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Poster presentation: The transcription factor NF-kappaB plays a pivotal role in the development and maintenance of the central nervous system and its constitutive activation in neurons has been previously reported. NF-kappaB is post-translationally activated upon phosphorylation of the IkappaBalpha inhibitory protein by the activated IkappaB kinase (IKKalpha/beta) and the subsequent degradation of IkappaBalpha by the proteasome. Recently, we had demonstrated an unexpected accumulation of three components of the NF-kappaB cascade in the axon initial segment (AIS): Activated IKK, phosphorylated IkappaBalpha and phosphorylated-p65(Ser536). These are all associated with detergent-insoluble cytoskeletal components of the AIS. We observed further compartimentalization as pIKKalpha/beta primarily associated with the membrane cytoskeleton, whereas pIkappaBalpha was sequestered to fasciculated microtubules. Colchicine-induced depolymerization of microtubules was associated with reduced sequestration of pIkappaBalpha in the AIS, which could be blocked by use of proteasome inhibitors like Mg-132 or Lactacystin. Concurrently, enhanced nuclear immunoreactivity for the NF-kappaB subunit p65 was noted. Using NF-kappaB-dependent reporter gene assays, a significant increase in NF-kappaB activity was observed after depolymerization of microtubules and this was inhibited by the microtubule-stabilizing drug paclitaxel. The use of transiently transfected, photoactivatable-GFP p65 fusion proteins will allow us to specifically analyse the compartimentalized signal transduction pathways in unique spatial and temporal resolution. Taken together, these observations provide strong evidence for compartmentalized activation of NF-kappaB in the AIS and modulation of neuronal NF-kappaB activity by microtubule dynamics.
Poster presentation: The transcription factor NF-kappaB plays a central role in the development and maintenance of the central nervous system and its constitutive activation in neurons has been repeatedly reported. Previous work from our laboratories (poster presentation: Compartimentalized NF-kappaB activity in the axon initial segment) had revealed an intriguing clustering of activated IKKalpha/beta and other downstream elements of an activated NF-kappaB cascade (phospho-IkappaBalpha, phospho-p65(Ser536)) in the axon initial segment (AIS). Accumulation of certain voltage-gated sodium channels (Na(v)1.2), M-type potassium channels (KCNQ2) as well as cytoskeletal anchoring proteins (AnkyrinG) characterise the AIS. However, it is not yet clear how AIS-localized IKK gets activated and whether this can be connected to the constitutive activation of NF-kappaB. Long-term blockade of sodium channels with tetrodotoxin, potassium-channels with linopirdine or NMDA-receptors with MK-801 did not elicit any change upon the constitutive activation of the pathway. Strikingly, the occurrence of phosphorylated IkappaBalpha was even unaltered by 24 h of incubation with protein synthesis inhibitors. Others have reported that impairment of NF-kappaB inhibits neuritogenesis. In this line we observed that the early initiation of IkappaBalpha phosphorylation was susceptible to inhibition of IKK in DIV1–2 neurons. We therefore aim to identify the interaction partners of the activated IKK complex in the AIS. Proteomic methods such as co-immunoprecipitation analyses and mass-spectrometry will help us to identify the key players in the initiation of constitutive IKK phosphorylation and activation in neurons.
Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
Methods: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
Conclusions: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
Trial registration: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.
The production of π±, K±, and (p¯¯¯)p is measured in pp collisions at s√=13 TeV in different topological regions. Particle transverse momentum (pT) spectra are measured in the ``toward'', ``transverse'', and ``away'' angular regions defined with respect to the direction of the leading particle in the event. While the toward and away regions contain the fragmentation products of the near-side and away-side jets, respectively, the transverse region is dominated by particles from the Underlying Event (UE). The relative transverse activity classifier, RT=NT/⟨NT⟩, is used to group events according to their UE activity, where NT is the measured charged-particle multiplicity per event in the transverse region and ⟨NT⟩ is the mean value over all the analysed events. The first measurements of identified particle pT spectra as a function of RT in the three topological regions are reported. The yield of high transverse momentum particles relative to the RT-integrated measurement decreases with increasing RT in both the toward and away regions, indicating that the softer UE dominates particle production as RT increases and validating that RT can be used to control the magnitude of the UE. Conversely, the spectral shapes in the transverse region harden significantly with increasing RT. This hardening follows a mass ordering, being more significant for heavier particles. The pT-differential particle ratios (p+p¯¯¯)/(π++π−) and (K++K−)/(π++π−) in the low UE limit (RT→0) approach expectations from Monte Carlo generators such as PYTHIA 8 with Monash 2013 tune and EPOS LHC, where the jet-fragmentation models have been tuned to reproduce e+e− results.
