Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients.

BACKGROUND: The development of targeted agents, such as osimertinib for EGFR-mutated non-small-cell lung cancer (NSCLC), has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinib-resistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whether those alterations and the activating EGFR mutations occur within a single cancer cell or in distinct cell populations is largely debated. PATIENTS AND METHODS: Tumor sequencing was used to identify the acquired resistance mechanisms to osimertinib in the MATCH-R trial (NCT0251782). We implemented single-cell next-generation sequencing to investigate tumor heterogeneity on patient's frozen tissues in which multiple alterations have been identified. Patient-derived models, cell lines, and patient-derived xenografts were exposed to specific inhibitors to investigate combination treatment strategies. RESULTS: Among the 45 patients included in MATCH-R who progressed on osimertinib, 9 developed a second targetable alteration (n = 2 FGFR3-TACC3, n = 1 KIF5B-RET, n = 1 STRN-ALK fusions; n = 2 BRAFV600E, n = 1 KRASG12V, n = 1 KRASG12R, n = 1 KRASG12D mutations). Single-cell analysis revealed that the two driver alterations coexist within one single cancer cell in the four patients whose frozen samples were fully contributive. A high degree of heterogeneity within samples and sequential acquisitions of molecular events were highlighted. A combination treatment concomitantly targeting the two driver alterations was required on the corresponding patient-derived models to restore cell sensitivity, which was consistent with clinical data showing efficacy of brigatinib in the patient with ALK fusion after progression to osimertinib and crizotinib administered sequentially. CONCLUSIONS: Distinct molecular driver alterations at osimertinib resistance coexist with initial EGFR mutations in single cancer cells. The clonal evolution of cancer cell populations emphasized their heterogeneity leading to osimertinib relapse. Combining two targeted treatments is effective to achieve clinical benefit.

Multiple modal and wavelength conversion process of a 10-Gbit/s signal in a 6-LP-mode fiber.

We demonstrate experimentally a simultaneous threefold modal and wavelength conversion process of a 10-Gbit/s On/Off keying signal in a 1.8-km long graded-index 6-LP-mode fiber. The principle of operation is based on a phase-matched inter-modal four-wave mixing phenomenon occurring between the fundamental mode and 3 higher-order modes of the fiber. The converted signals show well-opened eye-diagrams and error-free processing.

Reliability of hemostasis biomarkers is affected by time-dependent intra-patient variability.

Essentials Nucleosomes and free DNA are two newly described biomarkers in venous thromboembolism (VTE). Reliability of nucleosomes, plasma free DNA and conventional hemostasis markers were studied. Hemostasis biological parameters vary over a short time-frame in VTE patients. Hemostasis biological parameters also vary over a short time-frame in healthy controls. SUMMARY: Background Previous studies have associated neutrophil-derived circulating nucleosomes and plasma free DNA with venous thromboembolism (VTE). However, there are few data concerning these two biomarkers and no studies have compared the reliability of nucleosomes and plasma free DNA against that of conventional hemostasis markers. Objectives We performed a 3-year prospective study of nucleosomes and plasma free DNA levels in comparison with conventional hemostatic biomarkers and blood cells. Patients/Methods Fifteen healthy controls and 22 randomly selected patients with a history of VTE were followed monthly for 6 months. The reliability of these markers was evaluated by the intraclass correlation coefficient (ICCs). Results and Conclusions In healthy controls and patients, we found a low reliability for nucleosomes and plasma free DNA, with ICCs at 0.538 (95% confidence interval [CI], 0.334-0.764) and 0.091 (95% CI, -0.026-0.328), respectively, in the healthy controls, and at 0.213 (95% CI, 0.042-0.463) and 0.161 (CI 95%, 0.008-0.398) in the patient group. For the conventional hemostasis biomarkers and for blood cells, reliability ranged from poor to good in the healthy volunteers and from poor to acceptable in the patient group. Our study shows for the first time that hemostasis biological parameters spontaneously vary over a short time-frame in VTE patients and, more surprisingly, in normal individuals. The clinical value of such intra-individual variations is currently unknown. This variability might mean reinterpreting diagnostic or prognostic models based on static evaluation of individuals. Studying the intrinsic value of individual patterns of markers' variability is warranted.

Coherent beam combining of a narrow-linewidth long-pulse Er3+-doped multicore fiber amplifier.

Active phase locking of a multicore erbium-doped fiber amplifier is demonstrated for 180 ns narrow-linewidth pulses at 1545 nm. A spatial light modulator is used at the input of the amplifier to control the optical phase of 7 beams injected in the hexagonally-arranged cores, ensuring efficient combining through a SPGD algorithm. At the output, combining is performed using a diffractive optical element. This experiment establishes multicore amplifiers as a promising way to scale the energy of Brillouin-limited pulsed amplifiers for LIDAR applications. We also present a simple lensless technique to measure phase shifts between pairs of adjacent channels that could be implemented in future active coherent combining systems.

