62 research outputs found
Increased efficacy and safety in the treatment of experimental liver cancer with a novel adenovirus-alphavirus hybrid vector
An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by alpha-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying mIL-12 gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy
Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice
Recombinant adenoviruses (Ad) are among the most extensively used vectors for liver gene transfer. One of the major limitations for the clinical application of these vectors is the inflammatory immune response associated with systemic administration of high dose of virus. We evaluated the effect of Ad administration route on the inflammatory immune response and liver transgene expression. We compared direct intrahepatic injection (IH) with the systemic administration via tail vein (IV). IH injection of Ad resulted in a lower inflammatory response and a higher transgene expression. When a relatively low dose of virus was used, IV administration resulted in no detectable protein expression but production of proinflammatory cytokines. In contrast, IH administration induced high levels of transgene expression and no inflammation, although we detected a transient hypertransaminemia, which fully resolved within days. Furthermore, IH injection resulted in a faster protein expression being more intense at the site of injection, whereas IV administration caused slower but diffuse liver expression. IH injection also reduced the spreading of the virus to other organs. Independently of the route, depletion of Kupffer cells significantly enhanced the transduction efficiency of Ad. This effect was stronger when using IV injection, indicating that IH injection partially overcomes Kupffer cell phagocytic activity. Moreover, the antitumor efficacy of high-capacity-Ad encoding murine interleukin-12 (IL-12) was significantly greater when the vector was administered by IH injection than when given IV. In conclusion, IH injection of adenovirus represents a safe and efficient administration route for clinical applications of gene therapy targeting the liver
Precise 3D track reconstruction algorithm for the ICARUS T600 liquid argon time projection chamber detector
Liquid Argon Time Projection Chamber (LAr TPC) detectors offer charged
particle imaging capability with remarkable spatial resolution. Precise event
reconstruction procedures are critical in order to fully exploit the potential
of this technology. In this paper we present a new, general approach of
three-dimensional reconstruction for the LAr TPC with a practical application
to track reconstruction. The efficiency of the method is evaluated on a sample
of simulated tracks. We present also the application of the method to the
analysis of real data tracks collected during the ICARUS T600 detector
operation with the CNGS neutrino beam.Comment: Submitted to Advances in High Energy Physic
Search for anomalies in the {\nu}e appearance from a {\nu}{\mu} beam
We report an updated result from the ICARUS experiment on the search for
{\nu}{\mu} ->{\nu}e anomalies with the CNGS beam, produced at CERN with an
average energy of 20 GeV and travelling 730 km to the Gran Sasso Laboratory.
The present analysis is based on a total sample of 1995 events of CNGS neutrino
interactions, which corresponds to an almost doubled sample with respect to the
previously published result. Four clear {\nu}e events have been visually
identified over the full sample, compared with an expectation of 6.4 +- 0.9
events from conventional sources. The result is compatible with the absence of
additional anomalous contributions. At 90% and 99% confidence levels the limits
to possible oscillated events are 3.7 and 8.3 respectively. The corresponding
limit to oscillation probability becomes consequently 3.4 x 10-3 and 7.6 x 10-3
respectively. The present result confirms, with an improved sensitivity, the
early result already published by the ICARUS collaboration
Treatment of chronic viral hepatitis in woodchucks by prolonged intrahepatic expression of interleukin-12
Chronic hepatitis B is a major cause of liver-related death worldwide. Interleukin-12 (IL-12) induction accompanies viral clearance in chronic hepatitis B virus infection. Here, we tested the therapeutic potential of IL-12 gene therapy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), an infection that closely resembles chronic hepatitis B. The woodchucks were treated by intrahepatic injection of a helper-dependent adenoviral vector encoding IL-12 under the control of a liver-specific RU486-responsive promoter. All woodchucks with viral loads below 10(10) viral genomes (vg)/ml showed a marked and sustained reduction of viremia that was accompanied by a reduction in hepatic WHV DNA, a loss of e antigen and surface antigen, and improved liver histology. In contrast, none of the woodchucks with higher viremia levels responded to therapy. The antiviral effect was associated with the induction of T-cell immunity against viral antigens and a reduction of hepatic expression of Foxp3 in the responsive animals. Studies were performed in vitro to elucidate the resistance to therapy in highly viremic woodchucks. These studies showed that lymphocytes from healthy woodchucks or from animals with low viremia levels produced gamma interferon (IFN-gamma) upon IL-12 stimulation, while lymphocytes from woodchucks with high viremia failed to upregulate IFN-gamma in response to IL-12. In conclusion, IL-12-based gene therapy is an efficient approach to treat chronic hepadnavirus infection in woodchucks with viral loads below 10(10) vg/ml. Interestingly, this therapy is able to break immunological tolerance to viral antigens in chronic WHV carriers
Experimental search for the LSND anomaly with the ICARUS detector in the CNGS neutrino beam
We report an early result from the ICARUS experiment on the search for nu_mu
to nu_e signal due to the LSND anomaly. The search was performed with the
ICARUS T600 detector located at the Gran Sasso Laboratory, receiving CNGS
neutrinos from CERN at an average energy of about 20 GeV, after a flight path
of about 730 km. The LSND anomaly would manifest as an excess of nu_e events,
characterized by a fast energy oscillation averaging approximately to
sin^2(1.27 Dm^2_new L/ E_nu) = 1/2. The present analysis is based on 1091
neutrino events, which are about 50% of the ICARUS data collected in 2010-2011.
