An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants

To assess sildenafil and N-desmethyl sildenafil (DMS) exposure in infants receiving sildenafil for the treatment of pulmonary hypertension (PH)

Lipid and metabolite profiles of human brain tumors by desorption electrospray ionization-MS

Examination of tissue sections using desorption electrospray ionization (DESI)-MS revealed phospholipid-derived signals that differ between gray matter, white matter, gliomas, meningiomas, and pituitary tumors, allowing their ready discrimination by multivariate statistics. A set of lower mass signals, some corresponding to oncometabolites, including 2-hydroxyglutaric acid and N-acetyl-aspartic acid, was also observed in the DESI mass spectra, and these data further assisted in discrimination between brain parenchyma and gliomas. The combined information from the lipid and metabolite MS profiles recorded by DESI-MS and explored using multivariate statistics allowed successful differentiation of gray matter (n = 223), white matter (n = 66), gliomas (n = 158), meningiomas (n = 111), and pituitary tumors (n = 154) from 58 patients. A linear discriminant model used to distinguish brain parenchyma and gliomas yielded an overall sensitivity of 97.4% and a specificity of 98.5%. Furthermore, a discriminant model was created for tumor types (i.e., glioma, meningioma, and pituitary), which were discriminated with an overall sensitivity of 99.4% and a specificity of 99.7%. Unsupervised multivariate statistics were used to explore the chemical differences between anatomical regions of brain parenchyma and secondary infiltration. Infiltration of gliomas into normal tissue can be detected by DESI-MS. One hurdle to implementation of DESI-MS intraoperatively is the need for tissue freezing and sectioning, which we address by analyzing smeared biopsy tissue. Tissue smears are shown to give the same chemical information as tissue sections, eliminating the need for sectioning before MS analysis. These results lay the foundation for implementation of intraoperative DESI-MS evaluation of tissue smears for rapid diagnosis

Concerns about losing face moderate the effect of visual perspective on health-related intentions and behaviors

Visualizing oneself engaging in future actions has been shown to increase the likelihood of actually engaging in the visualized action. In three studies, we examined the effect of perspective taken to visualize a future action (first-person vs. third-person) as a function of the degree to which individuals worry about others’ evaluation of themselves (face) and whether the visualized behavior is public or private. Across all studies, the effect of visual perspective was present only for participants with high level of face. In this group, the third-person visualization induced stronger intentions to engage in the behavior when the imagined behavior was public (Study 1), whereas the first-person visualization induced stronger intentions and greater likelihood to engage in that behavior when it was private (Study 2). The influence of the first-person perspective on flossing behavior was eliminated when people with high levels of face were encouraged to consider inter-personal consequences of the action (Study 3). Results are discussed in the light of recent theorizing on the cognitive consequences of taking a third-person versus a first-person perspective in visual imagery

Statistical equilibrium and ion cyclotron absorption/emission in strongly magnetized plasmas

We calculate the transition rates between proton Landau levels due to non-radiative and radiative Coulomb collisions in an electron-proton plasma with strong magnetic field B. Both electron-proton collisions and proton-proton collisions are considered. The roles of the first-order cyclotron absorption and second-order free-free absorption and scattering in determining the line strength and shape as well as the continuum are analysed in detail. We solve the statistical balance equation for the populations of proton Landau levels. For temperatures \sim 10^6-10^7 K, the deviations of the proton populations from LTE are appreciable at density \rho < 0.1 B_{14}^{3.5} g cm^{-3}, where B_{14}=B/(10^{14} G). We present general formulae for the plasma emissivity and absorption coefficents under a wide range of physical conditions. Our results are useful for studying the possibility and the conditions of proton/ion cyclotron line formation in the near vicinity of highly magnetized neutron stars.Comment: 17 pages, 8 figures, MNRAS, accepte

Swift and Fermi observations of the early afterglow of the short Gamma-Ray Burst 090510

We present the observations of GRB090510 performed by the Fermi Gamma-Ray Space Telescope and the Swift observatory. This is a bright, short burst that shows an extended emission detected in the GeV range. Furthermore, its optical emission initially rises, a feature so far observed only in long bursts, while the X-ray flux shows an initial shallow decrease, followed by a steeper decay. This exceptional behavior enables us to investigate the physical properties of the GRB outflow, poorly known in short bursts. We discuss internal shock and external shock models for the broadband energy emission of this object.Comment: Comments: Submitted to ApJ Letters. Contact Authors: Massimiliano De Pasquale ([email protected]), Mathew Page ([email protected]), Kenji Toma ([email protected]), Veronique Pelassa ([email protected]). Minor change in the authorlis

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival