Dose-effect of interleukin-10 and its immunoregulatory role in Crohn's disease.

BACKGROUND: Interleukin-10 (IL-10) is currently being extensively studied in clinical trials for the treatment of Crohn's disease (CD). Only marginal effects have, however, been reported, and the dose-response curve was bell-shaped contrasting with the reported data from in vitro experiments. AIM: To use another in vitro model to analyze the effect of rhIL-10 and rhIL-4 on the spontaneous mucosal TNF-alpha secretion in patients with CD, and to characterize the phenotype of the cells targeted by rhIL-10. METHODS: Non-inflamed colon biopsies from CD patients were cultured for 16 hours in presence of different concentrations of rhIL-10 or rhIL-4. The numbers of TNF-alpha-secreting cells among isolated lamina propria mononuclear cells (LPMNC) were estimated by Elispot. RESULTS: Both rhIL-10 and rhIL-4 down-regulate TNF-alpha secretion by LPMNC from CD patients, with a more pronounced effect with rhIL-10. These effects were closely linked to the cytokine concentrations used, with a bell-shaped dose-response curve. Residual TNF-alpha secretion, in the presence of optimal rhIL-10 concentration was mainly attributable to CD3+ T cells. In contrast, at higher rhIL-10 concentrations, CD3- cells contributed significantly to the TNF-alpha secretion. CONCLUSIONS: The in vitro model we used, demonstrates that IL-4, but mostly IL-10, efficiently suppresses TNF-alpha secretion in LPMNC from CD patients, with a dose-response curve similar to results obtained in vivo. Resistance at high rhIL-10 concentrations was associated with a change in the phenotype of TNF-alpha-secreting cells.

Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial.

BACKGROUND: Trastuzumab (Herceptin(R)) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. PATIENTS AND METHODS: HERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. RESULTS: The overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54-0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1-2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26-1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). CONCLUSIONS: Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Comparison of the experimental, semi-experimental and ab initio equilibrium structures of acetylene: Influence of relativisitic effects and of the diagonal Born-Oppenheimer corrections

The equilibrium structure of acetylene (also named ethyne) has been reinvestigated to resolve the small discrepancies noted between different determinations. The size of the system as well as the large amount of available experimental data provides the quite unique opportunity to check the magnitude and relevance of various contributions to equilibrium structure as well as to verify the accuracy of experimental results. With respect to pure theoretical investigation, quantum-chemical calculations at the coupled-cluster level have been employed together with extrapolation to the basis set limit, consideration of higher excitations in the cluster operator, inclusion of core correlation effects as well as relativistic and diagonal Born-Oppenheimer corrections. In particular, it is found that the extrapolation to the complete basis set limit, the inclusion of higher excitations in the electronic-correlation treatment and the relativistic corrections are of the same order of magnitude. It also appears that a basis set as large as a core-valence quintuple-zeta set is required for accurately accounting for the inner-shell correlation contribution. From a pure experimental point of view, the equilibrium structure has been determined using very accurate rotational constants recently obtained by a global analysis (that is to say that all non-negligible interactions are explicitely included in the Hamiltonian matrix) of rovibrational spectra. Finally, a semi-experimental equilibrium structure (where the equilibrium rotational constants are obtained from the experimental ground state rotational constants and computed rovibrational corrections) has been obtained from the available experimental ground-state rotational constants for ten isotopic species corrected for computed vibrational corrections. Such a determination led to the revision of the ground-state rotational constants of two isotopologues, thus showing that structural determination is a good method to identify errors in experimental rotational constants. The three structures are found in a very good agreement, and our recommended values are rCC 120.2958(7) pm and rCH 106.164(1) pm. © 2011 American Institute of Physics.