Small Noncoding RNA Expression in Cancer

Despite an inability to encode proteins, small noncoding RNAs (sncRNAs) have critical functions in the regulation of gene expression. They have demonstrated roles in cancer development and progression and are frequently dysregulated. Here we review the biogenesis and mechanism of action, expression patterns, and detection methods of two types of sncRNAs frequently described in cancer: miRNAs and piRNAs. Both miRNAs and piRNAs have been observed to play both oncogenic and tumor-suppressive roles, with miRNAs acting to directly regulate the mRNA of key cancer-associated genes, while piRNAs play crucial roles in maintaining the integrity of the epigenetic landscape. Elucidating these important functions of sncRNAs in normal and cancer biology relies on numerous in silico workflows and tools to profile sncRNA expression. Thus, we also discuss the key detection methods for cancer-relevant sncRNAs, including the discovery of genes that have yet to be described

Linkages between Cigarette Smoking Outcome Expectancies and Negative Emotional Vulnerability

The present investigation examined whether smoking outcome expectancies, as measured by the Smoking Consequences Questionnaire (SCQ; [Brandon, T.H., & Baker, T.B., (1991). The Smoking Consequences Questionnaire: The subjective expected utility of smoking in college students. Psychological Assessment, 3, 484–491.]), were incrementally related to emotional vulnerability factors among an adult sample of 202 daily cigarette smokers (44.6% women; Mage= 23.78 years, SD = 9.69 years). After controlling for cigarettes smoked/day, past 30-day marijuana use, current alcohol consumption, and coping style, negative reinforcement/negative affect reduction outcome expectancies were significantly associated with greater levels of negative affectivity, emotional dysregulation, and anxiety sensitivity. The observed effects for negative reinforcement/negative affect reduction also were independent of shared variance with other outcome expectancies. Negative personal consequences outcome expectancies were significantly and incrementally related to anxiety sensitivity, but not negative affectivity or emotional dysregulation. Findings are discussed in terms of the role of negative reinforcement/ negative affect reduction smoking outcome expectancies and clinically-relevant negative emotional vulnerability for better understanding cigarette smoking-negative mood problem

Injury Rates in Age-Only Versus Age-and-Weight Playing Standard Conditions in American Youth Football

BACKGROUND: American youth football leagues are typically structured using either age-only (AO) or age-and-weight (AW) playing standard conditions. These playing standard conditions group players by age in the former condition and by a combination of age and weight in the latter condition. However, no study has systematically compared injury risk between these 2 playing standards. PURPOSE: To compare injury rates between youth tackle football players in the AO and AW playing standard conditions. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Athletic trainers evaluated and recorded injuries at each practice and game during the 2012 and 2013 football seasons. Players (age, 5-14 years) were drawn from 13 recreational leagues across 6 states. The sample included 4092 athlete-seasons (AW, 2065; AO, 2027) from 210 teams (AW, 106; O, 104). Injury rate ratios (RRs) with 95% CIs were used to compare the playing standard conditions. Multivariate Poisson regression was used to estimate RRs adjusted for residual effects of age and clustering by team and league. There were 4 endpoints of interest: (1) any injury, (2) non-time loss (NTL) injuries only, (3) time loss (TL) injuries only, and (4) concussions only. RESULTS: Over 2 seasons, the cohort accumulated 1475 injuries and 142,536 athlete-exposures (AEs). The most common injuries were contusions (34.4%), ligament sprains (16.3%), concussions (9.6%), and muscle strains (7.8%). The overall injury rate for both playing standard conditions combined was 10.3 per 1000 AEs (95% CI, 9.8-10.9). The TL injury, NTL injury, and concussion rates in both playing standard conditions combined were 3.1, 7.2, and 1.0 per 1000 AEs, respectively. In multivariate Poisson regression models controlling for age, team, and league, no differences were found between playing standard conditions in the overall injury rate (RRoverall, 1.1; 95% CI, 0.4-2.6). Rates for the other 3 endpoints were also similar (RRNTL, 1.1 [95% CI, 0.4-3.0]; RRTL, 0.9 [95% CI, 0.4-1.9]; RRconcussion, 0.6 [95% CI, 0.3-1.4]). CONCLUSION: For the injury endpoints examined in this study, the injury rates were similar in the AO and AW playing standards. Future research should examine other policies, rules, and behavioral factors that may affect injury risk within youth football

GREAT3 results I: systematic errors in shear estimation and the impact of real galaxy morphology

