Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas

Identification of novel prognostic biomarkers typically requires a large dataset which provides sufficient statistical power for discovery research. To this end, we took advantage of the high‐throughput data from The Cancer Genome Atlas (TCGA) to identify a set of prognostic biomarkers in head and neck squamous cell carcinomas (HNSCC) including oropharyngeal squamous cell carcinoma (OPSCC) and other subtypes. In this study, we analyzed miRNA‐seq data obtained from TCGA patients to identify prognostic biomarkers for OPSCC. The identified miRNAs were further tested with an independent cohort. miRNA‐seq data from TCGA was also analyzed to identify prognostic miRNAs in oral cavity squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC). Our study identified that miR‐193b‐3p and miR‐455‐5p were positively associated with survival, and miR‐92a‐3p and miR‐497‐5p were negatively associated with survival in OPSCC. A combined expression signature of these four miRNAs was prognostic of overall survival in OPSCC, and more importantly, this signature was validated in an independent OPSCC cohort. Furthermore, we identified four miRNAs each in OSCC and LSCC that were prognostic of survival, and combined signatures were specific for subtypes of HNSCC. A robust 4‐miRNA prognostic signature in OPSCC, as well as prognostic signatures in other subtypes of HNSCC, was developed using sequencing data from TCGA as the primary source. This demonstrates the power of using TCGA as a potential resource to develop prognostic tools for improving individualized patient care

Development of ovine placental lactogen deficient pregnancies, The

2014 Fall.Includes bibliographical references.Intrauterine growth restriction (IUGR) results in significant fetal and neonatal mortalities and morbidities. Additionally, infants surviving IUGR experience increased incidence of heart disease, diabetes, hypertension and stroke during adulthood. A major placental secretory product, placental lactogen (PL), is found at high levels in maternal and fetal circulation, and is significantly reduced in both human and sheep IUGR pregnancies. While the exact function of PL has not been defined for any species, it is thought to modulate the mobilization of maternal nutrients to the fetus. Recently, the development of lentiviral-mediated expression of short hairpin RNA (shRNA) within sheep conceptuses has provided a means of examining placental gene function in sheep. The objective of this research was to generate ovine PL (oPL) deficient sheep pregnancies using lentivirus targeting the degradation of oPL mRNA, in order to assess the function of PL during pregnancy. We hypothesize that oPL deficiency during pregnancy will lead to IUGR near term. To test our hypothesis a preliminary study was conducted to evaluate the in vivo efficacy of lentiviral-oPL targeting vectors in the sheep placenta at 55 days gestational age (dGA). Efficiency of oPLmRNA degradation was first measured in vitro using twelve promoter-targeting sequence combinations, tested in three cell lines overexpressing oPL. Two oPL target sequences (tg2 and tg6) were used, as either shRNA or shRNAmiR (microRNA mimic) sequences. Subsequently, three lentiviral constructs; hLL3.7 tg6 (human U6 promoter expressing oPL tg6 shRNA), hEF-1 tg2 (human elongation factor-1α promoter expressing oPL tg 2 shRNAmiR) and oPGK tg6 (ovine phosphoglycerate kinase-1 promoter expressing oPL tg 6 shRNAmiR), were selected to be tested in vivo. Day 9 blastocysts were harvested from naturally mated donor ewes, infected with one of the lentiviral constructs, and 2 to 3 blastocysts were surgically transferred to recipient ewes. At 55 dGA, uterine vein (UtV) blood and placental tissues were collected for analysis of oPL expression, and compared to naturally mated controls (NMC). Based on a 95% confidence interval created from UtV oPL concentrations in NMC pregnancies (n=4), 3 out of 4 hLL3.7 tg6 pregnancies, 3 out of 4 hEF tg2 pregnancies and 4 out of 4 oPGK tg6 pregnancies were classified as responder pregnancies. Compared to NMC pregnancies, UtV oPL concentrations were significantly reduced (P≤0.05) in responder pregnancies. While we hypothesized that oPL deficiency will result in IUGR near-term, at 55 dGA there were no differences in fetal weights. To test our overall hypothesis, we generated 8 hEF-1-SC (human elongation factor-1α promoter expressing scrambled control shRNAmiR), 9 hEF-1 tg2, 7 hEF-1 tg6 (human elongation factor-1α promoter expressing oPL tg6 shRNAmiR) and 9 hLL3.7 tg6 singleton pregnancies that were harvested at 135 dGA. Based on two standard deviations below the mean placental weight of the hEF-1 SC pregnancies, 2 out of 7 hEF-1 tg6 pregnancies and 6 out of 9 hLL3.7 tg6 pregnancies were classified as tg6 responder pregnancies (tg6). Tg6 pregnancies resulted in significantly decreased (P≤0.05) oPL mRNA concentrations, placental weight and fetal body weight compared to the controls at 135 days of gestation. These data confirm the effect of lentiviral-oPL targeting vectors and suggest that oPL plays a significant role in early placental development. Interestingly, we also observed that tg6 pregnancies had significantly increased (P≤0.05) placental efficiency relative to controls, which may function as a coping mechanism to maintain pregnancy in the face of oPL deficiency. Uterine artery to uterine vein glucose gradients were also increased (P≤0.05) in tg6 pregnancies compared to controls, which may be indicative of increased glucose uptake by the placenta in order to maintain function. Further analysis revealed that circulating fetal insulin tended to be decreased in the umbilical artery (P≤0.10) of tg6 fetuses relative to control fetuses, thus supporting a role for oPL in altering fetal insulin production. Finally, mRNA concentrations of insulin-like growth factors (IGF) -I and -II, and insulin-like growth factor binding proteins (IGFBP) -2 and -3 were significantly reduced (P≤0.05) in fetal liver tissue of tg6 fetuses compared to the controls. While this could be an indirect result of IUGR, oPL may well induce the expression of fetal insulin-like growth factors during in utero development. Based on these results, our hypothesis that oPL deficiency during gestation would result in intrauterine growth restriction appears correct. Surprisingly, it appears that oPL may have its greatest impact during early pregnancy when the placenta is developing, however the presence of adequate oPL is likely to be important throughout gestation for healthy fetal growth

