High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.</p

Prossimi Passi

Documento conclusivo e programmatico del Primo convegno nazionale del gruppo di lavoro Openscience della Consulta dei presidenti degli enti pubblici di ricerca. https://agenda.infn.it/e/ConvegnoOpenscienceCoPER202

Geographical heterogeneity of clinical and serological phenotypes of systemic sclerosis observed at tertiary referral centres. The experience of the Italian SIR-SPRING registry and review of the world literature

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature.Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 +/- 26.9 yrs.; mean disease duration 8.9 +/- 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas.Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches.Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities

Covid-19 And Rheumatic Autoimmune Systemic Diseases: Role of Pre-Existing Lung Involvement and Ongoing Treatments

The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations

DEEP MORPHOLOGICAL and SPECTRAL STUDY of the SNR RCW 86 with FERMI-LAT

RCW 86 is a young supernova remnant (SNR) showing a shell-type structure at several wavelengths and is thought to be an efficient cosmic-ray (CR) accelerator. Earlier \textit{Fermi} Large Area Telescope results reported the detection of $\gamma$-ray emission coincident with the position of RCW 86 but its origin (leptonic or hadronic) remained unclear due to the poor statistics. Thanks to 6.5 years of data acquired by the \textit{Fermi}-LAT and the new event reconstruction Pass 8, we report the significant detection of spatially extended emission coming from RCW 86. The spectrum is described by a power-law function with a very hard photon index ($\Gamma = 1.42 \pm 0.1_{\rm stat} \pm 0.06_{\rm syst}$) in the 0.1--500 GeV range and an energy flux above 100 MeV of ($2.91$ $\pm$ $0.8_{\rm stat}$ $\pm$ $0.12_{\rm syst}$) $\times$ $10^{-11}$ erg cm$^{-2}$ s$^{-1}$. Gathering all the available multiwavelength (MWL) data, we perform a broadband modeling of the nonthermal emission of RCW 86 to constrain parameters of the nearby medium and bring new hints about the origin of the $\gamma$-ray emission. For the whole SNR, the modeling favors a leptonic scenario in the framework of a two-zone model with an average magnetic field of 10.2 $\pm$ 0.7 $\mu$G and a limit on the maximum energy injected into protons of 2 $\times$ 10$^{49}$ erg for a density of 1 cm$^{-3}$. In addition, parameter values are derived for the North-East (NE) and South-West (SW) regions of RCW 86, providing the first indication of a higher magnetic field in the SW region.The Fermi LAT Collaboration acknowledges generous ongoing support from a number of agencies and institutes that have supported both the development and the operation of the LAT as well as scientific data analysis. These include the National Aeronautics and Space Administration and the Department of Energy in the United States, the Commissariat à l’Energie Atomique and the Centre National de la Recherche Scientifique / Institut National de Physique Nucléaire et de Physique des Particules in France, the Agenzia Spaziale Italiana and the Istituto Nazionale di Fisica Nucleare in Italy, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), High Energy Accelerator Research Organization (KEK) and Japan Aerospace Exploration Agency (JAXA) in Japan, and the K. A. Wallenberg Foundation, the Swedish Research Council and the Swedish National Space Board in Sweden. Additional support for science analysis during the operations phase is gratefully acknowledged from the Istituto Nazionale di Astrofisica in Italy and the Centre National d’Études Spatiales in France. GD and EG are members of CIC-CONICET (Argentina), LD is Fellow of CONICET (Argentina). They are supported through grants from CONICET and ANPCyT (Argentina). We acknowledge to Estela Reynoso and Anne Green who collaborated in the first stages of the HI data acquisition and preocessing.This is the author accepted manuscript. It first appeared from the Institute of Physics via http://dx.doi.org/10.3847/0004-637X/819/2/9

The Third Fermi Large Area Telescope Catalog of Gamma-ray Pulsars

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems co-located with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to $\leq 11$ known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with 6 undetected in radio. Overall, >235 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot E$ decreases to its observed minimum near $10^{33}$ erg s$^{-1}$, approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties and fit results to guide and be compared with modeling results.Comment: 142 pages. Accepted by the Astrophysical Journal Supplemen

Physics beyond the standard model with kaons at NA62

The NA62 experiment at CERN Super Proton Synchrotron was designed to measure BR(K+ \u2192 \u3c0+\u3bdv\u304) with an in-fight technique, never used before for this measurement. This decay is characterised by a very precise prediction in the Standard Model. Its branching ratio, which is expected to be less than 10-10, is one of the best candidates to indicate indirect effects of new physics beyond SM at the highest mass scales. NA62 result on K+ \u2192 \u3c0+\u3bdv\u304 from the full 2016 data set is described. Also a search for an invisible dark photon A\u2032 has been performed, exploiting the efficient photon-veto capability and high resolution tracking of the NA62. The signal stems from the chain K+ \u2192 \u3c0+\u3c00 followed by \u3c00 \u2192 A\u2032\u3b3. No significant statistical excess has been identified. Upper limits on the dark photon coupling to the ordinary photon as a function of the dark photon mass have been set, improving on the previous limits over the mass range 60 - 110 MeV/c2

Search for π⁰ decays to invisible particles

The NA62 experiment at the CERN SPS reports a study of a sample of 4 × 109 tagged π0 mesons from K+ → π+π0(γ), searching for the decay of the π0 to invisible particles. No signal is observed in excess of the expected background fluctuations. An upper limit of 4.4 × 10−9 is set on the branching ratio at 90% confidence level, improving on previous results by a factor of 60. This result can also be interpreted as a model- independent upper limit on the branching ratio for the decay K+ → π+X, where X is a particle escaping detection with mass in the range 0.110–0.155 GeV/c2 and rest lifetime greater than 100 ps. Model-dependent upper limits are obtained assuming X to be an axion-like particle with dominant fermion couplings or a dark scalar mixing with the Standard Model Higgs boson

Searches for lepton number violating K+ decays

The NA62 experiment at CERN reports a search for the lepton number violating decays K+→π−e+e+ and K+→π−μ+μ+ using a data sample collected in 2017. No signals are observed, and upper limits on the branching fractions of these decays of 2.2 x 10^-10 and 4.2 x 10^-11 are obtained, respectively, at 90% confidence level. These upper limits improve on previously reported measurements by factors of 3 and 2, respectively