525 research outputs found
Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC
Background The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated. Objective We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value. Patients and Methods Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score >= 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors. Results Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively. Conclusions Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival
A data-driven methodology reveals novel myofiber clusters in older human muscles
Skeletal muscles control posture, mobility and strength, and influence whole-body metabolism. Muscles are built of different types of myofibers, each having specific metabolic, molecular, and contractile properties. Fiber classification is, therefore, regarded the key for understanding muscle biology, (patho-) physiology. The expression of three myosin heavy chain (MyHC) isoforms, MyHC-1, MyHC-2A, and MyHC-2X, marks myofibers in humans. Typically, myofiber classification is performed by an eye-based histological analysis. This classical approach is insufficient to capture complex fiber classes, expressing more than one MyHC-isoform. We, therefore, developed a methodological procedure for high-throughput characterization of myofibers on the basis of multiple isoforms. The mean fluorescence intensity of the three most abundant MyHC isoforms was measured per myofiber in muscle biopsies of 56 healthy elderly adults, and myofiber classes were identified using computational biology tools. Unsupervised clustering revealed the existence of six distinct myofiber clusters. A comparison with the visual assessment of myofibers using the same images showed that some of these myofiber clusters could not be detected or were frequently misclassified. The presence of these six clusters was reinforced by RNA expressions levels of sarcomeric genes. In addition, one of the clusters, expressing all three MyHC isoforms, correlated with histological measures of muscle health. To conclude, this methodological procedure enables deep characterization of the complex muscle heterogeneity. This study opens opportunities to further investigate myofiber composition in comparative studies.Development and application of statistical models for medical scientific researc
Reconstruction of the gravitational wave signal during the Virgo science runs and independent validation with a photon calibrator
The Virgo detector is a kilometer-scale interferometer for gravitational wave
detection located near Pisa (Italy). About 13 months of data were accumulated
during four science runs (VSR1, VSR2, VSR3 and VSR4) between May 2007 and
September 2011, with increasing sensitivity.
In this paper, the method used to reconstruct, in the range 10 Hz-10 kHz, the
gravitational wave strain time series from the detector signals is
described. The standard consistency checks of the reconstruction are discussed
and used to estimate the systematic uncertainties of the signal as a
function of frequency. Finally, an independent setup, the photon calibrator, is
described and used to validate the reconstructed signal and the
associated uncertainties.
The uncertainties of the time series are estimated to be 8% in
amplitude. The uncertainty of the phase of is 50 mrad at 10 Hz with a
frequency dependence following a delay of 8 s at high frequency. A bias
lower than and depending on the sky direction of the GW is
also present.Comment: 35 pages, 16 figures. Accepted by CQ
Coalescing Binary Neutron Stars
Coalescing compact binaries with neutron star or black hole components
provide the most promising sources of gravitational radiation for detection by
the LIGO/VIRGO/GEO/TAMA laser interferometers now under construction. This fact
has motivated several different theoretical studies of the inspiral and
hydrodynamic merging of compact binaries. Analytic analyses of the inspiral
waveforms have been performed in the Post-Newtonian approximation. Analytic and
numerical treatments of the coalescence waveforms from binary neutron stars
have been performed using Newtonian hydrodynamics and the quadrupole radiation
approximation. Numerical simulations of coalescing black hole and neutron star
binaries are also underway in full general relativity. Recent results from each
of these approaches will be described and their virtues and limitations
summarized.Comment: Invited Topical Review paper to appear in Classical and Quantum
Gravity, 35 pages, including 5 figure
Scientific Objectives of Einstein Telescope
The advanced interferometer network will herald a new era in observational
astronomy. There is a very strong science case to go beyond the advanced
detector network and build detectors that operate in a frequency range from 1
Hz-10 kHz, with sensitivity a factor ten better in amplitude. Such detectors
will be able to probe a range of topics in nuclear physics, astronomy,
cosmology and fundamental physics, providing insights into many unsolved
problems in these areas.Comment: 18 pages, 4 figures, Plenary talk given at Amaldi Meeting, July 201
Calibration and sensitivity of the Virgo detector during its second science run
The Virgo detector is a kilometer-length interferometer for gravitational
wave detection located near Pisa (Italy). During its second science run (VSR2)
in 2009, six months of data were accumulated with a sensitivity close to its
design. In this paper, the methods used to determine the parameters for
sensitivity estimation and gravitational wave reconstruction are described. The
main quantities to be calibrated are the frequency response of the mirror
actuation and the sensing of the output power. Focus is also put on their
absolute timing. The monitoring of the calibration data as well as the
parameter estimation with independent techniques are discussed to provide an
estimation of the calibration uncertainties. Finally, the estimation of the
Virgo sensitivity in the frequency-domain is described and typical
sensitivities measured during VSR2 are shown.Comment: 30 pages, 23 figures, 1 table. Published in Classical and Quantum
Gravity (CQG), Corrigendum include
Virgo calibration and reconstruction of the gravitational wave strain during VSR1
Virgo is a kilometer-length interferometer for gravitational waves detection
located near Pisa. Its first science run, VSR1, occured from May to October
2007. The aims of the calibration are to measure the detector sensitivity and
to reconstruct the time series of the gravitational wave strain h(t). The
absolute length calibration is based on an original non-linear reconstruction
of the differential arm length variations in free swinging Michelson
configurations. It uses the laser wavelength as length standard. This method is
used to calibrate the frequency dependent response of the Virgo mirror
actuators and derive the detector in-loop response and sensitivity within ~5%.
The principle of the strain reconstruction is highlighted and the h(t)
systematic errors are estimated. A photon calibrator is used to check the sign
of h(t). The reconstructed h(t) during VSR1 is valid from 10 Hz up to 10 kHz
with systematic errors estimated to 6% in amplitude. The phase error is
estimated to be 70 mrad below 1.9 kHz and 6 micro-seconds above.Comment: 8 pages, 8 figures, proceedings of Amaldi 8 conference, to be
published in Journal of Physics Conference Series (JPCS). Second release:
correct typo
A Cross-correlation method to search for gravitational wave bursts with AURIGA and Virgo
We present a method to search for transient GWs using a network of detectors
with different spectral and directional sensitivities: the interferometer Virgo
and the bar detector AURIGA. The data analysis method is based on the
measurements of the correlated energy in the network by means of a weighted
cross-correlation. To limit the computational load, this coherent analysis step
is performed around time-frequency coincident triggers selected by an excess
power event trigger generator tuned at low thresholds. The final selection of
GW candidates is performed by a combined cut on the correlated energy and on
the significance as measured by the event trigger generator. The method has
been tested on one day of data of AURIGA and Virgo during September 2005. The
outcomes are compared to the results of a stand-alone time-frequency
coincidence search. We discuss the advantages and the limits of this approach,
in view of a possible future joint search between AURIGA and one
interferometric detector.Comment: 11 pages, 6 figures, submitted to CQG special issue for Amaldi 7
Proceeding
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