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Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy.
The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates β₯98% of peripheral immune cells with β₯4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery
Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries
<p>Abstract</p> <p>Background</p> <p>Shifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials.</p> <p>Methods</p> <p>Rates of Clinical Trial Applications (CTA) for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies.</p> <p>Results</p> <p>Since 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth). For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (<it>P </it>< 0.05) except for Germany) in clinical drug trials. The decrease in the UK was caused by a sharp fall in academic trial activities. Across the six analyzed countries, no EU-wide trial-phase-specific patterns or trends were observed.</p> <p>Conclusions</p> <p>The EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to the decreases in trial numbers in Germany and the UK. In the latter case, national research governance concerns had a share in the country's marked decline. However, different EU member states successfully developed best practices, which a new European legislation should take into consideration to resume Europe's attractiveness and international competitiveness for the conduct of clinical trials.</p
An Elementary Quantum Network of Single Atoms in Optical Cavities
Quantum networks are distributed quantum many-body systems with tailored
topology and controlled information exchange. They are the backbone of
distributed quantum computing architectures and quantum communication. Here we
present a prototype of such a quantum network based on single atoms embedded in
optical cavities. We show that atom-cavity systems form universal nodes capable
of sending, receiving, storing and releasing photonic quantum information.
Quantum connectivity between nodes is achieved in the conceptually most
fundamental way: by the coherent exchange of a single photon. We demonstrate
the faithful transfer of an atomic quantum state and the creation of
entanglement between two identical nodes in independent laboratories. The
created nonlocal state is manipulated by local qubit rotation. This efficient
cavity-based approach to quantum networking is particularly promising as it
offers a clear perspective for scalability, thus paving the way towards
large-scale quantum networks and their applications.Comment: 8 pages, 5 figure
Modelling radiation-induced cell cycle delays
Ionizing radiation is known to delay the cell cycle progression. In
particular after particle exposure significant delays have been observed and it
has been shown that the extent of delay affects the expression of damage such
as chromosome aberrations. Thus, to predict how cells respond to ionizing
radiation and to derive reliable estimates of radiation risks, information
about radiation-induced cell cycle perturbations is required. In the present
study we describe and apply a method for retrieval of information about the
time-course of all cell cycle phases from experimental data on the mitotic
index only. We study the progression of mammalian cells through the cell cycle
after exposure. The analysis reveals a prolonged block of damaged cells in the
G2 phase. Furthermore, by performing an error analysis on simulated data
valuable information for the design of experimental studies has been obtained.
The analysis showed that the number of cells analyzed in an experimental sample
should be at least 100 to obtain a relative error less than 20%.Comment: 19 pages, 11 figures, accepted for publication in Radiation and
Environmental Biophysic
Out-of-equilibrium physics in driven dissipative coupled resonator arrays
Coupled resonator arrays have been shown to exhibit interesting many- body
physics including Mott and Fractional Hall states of photons. One of the main
differences between these photonic quantum simulators and their cold atoms
coun- terparts is in the dissipative nature of their photonic excitations. The
natural equi- librium state is where there are no photons left in the cavity.
Pumping the system with external drives is therefore necessary to compensate
for the losses and realise non-trivial states. The external driving here can
easily be tuned to be incoherent, coherent or fully quantum, opening the road
for exploration of many body regimes beyond the reach of other approaches. In
this chapter, we review some of the physics arising in driven dissipative
coupled resonator arrays including photon fermionisa- tion, crystallisation, as
well as photonic quantum Hall physics out of equilibrium. We start by briefly
describing possible experimental candidates to realise coupled resonator arrays
along with the two theoretical models that capture their physics, the
Jaynes-Cummings-Hubbard and Bose-Hubbard Hamiltonians. A brief review of the
analytical and sophisticated numerical methods required to tackle these systems
is included.Comment: Chapter that appeared in "Quantum Simulations with Photons and
Polaritons: Merging Quantum Optics with Condensed Matter Physics" edited by
D.G.Angelakis, Quantum Science and Technology Series, Springer 201
Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy
The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates >= 98% of peripheral immune cells with >= 4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery
Branch Mode Selection during Early Lung Development
Many organs of higher organisms, such as the vascular system, lung, kidney,
pancreas, liver and glands, are heavily branched structures. The branching
process during lung development has been studied in great detail and is
remarkably stereotyped. The branched tree is generated by the sequential,
non-random use of three geometrically simple modes of branching (domain
branching, planar and orthogonal bifurcation). While many regulatory components
and local interactions have been defined an integrated understanding of the
regulatory network that controls the branching process is lacking. We have
developed a deterministic, spatio-temporal differential-equation based model of
the core signaling network that governs lung branching morphogenesis. The model
focuses on the two key signaling factors that have been identified in
experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well
as the SHH receptor patched (Ptc). We show that the reported biochemical
interactions give rise to a Schnakenberg-type Turing patterning mechanisms that
allows us to reproduce experimental observations in wildtype and mutant mice.
