Synthesis and Biological Evaluation (in Vitro and in Vivo) of Cyclic RGD Peptidomimetic - Paclitaxel Conjugates Targeting Integrin alphaVbeta3

A small library of integrin ligand - Paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the Paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified alphaVbeta3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of Paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin alphaVbeta3, making them attractive to be tested in in vivo models. Cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity than Paclitaxel, despite the lower (ca. half) molar dosage used

Saying It in Graphics: From Intentions to Visualizations

We propose a methodology for automatically realizing communicative goals in graphics. It features a task model that mediates the communicative intent and the selection of graphical techniques. The methodology supports the following functions: isolating assertions presentable in graphics; mapping such assertions into tasks for the potential reader, and selecting graphical techniques that support those tasks. We illustrate the methodology by redesigning a textual argument into a multimedia one with the same rhetorical and content structures but employing graphics to achieve some of the intentions. 1

First observation of the cosmic ray shadow of the Moon and the Sun with KM3NeT/ORCA

This article reports the first observation of the Moon and the Sun shadows in the sky distribution of cosmic-ray induced muons measured by the KM3NeT/ORCA detector. The analysed data-taking period spans from February 2020 to November 2021, when the detector had 6 Detection Units deployed at the bottom of the Mediterranean Sea, each composed of 18 Digital Optical Modules. The shadows induced by the Moon and the Sun were detected at their nominal position with a statistical significance of 4.2 σ and 6.2 σ , and an angular resolution of σres= 0. 49 ∘ and σres= 0. 66 ∘ , respectively, consistent with the prediction of 0. 53 ∘ from simulations. This early result confirms the effectiveness of the detector calibration, in time, position and orientation and the accuracy of the event direction reconstruction. This also demonstrates the performance and the competitiveness of the detector in terms of pointing accuracy and angular resolution

Searches for neutrinos in the direction of radio-bright blazars with the ANTARES telescope

Active galaxies, especially blazars, are among the most promising neutrino source candidates. To date, ANTARES searches for these objects considered GeV-TeV $\gamma$-ray bright blazars. Here, a statistically complete radio-bright blazar sample is used as the target for searches of origins of neutrinos collected by the ANTARES neutrino telescope over 13 years of operation. The hypothesis of a neutrino-blazar directional correlation is tested by pair counting and by a complementary likelihood-based approach. The resulting post-trial $p$-value is $3.0\%$ ($2.2\sigma$ in the two-sided convention), possibly indicating a correlation. Additionally, a time-dependent analysis is performed to search for temporal clustering of neutrino candidates as a mean of detecting neutrino flares in blazars. None of the investigated sources alone reaches a significant flare detection level. However, the presence of 18 sources with a pre-trial significance above $3\sigma$ indicates a $p=1.4\%$ ($2.5\sigma$ in the two-sided convention) detection of a time-variable neutrino flux. An \textit{a posteriori} investigation reveals an intriguing temporal coincidence of neutrino, radio, and $\gamma$-ray flares of the J0242+1101 blazar at a $p=0.5\%$ ($2.9\sigma$ in the two-sided convention) level. Altogether, the results presented here suggest a possible connection of neutrino candidates detected by the ANTARES telescope with radio-bright blazars

Search for neutrino counterparts to the gravitational wave sources from O3 catalogues with the ANTARES detector

Since 2015 the LIGO and Virgo interferometers have detected gravitational waves from almost one hundred coalescences of compact objects (black holes and neutron stars). This article presents the results of a search performed with data from the ANTARES telescope to identify neutrino counterparts to the gravitational wave sources detected during the third LIGO/Virgo observing run and reported in the catalogues GWTC-2, GWTC-2.1, and GWTC-3. This search is sensitive to all-sky neutrinos of all flavours and of energies $>100\,$GeV, thanks to the inclusion of both track-like events (mainly induced by $\nu_\mu$ charged-current interactions) and shower-like events (induced by other interaction types). Neutrinos are selected if they are detected within $\pm 500\,$s from the GW merger and with a reconstructed direction compatible with its sky localisation. No significant excess is found for any of the 80 analysed GW events, and upper limits on the neutrino emission are derived. Using the information from the GW catalogues and assuming isotropic emission, upper limits on the total energy $E_{\rm tot, \nu}$ and on the fraction of the total energy budget $f_\nu = E_{\rm tot, \nu}/E_{\rm rad}$ emitted as neutrinos of all flavours are also computed. Finally, a stacked analysis of all the 72 binary black hole mergers (respectively the 7 neutron star - black hole merger candidates) has been performed to constrain the typical neutrino emission within this population, leading to the limits: $E_{\rm tot, \nu} < 4.0 \times 10^{53}\,$erg and $f_\nu < 0.15$ (respectively, $E_{\rm tot, \nu} < 3.2 \times 10^{53}\,$erg and $f_\nu < 0.88$) for $E^{-2}$ spectrum and isotropic emission. Other assumptions including softer spectra and non-isotropic scenarios have also been tested.Comment: 13 pages, 4 figure