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

Dynamic Measurements of Membrane Insertion Potential of Synthetic Cell Penetrating Peptides

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Langmuir, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/la403370p.Cell penetrating peptides (CPPs) have been established as excellent candidates for mediating drug delivery into cells. When designing synthetic CPPs for drug delivery applications, it is important to understand their ability to penetrate the cell membrane. In this paper, anionic or zwitterionic phospholipid monolayers at the air-water interface are used as model cell membranes to monitor the membrane insertion potential of synthetic CPPs. The insertion potential of CPPs having different cationic and hydrophobic amino acids were recorded using a Langmuir monolayer approach that records peptide adsorption to model membranes. Fluorescence microscopy was used to visualize alterations in phospholipid packing due to peptide insertion. All CPPs had the highest penetration potential in the presence of anionic phospholipids. In addition, two of three amphiphilic CPPs inserted into zwitterionic phospholipids, but none of the hydrophilic CPPs did. All the CPPs studied induced disruptions in phospholipid packing and domain morphology, which were most pronounced for amphiphilic CPPs. Overall, small changes to amino acids and peptide sequences resulted in dramatically different insertion potentials and membrane reorganization. Designers of synthetic CPPs for efficient intracellular drug delivery should consider small nuances in CPP electrostatic and hydrophobic properties

The Geneva-Copenhagen survey of the Solar neighbourhood: Ages, metallicities, and kinematic properties of 14,000 F and G dwarfs

We present and discuss new determinations of metallicity, rotation, age, kinematics, and Galactic orbits for a complete, magnitude-limited, and kinematically unbiased sample of 16,682 nearby F and G dwarf stars. Our 63,000 new, accurate radial-velocity observations for nearly 13,500 stars allow identification of most of the binary stars in the sample and, together with published data complete the kinematic information for 14,139 stars. A major effort has been devoted to the determination of new isochrone ages for all stars for which this is possible. Particular attention has been given to a realistic treatment of statistical biases and error estimates, as standard techniques tend to underestimate these effects and introduce spurious features in the age distributions. We demonstrate, however, how strong observational and theoretical biases cause the distribution of the observed ages to be very different from that of the true age distribution of the sample. Our first results confirm the lack of metal-poor G dwarfs relative to closed-box model predictions (the ``G dwarf problem''), the existence of radial metallicity gradients in the disk, the small change in mean metallicity of the thin disk since its formation and the substantial scatter in metallicity at all ages, and the continuing kinematic heating of the thin disk with an efficiency consistent with that expected for a combination of spiral arms and giant molecular clouds. Distinct features in the distribution of the V component of the space motion are extended in age and metallicity, corresponding to the effects of stochastic spiral waves rather than classical moving groups, and may complicate the identification of thick-disk stars from kinematic criteria. (abridged)Comment: 33 pages, 32 figure

Uniform Atmospheric Retrieval Analysis of Ultracool Dwarfs I : Characterizing Benchmarks, Gl570D and HD3651B

Michael Line, et al, 'UNIFORM ATMOSPHERIC RETRIEVAL ANALYSIS OF ULTRACOOL DWARFS. I. CHARACTERIZING BENCHMARKS, Gl 570D AND HD 3651B', The Astrophysical Journal, Vol. 802 (2), July 2015, doi: https://doi.org/10.1088/0004-637X/807/2/183, published by IOP.Interpreting the spectra of brown dwarfs is key to determining the fundamental physical and chemical processes occurring in their atmospheres. Powerful Bayesian atmospheric retrieval tools have recently been applied to both exoplanet and brown dwarf spectra to tease out the thermal structures and molecular abundances to understand those processes. In this manuscript we develop a significantly upgraded retrieval method and apply it to the SpeX spectral library data of two benchmark late T-dwarfs, Gl570D and HD3651B, to establish the validity of our upgraded forward model parameterization and Bayesian estimator. Our retrieved metallicities, gravities, and effective temperature are consistent with the metallicity and presumed ages of the systems. We add the carbon-to-oxygen ratio as a new dimension to benchmark systems and find good agreement between carbon-to-oxygens ratio derived in the brown dwarfs and the host stars. Furthermore, we have for the first time unambiguously determined the presence of ammonia in the low-resolution spectra of these two late T-dwarfs. We also show that the retrieved results are not significantly impacted by the possible presence of clouds, though some quantities are significantly impacted by uncertainties in photometry. This investigation represents a watershed study in establishing the utility of atmospheric retrieval approaches on brown dwarf spectra.Peer reviewedFinal Published versio

CNS Delivery Via Adsorptive Transcytosis

Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity—like the cationization strategy—as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics

Internet-based interventions for adults with hearing loss, tinnitus and vestibular disorders: protocol for a systematic review

Background: Internet-based interventions are emerging as an alternative way of delivering accessible healthcare for various conditions including hearing and balance disorders. A comprehensive review regarding the evidence-base of Internet-based interventions for auditory-related conditions is required to determine the existing evidence of their efficacy and effectiveness. The objective of the current protocol is to provide the methodology for a systematic review regarding the effects of Internet-based interventions for adults with hearing loss, tinnitus and vestibular disorders. Method: This protocol was developed according to the Preferred Reporting Items for Systematic reviews and Meta-analyses for Protocols (PRISMA-P) 2015 guidelines. Electronic database searches will include EBSCOhost, PubMed and Cochrane Central Register performed by two researchers. This will be complemented by searching other resources such as the reference lists for included studies to identify studies meeting the eligibility for inclusion with regard to study designs, participants, interventions, comparators and outcomes. The Cochrane risk of bias tool (RoB 2) for randomised trials will be used for the bias assessments in the included studies. Criteria for conducting meta-analyses were defined. Discussion: The result of this systematic review will be of value to establish the effects of Internet-based interventions for hearing loss, tinnitus and vestibular disorders. This will be of importance to guide future planning of auditory intervention research and clinical services by healthcare providers, researchers, consumers and stakeholders

Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1

Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TR alpha 1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS- and QTend-durations. The mice have a body temperature 0.5 degrees C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TR alpha 1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperatur

BREAD PROPERTIES AND BAKING TECHNOLOGY - PREPARATIONS FOR AN INSITU TIME-RESOLVED 4D SYNCHROTRON X-RAY TOMOGRAPHY STUDY USING A COMBINATION MICROWAVE OVEN

There is a need in food industry to produce high quality bread and bakery products with reduced energy use. Microwave baking provides fast volumetric heating and is significantly more energy efficient than conventional baking alone