Incorporating Cardiac Substructures Into Radiation Therapy For Improved Cardiac Sparing

Growing evidence suggests that radiation therapy (RT) doses to the heart and cardiac substructures (CS) are strongly linked to cardiac toxicities, though only the heart is considered clinically. This work aimed to utilize the superior soft-tissue contrast of magnetic resonance (MR) to segment CS, quantify uncertainties in their position, assess their effect on treatment planning and an MR-guided environment. Automatic substructure segmentation of 12 CS was completed using a novel hybrid MR/computed tomography (CT) atlas method and was improved upon using a 3-dimensional neural network (U-Net) from deep learning. Intra-fraction motion due to respiration was then quantified. The inter-fraction setup uncertainties utilizing a novel MR-linear accelerator were also quantified. Treatment planning comparisons were performed with and without substructure inclusions and methods to reduce radiation dose to sensitive CS were evaluated. Lastly, these described technologies (deep learning U-Net) were translated to an MR-linear accelerator and a segmentation pipeline was created. Automatic segmentations from the hybrid MR/CT atlas was able to generate accurate segmentations for the chambers and great vessels (Dice similarity coefficient (DSC) \u3e 0.75) but coronary artery segmentations were unsuccessful (DSC\u3c0.3). After implementing deep learning, DSC for the chambers and great vessels was ≥0.85 along with an improvement in the coronary arteries (DSC\u3e0.5). Similar accuracy was achieved when implementing deep learning for MR-guided RT. On average, automatic segmentations required ~10 minutes to generate per patient and deep learning only required 14 seconds. The inclusion of CS in the treatment planning process did not yield statistically significant changes in plan complexity, PTV, or OAR dose. Automatic segmentation results from deep learning pose major efficiency and accuracy gains for CS segmentation offering high potential for rapid implementation into radiation therapy planning for improved cardiac sparing. Introducing CS into RT planning for MR-guided RT presented an opportunity for more effective sparing with limited increase in plan complexity

Kinetic Characterization of Salmonella FliK-FlhB Interactions Demonstrates Complexity of the Type III Secretion Substrate-Specificity Switch

The bacterial flagellum is a complex macromolecular machine consisting of more than 20000 proteins, most of which must be exported from the cell via a dedicated Type III secretion apparatus. At a defined point in flagellar morphogenesis, hook completion is sensed and the apparatus switches substrate specificity type from rod and hook proteins to filament ones. How the switch works is a subject of intense interest. FIiK and F1hBs play central roles. In the present study, two optical biosensing methods were used to characterize FIiK-F1hB interactions using wild-type and two variant FlhBs from mutants with severe flagellar structural defects. Binding was found to be complex with fast and slow association and dissociation components. Surprisingly, wild-type and variant FlhBs had similar kinetic profiles and apparent affinities, which ranged between I and 10.5 μM, suggesting that the specificity switch is more complex than presently understood. Other binding experiments provided evidence for a conformational change after binding. Liquid chromatography-mass spectrometry (LC-MS) and NMR experiments were performed to identify a cyclic intermediate product whose existence supports the mechanism of autocatalytic cleavage at FlhB residue N269. The present results show that while autocatalytic cleavage is necessary for proper substrate specificity switching, it does not result in an altered interaction with FIiK. strongly suggesting the involvement of other proteins in the mechanism

Architecture of Kepler's Multi-transiting Systems: II. New investigations with twice as many candidates

We report on the orbital architectures of Kepler systems having multiple planet candidates identified in the analysis of data from the first six quarters of Kepler data and reported by Batalha et al. (2013). These data show 899 transiting planet candidates in 365 multiple-planet systems and provide a powerful means to study the statistical properties of planetary systems. Using a generic mass-radius relationship, we find that only two pairs of planets in these candidate systems (out of 761 pairs total) appear to be on Hill-unstable orbits, indicating ~96% of the candidate planetary systems are correctly interpreted as true systems. We find that planet pairs show little statistical preference to be near mean-motion resonances. We identify an asymmetry in the distribution of period ratios near first-order resonances (e.g., 2:1, 3:2), with an excess of planet pairs lying wide of resonance and relatively few lying narrow of resonance. Finally, based upon the transit duration ratios of adjacent planets in each system, we find that the interior planet tends to have a smaller transit impact parameter than the exterior planet does. This finding suggests that the mode of the mutual inclinations of planetary orbital planes is in the range 1.0-2.2 degrees, for the packed systems of small planets probed by these observations.Comment: Accepted to Ap

