Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy

Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose β-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in β2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of β-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. β-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.Fil: Solernó, Luisina María. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Sobol, Natasha Tatiana. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gottardo, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Capobianco, Carla Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; ArgentinaFil: Ferrero, Maximiliano Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Vásquez, Liliana. Universidad de San Martín de Porres; PerúFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital El Cruce Doctor Nestor Carlos Kirchner. Centro de Medicina Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garona, Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentin

Input of NAcGlc6SO3 epitopes (sulfotopes) present in Trypanosoma cruzi glycoproteins, and their specific antibodies, in the infection and immune pathogenesis of experimental Chagas disease

Background: Trypanosoma cruzi, the causative agent of Chagas disease contains a major antigen, cruzipain (Cz). The C-terminal domain (C-T) of this glycoprotein bears N-linked high mannose type sulfated oligosaccharide chains and is responsible for most antibodiesinnaturalandexperimentalinfections.Miceimmunization with C-T has shown that sulfate moieties of Cz molecule are targets for specific immune responses and responsible for cardiac ultrastructural abnormalities in absence of infection. Methods & Materials: After the molecular characterization of these sufotopes, BALB/c mice were immunized with Cz/C-T, prior and after desulfation treatment, and with NAcGlc6SO3-BSA, to be furthersublethallychallengedwithtrypomastigotestoinvestigate whether they are involved in immunepathogenesis and/or infection of experimental Chagas disease. Results: C-T-immunized mice showed low IL-4 levels and elevated IFN- concentration by capture ELISA using C-T as stimulus and a cytokines profile compatible with a mixed response showing: Th2 tendency with excessively high IFN and raised IL-17 levels. By contrast, dC-T-immunized-mice presented undetectable IL-4 levels, low IFN- level and a cytokines profile like that of control but with a significantly elevated IL-10 value. In addition, ultrastructuralcardiacalterationsandmainimmunorecognitionof fibrils and mitochondria were observed in C-T-immunized mice bothconfrontedwithpolyclonalanti-CzandmyosinadsorbedantiCz sera. After sublethal challenge, elevated parasitaemias were observed. Mortality was 20 and 80% in C-T and dC-T immunized mice, respectively and mice from dC-T group that survived presentedseveremusclealterations.BSA-NAcGlc6SO3-immunized mice mounted a predominant IgG1and IgG2b immune response followed by IgG2a, demonstrating the immunodominance of the sulfotope and a vigorous mice memory T cells response, similarly toC-T-immunizedmice.Aftersublethalinfection,miceimmunized with the sulfotope displayed excessively elevated parasitemias, similarIFN-levelsandsignificantlowermortalitypercentagethan those from BSA-NAcGlc control group. Furthermore, mice treated by passive transference of sulfate-specific IgGs purified from sera of BSA-NAcGlc6SO3-immunized mice, exhibited ultrastructural alterations in cardiac tissue. After challenge, those treated with sulfate-specific IgGs presented higher parasitemias than controls Conclusion:Altogether,thesefindingshavedemonstratedthat sulfotopes and their specific antibodies display a dual role, participating in the host-tissue immunopathogenicity of experimental Chagas disease and favoring the infection by T. cruziFil: Soprano, Luciana Lía. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferrero, Maximiliano Ruben. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Olgiati, María Laura. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Landoni, Malena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; ArgentinaFil: Garcia, Gabriela Andrea. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Esteva, Mónica Inés. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; ArgentinaFil: Couto, Alicia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; ArgentinaFil: Duschak, Vilma Gladys. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”. Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben”; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina18th International Congress of Infectious diseasesBuenos AiresArgentinaInternational Society of Infectious Disease

Multiplicity dependence of light (anti-)nuclei production in p–Pb collisions at sNN=5.02 TeV

The measurement of the deuteron and anti-deuteron production in the rapidity range −1 < y < 0 as a function of transverse momentum and event multiplicity in p–Pb collisions at √sNN = 5.02 TeV is presented. (Anti-)deuterons are identified via their specific energy loss dE/dx and via their time-of- flight. Their production in p–Pb collisions is compared to pp and Pb–Pb collisions and is discussed within the context of thermal and coalescence models. The ratio of integrated yields of deuterons to protons (d/p) shows a significant increase as a function of the charged-particle multiplicity of the event starting from values similar to those observed in pp collisions at low multiplicities and approaching those observed in Pb–Pb collisions at high multiplicities. The mean transverse particle momenta are extracted from the deuteron spectra and the values are similar to those obtained for p and particles. Thus, deuteron spectra do not follow mass ordering. This behaviour is in contrast to the trend observed for non-composite particles in p–Pb collisions. In addition, the production of the rare 3He and 3He nuclei has been studied. The spectrum corresponding to all non-single diffractive p-Pb collisions is obtained in the rapidity window −1 < y < 0 and the pT-integrated yield dN/dy is extracted. It is found that the yields of protons, deuterons, and 3He, normalised by the spin degeneracy factor, follow an exponential decrease with mass number

Higher-order correlations between different moments of two flow amplitudes in Pb−-Pb collisions at sNN=5.02\sqrt{s_{\rm NN}}=5.02 TeV

International audienceThe correlations between different moments of two flow amplitudes, extracted with the recently developed asymmetric cumulants, are measured in Pb$-$Pb collisions at $\sqrt{s_{\rm NN}} = 5.02$ TeV recorded by the ALICE detector at the LHC. The magnitudes of the measured observables show a dependence on the different moments as well as on the collision centrality, indicating the presence of non-linear response in all even moments up to the eighth. Furthermore, the higher-order asymmetric cumulants show different signatures than the symmetric and lower-order asymmetric cumulants. Comparisons with state-of-the-art event generators using two different parameterizations obtained from Bayesian optimization show differences between data and simulations in many of the studied observables, indicating a need for further tuning of the models behind those event generators. These results provide new and independent constraints on the initial conditions and transport properties of the system created in heavy-ion collisions

First measurement of the ∣t∣|t|-dependence of incoherent J/ψ\psi photonuclear production

International audienceThe first measurement of the cross section for incoherent photonuclear production of J/$\psi$ vector meson as a function of the Mandelstam $|t|$ variable is presented. The measurement was carried out with the ALICE detector at midrapidity, $|y|<0.8$, using ultra-peripheral collisions of Pb nuclei at a centre-of-mass energy per nucleon pair $\sqrt{s_{\mathrm{NN}}} = 5.02$ TeV. This rapidity interval corresponds to a Bjorken-$x$ range $(0.3$$-$$1.4)\times 10^{-3}$. Cross sections are reported in five $|t|$ intervals in the range $0.04<|t|<1$~GeV$^2$ and compared to the predictions of different models. Models that ignore quantum fluctuations of the gluon density in the colliding hadron predict a $|t|$-dependence of the cross section much steeper than in data. The inclusion of such fluctuations in the same models provides a better description of the data

