Cutting Edge: Proangiogenic Properties of Alternatively Activated Dendritic Cells

Abstract Angiogenesis plays an important role in tissue remodeling and repair during the late phase of inflammation. In the present study, we show that human dendritic cells (DC) that matured in the presence of anti-inflammatory molecules such as calcitriol, PGE2, or IL-10 (alternatively activated DC) selectively secrete the potent angiogenic cytokine vascular endothelial growth factor (VEGF) isoforms VEGF165 and VEGF121. No VEGF production was observed in immature or classically activated DC. Also, the capacity to produce VEGF was restricted to the myeloid DC subset. When implanted in the chick embryo chorioallantoic membrane, alternatively activated DC elicit a marked angiogenic response, which is inhibited by neutralizing anti-VEGF Abs and by the VEGFR-2 inhibitor SU5416. Therefore, alternatively activated DC may contribute to the resolution of the inflammatory reaction by promoting VEGF-induced angiogenesis

Identification and characterization of an endogenous chemotactic ligand specific for FPRL2

Chemotaxis of dendritic cells (DCs) and monocytes is a key step in the initiation of an adequate immune response. Formyl peptide receptor (FPR) and FPR-like receptor (FPRL)1, two G protein–coupled receptors belonging to the FPR family, play an essential role in host defense mechanisms against bacterial infection and in the regulation of inflammatory reactions. FPRL2, the third member of this structural family of chemoattractant receptors, is characterized by its specific expression on monocytes and DCs. Here, we present the isolation from a spleen extract and the functional characterization of F2L, a novel chemoattractant peptide acting specifically through FPRL2. F2L is an acetylated amino-terminal peptide derived from the cleavage of the human heme-binding protein, an intracellular tetrapyrolle-binding protein. The peptide binds and activates FPRL2 in the low nanomolar range, which triggers intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of extracellular signal–regulated kinase 1/2 mitogen-activated protein kinases through the Gi class of heterotrimeric G proteins. When tested on monocytes and monocyte-derived DCs, F2L promotes calcium mobilization and chemotaxis. Therefore, F2L appears as a new natural chemoattractant peptide for DCs and monocytes, and the first potent and specific agonist of FPRL2

Comparing story reading and video watching as two distinct forms of vicarious contact: An experimental intervention among elementary school children

Research has shown that vicarious contact, that is observing an interaction between ingroup and outgroup members, can improve intergroup relations. Although vicarious contact has been operationalized in different ways, mainly via story reading or video watching, an experimental comparison of these different strategies is still missing. We conducted a school intervention with the aim of comparing the two most used forms of vicarious contact, namely story reading and video watching. Elementary schoolchildren without disabilities (N = 292) were assigned to one of three different conditions: reading a story; watching a video; control. In the two vicarious contact conditions, participants read or watched the story of a child with disability becoming friends with children without disabilities; in the control condition, participants only completed the dependent measures. Results revealed that, in general, both vicarious contact conditions were equally effective in improving outgroup attitudes and behavioural intentions. In addition, they operated with the same strength through the same underlying processes (IOS, ingroup norms). We discuss theoretical and practical implications in the context of vicarious contact as a prejudice-reduction intervention

Prevalence and trends of markers of hepatitis B virus, hepatitis C virus and human Immunodeficiency virus in Argentine blood donors

