Peroxynitrite activates ERK via Raf-1 and MEK, independently from EGF receptor and p21Ras in H9C2 cardiomyocytes

Peroxynitrite is a potent oxidant and nitrating species proposed as a direct effector of myocardial damage in a wide range of cardiac diseases. Whether peroxynitrite also acts indirectly, by modulating cell signal transduction pathways in the myocardium, has not been investigated. Here, we examined the ability of peroxynitrite to activate extracellular signal-related kinase (ERK), a MAP kinase which has been linked with hypertrophic and anti-apoptotic responses in the heart, in cultured H9C2 cardiomyocytes. Peroxynitrite elicited a concentration- and time-dependent activation of ERK, secondary to the upstream activation of MEK 1 (ERK kinase). Activation of MEK-ERK by peroxynitrite was related to the upstream activation of Raf-1 kinase, as ERK and MEK phosphorylation were prevented by the Raf-1 inhibitor BAY43-9006. These effects of peroxynitrite were not associated with the activation of p21(Ras), known as a common signaling target of cellular oxidative stress. In contrast to ERK activation mediated by the epidermal growth factor (EGF), ERK activation by peroxynitrite was not prevented by AG1478 (EGF receptor inhibitor). Peroxynitrite acted through oxidative, but not nitrative chemistry, as ERK remained activated while nitration was prevented by the flavanol epicatechin. In addition to ERK, peroxynitrite also potently activated two additional members of the MAP kinase family of signaling proteins, JNK and p38. Thus, peroxynitrite activates ERK in cardiomyocytes through an unusual signaling cascade involving Raf-1 and MEK 1, independently from EGFR and P21(Ras), and also acts as a potent activator of JNK and p38. These results provide the novel concept that peroxynitrite may represent a previously unrecognized signaling molecule in various cardiac pathologies

Longitudinal analysis of DC subsets in patients with ovarian cancer: Implications for immunotherapy.

The use of circulating cDC1 to generate anti-cancer vaccines is among the most promising approaches to overcome the limited immunogenicity and clinical efficacy of monocyte-derived DC. However, the recurrent lymphopenia and the reduction of DC numbers and functionality in patients with cancer may represent an important limitation of such approach. In patients with ovarian cancer (OvC) that had received chemotherapy, we previously showed that cDC1 frequency and function were reduced. We recruited healthy donors (HD, n=7) and patients with OvC at diagnosis and undergoing interval debulking surgery (IDS, n=6), primary debulking surgery (PDS, n=6) or at relapse (n=8). We characterized longitudinally phenotypic and functional properties of peripheral DC subsets by multiparametric flow cytometry. We show that the frequency of cDC1 and the total CD141+ DC capacity to take up antigen are not reduced at the diagnosis, while their TLR3 responsiveness is partially impaired in comparison with HD. Chemotherapy causes cDC1 depletion and increase in cDC2 frequency, but mainly in patients belonging to the PDS group, while in the IDS group both total lymphocytes and cDC1 are preserved. The capacity of total CD141 <sup>+</sup> DC and cDC2 to take up antigen is not impacted by chemotherapy, while the activation capacity upon Poly(I:C) (TLR3L) stimulation is further decreased. Our study provides new information about the impact of chemotherapy on the immune system of patients with OvC and sheds a new light on the importance of considering timing with respect to chemotherapy when designing new vaccination strategies that aim at withdrawing or targeting specific DC subsets

SU(3) Mixing for Excited Mesons

The SU(3)-flavor symmetry breaking and the quark-antiquark annihilation mechanism are taken into account for describing the singlet-octet mixing for several nonets assigned by Particle Data Group(PDG). This task is approached with the mass matrix formalism

Determination of the b quark mass at the M_Z scale with the DELPHI detector at LEP

An experimental study of the normalized three-jet rate of b quark events with respect to light quarks events (light= \ell \equiv u,d,s) has been performed using the CAMBRIDGE and DURHAM jet algorithms. The data used were collected by the DELPHI experiment at LEP on the Z peak from 1994 to 2000. The results are found to agree with theoretical predictions treating mass corrections at next-to-leading order. Measurements of the b quark mass have also been performed for both the b pole mass: M_b and the b running mass: m_b(M_Z). Data are found to be better described when using the running mass. The measurement yields: m_b(M_Z) = 2.85 +/- 0.18 (stat) +/- 0.13 (exp) +/- 0.19 (had) +/- 0.12 (theo) GeV/c^2 for the CAMBRIDGE algorithm. This result is the most precise measurement of the b mass derived from a high energy process. When compared to other b mass determinations by experiments at lower energy scales, this value agrees with the prediction of Quantum Chromodynamics for the energy evolution of the running mass. The mass measurement is equivalent to a test of the flavour independence of the strong coupling constant with an accuracy of 7 permil.Comment: 24 pages, 10 figures, Accepted by Eur. Phys. J.