Next-generation sequencing of prostate cancer: genomic and pathway alterations, potential actionability patterns, and relative rate of use of clinical-grade testing.

Despite being one of the most common cancers, treatment options for prostate cancer are limited. Novel approaches for advanced disease are needed. We evaluated the relative rate of use of clinical-grade next generation sequencing (NGS) in prostate cancer, as well as genomic alterations identified and their potential actionability. Of 4864 patients from multiple institutions for whom NGS was ordered by physicians, only 67 (1.4%) had prostate cancer, representing 1/10 the ordering rate for lung cancer. Prostate cancers harbored 148 unique alterations affecting 63 distinct genes. No two patients had an identical molecular portfolio. The median number of characterized genomic alterations per patient was 3 (range, 1 to 9). Fifty-six of 67 patients (84%) had ≥ 1 potentially actionable alteration. TMPRSS2 fusions affected 28.4% of patients. Genomic aberrations were most frequently detected in TP53 (55.2% of patients), PTEN (29.9%), MYC (17.9%), PIK3CA (13.4%), APC (9.0%), BRCA2 (9.0%), CCND1 (9.0%), and RB1 genes (9.0%). The PI3K (52.2% of patients), WNT (13.5%), DNA repair (17.9%), cell cycle (19.4%), and MAPK (14.9%) machinery were commonly impacted. A minority of patients harbored BRAF, NTRK, ERBB2, or mismatch repair gene abnormalities, which are highly druggable in some cancers. Only ~ 10% of prostate cancer trials (clinicaltrials.gov, year 2017) applied a (non-hormone) biomarker before intervention. In conclusion, though use of clinical-grade NGS is relatively low and only a minority of trials deploy DNA-based biomarkers, many prostate cancer-associated molecular alterations may be pharmacologically tractable with genomcially targeted therapy or, in the case of mismatch repair anomalies, with checkpoint inhibitor immunotherapy

Genomic landscape of salivary gland tumors.

Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc. (Lexington, MA). There were 354 total aberrations, with 240 distinct aberrations identified in this patient population. Only 10 individuals (8.5%) had a molecular portfolio that was identical to any other patient (with four different portfolios amongst the ten patients). The most common abnormalities involved the TP53 gene (36/117 [30.8% of patients]), cyclin pathway (CCND1, CDK4/6 or CDKN2A/B) (31/117 [26.5%]) and PI3K pathway (PIK3CA, PIK3R1, PTEN or AKT1/3) (28/117 [23.9%]). In multivariate analysis, statistically significant co-existing aberrations were observed as follows: TP53 and ERBB2 (p = 0.01), cyclin pathway and MDM2 (p = 0.03), and PI3K pathway and HRAS (p = 0.0001). We were able to identify possible cognate targeted therapies in most of the patients (107/117 [91.5%]), including FDA-approved drugs in 80/117 [68.4%]. In conclusion, salivary gland tumors were characterized by multiple distinct aberrations that mostly differed from patient to patient. Significant associations between aberrations in TP53 and ERBB2, the cyclin pathway and MDM2, and HRAS and the PI3K pathway were identified. Most patients had actionable alterations. These results provide a framework for tailored combinations of matched therapies

The Roles of Non-Cognitive and Cognitive Skills in the Life Course Development of Adult Health Inequalities

Previous research has suggested that greater cognitive skill is protective against the development of socio-economic health inequalities across the life course, but the relative role of non-cognitive skills has been less investigated in this context. Using the prospective UK 1958 National Child Development Study (N = 18,558), higher factor scores for adolescent non-cognitive skills (NCS; i.e. a combination of work habits and pro-social behaviours) and mean cognitive skill (CS) at age 16 were examined with a path analysis model in relation to socioeconomic status (SES) across the life course (at ages 16, 33 and 50) and poor self-reported health at age 50. Adjusting for adolescent NCS explained over a third of the association between education and health, but the path between social class at age 50 and health was unaffected. Adjustment for CS explained larger proportions of the paths to adult health inequalities; and paths between CS and SES across the life course were stronger than the same paths with NCS. However, NCS was still independently associated with paths to later health inequalities in fully adjusted models, and both types of skill had equivalent inverse direct effects with poor health (OR: 0.82 [95% CI 0.73,0.93] vs 0.83 [0.72,0.96], respectively). Since NCS retained independent associations with SES and health across the life course, they could be a target for policies aimed at ameliorating the production of health inequalities for a wide range of children, regardless of their cognitive skill

EXONEST: The Bayesian Exoplanetary Explorer

The fields of astronomy and astrophysics are currently engaged in an unprecedented era of discovery as recent missions have revealed thousands of exoplanets orbiting other stars. While the Kepler Space Telescope mission has enabled most of these exoplanets to be detected by identifying transiting events, exoplanets often exhibit additional photometric effects that can be used to improve the characterization of exoplanets. The EXONEST Exoplanetary Explorer is a Bayesian exoplanet inference engine based on nested sampling and originally designed to analyze archived Kepler Space Telescope and CoRoT (Convection Rotation et Transits plan\'etaires) exoplanet mission data. We discuss the EXONEST software package and describe how it accommodates plug-and-play models of exoplanet-associated photometric effects for the purpose of exoplanet detection, characterization and scientific hypothesis testing. The current suite of models allows for both circular and eccentric orbits in conjunction with photometric effects, such as the primary transit and secondary eclipse, reflected light, thermal emissions, ellipsoidal variations, Doppler beaming and superrotation. We discuss our new efforts to expand the capabilities of the software to include more subtle photometric effects involving reflected and refracted light. We discuss the EXONEST inference engine design and introduce our plans to port the current MATLAB-based EXONEST software package over to the next generation Exoplanetary Explorer, which will be a Python-based open source project with the capability to employ third-party plug-and-play models of exoplanet-related photometric effects.Comment: 30 pages, 8 figures, 5 tables. Presented at the 37th International Workshop on Bayesian Inference and Maximum Entropy Methods in Science and Engineering (MaxEnt 2017) in Jarinu/SP Brasi