We present first results from the third GRavitational lEnsing Accuracy Testing (GREAT3) challenge, the third in a sequence of challenges for testing methods of inferring weak gravitational lensing shear distortions from simulated galaxy images. GREAT3 was divided into experiments to test three specific questions, and included simulated space- and ground-based data with constant or cosmologically-varying shear fields. The simplest (control) experiment included parametric galaxies with a realistic distribution of signal-to-noise, size, and ellipticity, and a complex point spread function (PSF). The other experiments tested the additional impact of realistic galaxy morphology, multiple exposure imaging, and the uncertainty about a spatially-varying PSF; the last two questions will be explored in Paper II. The 24 participating teams competed to estimate lensing shears to within systematic error tolerances for upcoming Stage-IV dark energy surveys, making 1525 submissions overall. GREAT3 saw considerable variety and innovation in the types of methods applied. Several teams now meet or exceed the targets in many of the tests conducted (to within the statistical errors). We conclude that the presence of realistic galaxy morphology in simulations changes shear calibration biases by $\sim 1$ per cent for a wide range of methods. Other effects such as truncation biases due to finite galaxy postage stamps, and the impact of galaxy type as measured by the S\'{e}rsic index, are quantified for the first time. Our results generalize previous studies regarding sensitivities to galaxy size and signal-to-noise, and to PSF properties such as seeing and defocus. Almost all methods' results support the simple model in which additive shear biases depend linearly on PSF ellipticity.Comment: 32 pages + 15 pages of technical appendices; 28 figures; submitted to MNRAS; latest version has minor updates in presentation of 4 figures, no changes in content or conclusion

A small satellite version of a soft x-ray polarimeter

We describe a new implementation of a broad-band soft X-ray polarimeter, substantially based on a previous design. This implementation, the Pioneer Soft X-ray Polarimeter (PiSoX) is a SmallSat, designed for NASA’s call for Astrophysics Pioneers, small missions that could be CubeSats, balloon experiments, or SmallSats. As in REDSoX, the grating arrangement is designed optimally for the purpose of polarimetry with broad-band focussing optics by matching the dispersion of the spectrometer channels to laterally graded multilayers (LGMLs). The system can achieve polarization modulation factors over 90%. For PiSoX, the optics are lightweight Si mirrors in a one-bounce parabolic configuration. High efficiency, blazed gratings from opposite sectors are oriented to disperse to a LGML forming a channel covering the wavelength range from 35 Å to 75 Å (165 - 350 eV). Upon satellite rotation, the intensities of the dispersed spectra, after reflection and polarizing by the LGMLs, give the three Stokes parameters needed to determine a source’s linear polarization fraction and orientation. The design can be extended to higher energies as LGMLs are developed further. We describe examples of the potential scientific return from instruments based on this design

A Small Satellite Version of a Broad-band Soft X-ray Polarimeter

We describe a new implementation of a broad-band soft X-ray polarimeter, substantially based on a previous design. This implementation, the Pioneer Soft X-ray Polarimeter (PiSoX) is a SmallSat, designed for NASA's call for Astrophysics Pioneers, small missions that could be CubeSats, balloon experiments, or SmallSats. As in the REDSoX Polarimeter, the grating arrangement is designed optimally for the purpose of polarimetry with broad-band focussing optics by matching the dispersion of the spectrometer channels to laterally graded multilayers (LGMLs). The system can achieve polarization modulation factors over 90%. For PiSoX, the optics are lightweight Si mirrors in a one-bounce parabolic configuration. High efficiency, blazed gratings from opposite sectors are oriented to disperse to a LGML forming a channel covering the wavelength range from 35 to 75 Angstroms (165 - 350 eV). Upon satellite rotation, the intensities of the dispersed spectra, after reflection and polarizing by the LGMLs, give the three Stokes parameters needed to determine a source's linear polarization fraction and orientation. The design can be extended to higher energies as LGMLs are developed further. We describe examples of the potential scientific return from instruments based on this design.Comment: 20 pages, 8 figures, to appear in Proceedings SPIE, volume 1144

Model-Informed Drug Development:Steps Toward Harmonized Guidance

Global alignment of expectations is required to achieve consistency in the planning, conduct, reporting, and regulatory review of modelinformed drug development (MIDD) applications. An International Council for Harmonization (ICH) MIDD general principles guideline has been positioned to provide a common standard of practice including a framework for risk-based assessment of MIDD-derived evidence within the context of global regulatory decision-making. This perspective provides the background, our viewpoints, and the next steps in the development of this guideline

Aberrant Expression of Pseudogene-Derived lncRNAs as an Alternative Mechanism of Cancer Gene Regulation in Lung Adenocarcinoma

Transcriptome sequencing has led to the widespread identification of long non-coding RNAs (lncRNAs). Subsequently, these genes have been shown to hold functional importance in human cellular biology, which can be exploited by tumors to drive the hallmarks of cancer. Due to the complex tertiary structure and unknown binding motifs of lncRNAs, there is a growing disparity between the number of lncRNAs identified and those that have been functionally characterized. As such, lncRNAs deregulated in cancer may represent critical components of cancer pathways that could serve as novel therapeutic intervention points. Pseudogenes are non-coding DNA sequences that are defunct relatives of their protein-coding parent genes but retain high sequence similarity. Interestingly, certain lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans particularly because of this sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that aberrant expression of lncRNAs overlapping pseudogene loci provides an alternative mechanism of cancer gene deregulation. Using RNA-sequencing data from two cohorts of lung adenocarcinoma, each paired with patient-matched non-malignant lung samples, we discovered 104 deregulated pseudogene-derived lncRNAs. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) had lncRNA protein-coding parent gene expression that was significantly associated with survival. Here, we uncover evidence to suggest the lncRNA-pseudogene-protein-coding gene axis as a prominent mechanism of cancer gene regulation in lung adenocarcinoma, and highlights the clinical utility of exploring the non-coding regions of the cancer transcriptome