In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then ...assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC).
Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance.
From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported.
Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.
NCT02034981.
A
bstract
We explore the phenomenology of models containing one Vector-Like Quark (VLQ),
t′
, which can decay into the Standard Model (SM) top quark,
t
, and a new spin-0 neutral boson,
S
, the ...latter being either a scalar or pseudoscalar state. We parametrise the underlying interactions in terms of a simplified model which enables us to capture possible Beyond the SM (BSM) scenarios. We discuss in particular three such scenarios: one where the SM state is supplemented by an additional scalar, one which builds upon a 2-Higgs Doublet Model (2HDM) framework and another which realises a Composite Higgs Model (CHM) through partial compositeness. Such exotic decays of the
t′
can be competitive with decays into SM particles, leading to new possible discovery channels at the Large Hadron Collider (LHC). Assuming
t′
pair production via strong interactions, we design signal regions optimised for one
t′ → S t
transition (while being inclusive on the other
t
¯
′
decay, and vice versa), followed by the decay of
S
into the two very clean experimental signatures
S → γ γ
and
S → Z
(
→ ℓ
+
ℓ
−
)
γ
. We perform a dedicated signal- to-background analysis in both channels, by using Monte Carlo (MC) event simulations modelling the dynamics from the proton-proton to the detector level. Under the assumption of BR(
t′ → S t
) = 100%, we are therefore able to realistically quantify the sensitivity of the LHC to both the
t′
and
S
masses, assuming both current and foreseen luminosities. This approach paves the way for the LHC experiments to surpass current VLQ search strategies based solely on
t′
decays into SM bosons (
W
±
, Z
,
h
).
This study arose from the need to relate specific terroir aspects with experienced sensory properties of Gewürztraminer wines from Tramin (northern Italy). A multidisciplinary approach was used to ...investigate seven vineyards’ ecological characteristics, including geology and geographical features. A geopedological method using Vineyard Geological Identity (VGI) and Solar Radiation Identity (SRI) for topoclimatic classification, as well as multi-parameter measuring stations of air and soils, elicited analytical data for qualitative and quantitative terroir characterisations. Furthermore, wide-ranging and targeted oenological and chemical analyses were conducted on grapes, musts and wines to correlate their biochemical compositions with the measured terroir conditions. The study identified strong connections between vineyard geo-identity and wine mineral fingerprint, confirming mineral traceability of Rb/Sr ratio and of some minerals common to the local geology, such as Ba, Rb, Mn and Be. In particular, the most differing geo-mineral and physical soil conditions of two studied vineyards are apparent in the oenological components, flavours and aromas of their musts and finished wines. Amino acids, primary varietal aromas and polyphenols, thiol compounds with tropical scents, phenolic compounds with spicy notes and terpenic compounds, such as geraniol and citronellol, were related differently between fine-textured, more siliceous soils of glacial origin and coarser-textured, more dolomitic soils of local debris flow origin.
Abstract In this study we compared retrospectively the autopsy and the CT-scan findings in 47 gunshot victims (96 wounds) in order to assess the accuracy of the two methods in injury and ballistic ...diagnoses. Firing distance was determined in 46 wounds (47.9%). Firing range was determined by autopsy alone in 37 cases (80.5%) and by CT-scan alone in three cases (6.5%). In the six remaining cases (13%), autopsy and CT-scan reports concluded both to the same firing range. Entrance wounds were detected concordantly by both CT-scan and autopsy in 63 of the 91 penetrating wounds (69.2%). Exit wounds were present in 69 shots. They were concordantly detected by autopsy and CT-scan in 36 cases (52.2%). It was possible at CT imaging to determine the track of the bullet in up to 62 wounds (72.1%). CT-scan was superior to autopsy in determining two items: face fractures and pneumencephalon. CT scan was of limited value in demonstrating skull base fractures and contusions of the brain. There was good correspondence in demonstrating subarachnoid hemorrhage. CT-scan was accurate to demonstrate presence of gas, either in the pleural cavity (pneumothorax) or in the vessels’ lumen (air embolism). Both autopsy and CT-scan were concordant in demonstrating thoracic well injuries, heart lacerations and intra thoracic hemorrhage. CT-scan was far below autopsy in detecting solid organs injuries except for kidneys. The present survey shows that CT-scan is second to none in demonstrating features as pneumencephalon, facial fractures, midline shifts, air embolism, pneumothorax, and pelvic bones fractures. It may contribute to determine the firing range in cases of contact-range and of intermediate range though the firing range assessment remains beyond post-mortem imaging possibilities, at least at the current state of knowledge.
Abstract Aims Aim of the paper was to summarize the literature about the effect of dietary lipids on activity of paraoxonase-1 (PON1), a multifunctional enzyme associated with high density ...lipoprotein (HDL). PON1 exerts a protective effect against oxidative damage of cells and lipoproteins and modulates the susceptibility of HDL and LDL to atherogenic modifications such as homocysteinylation. Data synthesis The present review shows evidence that the amount and the composition of dietary lipids are key factors in the modulation of PON1. The effect of dietary lipids is also modulated by PON1 polymorphisms. The molecular mechanisms involved include an effect on PON1 hepatic synthesis or secretion and/or modification of PON1 interactions with HDL. Changes of PON1 activity could also be related to dietary intake of oxidized lipids that behave as PON1 inhibitors. Conclusion Dietary fatty acids by the modulation of PON1 gene expression and activity could constitute an useful approach for the prevention of human diseases associated with oxidative damage.
