620 research outputs found
L-MTP-PE and zoledronic acid combination in osteosarcoma: pre-clinical evidence of positive therapeutic combination for clinical transfer
Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by
osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic
Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for
the treatment of osteosarcoma and Ewing sarcoma. The beneicial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl
Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated
to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential
therapeutic beneit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma,
as a prerequisite before translation to patients. The effects of ZA (100 µg/kg) and L-mifamurtide (1 mg/kg) were
investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation,
spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological
and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection
and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association
induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide
has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor
site whatever the treatment. This study evidenced for the irst time a signiicant inhibition of primary osteosarcoma
progression when both drugs are combined. This result constitutes a irst proof-of-principle for clinical application in osteosarcoma patients
Development of a SiPM Camera for a Schwarzschild-Couder Cherenkov Telescope for the Cherenkov Telescope Array
We present the development of a novel 11328 pixel silicon photomultiplier
(SiPM) camera for use with a ground-based Cherenkov telescope with
Schwarzschild-Couder optics as a possible medium-sized telescope for the
Cherenkov Telescope Array (CTA). The finely pixelated camera samples air-shower
images with more than twice the optical resolution of cameras that are used in
current Cherenkov telescopes. Advantages of the higher resolution will be a
better event reconstruction yielding improved background suppression and
angular resolution of the reconstructed gamma-ray events, which is crucial in
morphology studies of, for example, Galactic particle accelerators and the
search for gamma-ray halos around extragalactic sources. Packing such a large
number of pixels into an area of only half a square meter and having a fast
readout directly attached to the back of the sensors is a challenging task. For
the prototype camera development, SiPMs from Hamamatsu with through silicon via
(TSV) technology are used. We give a status report of the camera design and
highlight a number of technological advancements that made this development
possible.Comment: 8 pages, 5 figures, In Proceedings of the 34th International Cosmic
Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions
at arXiv:1508.0589
Active Galactic Nuclei under the scrutiny of CTA
Active Galactic Nuclei (hereafter AGN) produce powerful outflows which offer
excellent conditions for efficient particle acceleration in internal and
external shocks, turbulence, and magnetic reconnection events. The jets as well
as particle accelerating regions close to the supermassive black holes
(hereafter SMBH) at the intersection of plasma inflows and outflows, can
produce readily detectable very high energy gamma-ray emission. As of now, more
than 45 AGN including 41 blazars and 4 radiogalaxies have been detected by the
present ground-based gamma-ray telescopes, which represents more than one third
of the cosmic sources detected so far in the VHE gamma-ray regime. The future
Cherenkov Telescope Array (CTA) should boost the sample of AGN detected in the
VHE range by about one order of magnitude, shedding new light on AGN population
studies, and AGN classification and unification schemes. CTA will be a unique
tool to scrutinize the extreme high-energy tail of accelerated particles in
SMBH environments, to revisit the central engines and their associated
relativistic jets, and to study the particle acceleration and emission
mechanisms, particularly exploring the missing link between accretion physics,
SMBH magnetospheres and jet formation. Monitoring of distant AGN will be an
extremely rewarding observing program which will inform us about the inner
workings and evolution of AGN. Furthermore these AGN are bright beacons of
gamma-rays which will allow us to constrain the extragalactic infrared and
optical backgrounds as well as the intergalactic magnetic field, and will
enable tests of quantum gravity and other "exotic" phenomena.Comment: 28 pages, 23 figure
A Search for Very High-Energy Gamma Rays from the Missing Link Binary Pulsar J1023+0038 with VERITAS
The binary millisecond radio pulsar PSR J1023+0038 exhibits many
characteristics similar to the gamma-ray binary system PSR B1259--63/LS 2883,
making it an ideal candidate for the study of high-energy non-thermal emission.