Data-driven precision determination of the material budget in ALICE

The knowledge of the material budget with a high precision is fundamental for measurements of direct photon production using the photon conversion method due to its direct impact on the total systematic uncertainty. Moreover, it influences many aspects of the charged-particle reconstruction performance. In this article, two procedures to determine data-driven corrections to the material-budget description in ALICE simulation software are developed. One is based on the precise knowledge of the gas composition in the Time Projection Chamber. The other is based on the robustness of the ratio between the produced number of photons and charged particles, to a large extent due to the approximate isospin symmetry in the number of produced neutral and charged pions. Both methods are applied to ALICE data allowing for a reduction of the overall material budget systematic uncertainty from 4.5% down to 2.5%. Using these methods, a locally correct material budget is also achieved. The two proposed methods are generic and can be applied to any experiment in a similar fashion.The knowledge of the material budget with a high precision is fundamental for measurements of direct photon production using the photon conversion method due to its direct impact on the total systematic uncertainty. Moreover, it influences many aspects of the charged-particle reconstruction performance. In this article, two procedures to determine data-driven corrections to the material-budget description in ALICE simulation software are developed. One is based on the precise knowledge of the gas composition in the Time Projection Chamber. The other is based on the robustness of the ratio between the produced number of photons and charged particles, to a large extent due to the approximate isospin symmetry in the number of produced neutral and charged pions. Both methods are applied to ALICE data allowing for a reduction of the overall material budget systematic uncertainty from 4.5% down to 2.5%. Using these methods, a locally correct material budget is also achieved. The two proposed methods are generic and can be applied to any experiment in a similar fashion

Measurement of Non-prompt D0\rm D^0-meson Elliptic Flow in Pb-Pb Collisions at sNN\sqrt{s_{\rm NN}} = 5.02 TeV

International audienceThe elliptic flow ($v_2$) of $\rm D^0$ mesons from beauty-hadron decays (non-prompt $\rm D^0$) was measured in midcentral (30-50%) Pb-Pb collisions at a centre-of-mass energy per nucleon pair $\sqrt{s_{\rm NN}}$ = 5.02 TeV with the ALICE detector at the LHC. The $\rm D^0$ mesons were reconstructed at midrapidity ($|y|<0.8$) from their hadronic decay $\mathrm{D^0 \to K^-\pi^+}$, in the transverse momentum interval $2 < p_{\rm T} < 12$ GeV/$c$. The result indicates a positive $v_2$ for non-prompt $\rm D^0$ mesons with a significance of 2.7$\sigma$. The non-prompt $\rm D^0$-meson $v_2$ is lower than that of prompt non-strange D mesons with 3.2$\sigma$ significance in $2 < p_{\rm T} < 8$ GeV/$c$, and compatible with the $v_2$ of beauty-decay electrons. Theoretical calculations of beauty-quark transport in a hydrodynamically expanding medium describe the measurement within uncertainties

Skewness and kurtosis of mean transverse momentum fluctuations at the LHC energies

International audienceThe first measurements of skewness and kurtosis of mean transverse momentum ($\langle p_\mathrm{T}\rangle$) fluctuations are reported in Pb$-$Pb collisions at $\sqrt{s_\mathrm{NN}}$ = 5.02 TeV, Xe$-$Xe collisions at $\sqrt{s_\mathrm{NN}}$$=$ 5.44 TeV and pp collisions at $\sqrt{s} = 5.02$ TeV using the ALICE detector. The measurements are carried out as a function of system size $\langle \mathrm{d}N_\mathrm{ch}/\mathrm{d}\eta\rangle_{|\eta|<0.5}^{1/3}$, using charged particles with transverse momentum ($p_\mathrm{T}$) and pseudorapidity ($\eta$), in the range $0.2 < p_\mathrm{T} < 3.0$ GeV/$c$ and $|\eta| < 0.8$, respectively. In Pb$-$Pb and Xe$-$Xe collisions, positive skewness is observed in the fluctuations of $\langle p_\mathrm{T}\rangle$ for all centralities, which is significantly larger than what would be expected in the scenario of independent particle emission. This positive skewness is considered a crucial consequence of the hydrodynamic evolution of the hot and dense nuclear matter created in heavy-ion collisions. Furthermore, similar observations of positive skewness for minimum bias pp collisions are also reported here. Kurtosis of $\langle p_\mathrm{T}\rangle$ fluctuations is found to be in good agreement with the kurtosis of Gaussian distribution, for most central Pb$-$Pb collisions. Hydrodynamic model calculations with MUSIC using Monte Carlo Glauber initial conditions are able to explain the measurements of both skewness and kurtosis qualitatively from semicentral to central collisions in Pb--Pb system. Color reconnection mechanism in PYTHIA8 model seems to play a pivotal role in capturing the qualitative behavior of the same measurements in pp collisions