Salivary Cortisol Analysis in Collegiate Female Lacrosse Athletes

International Journal of Exercise Science 16(6): 242-251, 2023. Cortisol is a hormone that corresponds to physiological and emotional stress. The purpose of this study was to 1) evaluate the changes in cortisol in female Division I collegiate lacrosse players (n = 15) throughout the competitive season, and 2) evaluate the correlation between cortisol and athlete wellness and workload. Salivary cortisol samples were collected weekly in the morning throughout the entirety of the 2021 competitive season (12 weeks). Subjective athlete total wellness scores and sub-scores (muscle soreness, sleep quality, fatigue, and stress) were taken on the same days. Objective total weekly Athlete Load (AL, an amalgam workload metric) were tabulated from the previous training week. A significant effect of time was found on wellness (p \u3c 0.001) and AL (p \u3c 0.001) over the twelve weeks with weekly differences, such as weeks with more than one game, weeks with no games, weeks with students in quarantine (not competing), or weeks with academic stressors such as final exams. There were no weekly differences in cortisol (p = 0.058). Cortisol had negligible correlations with wellness (r = -0.010, p = 0.889) and AL (r = 0.083, p = 0.272) during the competitive season. These findings suggest that cortisol changed little for athletes throughout the season although training volume and wellness did. Thus, assessing acute responses of cortisol may prove to be more beneficial to evaluating athletes’ stress

Evaluating the Readiness of Special Education Doctoral Students to Apply the Standards of Evidence-Based Practice to Single-Case Research

How well doctoral students in special education are prepared to evaluate research as evidence-based practice (EBP) is likely to impact their careers, as well as the teachers they will train. In developing a method for evaluating the readiness of small cohort groups of doctoral students to apply a research-based model of EBP, an instrument and procedure were refined in a pilot evaluation and implemented within a multiple baseline design across participants. Participants’ independent and instrument-guided performance in rating published research was compared to the ratings of two experts in single-case research design, yielding proportions of agreement across evaluation conditions. Results indicated group readiness to independently conduct the EBP evaluation and individual differences in readiness indicating the need for remediation

Upgrades to the ISS Water Recovery System

The International Space Station Water Recovery System (WRS) is comprised of the Water Processor Assembly (WPA) and the Urine Processor Assembly (UPA). The WRS produces potable water from a combination of crew urine (first processed through the UPA), crew latent, and Sabatier product water. Though the WRS has performed well since operations began in November 2008, several modifications have been identified to improve the overall system performance. These modifications can reduce resupply and improve overall system reliability, which is beneficial for the ongoing ISS mission as well as for future NASA manned missions. The following paper details efforts to reduce the resupply mass of the WPA Multifiltration Bed, develop improved catalyst for the WPA Catalytic Reactor, evaluate optimum operation of UPA through parametric testing, and improve reliability of the UPA fluids pump and Distillation Assembly

Improving Activity and Engagement for Patients with Dementia

This is the second in a short series that presents case study examples of the positive work achieved by trusts that participated in the Royal College of Nursing’s development programme to improve dementia care in acute hospitals. Staff often think that there is insufficient time to get to know patients and carers, especially with large and challenging workloads. Combined with a lack of activities and stimulation for patients with dementia in hospital, this can result in poor engagement and a disconnect between staff and patients. To improve these relationships and give staff more time with patients, Cambridge University Hospitals NHS Foundation Trust has introduced bay nursing for patients with dementia, where one nurse is responsible for monitoring a bay alongside a healthcare assistant for an entire shift. Part of Betsi Cadwaladr University Health Board, Glan Clwyd Hospital in North Wales has focused on improving stimulation by creating an activity room with a specially trained activity worker, providing a relaxed and friendly setting where patients with dementia can take part in a range of activities and have lunch together

In-situ Observation of AlN Formation from Ni-Al Solution Using an Electromagnetic Levitation Technique

Aluminum nitride is a promising substrate material for AlGaN-based UV-LED. In order to develop a robust growth processing route for AlN single crystals, fundamental studies of solution growth experiments using Ni-Al alloy melts as a new solution system were performed. Al can be stably kept in solution the Ni-Al liquid even at high temperature; in addition, the driving force of the AlN formation reaction from solution can be controlled by solution composition and temperature. To investigate AlN crystal growth behavior we developed an in situ observation system using an electromagnetic levitation technique. AlN formation behavior, including nucleation and growth, was quantitatively analyzed by an image processing pipeline. The nucleation rate of AlN decreased with increasing growth temperature and decreasing aluminum composition. In addition, hexagonal c-axis oriented AlN crystal successfully grew on the levitated Ni-40 mol%Al droplet reacted at low driving force (1960 K), on the other hand, AlN crystal with dendritic morphology appeared on the sample with higher driving force (Ni-50 mol%Al, 1960 K). Thus, the nucleation rate and crystal morphology were dominated by the driving force of the AlN formation reaction