Immunogenity of the pneumococcal polysaccharide vaccine in COPD patients. The effect of systemic steroids

AbstractRationale: To investigate if systemic steroids influence the antibody response to the 23-valent pneumococcal polysaccaride vaccine (23-PPV) in COPD patients.Patients and methods: COPD patients on: (a)⩾10mg of prednisolone/day (SS, n=30); (b) inhalative steroids (IS, n=30); (c) controls without COPD (CG, n=29) were vaccinated with 23-PPV. The concentration (μg/ml) of capsular specific anti-pneumococcal IgG antibodies (AB) for the serotypes (PNC) 4,6B,9V,14,18C,19F,23F were measured by Elisa technique before, 3 and 12 months (m) after vaccination. Non-responders were defined when AB-concentrations did neither doubled nor reach ⩾1μg/ml.Results: N=24 (CG), n=29 (IS), n=18 (SS) patients completed the study (mean age 64yrs.). Serious adverse events were not observed. Geometric mean (GM) AB-concentration of all serotypes increased significantly (CG, IS, SS) 3 and 12m after vaccination (P<0.05). The percentage of non-responders ranged between 16% (PNC 19F, IS) and 65% (PNC 4, SS) after 3m and 21% (PNC 19F, IS) and 82% (PNC 4, CG) after 12m. Neither post-vaccine AB-concentrations (3 and 12m) nor the rate of non-responders differed significantly between patients on systemic steroids and the other groups (IS, CG).Conclusions: Systemic steroids did not influence the AB-response. In all groups mean AB-concentration increased significantly after vaccination but an important percentage of subjects of all three groups were non-responders

Maximally inhomogeneous G\"{o}del-Farnsworth-Kerr generalizations

It is pointed out that physically meaningful aligned Petrov type D perfect fluid space-times with constant zero-order Riemann invariants are either the homogeneous solutions found by G\"{o}del (isotropic case) and Farnsworth and Kerr (anisotropic case), or new inhomogeneous generalizations of these with non-constant rotation. The construction of the line element and the local geometric properties for the latter are presented.Comment: 4 pages, conference proceeding of Spanish Relativity Meeting (ERE 2009, Bilbao

Rotating solenoidal perfect fluids of Petrov type D

We prove that aligned Petrov type D perfect fluids for which the vorticity vector is not orthogonal to the plane of repeated principal null directions and for which the magnetic part of the Weyl tensor with respect to the fluid velocity has vanishing divergence, are necessarily purely electric or locally rotationally symmetric. The LRS metrics are presented explicitly.Comment: 6 pages, no figure

Expanding perfect fluid generalizations of the C-metric

We reexamine Petrov type D gravitational fields generated by a perfect fluid with spatially homogeneous energy density and in which the flow lines form a timelike non-shearing and non-rotating congruence. It is shown that the anisotropic such spacetimes, which comprise the vacuum C-metric as a limit case, can have \emph{non-zero} expansion, contrary to the conclusion in the original investigation by Barnes (Gen. Rel. Grav. 4, 105 (1973)). This class consists of cosmological models with generically one and at most two Killing vectors. We construct their line element and discuss some important properties. The methods used in this investigation incite to deduce testable criteria regarding shearfree normality and staticity op Petrov type $D$ spacetimes in general, which we add in an appendix.Comment: 16 pages, extended and amended versio

Silent universes with a cosmological constant

We study non-degenerate (Petrov type I) silent universes in the presence of a non-vanishing cosmological constant L. In contrast to the L=0 case, for which the orthogonally spatially homogeneous Bianchi type I metrics most likely are the only admissible metrics, solutions are shown to exist when L is positive. The general solution is presented for the case where one of the eigenvalues of the expansion tensor is 0.Comment: 11 pages; several typos corrected which were still present in CGQ version; minor change

Dynamical mean-field theory for bosons

We discuss the recently developed bosonic dynamical mean-field (B-DMFT) framework, which maps a bosonic lattice model onto the selfconsistent solution of a bosonic impurity model with coupling to a reservoir of normal and condensed bosons. The effective impurity action is derived in several ways: (i) as an approximation to the kinetic energy functional of the lattice problem, (ii) using a cavity approach, and (iii) by using an effective medium approach based on adding a one-loop correction to the selfconsistently defined condensate. To solve the impurity problem, we use a continuous-time Monte Carlo algorithm based on a sampling of a perturbation expansion in the hybridization functions and the condensate wave function. As applications of the formalism we present finite temperature B-DMFT phase diagrams for the bosonic Hubbard model on a 3d cubic and 2d square lattice, the condensate order parameter as a function of chemical potential, critical exponents for the condensate, the approach to the weakly interacting Bose gas regime for weak repulsions, and the kinetic energy as a function of temperature.Comment: 26 pages, 19 figure

