Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity

A successfully treated case of herpes simplex encephalitis complicated by subarachnoid bleeding: a case report

<p>Abstract</p> <p>Introduction</p> <p>Histopathologically, herpes simplex virus type 1 causes hemorrhagic necrosis. Overt hemorrhage is infrequent in herpes simplex virus encephalitis but can lead to poor outcomes. This report describes a successfully treated case of herpes simplex virus encephalitis associated with subarachnoid bleeding in which real-time polymerase chain reaction was useful for diagnosis.</p> <p>Case presentation</p> <p>A 30-year-old previously healthy Japanese woman who had fever and headache for five days presented with disorganised speech, unusual behavior and delusional thinking. Real-time polymerase chain reaction amplification of herpes simplex virus type 1 in cerebrospinal fluid was positive (38,000 copies/mL) and antivirus treatment was started. During the course of her illness, the level of her consciousness decreased in association with desaturation and tachycardia. Thrombosis of the right pulmonary artery trunk with pulmonary embolism was evident on enhanced chest computed tomography. In addition, cranial computed tomography revealed subarachnoid and intraventricular bleeding. Intravenous heparin (12,000 U/day) was started and the dose was adjusted according to the activated partial thromboplastin time for about a month (maximum dose of heparin, 20,400 U/day). After the treatments, her Glasgow coma score increased and the thrombosis of the pulmonary artery trunk had disappeared.</p> <p>Conclusions</p> <p>The present case raises the question of whether anticoagulant treatment is safe in patients with herpes simplex virus encephalitis complicated by subarachnoid bleeding.</p

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency

Cerebrospinal fluid biomarkers of brain injury, inflammation and synaptic autoimmunity predict long-term neurocognitive outcome in herpes simplex encephalitis

OBJECTIVES: To investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE). METHODS: A total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/CSF sampling and brain MRI the first 3 months along with cognitive assessment by Mattis Dementia Rating Scale (MDRS) during 24 months. CSF samples were analyzed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The pre-defined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months. RESULTS: Impaired cognitive performance significantly correlated with NFL levels (rho = -0.36, p = 0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-NMDAR (beta = -0.6249, p = 0.024) and age (z-score beta = -0.2784, p = 0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006). CONCLUSIONS: Our findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE

A global customer experience management architecture

Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works. A. Cuadra-Sanchez, M. Cutanda-Rodriguez, I. Perez-Mateos, A. Aurelius, K. Brunnstrom, J. Laulajainen, M. Varela, and J. E. López de Vergara, "A global customer experience management architecture", in Future Network and Mobile Summit, 2012, 1-8The quality of experience (QoE) is one of the main research lines in ITC industry, which seeks to manage quality as perceived by users. This document analyzes and describes requirements of a QoE driven management system architecture, which has been designed in the Celtic IPNQSIS project. The architecture is grouped into different levels: Data acquisition level, Monitoring level and Control Level. Each level comprises a specific set of capacities, such as Data collector, or Traffic Monitor amongst others. The architecture described in this paper constitutes the guidelines of the IPNQSIS project in terms of a QoE ecosystem that will settle the basis of global customer experience management architecture.This work is carried out in the framework of the Celtic and EUREKA initiative IPNQSIS (IP Network Monitoring for Quality of Service Intelligent Support) and has been partially funded by CDTI under Spanish PRINCE (PRoducto INdustrial para la gestión de la Calidad de Experiencia) project, meanwhile the Swedish part of the project is co funded by VINNOVA and the work of Finnish partners has been partially funded by Tekes

A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours

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Комплексный подход к борьбе с асфальтосмолопарафиновыми отложениями на Ванкорском нефтегазовом месторождении (Красноярский край)

Определены наиболее эффективные растворители для удаления промысловых АСПО при низких температурах. Проанализированы условия влияния растворителей на процессы кристаллизации и плавления промысловых парафинов в АСПО. Предложен комплекс мероприятий, направленных на борьбу с асфальтосмолопарафиновыми отложениями на Ванкорском месторождении.The most effective solvents for the removal of industrial ARPD at low temperatures have been determined. The conditions for the influence of solvents on the crystallization and melting of commercial paraffins in ARPD are analyzed. A set of measures is proposed to combat asphalt-resin-paraffin deposits in the Vankor field

Viral Encephalitis in England, 1989–1998: What Did We Miss?

We analyzed hospitalizations in England from April 1, 1989, to March 31, 1998, and identified approximately 700 cases, 46 fatal, from viral encephalitis that occurred during each year; most (60%) were of unknown etiology. Of cases with a diagnosis, the largest proportion was herpes simplex encephalitis. Using normal and Poisson regression, we identified six possible clusters of unknown etiology. Over 75% of hospitalizations are not reported through the routine laboratory and clinical notification systems, resulting in underdiagnosis of viral encephalitis in England. Current surveillance greatly underascertains incidence of the disease and existence of clusters; in general, outbreaks are undetected. Surveillance systems must be adapted to detect major changes in epidemiology so that timely control measures can be implemented