Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated ...a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed.
Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8–1.1Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point.
A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P<0.001) and PFS, by univariate (P<0.001) and multivariate analysis (P<0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18months) while the median PFS for TMBlow was 2months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point.
TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.
Legionella pneumophila is the most common cause of the severe respiratory infection known as Legionnaires' disease. However, the microorganism is typically a symbiont of free-living amoeba, and our ...understanding of the bacterial factors that determine human pathogenicity is limited. Here we carried out a population genomic study of 902 L. pneumophila isolates from human clinical and environmental samples to examine their genetic diversity, global distribution and the basis for human pathogenicity. We find that the capacity for human disease is representative of the breadth of species diversity although some clones are more commonly associated with clinical infections. We identified a single gene (lag-1) to be most strongly associated with clinical isolates. lag-1, which encodes an O-acetyltransferase for lipopolysaccharide modification, has been distributed horizontally across all major phylogenetic clades of L. pneumophila by frequent recent recombination events. The gene confers resistance to complement-mediated killing in human serum by inhibiting deposition of classical pathway molecules on the bacterial surface. Furthermore, acquisition of lag-1 inhibits complement-dependent phagocytosis by human neutrophils, and promoted survival in a mouse model of pulmonary legionellosis. Thus, our results reveal L. pneumophila genetic traits linked to disease and provide a molecular basis for resistance to complement-mediated killing.
The Twentieth Century Reanalysis Project Compo, G. P.; Whitaker, J. S.; Sardeshmukh, P. D. ...
Quarterly journal of the Royal Meteorological Society,
January 2011 Part A, 2011, 2011-01-00, 20110101, 2011-01-01, Letnik:
137, Številka:
654
Journal Article
A series of cryogenic, layered deuterium-tritium (DT) implosions have produced, for the first time, fusion energy output twice the peak kinetic energy of the imploding shell. These experiments at the ...National Ignition Facility utilized high density carbon ablators with a three-shock laser pulse (1.5 MJ in 7.5 ns) to irradiate low gas-filled (0.3 mg/cc of helium) bare depleted uranium hohlraums, resulting in a peak hohlraum radiative temperature ∼290 eV. The imploding shell, composed of the nonablated high density carbon and the DT cryogenic layer, is, thus, driven to velocity on the order of 380 km/s resulting in a peak kinetic energy of ∼21 kJ, which once stagnated produced a total DT neutron yield of 1.9×10^{16} (shot N170827) corresponding to an output fusion energy of 54 kJ. Time dependent low mode asymmetries that limited further progress of implosions have now been controlled, leading to an increased compression of the hot spot. It resulted in hot spot areal density (ρr∼0.3 g/cm^{2}) and stagnation pressure (∼360 Gbar) never before achieved in a laboratory experiment.
Plasma Collision in a Gas Atmosphere Le Pape, S; Divol, L; Huser, G ...
Physical review letters,
2020-Jan-17, Letnik:
124, Številka:
2
Journal Article
Recenzirano
Odprti dostop
We present a study on the impact of a gas atmosphere on the collision of two counterpropagating plasmas (gold and carbon). Imaging optical Thomson scattering data of the plasma collision with and ...without helium in between have been obtained at the Omega laser facility. Without gas, we observed large scale mixing of colliding gold and carbon ions. Once ambient helium is added, the two plasmas remain separated. The difference in ionic temperature is consistent with a reduction of the maximum Mach number of the flow from M=7 to M=4. It results in a reduction of a factor ∼10 of the counterstreaming ion-ion mean free path. By adding a low-density ambient gas, it is possible to control the collision of two high-velocity counterstreaming plasma, transitioning from an interpenetrating regime to a regime in agreement with a hydrodynamic description.
The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease (HD), prior to the point of ...traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis.
We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor.
Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies.
These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.
ABSTRACT We present and analyse a new tidal disruption event (TDE), AT2017eqx at redshift z = 0.1089, discovered by Pan-STARRS and ATLAS. The position of the transient is consistent with the nucleus ...of its host galaxy; the spectrum shows a persistent blackbody temperature T ≳ 20 000 K with broad H i and He ii emission; and it peaks at a blackbody luminosity of L ≈ 1044 erg s−1. The lines are initially centred at zero velocity, but by 100 d, the H i lines disappear while the He ii develops a blueshift of ≳ 5000 km s−1. Both the early- and late-time morphologies have been seen in other TDEs, but the complete transition between them is unprecedented. The evolution can be explained by combining an extended atmosphere, undergoing slow contraction, with a wind in the polar direction becoming visible at late times. Our observations confirm that a lack of hydrogen a TDE spectrum does not indicate a stripped star, while the proposed model implies that much of the diversity in TDEs may be due to the observer viewing angle. Modelling the light curve suggests AT2017eqx resulted from the complete disruption of a solar-mass star by a black hole of ∼106.3 M⊙. The host is another Balmer-strong absorption galaxy, though fainter and less centrally concentrated than most TDE hosts. Radio limits rule out a relativistic jet, while X-ray limits at 500 d are among the deepest for a TDE at this phase.
The spin of Cygnus X-1 is measured by fitting reflection models to Suzaku data covering the energy band 0.9-400 keV. The inner radius of the accretion disc is found to lie within 2 gravitational ...radii (r
g=GM/c
2), and a value of
is obtained for the dimensionless black hole spin. This agrees with recent measurements using the continuum fitting method by Gou et al. and of the broad iron line by Duro et al. The disc inclination is measured at
, which is consistent with the recent optical measurement of the binary system inclination by Orosz et al. of 27°± 0°.8. We pay special attention to the emissivity profile caused by irradiation of the inner disc by the hard power-law source. The X-ray observations and simulations show that the index q of that profile deviates from the commonly used, Newtonian, value of 3 within 3r
g, steepening considerably within 2r
g, as expected in the strong gravity regime.
Immersive technologies, like virtual and mixed reality, pose a novel challenge for our sensorimotor systems as they deliver simulated sensory inputs that may not match those of the natural ...environment. These include reduced fields of view, missing or inaccurate haptic information, and distortions of 3D space; differences that may impact the control of motor actions. For instance, reach-to-grasp movements without end-point haptic feedback are characterised by slower and more exaggerated movements. A general uncertainty about sensory input may also induce a more conscious form of movement control. We tested whether a more complex skill like golf putting was also characterized by more consciously controlled movement. In a repeated-measures design, kinematics of the putter swing and postural control were compared between (i) real-world putting, (ii) VR putting, and (iii) VR putting with haptic feedback from a real ball (i.e., mixed reality). Differences in putter swing were observed both between the real world and VR, and between VR conditions with and without haptic information. Further, clear differences in postural control emerged between real and virtual putting, with both VR conditions characterised by larger postural movements, which were more regular and less complex, suggesting a more conscious form of balance control. Conversely, participants actually reported less conscious awareness of their movements in VR. These findings highlight how fundamental movement differences may exist between virtual and natural environments, which may pose challenges for transfer of learning within applications to motor rehabilitation and sport.
HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the ...brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults.
The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease.
The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches.
The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.
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