. The latter yields higher values of the induced electrical field in depths up to about 30 mm, but for depths around 100 mm, the circular shape has a slight advantage. The validity of the model results was checked by experimental measurements in a tank with saline solution, where differences of about 12% were found. In view the accuracy limitations of the computational and measurement methods used, such differences are considered acceptable. CONCLUSION: We applied an optimization approach, using the calculus of variation, which allows to obtain a coil contour shape corresponding to a selected criterion. In this case, the optimal contour showed higher intensities for a longer line along the depth-axis. The method allows modifying the induced field structure and focussing the field to a selected zone or line

Immune checkpoint inhibitor associated vitiligo and its impact on survival in patients with metastatic melanoma: an Italian Melanoma Intergroup study

Background: Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. Methods: To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. Results: A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. Conclusions: Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration

The INFN-grid testbed

The Italian INFN-Grid Project is committed to set-up, run and manage an unprecedented nation-wide Grid infrastructure. The implementation and use of this INFN-Grid Testbed is presented and discussed. Particular care and attention are devoted to those activities, relevant for the management of the Testbed, carried out by the INFN within international Grid Projects

Organoiridium complexes : anticancer agents and catalysts

Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar Ir(I) complexes, such as Crabtree's hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir(III) complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d(6) Ir(III) centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C^C-chelating ligands can even stabilize Ir(IV) and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar Ir(I) complexes because of their structural and electronic similarity to Pt(II) anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich Ir(III) anticancer complexes. These complexes with the formula [(Cp(x))Ir(L^L')Z](0/n+) (with Cp* or extended Cp* and L^L' = chelated C^N or N^N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form Ir(III)-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert Ir(III) complexes as potent kinase inhibitors. Octahedral cyclometalated Ir(III) complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action

Fast-timing measurements in 95,96Mo

Half-lives of the 19/2+ and 21/2+ states in 95Mo and of the 8+ and 10+ states in 96Mo were measured. Matrix elements for yrast transitions in 95Mo and 96Mo are discussed.Comment: Proceedings of XIX International School on Nuclear Physics, Neutron Physics and Applications, Varna, Bulgaria, 2011, 5 pages, 6 figure