It has been the subject of multi-wavelength campaigns following the
disappearance of the pulsed radio emission in 2013 June, which revealed the
appearance of an accretion disk around the neutron star. We present the results
of very high-energy gamma-ray observations carried out by VERITAS before and
after this change of state. Searches for steady and pulsed emission of both
data sets yield no significant gamma-ray signal above 100 GeV, and upper limits
are given for both a steady and pulsed gamma-ray flux. These upper limits are
used to constrain the magnetic field strength in the shock region of the PSR
J1023+0038 system. Assuming that very high-energy gamma rays are produced via
an inverse-Compton mechanism in the shock region, we constrain the shock
magnetic field to be greater than 2 G before the disappearance of the
radio pulsar and greater than 10 G afterwards.Comment: 7 pages, 3 figures, accepted for publication in Ap
Murine Models for Trypanosoma brucei gambiense Disease Progression—From Silent to Chronic Infections and Early Brain Tropism
Trypanosoma brucei gambiense is responsible for more than 90% of reported cases of human African trypanosomosis (HAT). Infection can last for months or even years without major signs or symptoms of infection, but if left untreated, sleeping sickness is always fatal. In the present study, different T. b. gambiense field isolates from the cerebrospinal fluid of patients with HAT were adapted to growth in vitro. These isolates belong to the homogeneous Group 1 of T. b. gambiense, which is known to induce a chronic infection in humans. In spite of this, these isolates induced infections ranging from chronic to silent in mice, with variations in parasitaemia, mouse lifespan, their ability to invade the CNS and to elicit specific immune responses. In addition, during infection, an unexpected early tropism for the brain as well as the spleen and lungs was observed using bioluminescence analysis. The murine models presented in this work provide new insights into our understanding of HAT and allow further studies of parasite tropism during infection, which will be very useful for the treatment and the diagnosis of the disease
VERITAS and Multiwavelength Observations of the BL Lacertae Object 1ES 1741+196
We present results from multiwavelength observations of the BL Lacertae
object 1ES 1741+196, including results in the very-high-energy -ray
regime using the Very Energetic Radiation Imaging Telescope Array System
(VERITAS). The VERITAS time-averaged spectrum, measured above 180 GeV, is
well-modelled by a power law with a spectral index of
. The integral flux above 180
GeV is
m s, corresponding to 1.6% of the Crab Nebula flux on average.
The multiwavelength spectral energy distribution of the source suggests that
1ES 1741+196 is an extreme-high-frequency-peaked BL Lacertae object. The
observations analysed in this paper extend over a period of six years, during
which time no strong flares were observed in any band. This analysis is
therefore one of the few characterizations of a blazar in a non-flaring state.Comment: 8 pages, 5 figures. Accepted for publication in MNRA
Deep Broadband Observations of the Distant Gamma-ray Blazar PKS 1424+240
We present deep VERITAS observations of the blazar PKS 1424+240, along with
contemporaneous Fermi Large Area Telescope, Swift X-ray Telescope and Swift UV
Optical Telescope data between 2009 February 19 and 2013 June 8. This blazar
resides at a redshift of , displaying a significantly attenuated
gamma-ray flux above 100 GeV due to photon absorption via pair-production with
the extragalactic background light. We present more than 100 hours of VERITAS
observations from three years, a multiwavelength light curve and the
contemporaneous spectral energy distributions. The source shows a higher flux
of (2.1) ph ms above 120 GeV in 2009 and
2011 as compared to the flux measured in 2013, corresponding to
(1.02) ph ms above 120 GeV. The measured
differential very high energy (VHE; GeV) spectral indices are
3.80.3, 4.30.6 and 4.50.2 in 2009, 2011 and 2013,
respectively. No significant spectral change across the observation epochs is
detected. We find no evidence for variability at gamma-ray opacities of greater
than , where it is postulated that any variability would be small and
occur on longer than year timescales if hadronic cosmic-ray interactions with
extragalactic photon fields provide a secondary VHE photon flux. The data
cannot rule out such variability due to low statistics.Comment: ApJL accepted March 17, 201
A Structure-Based Approach for Detection of Thiol Oxidoreductases and Their Catalytic Redox-Active Cysteine Residues
Cysteine (Cys) residues often play critical roles in proteins, for example, in
the formation of structural disulfide bonds, metal binding, targeting proteins
to the membranes, and various catalytic functions. However, the structural
determinants for various Cys functions are not clear. Thiol oxidoreductases,
which are enzymes containing catalytic redox-active Cys residues, have been
extensively studied, but even for these proteins there is little understanding
of what distinguishes their catalytic redox Cys from other Cys functions.
Herein, we characterized thiol oxidoreductases at a structural level and
developed an algorithm that can recognize these enzymes by (i) analyzing amino
acid and secondary structure composition of the active site and its similarity
to known active sites containing redox Cys and (ii) calculating accessibility,
active site location, and reactivity of Cys. For proteins with known or modeled
structures, this method can identify proteins with catalytic Cys residues and
distinguish thiol oxidoreductases from the enzymes containing other catalytic
Cys types. Furthermore, by applying this procedure to Saccharomyces
cerevisiae proteins containing conserved Cys, we could identify the
majority of known yeast thiol oxidoreductases. This study provides insights into
the structural properties of catalytic redox-active Cys and should further help
to recognize thiol oxidoreductases in protein sequence and structure
databases
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