The kinetic parameters as well as the domain shape are based on experimental
data where available. The developed model is robust to small absolute and large
relative changes in the parameter values. At the same time there is a strong
regulatory potential in that the switching between branching modes can be
achieved by targeted changes in the parameter values. We note that the sequence
of different branching events may also be the result of different growth
speeds: fast growth triggers lateral branching while slow growth favours
bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is
sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio
Application of Graphene within Optoelectronic Devices and Transistors
Scientists are always yearning for new and exciting ways to unlock graphene's
true potential. However, recent reports suggest this two-dimensional material
may harbor some unique properties, making it a viable candidate for use in
optoelectronic and semiconducting devices. Whereas on one hand, graphene is
highly transparent due to its atomic thickness, the material does exhibit a
strong interaction with photons. This has clear advantages over existing
materials used in photonic devices such as Indium-based compounds. Moreover,
the material can be used to 'trap' light and alter the incident wavelength,
forming the basis of the plasmonic devices. We also highlight upon graphene's
nonlinear optical response to an applied electric field, and the phenomenon of
saturable absorption. Within the context of logical devices, graphene has no
discernible band-gap. Therefore, generating one will be of utmost importance.
Amongst many others, some existing methods to open this band-gap include
chemical doping, deformation of the honeycomb structure, or the use of carbon
nanotubes (CNTs). We shall also discuss various designs of transistors,
including those which incorporate CNTs, and others which exploit the idea of
quantum tunneling. A key advantage of the CNT transistor is that ballistic
transport occurs throughout the CNT channel, with short channel effects being
minimized. We shall also discuss recent developments of the graphene tunneling
transistor, with emphasis being placed upon its operational mechanism. Finally,
we provide perspective for incorporating graphene within high frequency
devices, which do not require a pre-defined band-gap.Comment: Due to be published in "Current Topics in Applied Spectroscopy and
the Science of Nanomaterials" - Springer (Fall 2014). (17 pages, 19 figures
The Ets dominant repressor En/Erm enhances intestinal epithelial tumorigenesis in ApcMin mice
<p>Abstract</p> <p>Background</p> <p>Ets transcription factors have been widely implicated in the control of tumorigenesis, with most studies suggesting tumor-promoting roles. However, few studies have examined Ets tumorigenesis-modifying functions <it>in vivo </it>using model genetic systems.</p> <p>Methods</p> <p>Using mice expressing a previously characterized Ets dominant repressor transgene in the intestinal epithelium (Villin-En/Erm), we examined the consequences of blocking endogenous Ets-mediated transcriptional activation on tumorigenesis in the Apc<sup>Min </sup>model of intestinal carcinoma.</p> <p>Results</p> <p>En/Erm expression in the intestine, at levels not associated with overt crypt-villus dysmorphogenesis, results in a marked increase in tumor number in Apc<sup>Min </sup>animals. Moreover, when examined histologically, tumors from En/Erm-expressing animals show a trend toward greater stromal invasiveness. Detailed analysis of crypt-villus homeostasis in these En/Erm transgenic animals suggests increased epithelial turnover as one possible mechanism for the enhanced tumorigenesis.</p> <p>Conclusion</p> <p>Our findings provide <it>in vivo </it>evidence for a tumor-restricting function of endogenous Ets factors in the intestinal epithelium.</p
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