Stem cells for brain repair in neonatal hypoxia-ischemia

Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain

HTLV-1 propels thymic human T cell development in “human immune system” Rag2-/- IL-2R γc-/- Mice

Alteration of early haematopoietic development is thought to be responsible for the onset of immature leukemias and lymphomas. We have previously demonstrated that TaxHTLV-1 interferes with ß-selection, an important checkpoint of early thymopoiesis, indicating that human T-cell leukemia virus type 1 (HTLV-1) infection has the potential to perturb thymic human αβ T-cell development. To verify that inference and to clarify the impact of HTLV-1 infection on human T-cell development, we investigated the in vivo effects of HTLV-1 infection in a “Human Immune System” (HIS) Rag2-/-γc-/- mouse model. These mice were infected with HTLV-1, at a time when the three main subpopulations of human thymocytes have been detected. In all but two inoculated mice, the HTLV-1 provirus was found integrated in thymocytes; the proviral load increased with the length of the infection period. In the HTLV-1-infected mice we observed alterations in human T-cell development, the extent of which correlated with the proviral load. Thus, in the thymus of HTLV-1-infected HIS Rag2-/-γc-/- mice, mature single-positive (SP) CD4+ and CD8+ cells were most numerous, at the expense of immature and double-positive (DP) thymocytes. These SP cells also accumulated in the spleen. Human lymphocytes from thymus and spleen were activated, as shown by the expression of CD25: this activation was correlated with the presence of tax mRNA and with increased expression of NF-kB dependent genes such as bfl-1, an anti-apoptotic gene, in thymocytes. Finally, hepato-splenomegaly, lymphadenopathy and lymphoma/thymoma, in which Tax was detected, were observed in HTLV-1-infected mice, several months after HTLV-1 infection. These results demonstrate the potential of the HIS Rag2-/-γc-/- animal model to elucidate the initial steps of the leukemogenic process induced by HTLV-1

ROR1 Is Expressed in Human Breast Cancer and Associated with Enhanced Tumor-Cell Growth

Receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is expressed during embryogenesis and by certain leukemias, but not by normal adult tissues. Here we show that the neoplastic cells of many human breast cancers express the ROR1 protein and high-level expression of ROR1 in breast adenocarcinoma was associated with aggressive disease. Silencing expression of ROR1 in human breast cancer cell lines found to express this protein impaired their growth in vitro and also in immune-deficient mice. We found that ROR1 could interact with casein kinase 1 epsilon (CK1ε) to activate phosphoinositide 3-kinase-mediated AKT phosphorylation and cAMP-response-element-binding protein (CREB), which was associated with enhanced tumor-cell growth. Wnt5a, a ligand of ROR1, could induce ROR1-dependent signaling and enhance cell growth. This study demonstrates that ROR1 is expressed in human breast cancers and has biological and clinical significance, indicating that it may be a potential target for breast cancer therapy

Stem cells for brain repair in neonatal hypoxia-ischemia

Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain

Distinct expression pattern of IFN-\u3b1 and TNF-\u3b1 in juvenile idiopathic arthritis synovial tissue

Objectives. Recent laboratory and clinical data suggest that two prototype autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis are mainly driven by distinct cytokines, interferon (IFN)-\u3b1 and tumour necrosis factor (TNF)-\u3b1, respectively. We here investigated the presence and characteristics of natural type I IFN-producing cells (IPCs), as well as IFN-\u3b1 and TNF-\u3b1 expression at sites of inflammation in juvenile idiopathic arthritis (JIA). Methods. Peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNCs) (n = 25 each) from JIA patients with active disease were studied. IPCs were identified as BCDA-2+ CD123+ HLA-DR+ CD45RA+ cells, and dendritic cells (DCs) as CD11c+ CD14-/lowlin- cells by flow cytometry. IPCs and DCs were analysed for Toll-like receptor-7 and -9 mRNA expression by real-time polymerase chain reaction. IFN-\u3b1 was measured by enzyme-linked immunosorbent assay in serum, SF and in supernatants of influenza virus-infected, cultured IPCs. Synovial tissues of n = 6 additional JIA patients were analysed by immunohistochemistry using mAbs against CD123, IFN-\u3b1, TNF-\u3b1, CD3, CD19 and CD138. Results. IPCs were enriched in SF MNCs compared with PB MNCs in all JIA patients. Influenza-induced, but no spontaneous IFN-\u3b1 release was detected from SF IPCs, and serum and SF IFN-\u3b1 levels were not elevated. Nonetheless, in synovial tissue IFN-\u3b1 producing cells accumulated at inflammatory lymph-follicular-like structures, while TNF-\u3b1 producing cells were mostly found at the lining and sublining layers. Conclusions. These data suggest that besides TNF-\u3b1-expressing cells, IFN-\u3b1-producing IPCs are involved in initiation, maintenance or regulation of the inflammatory response in JIA. \ua9 2007 Oxford University Press

Spectroscopic and electrochemical properties of 1- or 2-alkyl substituted 5- and 6-nitroindazoles

In the framework of our general interest on the reactivity and on the pharmacological activity of heterocyclic compounds, we have examined the behaviour of some variously substituted 5- and 6-nitroindazoles. Remembering that nitroreduction processes are often essential steps for their biological activity we have collected NMR, ESR, and CV data and carried out DFT computations to gain a deep picture of electronic distribution and of reduction processes as a function of the chemical structure of the examined substrates. Interestingly, DFT computations have furnished strong support to experimental data. Moreover, the comparison between the general behaviour of 1- and 2-alkyl substituted nitroindazoles has furnished further confirmation to the known different electronic distribution in these two classes of compounds, while CV data have evidenced the ability of N1-H nitroindazoles to give rise to the formation of a dime

Battles through and about statistics in French pay equity bargaining: The politics of quantification at workplace level

International audienceThis article proposes to study the discreet ‘battles of numbers’ at workplace level, particularly exacerbated on pay equity, in relation to its potential additional costs for employers. Figures are at once a framework, an object and a resource for power struggles between social partners. This approach is inspired by ‘statactivism’, a research perspective that studies the ways and contexts in which statistics can become tools for social mobilization. In a European context where bargaining is increasingly decentralized to company level, we argue that researchers should pay attention to statistical resources and quantification skills of negotiators, both on the management and unions side. They should also include in their analytical framework the influence of experts and specialists who advise social partners on how to strategically produce and use gender‐sensitive statistics. In this article, two case studies allow us to open the ‘black box’ of equality bargaining, revealing challenges and controversies of gender pay reporting