Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients

Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML

Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+ TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.Peer reviewe

T Lymphocyte Dynamics in Inflammatory Bowel Diseases: Role of the Microbiome

Humans have coevolved with a complex community of bacterial species also referred to as the microbiome, which reciprocally provides critical contributions to human metabolism and immune system development. Gut microbiome composition differs significantly between individuals depending on host genetics, diet, and environmental factors. A dysregulation of the symbiotic nature of the intestinal host-microbial relationship and an aberrant and persistent immune response are the fundamental processes involved in inflammatory bowel diseases (IBD). Considering the essential role of T cells in IBD and the contributing role of the microbiome in shaping the immune response during the pathogenesis of IBD, this review focuses on the complex relationship, interplay, and communication between the gut microbiome and T cells, including their differentiation into different subsets of effector or regulatory cells

The CERN/ISOLDE Laser Ion Source

Laser resonance photo-ionization an essential aspect of radioactive ion beam production for fundamental and applied physics research. The laser ion source of the ISOLDE facility, described here, is the most versatile of its type worldwide

NHE3 modulates the severity of colitis in IL-10-deficient mice.

NHE3, the major intestinal Na(+)/H(+) exchanger, was shown to be downregulated and/or inhibited in patients with inflammatory bowel disease (IBD), a phenomenon believed to contribute to inflammation-associated diarrhea. NHE3(-/-) mice spontaneously develop colitis and demonstrate high susceptibility to dextran sulfate-induced mucosal injury. We investigated the effects of NHE3 deficiency on the development of chronic colitis in an IL-10 knockout (KO) mouse model of Crohn's disease. NHE3(-/-) mice were first backcrossed to 129/SvEv mice for >10 generations, with no apparent changes in their survival or phenotype. These mice were crossed with IL-10(-/-) mice on the same genetic background, and the phenotypes of 10-wk-old wild-type (WT), IL-10(-/-), NHE3(-/-), and IL-10(-/-)/NHE3(-/-) (double-KO) mice were studied. Histological and immunohistochemical examination of the colon established important architectural alterations, including increased neutrophilic and mononuclear cell infiltration in double- compared with single-KO mice. Double-KO mice demonstrated increased colonic expression of neutrophil collagenase matrix metalloproteinase-8 and the chemokines macrophage inflammatory protein-2, CXCL1, CXCL10, and CXCL11. Colonic IFNγ, IL-17, and IL-12/23 p40 protein secretion was significantly increased in double- compared with single-KO mice. IL-10(-/-)/NHE3(-/-) mouse colonic epithelium exhibited increased hallmarks of apoptosis, including a significantly increased number of cleaved caspase-3-positive surface epithelial cells. These results highlight the importance of NHE3 in the maintenance of intestinal barrier integrity and in modulating the inflammatory process in IL-10-deficient mice. Chronic NHE3 inhibition or underexpression observed in IBD may therefore contribute to the pathogenesis of IBD by influencing the extent of the epithelial barrier defect and affect the ultimate degree of inflammation

Large Shape Staggering in Neutron-Deficient Bi Isotopes

The changes in the mean-square charge radius (relative to Bi-209), magnetic dipole, and electric quadrupole moments of Bi-187,Bi-188,Bi-189,Bi-191 were measured using the in-source resonance-ionization spectroscopy technique at ISOLDE (CERN). A large staggering in radii was found in Bi-187,188,189(g), manifested by a sharp radius increase for the ground state of Bi-188 relative to the neighboring Bi-187,189(g). A large isomer shift was also observed for Bi-188(m). Both effects happen at the same neutron number, N = 10(5), where the shape staggering and a similar isomer shift were observed in the mercury isotopes. Experimental results are reproduced by mean-field calculations where the ground or isomeric states were identified by the blocked quasiparticle configuration compatible with the observed spin, parity, and magnetic moment.Peer reviewe

Enhancing the extraction of laser-ionized beams from an arc discharge ion source volume

The Versatile Arc Discharge and Laser Ion Source (VADLIS) is a recently established ion source for the CERN-ISOLDE radioactive ion beam facility. It offers either electron-impact ionization (VADIS-mode) or resonance laser ionization (RILIS-mode). The choice of operating mode depends on the element of interest or the required beam purity. Particle-in-cell simulations using the VSim software show that the ion extraction efficiency of the VADLIS in RILIS-mode can be improved if it is equipped with an insulated extractor plate, to which an optimal voltage can be applied. This enables optimization of the RILIS-mode ion extraction independently of the electron density. Experiments have been performed using a prototype VADLIS with an adjustable extractor plate voltage for the generation of gallium ion beams at the off-line separator as well as magnesium, molybdenum and mercury ion beams at ISOLDE. A factor >2 increase of the VADLIS efficiency in RILIS-mode has been achieved

Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection

Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro and exhibits a protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-κB. Although it has been demonstrated effective in reducing relapse rate in ulcerative colitis patients, curcumin's effectiveness in Crohn's disease (CD) or in Th-1/Th-17 mediated immune models of CD has not been evaluated. Therefore, we investigated the effects of dietary curcumin (0.1–1%) on the development of colitis, immune activation, and in vivo NF-κB activity in germ-free IL-10−/− or IL-10−/−;NF-κBEGFP mice colonized with specific pathogen-free microflora. Proximal and distal colon morphology showed a mild protective effect of curcumin only at 0.1%. Colonic IFN-γ and IL-12/23p40 mRNA expression followed similar pattern (∼50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN-γ by colonic explants and mesenteric lymph node cells was elevated in IL-10−/− mice and was not decreased by dietary curcumin. Surprisingly, activation of NF-κB in IL-10−/− mice (phospho-NF-κBp65) or in IL-10−/−;NF-κBEGFP mice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to downregulate NF-κB activity in IEC and IL-12/23p40 production by splenocytes and dendritic cells. In conclusion, curcumin demonstrates limited effectiveness on Th-1 mediated colitis in IL-10−/− mice, with moderately improved colonic morphology, but with no significant effect on pathogenic T cell responses and in situ NF-κB activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent