6,482 research outputs found
Physiological lentiviral vectors for the generation of improved CAR-T cells
Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor alpha (EF1 alpha)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-alpha) and interferon (IFN)-gamma after efficient destruction of CD19(+) lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19(+) pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AWLVs for the generation of improved CAR-T products
Development of an in vitro periodontal biofilm model for assessing antimicrobial and host modulatory effects of bioactive molecules
Background:
Inflammation within the oral cavity occurs due to dysregulation between microbial biofilms and the host response. Understanding how different oral hygiene products influence inflammatory properties is important for the development of new products. Therefore, creation of a robust host-pathogen biofilm platform capable of evaluating novel oral healthcare compounds is an attractive option. We therefore devised a multi-species biofilm co-culture model to evaluate the naturally derived polyphenol resveratrol (RSV) and gold standard chlorhexidine (CHX) with respect to anti-biofilm and anti-inflammatory properties.<p></p>
Methods:
An in vitro multi-species biofilm containing <i>S. mitis, F. nucleatum, P. Gingivalis</i> and <i>A. Actinomycetemcomitans</i> was created to represent a disease-associated biofilm and the oral epithelial cell in OKF6-TERT2. Cytotoxicity studies were performed using RSV and CHX. Multi-species biofilms were either treated with either molecule, or alternatively epithelial cells were treated with these prior to biofilm co-culture. Biofilm composition was evaluated and inflammatory responses quantified at a transcriptional and protein level.<p></p>
Results:
CHX was toxic to epithelial cells and multi-species biofilms at concentrations ranging from 0.01-0.2%. RSV did not effect multi-species biofilm composition, but was toxic to epithelial cells at concentrations greater than 0.01%. In co-culture, CHX-treated biofilms resulted in down regulation of the inflammatory chemokine IL-8 at both mRNA and protein level. RSV-treated epithelial cells in co-culture were down-regulated in the release of IL-8 protein, but not mRNA.<p></p>
Conclusions:
CHX possesses potent bactericidal properties, which may impact downstream inflammatory mediators. RSV does not appear to have bactericidal properties against multi-species biofilms, however it did appear to supress epithelial cells from releasing inflammatory mediators. This study demonstrates the potential to understand the mechanisms by which different oral hygiene products may influence gingival inflammation, thereby validating the use of a biofilm co-culture model.<p></p>
All-sky search for time-integrated neutrino emission from astrophysical sources with 7 years of IceCube data
Since the recent detection of an astrophysical flux of high energy neutrinos,
the question of its origin has not yet fully been answered. Much of what is
known about this flux comes from a small event sample of high neutrino purity,
good energy resolution, but large angular uncertainties. In searches for
point-like sources, on the other hand, the best performance is given by using
large statistics and good angular reconstructions. Track-like muon events
produced in neutrino interactions satisfy these requirements. We present here
the results of searches for point-like sources with neutrinos using data
acquired by the IceCube detector over seven years from 2008--2015. The
discovery potential of the analysis in the northern sky is now significantly
below , on average
lower than the sensitivity of the previously published analysis of four
years exposure. No significant clustering of neutrinos above background
expectation was observed, and implications for prominent neutrino source
candidates are discussed.Comment: 19 pages, 17 figures, 3 tables; ; submitted to The Astrophysical
Journa
Searches for sterile neutrinos with the IceCube detector
The IceCube neutrino telescope at the South Pole has measured the atmospheric muon neutrino spectrum as a function of zenith angle and energy in the approximate 320 GeV to 20 TeV range, to search for the oscillation signatures of light sterile neutrinos. No evidence for anomalous nu(mu) or (nu) over bar (mu) disappearance is observed in either of two independently developed analyses, each using one year of atmospheric neutrino data. New exclusion limits are placed on the parameter space of the 3 + 1 model, in which muon antineutrinos experience a strong Mikheyev-Smirnov-Wolfenstein-resonant oscillation. The exclusion limits extend to sin(2)2 theta(24) <= 0.02 at Delta m(2) similar to 0.3 eV(2) at the 90% confidence level. The allowed region from global analysis of appearance experiments, including LSND and MiniBooNE, is excluded at approximately the 99% confidence level for the global best-fit value of vertical bar U-e4 vertical bar(2)
Observation and Characterization of a Cosmic Muon Neutrino Flux from the Northern Hemisphere using six years of IceCube data
The IceCube Collaboration has previously discovered a high-energy
astrophysical neutrino flux using neutrino events with interaction vertices
contained within the instrumented volume of the IceCube detector. We present a
complementary measurement using charged current muon neutrino events where the
interaction vertex can be outside this volume. As a consequence of the large
muon range the effective area is significantly larger but the field of view is
restricted to the Northern Hemisphere. IceCube data from 2009 through 2015 have
been analyzed using a likelihood approach based on the reconstructed muon
energy and zenith angle. At the highest neutrino energies between 191 TeV and
8.3 PeV a significant astrophysical contribution is observed, excluding a
purely atmospheric origin of these events at significance. The
data are well described by an isotropic, unbroken power law flux with a
normalization at 100 TeV neutrino energy of
and a hard spectral index of . The observed spectrum is
harder in comparison to previous IceCube analyses with lower energy thresholds
which may indicate a break in the astrophysical neutrino spectrum of unknown
origin. The highest energy event observed has a reconstructed muon energy of
which implies a probability of less than 0.005% for
this event to be of atmospheric origin. Analyzing the arrival directions of all
events with reconstructed muon energies above 200 TeV no correlation with known
-ray sources was found. Using the high statistics of atmospheric
neutrinos we report the currently best constraints on a prompt atmospheric muon
neutrino flux originating from charmed meson decays which is below in
units of the flux normalization of the model in Enberg et al. (2008).Comment: 20 pages, 21 figure
The contribution of Fermi-2LAC blazars to the diffuse TeV-PeV neutrino flux
The recent discovery of a diffuse cosmic neutrino flux extending up to PeV
energies raises the question of which astrophysical sources generate this
signal. One class of extragalactic sources which may produce such high-energy
neutrinos are blazars. We present a likelihood analysis searching for
cumulative neutrino emission from blazars in the 2nd Fermi-LAT AGN catalogue
(2LAC) using an IceCube neutrino dataset 2009-12 which was optimised for the
detection of individual sources. In contrast to previous searches with IceCube,
the populations investigated contain up to hundreds of sources, the largest one
being the entire blazar sample in the 2LAC catalogue. No significant excess is
observed and upper limits for the cumulative flux from these populations are
obtained. These constrain the maximum contribution of the 2LAC blazars to the
observed astrophysical neutrino flux to be or less between around 10
TeV and 2 PeV, assuming equipartition of flavours at Earth and a single
power-law spectrum with a spectral index of . We can still exclude that
the 2LAC blazars (and sub-populations) emit more than of the observed
neutrinos up to a spectral index as hard as in the same energy range.
Our result takes into account that the neutrino source count distribution is
unknown, and it does not assume strict proportionality of the neutrino flux to
the measured 2LAC -ray signal for each source. Additionally, we
constrain recent models for neutrino emission by blazars.Comment: 18 pages, 22 figure
Neutrinos and Cosmic Rays Observed by IceCube
The core mission of the IceCube Neutrino observatory is to study the origin
and propagation of cosmic rays. IceCube, with its surface component IceTop,
observes multiple signatures to accomplish this mission. Most important are the
astrophysical neutrinos that are produced in interactions of cosmic rays, close
to their sources and in interstellar space. IceCube is the first instrument
that measures the properties of this astrophysical neutrino flux, and
constrains its origin. In addition, the spectrum, composition and anisotropy of
the local cosmic-ray flux are obtained from measurements of atmospheric muons
and showers. Here we provide an overview of recent findings from the analysis
of IceCube data, and their implications on our understanding of cosmic rays.Comment: Review article, to appear in Advances in Space Research, special
issue "Origins of Cosmic Rays
- …