Improved human observer performance in digital reconstructed radiograph verification in head and neck cancer radiotherapy.

Purpose: Digitally reconstructed radiographs (DRRs) are routinely used as an a priori reference for setup correction in radiotherapy. The spatial resolution of DRRs may be improved to reduce setup error in fractionated radiotherapy treatment protocols. The influence of finer CT slice thickness reconstruction (STR) and resultant increased resolution DRRs on physician setup accuracy was prospectively evaluated. Methods: Four head and neck patient CT-simulation images were acquired and used to create DRR cohorts by varying STRs at 0.5, 1, 2, 2.5, and 3 mm. DRRs were displaced relative to a fixed isocenter using 0–5 mm random shifts in the three cardinal axes. Physician observers reviewed DRRs of varying STRs and displacements and then aligned reference and test DRRs replicating daily KV imaging workflow. A total of 1,064 images were reviewed by four blinded physicians. Observer errors were analyzed using nonparametric statistics (Friedman’s test) to determine whether STR cohorts had detectably different displacement profiles. Post hoc bootstrap resampling was applied to evaluate potential generalizability. Results: The observer-based trial revealed a statistically significant difference between cohort means for observer displacement vector error (p = 0.02) and for Z-axis (p < 0.01). Bootstrap analysis suggests a 15% gain in isocenter translational setup error with reduction of STR from 3 mm to ≤2 mm, though interobserver variance was a larger feature than STR-associated measurement variance. Conclusions: Higher resolution DRRs generated using finer CT scan STR resulted in improved observer performance at shift detection and could decrease operator-dependent geometric error. Ideally, CT STRs ≤2 mm should be utilized for DRR generation in the head and break neck

Weight management for individuals with intellectual and developmental disabilities: Rationale and design for an 18 month randomized trial

Weight management for individuals with intellectual and developmental disabilities (IDD) has received limited attention. Studies on weight management in this population have been conducted over short time frames, in small samples with inadequate statistical power, infrequently used a randomized design, and have not evaluated the use of emerging effective dietary strategies such as pre-packaged meals (PMs). Low energy/fat PMs may be useful in individuals with IDD as they simplify meal planning, limit undesirable food choices, teach appropriate portion sizes, are convenient and easy to prepare, and when combined with fruits and vegetables provide a high volume, low energy dense meal. A randomized effectiveness trial will be conducted in 150 overweight/obese adults with mild to moderate IDD, and their study partners to compare weight loss (6 months) and weight maintenance (12 months) between 2 weight management approaches: 1. A Stop Light Diet enhanced with reduced energy/fat PMs (eSLD); and 2. A recommended care reduced energy/fat meal plan diet (RC). The primary aim is to compare weight loss (0–6 months) and weight maintenance (7–18 months) between the eSLD and RC diets. Secondarily, changes in chronic disease risk factors between the eSLD and RC diets including blood pressure, glucose, insulin, LDL-cholesterol, and HDL-cholesterol will be compared during both weight loss and weight maintenance. Finally, potential mediators of weight loss including energy intake, physical activity, data recording, adherence to the diet, study partner self-efficacy and daily stress related to dietary change will be explored

Giant Outer Transiting Exoplanet Mass (GOT 'EM) Survey. IV. Long-term Doppler Spectroscopy for 11 Stars Thought to Host Cool Giant Exoplanets

Discovering and characterizing exoplanets at the outer edge of the transit method's sensitivity has proven challenging owing to geometric biases and the practical difficulties associated with acquiring long observational baselines. Nonetheless, a sample of giant exoplanets on orbits longer than 100 days has been identified by transit hunting missions. We present long-term Doppler spectroscopy for 11 such systems with observation baselines spanning a few years to a decade. We model these radial velocity observations jointly with transit photometry to provide initial characterizations of these objects and the systems in which they exist. Specifically, we make new precise mass measurements for four long-period giant exoplanets (Kepler-111 c, Kepler-553 c, Kepler-849 b, and PH-2 b), we place new upper limits on mass for four others (Kepler-421 b, KOI-1431.01, Kepler-1513 b, and Kepler-952 b), and we show that several "confirmed" planets are in fact not planetary at all. We present these findings to complement similar efforts focused on closer-in short-period giant planets, and with the hope of inspiring future dedicated studies of cool giant exoplanets.Comment: 35 pages, 24 figures, 11 tables. Accepted for publication in ApJ Supplemen