Combination of GD2-directed bispecific trifunctional antibody therapy with Pd-1 immune checkpoint blockade induces anti-neuroblastoma immunity in a syngeneic mouse model

Introduction: Despite advances in treating high-risk neuroblastoma, 50-60% of patients still suffer relapse, necessitating new treatment options. Bispecific trifunctional antibodies (trAbs) are a promising new class of immunotherapy. TrAbs are heterodimeric IgG-like molecules that bind CD3 and a tumor-associated antigen simultaneously, whereby inducing a TCR-independent anti-cancer T cell response. Moreover, via their functional Fc region they recruit and activate cells of the innate immune system like antigen-presenting cells potentially enhancing induction of adaptive tumor-specific immune responses. Methods: We used the SUREK trAb, which is bispecific for GD2 and murine Cd3. Tumor-blind trAb and the monoclonal ch14.18 antibody were used as controls. A co-culture model of murine dendritic cells (DCs), T cells and a neuroblastoma cell line was established to evaluate the cytotoxic effect and the T cell effector function in vitro. Expression of immune checkpoint molecules on tumor-infiltrating T cells and the induction of an anti-neuroblastoma immune response using a combination of whole cell vaccination and trAb therapy was investigated in a syngeneic immunocompetent neuroblastoma mouse model (NXS2 in A/J background). Finally, vaccinated mice were assessed for the presence of neuroblastoma-directed antibodies. We show that SUREK trAb-mediated effective killing of NXS2 cells in vitro was strictly dependent on the combined presence of DCs and T cells. Results: Using a syngeneic neuroblastoma mouse model, we showed that vaccination with irradiated tumor cells combined with SUREK trAb treatment significantly prolonged survival of tumor challenged mice and partially prevent tumor outgrowth compared to tumor vaccination alone. Treatment led to upregulation of programmed cell death protein 1 (Pd-1) on tumor infiltrating T cells and combination with anti-Pd-1 checkpoint inhibition enhanced the NXS2-directed humoral immune response. Conclusion: Here, we provide first preclinical evidence that a tumor vaccination combined with SUREK trAb therapy induces an endogenous anti-neuroblastoma immune response reducing tumor recurrence. Furthermore, a combination with anti-Pd-1 immune checkpoint blockade might even further improve this promising immunotherapeutic concept in order to prevent relapse in high-risk neuroblastoma patients

GD2-directed bispecific trifunctional antibody outperforms dinutuximab beta in a murine model for aggressive metastasized neuroblastoma

Background: Neuroblastoma is the most common extracranial solid tumor of childhood. Patients with high-risk disease undergo extremely aggressive therapy and nonetheless have cure rates below 50%. Treatment with the ch14.18 monoclonal antibody (dinutuximab beta), directed against the GD2 disialoganglioside, improved 5-year event-free survival in high-risk patients when administered in postconsolidation therapy and was recently implemented in standard therapy. Relapse still occurred in 57% of these patients, necessitating new therapeutic options. Bispecific trifunctional antibodies (trAbs) are IgG-like molecules directed against T cells and cancer surface antigens, redirecting T cells (via their CD3 specificity) and accessory immune cells (via their functioning Fc-fragment) toward tumor cells. We sought proof-of-concept for GD2/CD3-directed trAb efficacy against neuroblastoma. Methods: We used two GD2-specific trAbs differing only in their CD3-binding specificity: EKTOMUN (GD2/human CD3) and SUREK (GD2/mouse Cd3). This allowed trAb evaluation in human and murine experimental settings. Tumor-blind trAb and the ch14.18 antibody were used as controls. A coculture model of human peripheral blood mononuclear cells (PBMCs) and neuroblastoma cell lines was established to evaluate trAb antitumor efficacy by assessing expression of T-cell surface markers for activation, proinflammatory cytokine release and cytotoxicity assays. Characteristics of tumor-infiltrating T cells and response of neuroblastoma metastases to SUREK treatment were investigated in a syngeneic immunocompetent neuroblastoma mouse model mimicking minimal residual disease. Results: We show that EKTOMUN treatment caused effector cell activation and release of proinflammatory cytokines in coculture with neuroblastoma cell lines. Furthermore, EKTOMUN mediated GD2-dependent cytotoxic effects in human neuroblastoma cell lines in coculture with PBMCs, irrespective of the level of target antigen expression. This effect was dependent on the presence of accessory immune cells. Treatment with SUREK reduced the intratumor Cd4/Cd8 ratio and activated tumor infiltrating T cells in vivo. In a minimal residual disease model for neuroblastoma, we demonstrated that single-agent treatment with SUREK strongly reduced or eliminated neuroblastoma metastases in vivo. SUREK as well as EKTOMUN demonstrated superior tumor control compared with the anti-GD2 antibody, ch14.18. Conclusions: Here we provide proof-of-concept for EKTOMUN preclinical efficacy against neuroblastoma, presenting this bispecific trAb as a promising new agent to fight neuroblastoma