Umbilical Cord Blood-Derived Therapies as a Treatment for Graft-Versus-Host Disease

Umbilical cord blood (UCB) has been increasingly used as a source of haematopoietic stem cells (HSCs) for transplantation. UCB transplantation (UCBT) has some advantages such as less stringent human leucocyte antigen (HLA) matching and lower impact of graft-versus-host disease (GvHD). UCBT is also characterised by a high rate of infections, graft failure, delayed engraftment and slow recovery of the immune system. UCB contains HSC as well as immune cells that could be considered to develop new treatments for the main complications post-UCBT but also to treat other diseases. GvHD remains a major complication post-CBT and post-haematopoietic stem cell transplantation (HSCT). In view of their ability to induce tolerance and suppress the functions of effector T cells, regulatory T (Treg) cells have been proposed as an adoptive therapy to modulate GvHD post-HSCT. In addition, we showed that UCB contains soluble NKG2D ligands that can modulate the functions of NKG2D expressing cells, making UCB plasma a product of interest to modulate inflammation and in particular skin GvHD. Here, we aim to describe some of the therapies currently developed using UCB, focusing on Treg cells and UCB plasma for the treatment of GvHD

Caractérisation et modélisation de la précipitation d'un alliage d'aluminium 319

National audienceUn modèle métallurgique représentant l'évolution de la nanostructure au cours du traitement thermique T5 d'un alliage d'aluminium de fonderie 319 a été réalisé. Ce modèle est fondé sur la physique du processus de coalescence (théorie LSW) de précipités sphériques (Al2Cu) dans une matrice (Al) saturée en soluté. Il permet d'obtenir une distribution de taille des précipités Al2Cu en fonction du traitement thermique appliqué et prend en compte les phénomènes de coalescence et de dissolution des précipités en fonction de leur taille. La simulation est assise sur des mesures de la taille et de la distribution de taille des particules par métallographie quantitative en microscopie électronique en transmission (MET). Celles-ci ont été couplées à des surrevenus de l'alliage depuis l'état T5 an de corroborer les résultats fournis par le modèle métallurgique. De plus, une caractérisation de la structure des précipités surviellis a été eectuée

Cord blood transplantation recapitulates fetal ontogeny with a distinct molecular signature that supports CD4+ T-cell reconstitution

Omission of in vivo T-cell depletion promotes rapid, thymic-independent CD4+-biased T-cell recovery after cord blood transplant. This enhanced T-cell reconstitution differs from that seen after stem cell transplant from other stem cell sources, but the mechanism is not known. Here, we demonstrate that the transcription profile of naive CD4+ T cells from cord blood and that of lymphocytes reconstituting after cord blood transplantation is similar to the transcription profile of fetal CD4+ T cells. This profile is distinct to that of naive CD4+ T cells from peripheral blood and that of lymphocytes reconstituting after T-replete bone marrow transplantation. The transcription profile of reconstituting naive CD4+ T cells from cord blood transplant recipients was upregulated in the T-cell receptor (TCR) signaling pathway and its transcription factor activator protein-1 (AP-1). Furthermore, a small molecule inhibitor of AP-1 proportionally inhibited cord blood CD4+ T-cell proliferation (P < .05). Together, these findings suggest that reconstituting cord blood CD4+ T cells reflect the properties of fetal ontogenesis, and enhanced TCR signaling is responsible for the rapid restoration of the unique CD4+ T-cell biased adaptive immunity after cord blood transplantation

Overvoltage Limitation Method of an Offshore Wind Farm with DC Series Parallel Collection Grid

This paper describes the characteristics of a series parallel wind farm (SPWF) topology and investigates the control strategy to ensure its safe operation. The SPWF was found to have advantages over other pure dc wind farm architectures in terms of lower construction cost and lower power losses in the collection system. However, unbalance power productions among the wind turbines cause the variations of their output voltages, which may endanger the safe operation of the entire wind farm. This paper proposes a global control strategy that prevents wind turbines from operating above their overvoltage capabilities.With an active participation of the onshore converter, the proposed strategy allows maximum power point tracking (MPPT) of the wind turbines. The practical limitations of this strategy are discussed and improvements are given. The feasibility of the proposed method is validated in a simulation of 300 MW wind farm developed in EMTP-RV

512 the cytokine release syndrome crucially contributes to the anti leukemic effects of cd44v6 car t cells

Background: Despite the remarkable clinical results of CD19 CAR-T cells in B-cell leukemias, their long-term efficacy is limited by the emergence of CD19-loss escape variants. Moreover, whether the cytokine release syndrome (CRS) is necessary for durable remissions is a matter of debate. Currently available xenograft models in NSG mice are not suited for studying the antitumor effects of CAR-T cells beyond 3-4 weeks, because of xenograft-versus-host disease (X-GVHD). Moreover, since NSG mice lack functional myeloid cells, the CRS does not develop. Aim: To verify whether the CRS contributes to the antileukemic effects of CAR in an innovative xenotolerant mouse model.Results: NSG mice triple transgenic for human IL-3, GM-CSF and SCF (NSG-3GS) were sub-lethally irradiated and injected intra-liver with human HSCs soon after birth, enabling an accelerated and better balanced lympho-hematopoietic reconstitution compared with NSG mice. Reconstituting human T cells were single CD4+/CD8+ T cells, representing all memory sub-populations. After ex vivo isolation and activation with CD3/CD28-beads and IL-7/IL-15, NSG-3GS T cells were transduced with a CD44v6 CAR, retaining an early-differentiated (stem-cell/central-memory) phenotype and full antitumor functionality against acute myeloid leukemia (AML). NSG-3GS-derived CD44v6 CAR T cells were subsequently infused in tumor-bearing secondary recipients previously humanized with autologous HSCs. CAR-T cells persisted in vivo for at least 6 months and mediated durable leukemia remissions (P<0.001 vs controls) in the absence of X-GVHD. Tumor clearance associated with an acute malaise syndrome, characterized by high fevers and a surge in human IL-6 levels, which was lethal in 30% of the mice. Differently from CD19 CAR-T cells, the CRS by CD44v6 CAR-T cells was significantly anticipated (3 vs 8 days), coinciding with human CD44v6+ monocyte depletion. In humanized mice, previous myeloid-cell depletion by clodronate administration completely prevented this syndrome, but associated with late leukemia relapses. Conversely, mice developing the CRS entered a state of durable and profound remission, as demonstrated by prolonged observation times and secondary transplantation. Conclusions: By using an innovative xenotolerant mouse model, we have demonstrated that the CRS is needed for sustained antileukemic effects by CD44v6 CAR-T cells

TATTOO-seq delineates spatial and cell type-specific regulatory programs in the developing limb

The coordinated differentiation of progenitor cells into specialized cell types and their spatial organization into distinct domains is central to embryogenesis. Here, we developed and applied an unbiased spatially resolved single-cell transcriptomics method to identify the genetic programs underlying the emergence of specialized cell types during mouse limb development and their spatial integration. We identify multiple transcription factors whose expression patterns are predominantly associated with cell type specification or spatial position, suggesting two parallel yet highly interconnected regulatory systems.We demonstrate that the embryonic limb undergoes a complex multiscale reorganization upon perturbation of one of its spatial organizing centers, including the loss of specific cell populations, alterations of preexisting cell states' molecular identities, and changes in their relative spatial distribution. Our study shows how multidimensional single-cell, spatially resolved molecular atlases can allow the deconvolution of spatial identity and cell fate and reveal the interconnected genetic networks that regulate organogenesis and its reorganization upon genetic alterations

Solving Harmonics Elimination Problem in Three-Phase Voltage controlled Inverter using Artificial Neural Networks

