1,453 research outputs found
In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donors and Recipients: Understanding the Quantitative Immuno-biology of Allogeneic Transplantation
Donor T cell mediated graft vs. host effects may result from the aggregate
alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA
in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT).
Whole exome sequencing has demonstrated extensive nucleotide sequence variation
in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in
the GVH direction (polymorphisms present in recipient and absent in donor) were
identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide
sequence flanking each SNP was obtained utilizing the ANNOVAR software package.
All possible nonameric-peptides encoded by the non-synonymous SNP were then
interrogated in-silico for their likelihood to be presented by the HLA class I
molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM
algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which
bound HLA with an IC50 of <500nM, and 2254 peptides/DRP with an IC50 of <50nM.
Unrelated donors generally had higher numbers of peptides presented by the HLA.
A similarly large library of presented peptides was identified when the data
was interrogated using the Net MHCPan algorithm. These peptides were uniformly
distributed in the various organ systems. The bioinformatic algorithm presented
here demonstrates that there may be a high level of minor histocompatibility
antigen variation in HLA-matched individuals, constituting an HLA-specific
alloreactivity potential. These data provide a possible explanation for how
relatively minor adjustments in GVHD prophylaxis yield relatively similar
outcomes in HLA matched and mismatched SCT recipients.Comment: Abstract: 235, Words: 6422, Figures: 7, Tables: 3, Supplementary
figures: 2, Supplementary tables:
Dynamics and Radiation of Young Type-Ia Supernova Remnants: Important Physical Processes
We examine and analyze the physical processes that should be taken into
account when modeling young type-Ia SNRs, with ages of several hundred years.
It is shown, that energy losses in the metal-rich ejecta can be essential for
remnants already at this stage of evolution. The influence of electron thermal
conduction and the rate of the energy exchange between electrons and ions on
the temperature distribution and the X-radiation from such remnants is studied.
The data for Tycho SNR from the XMM-Newton X-ray telescope have been employed
for the comparison of calculations with observations.Comment: 19 pages, 8 figure
Whole Exome Sequencing to Estimate Alloreactivity Potential Between Donors and Recipients in Stem Cell Transplantation
Whole exome sequencing was performed on HLA-matched stem cell donors and
transplant recipients to measure sequence variation contributing to minor
histocompatibility antigen differences between the two. A large number of
nonsynonymous single nucleotide polymorphisms were identified in each of the
nine unique donor-recipient pairs tested. This variation was greater in
magnitude in unrelated donors as compared with matched related donors.
Knowledge of the magnitude of exome variation between stem cell transplant
recipients and donors may allow more accurate titration of immunosuppressive
therapy following stem cell transplantation.Comment: 12 pages- main article, 29 pages total, 5 figures, 1 supplementary
figur
Analytic frameworks for assessing dialogic argumentation in online learning environments
Over the last decade, researchers have developed sophisticated online learning environments to support students engaging in argumentation. This review first considers the range of functionalities incorporated within these online environments. The review then presents five categories of analytic frameworks focusing on (1) formal argumentation structure, (2) normative quality, (3) nature and function of contributions within the dialog, (4) epistemic nature of reasoning, and (5) patterns and trajectories of participant interaction. Example analytic frameworks from each category are presented in detail rich enough to illustrate their nature and structure. This rich detail is intended to facilitate researchers’ identification of possible frameworks to draw upon in developing or adopting analytic methods for their own work. Each framework is applied to a shared segment of student dialog to facilitate this illustration and comparison process. Synthetic discussions of each category consider the frameworks in light of the underlying theoretical perspectives on argumentation, pedagogical goals, and online environmental structures. Ultimately the review underscores the diversity of perspectives represented in this research, the importance of clearly specifying theoretical and environmental commitments throughout the process of developing or adopting an analytic framework, and the role of analytic frameworks in the future development of online learning environments for argumentation
Allergen immunotherapy for IgE-mediated food allergy : a systematic review and meta-analysis