Spectral division amplification of a 40 nm bandwidth in a multicore Yb doped fiber and femtosecond pulse synthesis with in-fiber delay line.

A compact multicore ytterbium doped fiber amplifier has been implemented according to the spectral division scheme. It was shown that it allows amplification of pulses with about 40 nm wide spectrum. Compensation of the different spectral bands delay through bending and twist of the multicore ribbon fiber followed by appropriate setting of their phase permitted the synthesis of pulses close to 100 fs duration.

Dual-wavelength synchronous ultrashort pulses from a mode-locked Yb-doped multicore fiber laser with spatially dispersed gain.

A laser based on a ribbon multicore ytterbium doped fiber where different cores amplified different spectral bands, has been mode-locked with a single saturable absorber mirror. Tunable dual wavelength synchronized picosecond pulses were obtained. Compensation of differential cavity roundtrip times was achieved in the fiber.

Spatially dispersive amplification in a 12-core fiber and femtosecond pulse synthesis by coherent spectral combining.

A compact scheme is demonstrated for amplification and synthesis of ultrashort pulses by fiber amplifiers. Femtosecond pulses are split in 12 different spectral bands which are amplified separately in the 12 cores of a multicore ytterbium doped fiber. Combining the amplifier outputs together with the intensity and phase management of the spectral bands lead to short pulse synthesis with adjustable pulse shape. The scheme gave an x 92 enhancement in amplified power before the onset of nonlinear effects by comparison with standard stretcher free amplification in a single core fiber.

Enhancement of a nano cavity lifetime by induced slow light and nonlinear dispersions.

We start from a 2D photonic crystal nanocavity with moderate Q-factor and dynamically increase it by two order of magnitude by the joint action of coherent population oscillations and nonlinear refractive index.

Nanocavity linewidth narrowing and group delay enhancement by slow light propagation and nonlinear effects.

Slow light induced by coherent population oscillations and cavity dispersive nonlinear response are combined achieving 2 orders of magnitude enhancement of the group delay and an equivalent decreasing of the spectral linewidth of a L3 two-dimensional photonic crystal nanocavity.

Transient radiation-induced effects on solid core microstructured optical fibers.

We report transient radiation-induced effects on solid core microstructured optical fibers (MOFs). The kinetics and levels of radiation-induced attenuation (RIA) in the visible and near-infrared part of the spectrum (600 nm-2000 nm) were characterized. It is found that the two tested MOFs, fabricated by the stack-and-draw technique, present a good radiation tolerance. Both have similar geometry but one has been made with pure-silica tubes and the other one with Fluorine-doped silica tubes. We compared their pulsed X-ray radiation sensitivities to those of different classes of conventional optical fibers with pure-silica-cores or cores doped with Phosphorus or Germanium. The pulsed radiation sensitivity of MOFs seems to be mainly governed by the glass composition whereas their particular structure does not contribute significantly. Similarly for doped silica fibers, the measured spectral dependence of RIA for the MOFs cannot be correctly reproduced with the various absorption bands associated with the Si-related defects identified in the literature. However, our analysis confirms the preponderant role of self-trapped holes with their visible and infrared absorption bands in the transient behaviors of pure-silica of F-doped fibers. The results of this study showed that pure-silica or fluorine-doped MOFs, which offers specific advantages compared to conventional fibers, are promising for use in harsh environments due to their radiation tolerance.

Linear and nonlinear optical properties of gold nanoparticle-doped photonic crystal fiber.

We report on the production of air/silica photonic crystal fiber doped with gold nanoparticles. The stack-and-draw technique was used to combine a gold nanoparticles-doped silica core rod synthesized by the sol-gel route with capillaries drawn from commercially available silica tubes. The presence of nanoparticles in the core region was confirmed at the different steps of the process down to the fiber geometry, even after multiple drawings at ~2000 °C. Optical properties of the fiber were investigated and put in evidence the impact of gold nanoparticles on both linear and nonlinear transmission.

Optical properties of Bismuth-doped silica core photonic crystal fiber.

Optical properties of a Bismuth-doped pure silica sol-gel core photonic crystal fiber (PCF) were investigated. We report on the absorption, CW luminescence and time resolved luminescence spectra at different excitation wavelengths at room temperature. Complex structure of the energy levels of Bismuth-connected centers in pure silica glass is put in evidence.

White-light cw-pumped supercontinuum generation in highly GeO(2)-doped-core photonic crystal fibers.

GeO(2)-doped-core photonic crystal fibers show greatly enhanced Kerr and Raman responses with respect to pure silica without any significant modification of the group-velocity dispersion curve. We show that such fibers allow a significant improvement of cw-pumped supercontinuum generation. We report for the first time to our knowledge the generation of a white-light cw-pumped supercontinuum spanning from 470 nm to more than 1750 nm.