A novel concept of application of Artificial Neural Networks (ANN) for generating the optimum switching functions for the voltage and harmonic control of DC-to-AC bridge inverters is presented. In many research, the neural network is trained off line using the desired switching angles given by the classic harmonic elimination strategy to any value of the modulation index. This limits the utilisability and the precision in other modulation index values. In order to avoid this problem, a new training algorithm is developed without using the desired switching angles but it uses the desired solution of the elimination harmonic equation, i.e. first harmonics are equal to zero. Theoretical analysis of the proposed solving algorithm with neural networks is provided, and simulation results are given to show the high performance and technical advantages of the developed modulator

Calcisponges have a ParaHox gene and dynamic expression of dispersed NK homeobox genes

This study was funded by the Sars Centre core budget to M. Adamska. Sequencing was performed at the Norwegian High Throughput Sequencing Centre funded by the Norwegian Research Council. O.M.R. and D.E.K.F. acknowledge support from the BBSRC and the School of Biology, University of St Andrews.Sponges are simple animals with few cell types, but their genomes paradoxically contain a wide variety of developmental transcription factors1,2,3,4, including homeobox genes belonging to the Antennapedia (ANTP) class5,6, which in bilaterians encompass Hox, ParaHox and NK genes. In the genome of the demosponge Amphimedon queenslandica, no Hox or ParaHox genes are present, but NK genes are linked in a tight cluster similar to the NK clusters of bilaterians5. It has been proposed that Hox and ParaHox genes originated from NK cluster genes after divergence of sponges from the lineage leading to cnidarians and bilaterians5,7. On the other hand, synteny analysis lends support to the notion that the absence of Hox and ParaHox genes in Amphimedon is a result of secondary loss (the ghost locus hypothesis)8. Here we analysed complete suites of ANTP-class homeoboxes in two calcareous sponges, Sycon ciliatum and Leucosolenia complicata. Our phylogenetic analyses demonstrate that these calcisponges possess orthologues of bilaterian NK genes (Hex, Hmx and Msx), a varying number of additional NK genes and one ParaHox gene, Cdx. Despite the generation of scaffolds spanning multiple genes, we find no evidence of clustering of Sycon NK genes. All Sycon ANTP-class genes are developmentally expressed, with patterns suggesting their involvement in cell type specification in embryos and adults, metamorphosis and body plan patterning. These results demonstrate that ParaHox genes predate the origin of sponges, thus confirming the ghost locus hypothesis8, and highlight the need to analyse the genomes of multiple sponge lineages to obtain a complete picture of the ancestral composition of the first animal genome.PostprintPeer reviewe

Natural killer cells differentiated in vitro from cord blood CD34(+) cells are more advantageous for use as an immunotherapy than peripheral blood and cord blood natural killer cells

BACKGROUND AIMS: Natural killer (NK) cells have the potential to become a successful immunotherapy as they can target malignant cells without being direct effectors of graft-versus-host disease. Our group has previously shown that large numbers of functional NK cells can be differentiated in vitro from umbilical cord blood (CB) CD34(+) cells. To produce a clinically relevant and effective immunotherapy, we hypothesized that it is essential that the NK cells are able to proliferate and persist in vivo while maintaining an optimal activation status and killing capacity. METHODS: We evaluated the proliferation capacity, telomere length and terminal differentiation markers expressed by NK cells differentiated in vitro. We also determined how their cytotoxicity compared with peripheral blood (PB) NK cells and CBNK cells when targeting patient acute myeloid leukemia (AML) blasts and solid tumor cell lines. RESULTS: We found that the differentiated NK cells could respond to interleukin-2 and proliferate in vitro. Telomere length was significantly increased, whereas CD57 expression was significantly reduced compared with PBNK cells. The cytotoxicity of the differentiated NK cells was equivalent to that of the PBNK and CBNK cell controls, and priming consistently led to higher levels of killing of patient leukemic blasts and solid tumor cell lines in vitro. Interestingly, this activation step was not required to observe killing of patient AML blasts in vivo. CONCLUSION: We are able to generate NK cells from CBCD34(+) cells in high numbers, allowing for multiple infusions of highly cytotoxic NK cells that have potential to further proliferate in vivo, making them a desirable product for application as an immunotherapy in the clinic