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions

The TESS-Keck Survey: Science Goals and Target Selection

Space-based transit missions such as Kepler and TESS have demonstrated that planets are ubiquitous. However, the success of these missions heavily depends on ground-based radial velocity (RV) surveys, which combined with transit photometry can yield bulk densities and orbital properties. While most Kepler host stars are too faint for detailed follow-up observations, TESS is detecting planets orbiting nearby bright stars that are more amenable to RV characterization. Here we introduce the TESS-Keck Survey (TKS), an RV program using ~100 nights on Keck/HIRES to study exoplanets identified by TESS. The primary survey aims are investigating the link between stellar properties and the compositions of small planets; studying how the diversity of system architectures depends on dynamical configurations or planet multiplicity; identifying prime candidates for atmospheric studies with JWST; and understanding the role of stellar evolution in shaping planetary systems. We present a fully-automated target selection algorithm, which yielded 103 planets in 86 systems for the final TKS sample. Most TKS hosts are inactive, solar-like, main-sequence stars (4500 K < Teff < 6000 K) at a wide range of metallicities. The selected TKS sample contains 71 small planets (Rp < 4 Re), 11 systems with multiple transiting candidates, 6 sub-day period planets and 3 planets that are in or near the habitable zone of their host star. The target selection described here will facilitate the comparison of measured planet masses, densities, and eccentricities to predictions from planet population models. Our target selection software is publicly available (at https://github.com/ashleychontos/sort-a-survey) and can be adapted for any survey which requires a balance of multiple science interests within a given telescope allocation.Comment: 23 pages, 10 figures, 5 table

The TESS-Keck Survey XVII: Precise Mass Measurements in a Young, High Multiplicity Transiting Planet System using Radial Velocities and Transit Timing Variations

We present a radial velocity (RV) analysis of TOI-1136, a bright TESS system with six confirmed transiting planets, and a seventh single-transiting planet candidate. All planets in the system are amenable to transmission spectroscopy, making TOI-1136 one of the best targets for intra-system comparison of exoplanet atmospheres. TOI-1136 is young ($\sim$ 700 Myr), and the system exhibits transit timing variations (TTVs). The youth of the system contributes to high stellar variability on the order of 50 m s$^{-1}$, much larger than the likely RV amplitude of any of the transiting exoplanets. Utilizing 359 HIRES and APF RVs collected as a part of the TESS-Keck Survey (TKS), and 51 HARPS-N RVs, we experiment with a joint TTV-RV fit. With seven possible transiting planets, TTVs, more than 400 RVs, and a stellar activity model, we posit that we may be presenting the most complex mass recovery of an exoplanet system in the literature to date. By combining TTVs and RVs, we minimized GP overfitting and retrieved new masses for this system: (m$_{b-g}$ = 3.50$^{+0.8}_{-0.7}$, 6.32$^{+1.1}_{-1.3}$, 8.35$^{+1.8}_{-1.6}$, 6.07$^{+1.09}_{-1.01}$, 9.7$^{+3.9}_{-3.7}$, 5.6$^{+4.1}_{-3.2}$ M$_{\oplus}$). We are unable to significantly detect the mass of the seventh planet candidate in the RVs, but we are able to loosely constrain a possible orbital period near 80 days. Future TESS observations might confirm the existence of a seventh planet in the system, better constrain the masses and orbital properties of the known exoplanets, and generally shine light on this scientifically interesting system.Comment: Accepted for publication in the Astronomical Journa

The TESS-Keck Survey. XII. A Dense 1.8 R ⊕ Ultra-short-period Planet Possibly Clinging to a High-mean-molecular-weight Atmosphere after the First Gigayear

