TTK/MPS1 inhibitor OSU-13 targets the mitotic checkpoint and is a potential therapeutic strategy for myeloma.

Despite substantial recent advances in treatment, multiple myeloma (MM) remains an incurable disease, with a shortage of treatment options for patients with high-risk disease, warranting the need for novel therapeutic targets and treatment approaches. Threonine and tyrosine kinase (TTK), also known as monopolar spindle 1 (MPS1), is a kinase essential for the mitotic spindle checkpoint whose expression correlates to unfavorable prognosis in several cancers. Here, we report the importance of TTK in MM, and the effects of the TTK inhibitor OSU-13. Elevated TTK expression correlated with amplification/ gain of 1q21 and decreased overall and event-free survival in MM. Treatment with OSU-13 inhibited TTK activity efficiently and selectively at a similar concentration range to other TTK inhibitor clinical candidates. OSU-13 reduced proliferation and viability of primary human MM cells and cell lines, especially those with high 1q21 copy numbers, and triggered apoptosis through caspase 3 and 7 activation. In addition, OSU-13 induced DNA damage and severe defects in chromosome alignment and segregation, generating aneuploidy. In vivo, OSU-13 decreased tumor growth in mice with NCI-H929 xenografts. Collectively, our findings reveal that inhibiting TTK with OSU-13 is a potential therapeutic strategy for MM, particularly for a subset of high-risk patients with poor outcome.

A comparison of past and present computational methods for shape analysis of double-shell x-ray radiographs.

Implosion symmetry is a key requirement in achieving a robust burning plasma in inertial confinement fusion experiments. In double-shell capsule implosions, we are interested in the shape of the inner shell as it pushes on the fuel. Shape analysis is a popular technique for studying said symmetry during implosion. Combinations of filtering and contour-finding algorithms are studied for their promise in reliably recovering Legendre shape coefficients from synthetic radiographs of double-shell capsules with applied levels of noise. A radial lineout max(slope) method when used on an image pre-filtered with non-local means and a variant of the marching squares algorithm are able to recover p0, p2, and p4 maxslope Legendre shape coefficients with mean pixel discrepancy errors of 2.81 and 3.06, respectively, for the noisy synthetic radiographs we consider. This improves upon prior radial lineout methods paired with Gaussian filtering, which we show to be unreliable and whose performance is dependent on input parameters that are difficult to estimate.

Health Care Professionals' Perceptions of Caring for Patients with Substance Use Disorders during Pregnancy.

PURPOSE: Pregnant patients with substance use disorders (SUDs) may experience stigma and implicit and explicit bias from health care professionals when seeking prenatal care. This study explored the perceptions of health care professionals caring for pregnant women with SUDs and examined changes in their perceptions over time following attendance at an educational conference about SUDs. STUDY DESIGN AND METHODS: Evidence-based education was presented to health care professionals at a conference to reinforce the complex needs of pregnant women with SUDs. An adapted version of the Attitudes of Healthcare Providers Survey (AHPS) was administered at three intervals and assessed health care professionals' perceptions of pregnant women with SUDs. Data from the three time points were analyzed using repeated measures ANOVA. RESULTS: There was a significant decrease in mean AHPS scores between T1 (38.24 ± 8.93) and T2 (32.71 ± 7.77), p < .05, and then a significant increase in mean AHPS score between T2 and T3 (37.08 ± 8.45), p < .05. High mean scores on health care professionals' knowledge and competence were noted after the educational intervention but were not sustained over time. CLINICAL IMPLICATIONS: Education cannot change health care professional perceptions of pregnant individuals with SUD. Health care professionals need access to additional clinical and community resources. Nurse leaders must continue to advocate for institutional and community resources to meet referral, treatment, and follow-up needs during pregnancy. Reducing perceptions of stigma and acknowledging the impact of implicit bias toward pregnant women with SUD may reduce barriers and improve their care.

Neural network for 3D inertial confinement fusion shell reconstruction from single radiographs.

In inertial confinement fusion (ICF), x-ray radiography is a critical diagnostic for measuring implosion dynamics, which contain rich three-dimensional (3D) information. Traditional methods for reconstructing 3D volumes from 2D radiographs, such as filtered backprojection, require radiographs from at least two different angles or lines of sight (LOS). In ICF experiments, the space for diagnostics is limited, and cameras that can operate on fast timescales are expensive to implement, limiting the number of projections that can be acquired. To improve the imaging quality as a result of this limitation, convolutional neural networks (CNNs) have recently been shown to be capable of producing 3D models from visible light images or medical x-ray images rendered by volumetric computed tomography. We propose a CNN to reconstruct 3D ICF spherical shells from single radiographs. We also examine the sensitivity of the 3D reconstruction to different illumination models using preprocessing techniques such as pseudo-flatfielding. To resolve the issue of the lack of 3D supervision, we show that training the CNN utilizing synthetic radiographs produced by known simulation methods allows for reconstruction of experimental data as long as the experimental data are similar to the synthetic data. We also show that the CNN allows for 3D reconstruction of shells that possess low mode asymmetries. Further comparisons of the 3D reconstructions with direct multiple LOS measurements are justified.

Multi-chord fiber-coupled interferometry of supersonic plasma jets (invited).

A multi-chord fiber-coupled interferometer is being used to make time-resolved density measurements of supersonic argon plasma jets on the Plasma Liner Experiment. The long coherence length of the laser (>10 m) allows signal and reference path lengths to be mismatched by many meters without signal degradation, making for a greatly simplified optical layout. Measured interferometry phase shifts are consistent with a partially ionized plasma in which both positive and negative phase shift values are observed depending on the ionization fraction. In this case, both free electrons and bound electrons in ions and neutral atoms contribute to the index of refraction. This paper illustrates how the interferometry data, aided by numerical modeling, are used to derive total jet density, jet propagation velocity (~15-50 km/s), jet length (~20-100 cm), and 3D expansion.

Multi-chord fiber-coupled interferometer with a long coherence length laser.

This paper describes a 561 nm laser heterodyne interferometer that provides time-resolved measurements of line-integrated plasma electron density within the range of 10(15)-10(18) cm(-2). Such plasmas are produced by railguns on the plasma liner experiment, which aims to produce µs-, cm-, and Mbar-scale plasmas through the merging of 30 plasma jets in a spherically convergent geometry. A long coherence length, 320 mW laser allows for a strong, sub-fringe phase-shift signal without the need for closely matched probe and reference path lengths. Thus, only one reference path is required for all eight probe paths, and an individual probe chord can be altered without altering the reference or other probe path lengths. Fiber-optic decoupling of the probe chord optics on the vacuum chamber from the rest of the system allows the probe paths to be easily altered to focus on different spatial regions of the plasma. We demonstrate that sub-fringe resolution capability allows the interferometer to operate down to line-integrated densities of the order of 5 × 10(15) cm(-2).

Smooth-particle applied mechanics: Conservation of angular momentum with tensile stability and velocity averaging.

Smooth-particle applied mechanics (SPAM) provides several approaches to approximate solutions of the continuum equations for both fluids and solids. Though many of the usual formulations conserve mass, (linear) momentum, and energy, the angular momentum is typically not conserved by SPAM. A second difficulty with the usual formulations is that tensile stress states often exhibit an exponentially fast high-frequency short-wavelength instability, "tensile instability." We discuss these twin defects of SPAM and illustrate them for a rotating elastic body. We formulate ways to conserve angular momentum while at the same time delaying the symptoms of tensile instability for many sound-traversal times. These ideas should prove useful in more general situations.