Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1.

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses

Solar Contamination in Extreme-precision Radial-velocity Measurements: Deleterious Effects and Prospects for Mitigation

Solar contamination, due to moonlight and atmospheric scattering of sunlight, can cause systematic errors in stellar radial velocity (RV) measurements that significantly detract from the ~10 cm s−1 sensitivity required for the detection and characterization of terrestrial exoplanets in or near habitable zones of Sun-like stars. The addition of low-level spectral contamination at variable effective velocity offsets introduces systematic noise when measuring velocities using classical mask-based or template-based cross-correlation techniques. Here we present simulations estimating the range of RV measurement error induced by uncorrected scattered sunlight contamination. We explore potential correction techniques, using both simultaneous spectrometer sky fibers and broadband imaging via coherent fiber imaging bundles, that could reliably reduce this source of error to below the photon-noise limit of typical stellar observations. We discuss the limitations of these simulations, the underlying assumptions, and mitigation mechanisms. We also present and discuss the components designed and built into the NEID (NN-EXPLORE Exoplanet Investigations with Doppler spectroscopy) precision RV instrument for the WIYN 3.5 m telescope, to serve as an ongoing resource for the community to explore and evaluate correction techniques. We emphasize that while "bright time" has been traditionally adequate for RV science, the goal of 10 cm s−1 precision on the most interesting exoplanetary systems may necessitate access to darker skies for these next-generation instruments

The Epoch of Giant Planet Migration Planet Search Program. I. Near-Infrared Radial Velocity Jitter of Young Sun-like Stars

We present early results from the Epoch of Giant Planet Migration program, a precise RV survey of over one hundred intermediate-age ($\sim$20$-$200 Myr) G and K dwarfs with the Habitable-Zone Planet Finder spectrograph (HPF) at McDonald Observatory's Hobby-Eberly Telescope (HET). The goals of this program are to determine the timescale and dominant physical mechanism of giant planet migration interior to the water ice line of Sun-like stars. Here, we summarize results from the first 14 months of this program, with a focus on our custom RV pipeline for HPF, a measurement of the intrinsic near-infrared RV activity of young Solar analogs, and modeling the underlying population-level distribution of stellar jitter. We demonstrate on-sky stability at the sub-2 m s$^{-1}$ level for the K2 standard HD 3765 using a least-squares matching method to extract precise RVs. Based on a subsample of 29 stars with at least three RV measurements from our program, we find a median RMS level of 34 m s$^{-1}$. This is nearly a factor of 2 lower than the median RMS level in the optical of 60 m s$^{-1}$ for a comparison sample with similar ages and spectral types as our targets. The observed near-infrared jitter measurements for this subsample are well reproduced with a log-normal parent distribution with $\mu=4.15$ and $\sigma=1.02$. Finally, by compiling RMS values from previous planet search programs, we show that near-infrared jitter for G and K dwarfs generally decays with age in a similar fashion to optical wavelengths, albeit with a shallower slope and lower overall values for ages $\lesssim$1 Gyr

Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast

Long-term operation of a laser frequency comb with the Habitable Zone Planet Finder

Laser frequency combs are an ideal calibration source for precision astronomical spectrographs. We report on the demonstrated long term operation of a laser frequency comb that we designed and built as the primary calibrator for the Habitable Zone Planet Finder (HPF). The core technology of the comb is based on robust, polarization maintaining fiber coupled electro-optic modulators and broadband supercontinuum generation spanning 700-1600 nm in an efficient silicon nitride waveguide. The comb is continuously maintained on and ready to use, and since May 2018 the laser frequency comb has had a total uptime of 97%

Constrained modelling of instrumental radial velocity drift in precision Radial Velocity Spectrometers: Application to HPF

For precise measurement of the radial velocity change in a star, the precision of the wavelength solution is 4 orders more important than accuracy of the wavelength solution. Since the absolute wavelength solution model of a multi-order echelle spectrographs require a large number of parameters, it is better to track the change in wavelength solution over time instead of refitting the complete wavelength solution without any constrains. For stabilized spectrographs like The Habitable-Zone Planet Finder (HPF) and NEID, these changes in wavelength solution are significantly low order and can be modeled with only a few parameters. Table 1, shows an example of low order changes to dispersion solution we expect from various physical mechanisms in HPF or NEID

Evidence for He I 10830 \AA~ absorption during the transit of a warm Neptune around the M-dwarf GJ 3470 with the Habitable-zone Planet Finder

Understanding the dynamics and kinematics of out-flowing atmospheres of hot and warm exoplanets is crucial to understanding the origins and evolutionary history of the exoplanets near the evaporation desert. Recently, ground based measurements of the meta-stable Helium atom's resonant absorption at 10830 \AA~has become a powerful probe of the base environment which is driving the outflow of exoplanet atmospheres. We report evidence for the He I 10830 \AA~in absorption (equivalent width $\sim$ $0.012 \pm 0.002$ \AA) in the exosphere of a warm Neptune orbiting the M-dwarf GJ 3470, during three transits using the Habitable Zone Planet Finder (HPF) near infrared spectrograph. This marks the first reported evidence for He I 10830 \AA\, atmospheric absorption for a planet orbiting an M-dwarf. Our detected absorption is broad and its blueshifted wing extends to -36 km/sec, the largest reported in the literature to date. We modelled the state of Helium atoms in the exosphere of GJ3470b based on assumptions on the UV and X-ray flux of GJ 3470, and found our measurement of flux-weighted column density of meta-stable state Helium $(N_{He^2_3S} = 2.4 \times 10^{10} \mathrm{cm^{-2}})$, derived from our transit observations, to be consistent with model, within its uncertainties. The methodology developed here will be useful to study and constrain the atmospheric outflow models of other exoplanets like GJ 3470b which are near the edge of the evaporation desert.Comment: Accepted in Ap