Perceived ostracism and paranoia: A test of potential moderating effects of psychological flexibility and inflexibility

Ostracism is known to lead to negative psychological outcomes; however, little is known as to how ostracism may be a predictor of paranoid thoughts. The present paper examined the relationship between perceived ostracism and paranoid thoughts (social reference, persecution) by focusing on the potential moderating roles of psychological flexibility and inflexibility. As expected, data from a sample of 315 internet users (Mage = 31.5 years) showed that perceived ostracism was positively related to both social reference and persecution. Psychological flexibility did not moderate the ostracism-paranoid thought relationships. However, psychological inflexibility was a moderator of the ostracism-social reference relationship, but not for ostracism-persecution. Specifically, at both high and low levels of psychological inflexibility, there was a significant positive relationship between ostracism and social reference. These unexpected findings suggest that future research is needed to elucidate the mechanisms by which perceived ostracism may lead to paranoia

exoplanet : gradient-based probabilistic inference for exoplanet data & other astronomical time series

Funding: This research was partially conducted during the Exostar19 program at the Kavli Institute for Theoretical Physics at UC Santa Barbara, which was supported in part by the National Science Foundation under Grant No. NSF PHY-1748958."exoplanet" is a toolkit for probabilistic modeling of astronomical time series data, with a focus on observations of exoplanets, using PyMC3 (Salvatier et al., 2016). PyMC3 is a flexible and high-performance model-building language and inference engine that scales well to problems with a large number of parameters. "exoplanet" extends PyMC3's modeling language to support many of the custom functions and probability distributions required when fitting exoplanet datasets or other astronomical time series. While it has been used for other applications, such as the study of stellar variability, the primary purpose of "exoplanet" is the characterization of exoplanets or multiple star systems using time-series photometry, astrometry, and/or radial velocity. In particular, the typical use case would be to use one or more of these datasets to place constraints on the physical and orbital parameters of the system, such as planet mass or orbital period, while simultaneously taking into account the effects of stellar variability.Publisher PDFPeer reviewe

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer\u27s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 1

G359.97-0.038: A Hard X-Ray Filament Associated with a Supernova Shell-Molecular Cloud Interaction

We present the first high-energy X-ray (>10 keV) observations of the non-thermal filament G359.97-0.038 using the Nuclear Spectroscopic Telescope Array (NuSTAR). This filament is one of approximately 20 X-ray filaments of unknown origin located in the central 20 pc region in the Galactic Center near Sgr A^*. Its NuSTAR and Chandra broadband spectrum is characterized by a single power law with Γ = 1.3 ± 0.3 that extends from 2 to 50 keV, with an unabsorbed luminosity of 1.3 × 10^(33) erg s^(–1) (d/8 kpc)^2 in the 2-8 keV band. Despite possessing a cometary X-ray morphology that is typical of a pulsar wind nebula (PWN) in high-resolution Chandra imaging, our spatially resolved Chandra spectral analysis found no significant spectral softening along the filament as would be expected from particle synchrotron cooling. Coincident radio emission is detected using the Very Large Array at 5.5 and 8.3 GHz. We examine and subsequently discard a PWN or magnetic flux tube as the origin of G359.97-0.038. We use broadband spectral characteristics and a morphological analysis to show that G359.97-0.038 is likely an interaction site between the shell of Sgr A East and an adjacent molecular cloud. This is supported by CS molecular line spectroscopy and the presence of an OH maser