BACKGROUND: Transfusion-transmitted infections are a major problem associated with blood transfusion. The aim of this study was to determine prevalence and trends of HBV, HCV and HIV in blood donors in Argentina. METHODS: A retrospective study was carried out in blood donors of 27 transfusion centers covering the whole country over a period of eight years (2004-2011). Serologic screening assays for HBsAg, anti-HBc, anti-HCV, and anti-HIV were performed in all centers and nucleic acid amplification testing (NAT) was performed in 2 out of the 27 centers. RESULTS: The 2,595,852 samples tested nationwide from 2004 to 2011 showed that the prevalence of HBsAg decreased from 0.336% to 0.198% (p < 0.0001), that of anti-HBc from 2.391% to 2.007% (p < 0.0001), that of anti-HCV from 0.721% to 0.460%, (p < 0.0001) and that of anti-HIV from 0.208% to 0.200 (p = 0.075). The prevalence of HBV, HCV and HIV was unevenly distributed among the different regions of the country. Two out of 74,838 screening- negative samples were positive in NAT assays (1 HIV-RNA and 1 HCV-RNA); moreover, HBV-DNA, HCV-RNA and HIV-RNA were detected in 60.29, 24.54 and 66.67% of screening-positive samples of the corresponding assays. As regards donors age, positive HBV-DNA and HCV-RNA donors were significantly older than healthy donors (46.6, 50.5 and 39.5 y respectively, p < 0.001). CONCLUSIONS: Argentina has a low prevalence of HBsAg, anti-HCV and anti-HIV in blood donors, with a decreasing trend for HBsAg, anti-HBc and anti-HCV but not for anti-HIV over the last 8 years. The uneven distribution of transfusion-transmitted infections prevalence among the different regions of the country highlights the need to implement regional awareness campaigns and prevention. The discrepancy between samples testing positive for screening assays and negative for NAT assays highlights the problem of blood donors who test repeatedly reactive in screening assays but are not confirmed as positive upon further testing. The uneven distribution of age between healthy donors and NAT-positive donors could be related to changes in risks of these pathogens in the general population and might be attributed to a longer exposure to transmission risk factors in elderly people.Fil: Flichman, Diego Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blejer, Jorgelina L.. Fundación Hemocentro; ArgentinaFil: Livellara, Beatriz I.. Hospital Italiano; ArgentinaFil: Ré, Viviana Elizabeth. Universidad Nacional de Cordoba. Facultad de Medicina. Instituto de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bartoli, Sonia. Centro regional de Hemoterapia Jujuy; ArgentinaFil: Bustos, Juan A.. Banco de sangre San Jorge; ArgentinaFil: Ansola, Claudia P.. Provincia de Mendoza. Servicio de Hemoterapia; ArgentinaFil: Hidalgo, Susana. Hospital Dr. Enrique Vera Barros; ArgentinaFil: Cerda, Martín E.. Hospital Dr. Lucio Molas; ArgentinaFil: Levin, Alicia E.. Provincia de Mendoza. Servicio de Hemoterapia; ArgentinaFil: Huenul, Adriana. Hospital Artémides Zatti; ArgentinaFil: Riboldi, Victoria. Hospital Regional Río Gallegos; ArgentinaFil: Treviño, Elena M. C.. Universidad Nacional de Córdoba; ArgentinaFil: Salamone, Horacio J.. Fundación Favaloro; ArgentinaFil: Nuñez, Felix A.. Hospital Italiano; ArgentinaFil: Fernández, Robert J.. Fundación Hemocentro; ArgentinaFil: Reybaud, Juan F.. Fundación Favaloro; ArgentinaFil: Campos, Rodolfo Hector. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

Introduction: Pulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy.Methods: Thirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A "good response" was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO) &gt; 15% and PaO2 &gt; 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved.Results: Twenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease.Conclusions: Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics

Modeling of GERDA Phase II data

The GERmanium Detector Array (GERDA) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double-beta ($0\nu\beta\beta$) decay of $^{76}$Ge. The technological challenge of GERDA is to operate in a "background-free" regime in the region of interest (ROI) after analysis cuts for the full 100$\,$kg$\cdot$yr target exposure of the experiment. A careful modeling and decomposition of the full-range energy spectrum is essential to predict the shape and composition of events in the ROI around $Q_{\beta\beta}$ for the $0\nu\beta\beta$ search, to extract a precise measurement of the half-life of the double-beta decay mode with neutrinos ($2\nu\beta\beta$) and in order to identify the location of residual impurities. The latter will permit future experiments to build strategies in order to further lower the background and achieve even better sensitivities. In this article the background decomposition prior to analysis cuts is presented for GERDA Phase II. The background model fit yields a flat spectrum in the ROI with a background index (BI) of $16.04^{+0.78}_{-0.85} \cdot 10^{-3}\,$cts/(kg$\cdot$keV$\cdot$yr) for the enriched BEGe data set and $14.68^{+0.47}_{-0.52} \cdot 10^{-3}\,$cts/(kg$\cdot$keV$\cdot$yr) for the enriched coaxial data set. These values are similar to the one of Gerda Phase I despite a much larger number of detectors and hence radioactive hardware components