Photoproduction of K+^{+}K−^{-} pairs in ultra-peripheral collisions

International audienceK$^{+}$K$^{-}$ pairs may be produced in photonuclear collisions, either from the decays of photoproduced $\phi (1020)$ mesons, or directly as non-resonant K$^{+}$K$^{-}$ pairs. Measurements of K$^{+}$K$^{-}$ photoproduction probe the couplings between the $\phi (1020)$ and charged kaons with photons and nuclear targets. We present the first measurement of coherent photoproduction of K$^{+}$K$^{-}$ pairs on lead ions in ultra-peripheral collisions using the ALICE detector, including the first investigation of direct K$^{+}$K$^{-}$ production. There is significant K$^{+}$K$^{-}$ production at low transverse momentum, consistent with coherent photoproduction on lead targets. In the mass range $1.1 < M_{\rm{KK}} < 1.4$ GeV/$c^2$ above the $\phi (1020)$ resonance, for rapidity $|y_{\rm{KK}}|<0.8$ and $p_{\rm T,KK} < 0.1$ GeV/$c$, the measured coherent photoproduction cross section is $\mathrm{d}\sigma/\mathrm{d}y$ = 3.37 $\pm\ 0.61$ (stat.) $\pm\ 0.15$ (syst.) mb. The centre-of-mass energy per nucleon of the photon-nucleus (Pb) system $W_{\gamma \mathrm{Pb, n}}$ ranges from 33 to 188 GeV, far higher than previous measurements on heavy-nucleus targets. The cross section is larger than expected for $\phi (1020)$ photoproduction alone. The mass spectrum is fit to a cocktail consisting of $\phi (1020)$ decays, direct K$^{+}$K$^{-}$ photoproduction, and interference between the two. The confidence regions for the amplitude and relative phase angle for direct K$^{+}$K$^{-}$ photoproduction are presented

Photoproduction of K+^{+}K−^{-} pairs in ultra-peripheral collisions

International audienceK$^{+}$K$^{-}$ pairs may be produced in photonuclear collisions, either from the decays of photoproduced $\phi (1020)$ mesons, or directly as non-resonant K$^{+}$K$^{-}$ pairs. Measurements of K$^{+}$K$^{-}$ photoproduction probe the couplings between the $\phi (1020)$ and charged kaons with photons and nuclear targets. We present the first measurement of coherent photoproduction of K$^{+}$K$^{-}$ pairs on lead ions in ultra-peripheral collisions using the ALICE detector, including the first investigation of direct K$^{+}$K$^{-}$ production. There is significant K$^{+}$K$^{-}$ production at low transverse momentum, consistent with coherent photoproduction on lead targets. In the mass range $1.1 < M_{\rm{KK}} < 1.4$ GeV/$c^2$ above the $\phi (1020)$ resonance, for rapidity $|y_{\rm{KK}}|<0.8$ and $p_{\rm T,KK} < 0.1$ GeV/$c$, the measured coherent photoproduction cross section is $\mathrm{d}\sigma/\mathrm{d}y$ = 3.37 $\pm\ 0.61$ (stat.) $\pm\ 0.15$ (syst.) mb. The centre-of-mass energy per nucleon of the photon-nucleus (Pb) system $W_{\gamma \mathrm{Pb, n}}$ ranges from 33 to 188 GeV, far higher than previous measurements on heavy-nucleus targets. The cross section is larger than expected for $\phi (1020)$ photoproduction alone. The mass spectrum is fit to a cocktail consisting of $\phi (1020)$ decays, direct K$^{+}$K$^{-}$ photoproduction, and interference between the two. The confidence regions for the amplitude and relative phase angle for direct K$^{+}$K$^{-}$ photoproduction are presented