956 research outputs found
Type and gene location of kit mutations predict progression-free survival to first-line imatinib in gastrointestinal stromal tumors: A look into the exon
In previous studies on localized GISTs, KIT exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of KIT and PDGFRA mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the KIT exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of KIT exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) (p < 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (>7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PDGFRA PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier
Psychostimulant effect of the synthetic cannabinoid JWH-018 and AKB48: Behavioral, neurochemical, and dopamine transporter scan imaging studies in mice
JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA) D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health
Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1-CB2 heteroreceptor complexes
Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors and the effects of the compound on agonist activation of those receptors and of CB1-CB2 heteroreceptor complexes. Using [3H]-CP-55940, CBG competed with low micromolar Ki values the binding to CB1R and CB2R. Homogeneous binding in living cells, which is only possible for the CB2R, provided a nanomolar Ki value. In contrast, CBG competed the binding of [3H]-WIN-55,212-2 to CB2R but not to CB1R (2.7 versus >30 µM). The phytocannabinoid modulated signaling mediated by receptors and receptor heteromers even at low concentrations of 0.1-1 µM. cAMP, pERK, ÿ-arrestin recruitment and label-free assays in HEK-293T cells expressing the receptors and treated with endocannabinoids or selective agonists proved that CBG is a partial agonist of CB2R. The action on cells expressing heteromers was similar to that obtained in cells expressing the CB2R. The effect of CBG on CB1R was measurable but the underlying molecular mechanisms remain uncertain. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling
Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding
<p>Introduction - Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.</p>
<p>Materials and Methods - Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.</p>
<p>Results - There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].</p>
<p>Conclusions - The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.</p>
Polymer transport in random flow
The dynamics of polymers in a random smooth flow is investigated in the
framework of the Hookean dumbbell model. The analytical expression of the
time-dependent probability density function of polymer elongation is derived
explicitly for a Gaussian, rapidly changing flow. When polymers are in the
coiled state the pdf reaches a stationary state characterized by power-law
tails both for small and large arguments compared to the equilibrium length.
The characteristic relaxation time is computed as a function of the Weissenberg
number. In the stretched state the pdf is unstationary and exhibits
multiscaling. Numerical simulations for the two-dimensional Navier-Stokes flow
confirm the relevance of theoretical results obtained for the delta-correlated
model.Comment: 28 pages, 6 figure
A combined analysis technique for the search for fast magnetic monopoles with the MACRO detector
We describe a search method for fast moving ()
magnetic monopoles using simultaneously the scintillator, streamer tube and
track-etch subdetectors of the MACRO apparatus. The first two subdetectors are
used primarily for the identification of candidates while the track-etch one is
used as the final tool for their rejection or confirmation. Using this
technique, a first sample of more than two years of data has been analyzed
without any evidence of a magnetic monopole. We set a 90% CL upper limit to the
local monopole flux of in the
velocity range and for nucleon decay
catalysis cross section smaller than .Comment: 29 pages (12 figures). Accepted by Astroparticle Physic
Muon Energy Estimate Through Multiple Scattering with the Macro Detector
Muon energy measurement represents an important issue for any experiment
addressing neutrino induced upgoing muon studies. Since the neutrino
oscillation probability depends on the neutrino energy, a measurement of the
muon energy adds an important piece of information concerning the neutrino
system. We show in this paper how the MACRO limited streamer tube system can be
operated in drift mode by using the TDC's included in the QTPs, an electronics
designed for magnetic monopole search. An improvement of the space resolution
is obtained, through an analysis of the multiple scattering of muon tracks as
they pass through our detector. This information can be used further to obtain
an estimate of the energy of muons crossing the detector. Here we present the
results of two dedicated tests, performed at CERN PS-T9 and SPS-X7 beam lines,
to provide a full check of the electronics and to exploit the feasibility of
such a multiple scattering analysis. We show that by using a neural network
approach, we are able to reconstruct the muon energy for 40 GeV. The
test beam data provide an absolute energy calibration, which allows us to apply
this method to MACRO data.Comment: 25 pages, 11 figures, Submitted to Nucl. Instr. & Meth.
Final results of magnetic monopole searches with the MACRO experiment
We present the final results obtained by the MACRO experiment in the search
for GUT magnetic monopoles in the penetrating cosmic radiation, for the range
. Several searches with all the MACRO sub-detectors
(i.e. scintillation counters, limited streamer tubes and nuclear track
detectors) were performed, both in stand alone and combined ways. No candidates
were detected and a 90% Confidence Level (C.L.) upper limit to the local
magnetic monopole flux was set at the level of cm
s sr. This result is the first experimental limit obtained in
direct searches which is well below the Parker bound in the whole range
in which GUT magnetic monopoles are expected.Comment: 12 pages, Latex, 9 figures and 2 Table
Atmospheric neutrino induced muons in the MACRO detector
A measurement of the flux of neutrino-induced muons using the MACRO detector
is presented. Different event topologies, corresponding to different neutrino
parent energies can be detected. The upward throughgoing muon sample is the
larger event sample. The observed upward-throughgoing muons are 26% fewer than
expected and the zenith angle distribution does not fit with the expected one.
Assuming neutrino oscillations, both measurements suggest maximum mixing and
Dm2 of a few times 10-3 eV2. The other samples are due to the internally
produced events and to upward-going stopping muons. These data show a regular
deficit of observed events in each angular bin, as expected assuming neutrino
oscillations with maximum mixing, in agreement with the analysis of the
upward-throughgoing muon sample.Comment: 7 pages 6 figures to appear in the proceedings of XVIII International
Conference on Neutrino Physics and Astrophysics (Neutrino'98), Takayama,
Japan 4-9 June, 199
Measurement of the residual energy of muons in the Gran Sasso underground Laboratories
The MACRO detector was located in the Hall B of the Gran Sasso underground
Laboratories under an average rock overburden of 3700 hg/cm^2. A transition
radiation detector composed of three identical modules, covering a total
horizontal area of 36 m^2, was installed inside the empty upper part of the
detector in order to measure the residual energy of muons. This paper presents
the measurement of the residual energy of single and double muons crossing the
apparatus. Our data show that double muons are more energetic than single ones.
This measurement is performed over a standard rock depth range from 3000 to
6500 hg/cm^2.Comment: 28 pages, 9 figure
- …