Background: The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy. Methods: We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses. Results: We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses. Conclusions: AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.Peer reviewe
Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA
Inclusive photoproduction of D*+- mesons has been measured for photon-proton
centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality
Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of
37 pb^-1. Total and differential cross sections as functions of the D*
transverse momentum and pseudorapidity are presented in restricted kinematical
regions and the data are compared with next-to-leading order (NLO) perturbative
QCD calculations using the "massive charm" and "massless charm" schemes. The
measured cross sections are generally above the NLO calculations, in particular
in the forward (proton) direction. The large data sample also allows the study
of dijet production associated with charm. A significant resolved as well as a
direct photon component contribute to the cross section. Leading order QCD
Monte Carlo calculations indicate that the resolved contribution arises from a
significant charm component in the photon. A massive charm NLO parton level
calculation yields lower cross sections compared to the measured results in a
kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure
Measurement of the diffractive structure function in deep inelastic scattering at HERA
This paper presents an analysis of the inclusive properties of diffractive
deep inelastic scattering events produced in interactions at HERA. The
events are characterised by a rapidity gap between the outgoing proton system
and the remaining hadronic system. Inclusive distributions are presented and
compared with Monte Carlo models for diffractive processes. The data are
consistent with models where the pomeron structure function has a hard and a
soft contribution. The diffractive structure function is measured as a function
of \xpom, the momentum fraction lost by the proton, of , the momentum
fraction of the struck quark with respect to \xpom, and of . The \xpom
dependence is consistent with the form \xpoma where
in all bins of and
. In the measured range, the diffractive structure function
approximately scales with at fixed . In an Ingelman-Schlein type
model, where commonly used pomeron flux factor normalisations are assumed, it
is found that the quarks within the pomeron do not saturate the momentum sum
rule.Comment: 36 pages, latex, 11 figures appended as uuencoded fil
Clinical practice. Diagnosis and treatment of cow’s milk allergy
Introduction Cow's milk allergy (CMA) is thought to affect 2-3% of infants. The signs and symptoms are nonspecific and may be difficult to objectify, and as the diagnosis requires cow's milk elimination followed by challenge, often, children are considered cow's milk allergic without proven diagnosis. Diagnosis Because of the consequences, a correct diagnosis of CMA is pivotal. Open challenges tend to overestimate the number of children with CMA. The only reliable way to diagnose CMA is by double-blind, placebo-controlled challenge (DBPCFC). Therapy At present, the only proven treatment consists of elimination of cow's milk protein from the child's diet and the introduction of formulas based on extensively hydrolysed whey protein or casein; amino acid-based formula is rarely indicated. The majority of children will regain tolerance to cow's milk within the first 5 years of life. Conclusions Open challenges can be used to reject CMA, but for adequate diagnosis, DBPCFC is mandatory. In most children, CMA can be adequately treated with extensively hydrolysed whey protein or casein formulas
Measurement of Jet Shapes in Photoproduction at HERA
The shape of jets produced in quasi-real photon-proton collisions at
centre-of-mass energies in the range GeV has been measured using the
hadronic energy flow. The measurement was done with the ZEUS detector at HERA.
Jets are identified using a cone algorithm in the plane with a
cone radius of one unit. Measured jet shapes both in inclusive jet and dijet
production with transverse energies GeV are presented. The jet
shape broadens as the jet pseudorapidity () increases and narrows
as increases. In dijet photoproduction, the jet shapes have been
measured separately for samples dominated by resolved and by direct processes.
Leading-logarithm parton-shower Monte Carlo calculations of resolved and direct
processes describe well the measured jet shapes except for the inclusive
production of jets with high and low . The observed
broadening of the jet shape as increases is consistent with the
predicted increase in the fraction of final state gluon jets.Comment: 29 pages including 9 figure
Analogue peptides for the immunotherapy of human acute myeloid leukemia
Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies
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