Multi-Omics Analyses Detail Metabolic Reprogramming in Lipids, Carnitines, and Use of Glycolytic Intermediates between Prostate Small Cell Neuroendocrine Carcinoma and Prostate Adenocarcinoma.

As the most common cancer in men, prostate cancer is molecularly heterogeneous. Contributing to this heterogeneity are the poorly understood metabolic adaptations of the two main types of prostate cancer, i.e., adenocarcinoma and small cell neuroendocrine carcinoma (SCNC), the latter being more aggressive and lethal. Using transcriptomics, untargeted metabolomics and lipidomics profiling on LASCPC-01 (prostate SCNC) and LNCAP (prostate adenocarcinoma) cell lines, we found significant differences in the cellular phenotypes of the two cell lines. Gene set enrichment analysis on the transcriptomics data showed 62 gene sets were upregulated in LASCPC-01, while 112 gene sets were upregulated in LNCAP. ChemRICH analysis on metabolomics and lipidomics data revealed a total of 25 metabolite clusters were significantly different. LASCPC-01 exhibited a higher glycolytic activity and lower levels of triglycerides, while the LNCAP cell line showed increases in one-carbon metabolism as an exit route of glycolytic intermediates and a decrease in carnitine, a mitochondrial lipid transporter. Our findings pinpoint differences in prostate neuroendocrine carcinoma versus prostate adenocarcinoma that could lead to new therapeutic targets in each type

Measurement of Cough Aerodynamics in Healthy Adults.

ImportanceCough is a critical human reflex and also among the most frequent symptoms in medicine. Despite the prevalence of disordered cough in laryngeal pathologies, comprehensive and quantitative evaluation of cough in these patients is lacking.ObjectiveHerein we seek to establish normative values for cough aerodynamics to provide a population standard for reference in future studies.Design, setting, and participantsHealthy subjects were recruited from an outpatient clinic to perform voluntary cough. Subjects were instructed on the technique for maximal voluntary cough production with measurements recorded on pneumotachograph. Fifty-two subjects were studied, including 29 women and 23 men with a mean age of 51.6 and 52.3 years, respectively. Main Outcomes and Measures: Cough peak airflow, peak pressure, and expiratory rise time. Results were stratified by age, gender, and height.ResultsPeak airflow demonstrated significant differences across age, gender, and height, with flow increasing according to increasing height. Peak cough pressure also increased with height and was significantly greater in males versus females. Expiratory rise time, the time from glottal opening to peak airflow, did not vary with age or height but was statistically significantly longer in women.ConclusionsCough aerodynamics can be readily measured objectively in the outpatient setting. Expiratory rise time, peak flow, and peak pressure are important aspects of each cough epoch. Normative data provided herein can be used for future studies of patients with laryngotracheal disorders, and these cough parameters may prove to be simple, accessible, and repeatable outcome measures

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Examining the Relationship Between Star Player Characteristics and Brand Equity in Professional Sport Teams

The overarching purpose of this study was to examine the impact of star athletes on the consumer-based brand equity of professional sport teams. Through a comprehensive review of literature and a test of content validity by an expert panel, preliminary scales were developed to measure the characteristic attributes of star athletes and the areas of brand equity that were affected by these traits. Research participants (N = 195) were professional sport fans that responded to a survey questionnaire in a classroom setting. After conducting factor analyses on the results, two factors (On -Field and Off-Field) for the star characteristic variables and six factors (Brand Loyalty, Brand Awareness, Brand Image, Brand Value, Perceived Quality, and Brand Reputation) for the areas of brand equity emerged. Multiple regression analyses revealed that the On-Field and Off-Field factors combined to exert the greatest, significant effects on the Brand Awareness and Brand Image components

In Vitro Digestibility of Mountain-Grown Irrigated Perennial Legume, Grass and Forb Forages is Influenced by Elevated Non-Fibrous Carbohydrates and Plant Secondary Compounds

BACKGROUND Perennial legumes cultivated under irrigation in the Mountain West USA have non‐fibrous carbohydrate (NFC) concentrations exceeding 400 g kg−1, a level commonly found in concentrate‐based ruminant diets. Our objective was to determine the influence of NFC concentration and plant secondary compounds on in vitro rumen digestion of grass, legume and forb forages compared with digestion of their isolated neutral detergent fiber (NDF) fraction. Forages were composited from ungrazed paddocks of rotationally stocked, irrigated monoculture pastures between May and August 2016, frozen in the field, freeze‐dried, and ground. RESULTS The maximum rate (RMax) of gas production was greater for the legumes alfalfa (ALF; Medicago sativa L.) and birdsfoot trefoil (BFT; Lotus corniculatus L.) than for the legume cicer milkvetch (CMV; Astragalus cicer L.) the grass meadow brome (MBG; Bromus riparius Rehm.) and the non‐legume forb small burnet (SMB; Sanguisorba minor Scop.), and intermediate for the legume sainfoin (SNF; Onobrychis viciifolia Scop.). The RMax of isolated NDF was greatest for BFT and CMV, intermediate for ALF, SNF and SMB and least for MBG. CONCLUSIONS More than 900 g of organic matter kg−1 dry matter of legumes was digested after 96 h. Across forages, the extent of whole‐plant digestion increased with NFC and crude protein concentrations, decreased with NDF concentrations, and was modulated by secondary compounds. The extent of digestion of isolated NDF decreased with concentration of lignin and residual tannins