While microgravity exposure is known to cause deterioration of skeletal muscle performance, little is known regarding its effect on tendon structure and function. Hence, the aims of this study were ...to investigate the effects of simulated microgravity on the mechanical properties of human tendon and to assess the effectiveness of resistive countermeasures in preventing any detrimental effects. Eighteen men (aged 25-45 yr) underwent 90 days of bed rest: nine performed resistive exercise during this period (BREx group), and nine underwent bed rest only (BR group). Calf-raise and leg-press exercises were performed every third day using a gravity-independent flywheel device. Isometric plantar flexion contractions were performed by using a custom-built dynamometer, and ultrasound imaging was used to determine the tensile deformation of the gastrocnemius tendon during contraction. In the BR group, tendon stiffness estimated from the gradient of the tendon force-deformation relation decreased by 58% (preintervention: 124 +/- 67 N/mm; postintervention: 52 +/- 28 N/mm; P < 0.01), and the tendon Young's modulus decreased by 57% postintervention (P < 0.01). In the BREx group, tendon stiffness decreased by 37% (preintervention: 136 +/- 66 N/mm; postintervention: 86 +/- 47 N/mm; P < 0.01), and the tendon Young's modulus decreased by 38% postintervention (P < 0.01). The relative decline in tendon stiffness and Young's modulus was significantly (P < 0.01) greater in the BR group compared with the BREx group. Unloading decreased gastrocnemius tendon stiffness due to a change in tendon material properties, and, although the exercise countermeasures did attenuate these effects, they did not completely prevent them. It is suggested that the total loading volume was not sufficient to completely prevent alterations in tendon mechanical properties.
•Tile-drains complicate flow pattern and enhance ground/surface waters interplay.•To include tile-drains a complex and time-demanding set of numerical models is needed.•Numerical models allowed to ...assess capabilities/limitations of monitoring techniques.
Shallow lenses in reclaimed coastal areas are precious sources of freshwater for crop development, but their seasonal behaviour is seldom known in tile-drained fields. In this study, field monitoring and numerical modelling provide a robust conceptual model of these complex environments. Crop and meteorological data are used to implement an unsaturated flow model to reconstruct daily recharge. Groundwater fluxes and salinity, water table elevation, tile-drains’ discharge and salinity are used to calibrate a 2D density-dependent numerical model to quantify non-reactive solute transport within the aquifer–aquitard system. Results suggest that lateral fluxes in low hydraulic conductivity sediments are limited, while water table fluctuation is significant. The use of depth-integrated monitoring to calibrate the model results in poor efficiency, while multi-level soil profiles are crucial to define the mixing zone between fresh and brackish groundwater. Measured fluxes and chloride concentrations from tile-drains not fully compare with calculated ones due to preferential flow through cracks.
Abstract Purpose This study aimed at evaluating the computed tomography (CT) characteristics of resolving localized ground-glass opacities (GGOs) in a screening programme for lung cancer. Material ...and methods 280 patients at high-risk for lung cancer (221 men, 59 women; mean age, 58.6 years), divided into four groups (lung cancer history ( n = 83), head and neck cancer history ( n = 63), symptomatic ( n = 88) and asymptomatic ( n = 46) cigarette smokers), were included in a prospective trial with annual low-dose CT for lung cancer screening. We retrospectively reviewed all localized GGOs, analyzed the CT characteristics on initial CT scans and changes during follow-up (median 29.1 months). Variables associated with resolution of GGOs were tested using chi-square or Mann–Whitney tests. Results A total of 75 GGOs were detected in 37 patients; 54.7% were present at baseline and 45.3% appeared on annual CT. During follow-up, 56.2% persisted and 43.8% disappeared. The resolving localized GGOs were significantly more often lobular GGOs ( p = 0.006), polygonal in shape ( p = 0.02), mixed ( p = 0.003) and larger ( p < 0.0001) than non-resolving localized GGOs. Conclusion Localized GGOs are frequent and many disappeared on follow-up. CT characteristics of resolving GGOs show significant differences compared to persistent ones. This study emphasizes the importance of short-term CT follow-up in subjects with localized GGOs.
This paper describes the seismological analyses performed within the framework of the seismic microzonation study for the reconstruction of 138 municipalities damaged by the 2016–2017 sequence in ...Central Italy. Many waveforms were recorded over approximately 15 years at approximately 180 instrumented sites equipped with permanent or temporary stations in an area that includes all the damaged localities. Site response was assessed using earthquake and noise recordings at the selected stations through different parameters, such as spectral amplification curves, fundamental resonance frequencies, site-specific response spectra, and average amplification factors. The present study was a collaboration of many different institutions under the coordination of the Italian
Center for Seismic Microzonation and its applications
. The results were homogenized and gathered into site-specific forms, which represent the main deliverable for the benefit of Italian Civil Protection. It is remarkable that the bulk of this study was performed in a very short period (approximately 2 months) to provide quantitative information for detailed microzonation and future reconstruction of the damaged municipalities.
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