The extreme environments of ultra-short-period planets (USPs) make excellent laboratories to study how exoplanets obtain, lose, retain, and/or regain gaseous atmospheres. We present the confirmation and characterization of the USP TOI-1347 b, a 1.8±0.1 R⊕ planet on a 0.85 day orbit that was detected with photometry from the TESS mission. We measured radial velocities of the TOI-1347 system using Keck/HIRES and HARPS-N and found the USP to be unusually massive at 11.1±1.2 M⊕. The measured mass and radius of TOI-1347 b imply an Earth-like bulk composition. A thin H/He envelope (&gt;0.01% by mass) can be ruled out at high confidence. The system is between 1 and 1.8 Gyr old; therefore, intensive photoevaporation should have concluded. We detected a tentative phase curve variation (3σ) and a secondary eclipse (2σ) in TESS photometry, which if confirmed could indicate the presence of a high-mean-molecular-weight atmosphere. We recommend additional optical and infrared observations to confirm the presence of an atmosphere and investigate its composition

The TESS-Keck Survey. XXII. A Sub-Neptune Orbiting TOI-1437

Exoplanet discoveries have revealed a dramatic diversity of planet sizes across a vast array of orbital architectures. Sub-Neptunes are of particular interest; due to their absence in our own solar system, we rely on demographics of exoplanets to better understand their bulk composition and formation scenarios. Here, we present the discovery and characterization of TOI-1437 b, a sub-Neptune with a 18.84 day orbit around a near-solar analog (M⋆ = 1.10 ± 0.10 M☉, R⋆=1.17 ± 0.12 R☉). The planet was detected using photometric data from the Transiting Exoplanet Survey Satellite (TESS) mission and radial velocity (RV) follow-up observations were carried out as a part of the TESS-Keck Survey using both the HIRES instrument at Keck Observatory and the Levy Spectrograph on the Automated Planet Finder telescope. A combined analysis of these data reveal a planet radius of Rp = 2.24 ± 0.23 R⊕ and a mass measurement of Mp = 9.6 ± 3.9 M⊕). TOI-1437 b is one of few (∼50) known transiting sub-Neptunes orbiting a solar-mass star that has a RV mass measurement. As the formation pathway of these worlds remains an unanswered question, the precise mass characterization of TOI-1437 b may provide further insight into this class of planet

Physical Parameters of the Multiplanet Systems HD 106315 and GJ 9827

HD 106315 and GJ 9827 are two bright, nearby stars that host multiple super-Earths and sub-Neptunes discovered by K2 that are well suited for atmospheric characterization. We refined the planets' ephemerides through Spitzer transits, enabling accurate transit prediction required for future atmospheric characterization through transmission spectroscopy. Through a multiyear high-cadence observing campaign with Keck/High Resolution Echelle Spectrometer and Magellan/Planet Finder Spectrograph, we improved the planets' mass measurements in anticipation of Hubble Space Telescope transmission spectroscopy. For GJ 9827, we modeled activity-induced radial velocity signals with a Gaussian process informed by the Calcium II H&K lines in order to more accurately model the effect of stellar noise on our data. We measured planet masses of M_b = 4.87 ± 0.37 M_⊕, M_c = 1.92 ± 0.49 M_⊕, and M_d = 3.42 ± 0.62 M_⊕. For HD 106315, we found that such activity radial velocity decorrelation was not effective due to the reduced presence of spots and speculate that this may extend to other hot stars as well (T_(eff) > 6200 K). We measured planet masses of M_b = 10.5 ± 3.1 M_⊕ and M_c = 12.0 ± 3.8 M_⊕. We investigated all of the planets' compositions through comparison of their masses and radii to a range of interior models. GJ 9827 b and GJ 9827 c are both consistent with a 50/50 rock-iron composition, GJ 9827 d and HD 106315 b both require additional volatiles and are consistent with moderate amounts of water or hydrogen/helium, and HD 106315 c is consistent with a ~10% hydrogen/helium envelope surrounding an Earth-like rock and iron core