Optically detected magnetic resonance in bismuth-doped silica glass.

We report on the observation of optically detected magnetic resonance (ODMR) in bismuth-doped silica glass. To explain the results of the experiment we adopted the intramolecular charge transfer model for Bi(5+)O(n)(2-) molecules in the frame of a semiempirical molecular orbitals approach. The results of our calculations are in good agreement with observed features of luminescence and ODMR experiments.

Solid photonic bandgap fiber assisted by an extra air-clad structure for low-loss operation around 1.5 microm.

We demonstrate that our previous loss results [1] in an all-solid photonic bandgap fiber were in fact limited by bend loss. A new design, based on the addition of an extra ring of air holes on the outside of the all solid photonic bandgap structure, is then proposed, realized and characterized. We demonstrate that it significantly reduces both the fiber diameter and its sensitivity to bend loss.

Narrow-line, 1178nm CW bismuth-doped fiber laser with 6.4W output for direct frequency doubling.

We achieved a 0.2nm linewidth output at 1178nm with powers up to 6.4W in a linear 80m Bismuth-doped fiber cavity pumped by a 55W Yb fibre laser. The potential of frequency doubling of the non-polarized output at 1178nm in MgO doped periodically poled lithium niobate was demonstrated and resulted in 125mW average power at 589nm. The approach can be extended to a linearly-polarized large mode area format with under 0.1nm linewidth capable of scaling to Watts level in the 560-620nm range.

Exceptionally narrow homogeneous linewidth in erbium-doped glasses.

We show that rare-earth (RE-) doped glasses can have homogeneous linewidths as narrow as 287 kHz at (4)He temperatures. This is far narrower than others reported in glasses in the same temperature range and is suitable for precise spectral hole burning and spatial-spectral holographic applications. It is known that cw spectral hole burning linewidth measurements of RE ions in glasses are hindered by the presence of spectral diffusion but, even in glasses, application of a magnetic field can freeze out RE spin-spin interactions responsible for spectral diffusion and isolate the remaining contribution of two-level systems (TLSs). The Er(3+):2G2S glasses have unusually low TLS contributions, making it possible to study the real homogeneous linewidth using photon echo measurements. The contribution from TLSs is only 170 T(1.3) kHz when subjected to a field of 5 T.

Efficient Bragg gratings in phosphosilicate and germanosilicate photonic crystal fiber.

We present ArF laser-induced dynamics of Bragg grating (BG) growths in phosphosilicate-doped or germanosilicate-doped core photonic crystal fibers (PCFs). To this end, we have adapted the technique of H2 loading, usually used in conventional fiber, to the case of microstructured fiber, allowing both the concentration of hydrogen in the PCFs to be kept nearly constant for the time of the exposure and the BG spectra to be easily recorded. We compared the characteristics of BG growths in the two types of PCF to those in conventional step-index fibers. We then conducted a study of the thermal stability of the BGs in PCFs through 30 min of isochronal annealing. At the same time we discuss the role played by the microstructuration and the doping with regard to the grating contrast and the Bragg wavelength stability.

Fabrication and characterization of an all-solid 2D photonic bandgap fiber with a low-loss region (< 20 dB/km) around 1550 nm.

The fabrication and characterization of an all-solid photonic bandgap fiber is reported. The fiber presents a low-loss region (< 20 dB/km) around 1550 nm and can be used as single-mode even for a fiber core diameter as large as 20 microm. The fiber presents a zero dispersion at the short wavelength edge of the bandgap. The measured polarisation mode dispersion is wavelength dependent but remains small (few ps/km1/2). This fiber opens the possibility to realize low-loss large mode area bandgap fiber with a doped core and or Bragg gratings.

First determination of arthropod assemblages associated with Erica arborea L. and Erica scoparia L.

This study gathers the first data concerning the arthropod assemblages associated with Erica arborea L. and E. scoparia L. It demonstrates that it is necessary to sample at least ten Erica scoparia L. to give a representative image of its arthropod assemblage. This study reveals that neither plant size nor architecture nor floristic environment can explain the different patterns of colonisation of both species of Erica by the arthropod assemblages. If our attention is focused on the three main species collected on both species of Erica, it appears that the nearly exclusive presence of Sitona lineatus L. on E. arborea L. might be correlated with highly different concentrations in tannins between the two species of Erica. In contrast, the different patterns of colonisation and the number of individuals of Colaspidea oblonga Blanchard collected on both species of Erica might be linked to the life-history of this Chrysomelideae. Finally, the presence of Psallus crotchi Scott to the same extent on both Erica species can be connected to the destruction of its natural host-plant and to the similar concentrations of nitrogen, a limiting factor for sap-sucker's colonisation, in both Erica species.