The study of the azimuthal anisotropy of inclusive muons produced in p-Pb collisions at sNN−−−√=8.16 TeV, using the ALICE detector at the LHC is reported. The measurement of the second-order Fourier coefficient of the particle azimuthal distribution, v2, is performed as a function of transverse momentum pT in the 0-20% high-multiplicity interval at both forward (2.03<yCMS<3.53) and backward (−4.46<yCMS<−2.96) rapidities over a wide pT range, 0.5<pT<10 GeV/c, in which a dominant contribution of muons from heavy-flavour hadron decays is expected at pT>2 GeV/c. The v2 coefficient of inclusive muons is extracted using two different techniques, namely two-particle cumulants, used for the first time for heavy-flavour measurements, and forward-central two-particle correlations. Both techniques give compatible results. A positive v2 is measured at both forward and backward rapidities with a significance larger than 4.7σ and 7.6σ, respectively, in the interval 2<pT<6 GeV/c. Comparisons with previous measurements in p-Pb collisions at sNN−−−√=5.02 TeV, and with AMPT and CGC-based theoretical calculations are discussed. The findings impose new constraints on the theoretical interpretations of the origin of the collective behaviour in small collision systems.
In ultraperipheral collisions (UPCs) of relativistic nuclei without overlap of nuclear densities, the two nuclei are excited by the Lorentz-contracted Coulomb fields of their collision partners. In these UPCs, the typical nuclear excitation energy is below a few tens of MeV, and a small number of nucleons are emitted in electromagnetic dissociation (EMD) of primary nuclei, in contrast to complete nuclear fragmentation in hadronic interactions. The cross sections of emission of given numbers of neutrons in UPCs of 208Pb nuclei at sNN−−−√=5.02 TeV were measured with the neutron zero degree calorimeters (ZDCs) of the ALICE detector at the LHC, exploiting a similar technique to that used in previous studies performed at sNN−−−√=2.76 TeV. In addition, the cross sections for the exclusive emission of one, two, three, four, and five forward neutrons in the EMD, not accompanied by the emission of forward protons, and thus mostly corresponding to the production of 207,206,205,204,203Pb, respectively, were measured for the first time. The predictions from the available models describe the measured cross sections well. These cross sections can be used for evaluating the impact of secondary nuclei on the LHC components, in particular, on superconducting magnets, and also provide useful input for the design of the Future Circular Collider (FCC-hh).
Understanding the production mechanism of light (anti)nuclei is one of the key challenges of nuclear physics and has important consequences for astrophysics, since it provides an input for indirect darkmatter searches in space. In this paper, the latest results about the production of light (anti)nuclei in pp collisions at √ s = 13 TeV are presented, focusing on the comparison with the predictions of coalescence and thermal models. For the first time, the coalescence parameters B2 for deuterons and B3 for helions are compared with parameter-free theoretical predictions that are directly constrained by the femtoscopic measurement of the source radius in the same event class. A fair description of the data with a Gaussian wave function is observed for both deuteron and helion, supporting the coalescence mechanism for the production of light (anti)nuclei in pp collisions. This method paves the way for future investigations of the internal structure of more complex nuclear clusters, including the hypertriton.
The correlations between different moments of two flow amplitudes, extracted with the recently developed asymmetric cumulants, are measured in Pb-Pb collisions at √sNN = 5.02 TeV recorded by the ALICE detector at the CERN Large Hadron Collider. The magnitudes of the measured observables show a dependence on the different moments as well as on the collision centrality, indicating the presence of nonlinear 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 parametrizations 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.
The production of K∗(892)0 and ϕ(1020) mesons in proton-proton (pp) and lead-lead (Pb-Pb) collisions at sNN−−−√=5.02 TeV has been measured using the ALICE detector at the Large Hadron Collider (LHC). The transverse momentum (pT) distributions of K∗(892)0 and ϕ(1020) mesons have been measured at midrapidity (|y|<0.5) up to pT=20 GeV/c in inelastic pp collisions and for several Pb-Pb collision centralities. The collision centrality and collision energy dependence of the average transverse momenta agree with the radial flow scenario observed with stable hadrons, showing that the effect is stronger for more central collisions and higher collision energies. The K∗0/K ratio is found to be suppressed in Pb-Pb collisions relative to pp collisions: this indicates a loss of the measured K∗(892)0 signal due to rescattering of its decay products in the hadronic phase. In contrast, for the longer-lived ϕ(1020) mesons, no such suppression is observed. The nuclear modification factors (RAA) of K∗(892)0 and ϕ(1020) mesons are calculated using pp reference spectra at the same collision energy. In central Pb-Pb collisions for pT>8 GeV/c, the RAA values of K∗(892)0 and ϕ(1020) are below unity and observed to be similar to those of pions, kaons, and (anti)protons. The RAA values at high pT (>~8 GeV/c) for K∗(892)0 and ϕ(1020) mesons are in agreement within uncertainties for sNN−−−√=5.02 and 2.76 TeV.