Risk Factors for Abdominal Pain-Related Disorders of Gut-Brain Interaction in Adults and Children: A Systematic Review.

Background & aimsMany studies have assessed risk factors of irritable bowel syndrome (IBS) and other abdominal pain-related disorders of gut-brain interaction (AP-DGBI); however, the role of these factors is unclear due to heterogeneous study designs. The aim of this systematic review was to extensively evaluate the literature and determine clinical risk and protective factors for the presence and persistence of AP-DGBI in children and adults.MethodsA PubMed search identified studies investigating potential risk and protective factors for AP-DGBI in adults and children. Inclusion criteria included fully published studies with a control group; exclusion criteria included poor-quality studies (using a validated scale). For each factor, the proportion of studies that found the factor to be a risk factor, protective factor, or neither was summarized. The number of studies, diagnostic criteria, number of subjects, and average study quality rating provided further context. Whenever possible, a meta-analysis generated pooled odds ratios or mean difference.ResultsThe systematic review included 348 studies. Female sex, gastroenteritis, abuse, stress, psychological disorders, somatic symptoms, and poor sleep were consistent risk factors for developing AP-DGBI in adults and children. In adults, additional risk factors included obesity, smoking, and increased use of medical resources. Protective AP-DGBI factors in adults included social support and optimism; no studies for protective factors were found for children.ConclusionsThere are multiple risk factors for AP-DGBI in adults and children. These include female sex, gastroenteritis, abuse, stress, poor sleep, obesity, psychological disorders, and somatic symptoms. Additional studies are needed in children, on protective factors, and on factors associated with persistence of AP-DGBI

Socialization and Proactive Behavior: Multilevel Exploration of Research Productivity Drivers in U.S. Business Schools

We explore the joint relationship that organizational environment and individual proactive behavior have with the research performance of business school academics. We draw upon sociology of science research, “new careers” literature, and social capital research to build a multilevel model of individual research productivity emergence. The study looks at the interplay between organizational scripts and individual strategies as part of a microfoundations research program, and seeks to create consensus on the relative importance of each antecedent in supporting research outcomes. Our hypotheses are tested using a sample of 500 academics randomly selected from 25 research-intensive U.S. business schools ranked at the top of the University of Texas at Dallas ranking. The findings of the study demonstrate that both organizational environment and individual behavior influence the research performance of U.S. business school faculties, with collaboration behavior being the most important driver of research outcomes. These findings can inform decision making for academics at all stages of a research-active career. We hope that the developmental practices based on these results will become part of doctoral students’ training and will facilitate the students’ socialization into the research profession

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu