Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion.

Long-term results of organ transplantation are still limited by serious side effects of immunosuppressive drugs. A major issue, therefore, is to elaborate novel therapeutic protocols allowing withdrawal or minimization of immunosuppressive therapy after transplantation. We report on 3 patients prospectively enrolled in an original protocol designed to promote graft acceptance in living donor liver transplantation, using posttransplant conditioning with high doses of antithymocyte globulin followed by injection of donor-derived stem cells. In 2 patients, early immunosuppression withdrawal was possible, without subsequent graft deterioration. In these 2 cases, in vitro studies showed indices of immunological tolerance as assessed by specific hyporesponsiveness to donor alloantigens in mixed lymphocytes culture. In the third patient, acute rejection rapidly occurred after discontinuation of immunosuppression, and minimal immunosuppression has to be maintained during long-term follow-up. In this case, a clearly distinct immunoreactive profile was observed as compared to tolerant patients, as no specific modulation of the antidonor response was observed in vitro. Of note, no macrochimerism could be detected in any of the 3 patients during the follow-up. In conclusion, these clinical observations demonstrated that, despite the absence of macrochimerism, donor stem cells infusion combined with recipient conditioning may allow early immunosuppression withdrawal or minimization after liver transplantation.     

Patterns of care for non‐small cell lung cancer patients in Belgium: A population‐based study

Guidelines recommend surgery for Stage I‐II, chemoradiation for Stage III and systemic therapy for Stage IV non‐small cell lung cancer (NSCLC). However, patient related factors and patient preferences influence treatment decisions. We investigated patterns of care for Belgian NSCLC patients in 2010‐2011, based on population‐based data from the Belgian Cancer Registry and administrative databases. The relationship between patient characteristics, institutional diagnostic volume, type of treatment and survival was investigated. Overall, 20.8% of patients received no oncological treatment. 59% and 22.1% of Stage I‐II patients received primary surgery or (chemo)radiation respectively. 34% of Stage III patients received chemoradiation and 17% of Stage IIIA patients had surgery. 70% of Stage IV patients received chemotherapy or targeted therapy. Moderate variability between centres was observed. For Stage IV, systemic therapy was less frequently used in higher volume centres and 1‐year survival was lower in centres that had ≥ 50 new patients yearly. Although not all NSCLC patients received treatment as ideally recommended by guidelines, these results do not necessarily represent poor quality of care as patient characteristics and preferences need to be taken into account. Treatment options targeted towards patients with co‐morbidity or unfit patients is warranted to improve outcomes of all NSCLC patients.     

Inherent stochasticity during insulator–metal transition in VO2

Vanadium dioxide (VO₂), which exhibits a near-room-temperature insulator–metal transition, has great potential in applications of neuromorphic computing devices. Although its volatile switching property, which could emulate neuron spiking, has been studied widely, nanoscale studies of the structural stochasticity across the phase transition are still lacking. In this study, using in situ transmission electron microscopy and ex situ resistive switching measurement, we successfully characterized the structural phase transition between monoclinic and rutile VO₂ at local areas in planar VO₂/TiO₂ device configuration under external biasing. After each resistive switching, different VO₂ monoclinic crystal orientations are observed, forming different equilibrium states. We have evaluated a statistical cycle-to-cycle variation, demonstrated a stochastic nature of the volatile resistive switching, and presented an approach to study in-plane structural anisotropy. Our microscopic studies move a big step forward toward understanding the volatile switching mechanisms and the related applications of VO₂ as the key material of neuromorphic computing.