Two clear nu_e events have been found, compared with the expectation of 3.7 +/-
0.6 events from conventional sources. Within the range of our observations,
this result is compatible with the absence of a LSND anomaly. At 90% and 99%
confidence levels the limits of 3.4 and 7.3 events corresponding to oscillation
probabilities of 5.4 10^-3 and 1.1 10^-2 are set respectively. The result
strongly limits the window of open options for the LSND anomaly to a narrow
region around (Dm^2, sin^2(2 theta))_new = (0.5 eV^2, 0.005), where there is an
overall agreement (90% CL) between the present ICARUS limit, the published
limits of KARMEN and the published positive signals of LSND and MiniBooNE
Collaborations.Comment: 10 pages, 7 figure
A search for the analogue to Cherenkov radiation by high energy neutrinos at superluminal speeds in ICARUS
The OPERA collaboration has claimed evidence of superluminal {\nu}{_\mu}
propagation between CERN and the LNGS. Cohen and Glashow argued that such
neutrinos should lose energy by producing photons and e+e- pairs, through Z0
mediated processes analogous to Cherenkov radiation. In terms of the parameter
delta=(v^2_nu-v^2_c)/v^2_c, the OPERA result implies delta = 5 x 10^-5. For
this value of \delta a very significant deformation of the neutrino energy
spectrum and an abundant production of photons and e+e- pairs should be
observed at LNGS. We present an analysis based on the 2010 and part of the 2011
data sets from the ICARUS experiment, located at Gran Sasso National Laboratory
and using the same neutrino beam from CERN. We find that the rates and
deposited energy distributions of neutrino events in ICARUS agree with the
expectations for an unperturbed spectrum of the CERN neutrino beam. Our results
therefore refute a superluminal interpretation of the OPERA result according to
the Cohen and Glashow prediction for a weak current analog to Cherenkov
radiation. In particular no superluminal Cherenkov like e+e- pair or gamma
emission event has been directly observed inside the fiducial volume of the
"bubble chamber like" ICARUS TPC-LAr detector, setting the much stricter limit
of delta < 2.5 10^-8 at the 90% confidence level, comparable with the one due
to the observations from the SN1987A.Comment: 17 pages, 6 figure
Underground operation of the ICARUS T600 LAr-TPC: first results
Open questions are still present in fundamental Physics and Cosmology, like
the nature of Dark Matter, the matter-antimatter asymmetry and the validity of
the particle interaction Standard Model. Addressing these questions requires a
new generation of massive particle detectors exploring the subatomic and
astrophysical worlds. ICARUS T600 is the first large mass (760 ton) example of
a novel detector generation able to combine the imaging capabilities of the old
famous "bubble chamber" with an excellent energy measurement in huge electronic
detectors. ICARUS T600 now operates at the Gran Sasso underground laboratory,
studying cosmic rays, neutrino oscillation and proton decay. Physical
potentialities of this novel telescope are presented through few examples of
neutrino interactions reconstructed with unprecedented details. Detector design
and early operation are also reported.Comment: 14 pages, 8 figures, 2 tables. Submitted to Jins
Precision measurement of the neutrino velocity with the ICARUS detector in the CNGS beam
During May 2012, the CERN-CNGS neutrino beam has been operated for two weeks
for a total of 1.8 10^17 pot in bunched mode, with a 3 ns narrow width proton
beam bunches, separated by 100 ns. This tightly bunched beam structure allows a
very accurate time of flight measurement of neutrinos from CERN to LNGS on an
event-by-event basis. Both the ICARUS-T600 PMT-DAQ and the CERN-LNGS timing
synchronization have been substantially improved for this campaign, taking
ad-vantage of additional independent GPS receivers, both at CERN and LNGS as
well as of the deployment of the "White Rabbit" protocol both at CERN and LNGS.
The ICARUS-T600 detector has collected 25 beam-associated events; the
corresponding time of flight has been accurately evaluated, using all different
time synchronization paths. The measured neutrino time of flight is compatible
with the arrival of all events with speed equivalent to the one of light: the
difference between the expected value based on the speed of light and the
measured value is tof_c - tof_nu = (0.10 \pm 0.67stat. \pm 2.39syst.) ns. This
result is in agreement with the value previously reported by the ICARUS
collaboration, tof_c - tof_nu = (0.3 \pm 4.9stat. \pm 9.0syst.) ns, but with
improved statistical and systematic errors.Comment: 21 pages, 13 figures, 1 tabl
- …