Modeling of GERDA Phase II data

The GERmanium Detector Array (Gerda) experiment at the Gran Sasso underground laboratory (LNGS) of INFN is searching for neutrinoless double-beta (0νββ) decay of 76Ge. The technological challenge of Gerda is to operate in a “background-free” regime in the region of interest (ROI) after analysis cuts for the full 100 kg·yr target exposure of the experiment. A careful modeling and decomposition of the full-range energy spectrum is essential to predict the shape and composition of events in the ROI around Qββ for the 0νββ search, to extract a precise measurement of the half-life of the double-beta decay mode with neutrinos (2νββ) and in order to identify the location of residual impurities. The latter will permit future experiments to build strategies in order to further lower the background and achieve even better sensitivities. In this article the background decomposition prior to analysis cuts is presented for Gerda Phase II. The background model fit yields a flat spectrum in the ROI with a background index (BI) of 16.04+0.78−0.85⋅10−3 cts/(keV·kg·yr) for the enriched BEGe data set and 14.68+0.47−0.52⋅10−3 cts/(keV·kg·yr) for the enriched coaxial data set. These values are similar to the one of Phase I despite a much larger number of detectors and hence radioactive hardware components

Tumor-associated myeloid cells: new understandings on their metabolic regulation and their influence in cancer immunotherapy

Tumor-associated myeloid cells (TAMCs), mainly represented by tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), can promote tumor growth directly, by favouring tumor cell proliferation and survival, and indirectly, by creating an immunosuppressive microenvironment. Myeloid cells are characterized by an extreme phenotypical and functional plasticity. Immunometabolism is now emerging as a crucial aspect of TAMCs skewing towards pro-tumoral activities. The metabolic re-education of myeloid cells is a new strategy to boost their anti-tumor effector functions. Several anticancer therapies targeting TAMCs are already under investigation. Nowadays, the hot topic of cancer immunotherapy is represented by immune checkpoint inhibitors. These drugs unrestrain T cell-mediated tumor elimination by removing suppressive signals delivered by tumor-associated cells. The efficacy of immune checkpoint blockade can be enhanced using coordinated strategies to counteract the TAMCs-dependent impairment of immune adaptive responses. In the first part of the review, we will describe the association between metabolic reprogramming and TAMCs biological activities. In the second part, we will illustrate the potential of combination therapies associating TAMC-targeting drugs with immune checkpoint inhibitors

Molecular and epigenetic basis of macrophage polarized activation

Macrophages are unique cells for origin, heterogeneity and plasticity. At steady state most of macrophages are derived from fetal sources and maintained in adulthood through self-renewing. Despite sharing common progenitors, a remarkable heterogeneity characterized tissue-resident macrophages indicating that local signals educate them to express organ-specific functions. Macrophages are extremely plastic: chromatin landscape and transcriptional programs can be dynamically re-shaped in response to microenvironmental changes. Owing to their ductility, macrophages are crucial orchestrators of both initiation and resolution of immune responses and key supporters of tissue development and functions in homeostatic and pathological conditions. Herein, we describe current understanding of heterogeneity and plasticity of macrophages using the M1-M2 dichotomy as operationally useful simplification of polarized activation. We focused on the complex network of signaling cascades, metabolic pathways, transcription factors, and epigenetic changes that control macrophage activation. In particular, this network was addressed in sepsis, as a paradigm of a pathological condition determining dynamic macrophage reprogramming