Resistive switching in vanadium oxides has attracted much attention because of the potential applications in bioinspired neuromorphic computing and nonvolatile memories (1–4). In a basic neural network, neurons can generate nonlinear electric spikes under external excitations, while the synapses allow for the modulation of interconnected weights between neurons. In most hardware-based neuromorphic approaches, volatile switching devices (threshold switching) were used to emulate the artificial spiking neuronal behaviors, while nonvolatile switching memories were often used to mimic the synaptic functionalities (1). VO₂, whose insulator–metal transition (IMT) is above room temperature (T_IMT ∼340 K) (5), has been widely studied as a neuristor (6). It is considered a promising candidate for energy-efficient neurons due to its threshold spiking phenomenon. In pristine VO₂ it is believed that the resistive switching can be triggered by local Joule heating across the IMT, while nonthermal switching can be induced using defect engineering (7). Recently, both volatile and nonvolatile functionalities have been achieved in VO₂ based on different switching mechanisms (8). In previous work, in situ X-ray nanomapping was used to track the out-of-plane monoclinic and rutile Bragg peaks during resistive switching (9). However, up to now the nanoscale in-plane structural anisotropy and its intrinsic stochasticity have been rarely explored (10, 11): How the system returns from metallic state to insulating state and how the structural transition influences the switching. In addition, the control of the switching usually appears to be imprecise, i.e., the voltage necessary to initiate the phase transition is not a constant (even within a single grain) (12). Therefore, it is of critical importance to understand the stochastic behavior within the neuron device and the phase transition mechanism at nanoscale under external stimuli, since the switching has to be done a large number of times during the neuron firing process. In addition, the IMT of VO₂ nanodevices can show multiple jumps, which implies that the domain structures in VO₂ may influence the transition behavior (13). Also, many physical properties, such as electrical, magnetic, and optical properties, show significant changes during the IMT process (14–16).Here, we use in situ biasing transmission electron microscopy (TEM) with ex situ electrical transport measurement to characterize the structural phase transition across the volatile switching in VO₂. In-plane resistive switching was studied in epitaxial VO₂/TiO₂ (001) nanodevices. The original in-plane structural isotropy in the VO₂ rutile structure (R phase) will lead to anisotropy in the monoclinic phase (M1 phase) after resistive switching. Multiple monoclinic domains will form when the system returns to the insulating state. The IMT phase transition and the simultaneous electrical properties change have been systematically studied. Our results demonstrate that the structural anisotropy between different M1 VO₂ domains plays an important role in the insulating state. In addition, this study provides a thorough understanding of the volatile resistive switching process and shows that the intrinsic variability is a key issue in developing stochastic neuromorphic networks.     

Cultured Kaposi's sarcoma tumor cells exhibit a chemokine receptor repertoire that does not allow infection by HIV-1

Background  

HIV-1 is known to play a critical role in the pathogenesis of AIDS-associated Kaposi's sarcoma (KS). However, it remains controversial whether KS cells are target cells for HIV infection. The aim of this study was to investigate the expression of chemokine receptors in KS cell cultures and to determine whether these cells can be infected by HIV-1.     

Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression

There is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca(2+) mobilization and the glutamate-induced accumulation in [(35)S]GTP(γS) binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression.     

Inhibition of the CD40 pathway of monocyte activation by triazolopyrimidine

Blockade of the CD40/CD40L pathway of monocyte/macrophage activation represents a promising strategy for the treatment of several inflammatory disorders. So far, most pharmacological agents developed for that purpose target CD40L (CD154) expressed on activated T cells. Herein, we provide evidence that triazolopyrimidine, a chemical compound primarily developed for the prevention of arterial thrombosis, strongly inhibits the response of human monocytes to CD40 ligation. First, we found that triazolopyrimidine inhibits the production of IL-12, TNF-alpha, and IL-6 by monocytes activated by coculture with fibroblasts transfected with the CD40L gene as well as the induction of procoagulant activity at their membrane. This was related to a decreased expression of CD40 on monocytes exposed to triazolopyrimidine, an effect that was already apparent at the mRNA level. Furthermore, the addition of triazolopyrimidine to monocytes cultured with IL-4 and GM-CSF prevented their differentiation into fully competent dendritic cells (DC) as DC differentiated in the presence of triazolopyrimidine expressed less CD40 at their surface and were profoundly deficient in the production of IL-12 upon exposure to CD40L transfectants. We conclude that triazolopyrimidine strongly inhibits the CD40 pathway of monocyte activation at least in part by downregulating the gene expression of CD40.