Hypoxia regulates FGFR3 expression via HIF-1α and miR-100 and contributes to cell survival in non-muscle invasive bladder cancer

Background: Non-muscle invasive (NMI) bladder cancer is characterised by increased expression and activating mutations of FGFR3. We have previously investigated the role of microRNAs in bladder cancer and have shown that FGFR3 is a target of miR-100. In this study, we investigated the effects of hypoxia on miR-100 and FGFR3 expression, and the link between miR-100 and FGFR3 in hypoxia. Methods: Bladder cancer cell lines were exposed to normoxic or hypoxic conditions and examined for the expression of FGFR3 by quantitative PCR (qPCR) and western blotting, and miR-100 by qPCR. The effect of FGFR3 and miR-100 on cell viability in twodimensional (2-D) and three-dimensional (3-D) was examined by transfecting siRNA or mimic-100, respectively. Results: In NMI bladder cancer cell lines, FGFR3 expression was induced by hypoxia in a transcriptional and HIF-1a-dependent manner. Increased FGFR3 was also in part dependent on miR-100 levels, which decreased in hypoxia. Knockdown of FGFR3 led to a decrease in phosphorylation of the downstream kinases mitogen-activated protein kinase (MAPK) and protein kinase B (PKB), which was more pronounced under hypoxic conditions. Furthermore, transfection of mimic-100 also decreased phosphorylation of MAPK and PKB. Finally, knocking down FGFR3 profoundly decreased 2-D and 3-D cell growth, whereas introduction of mimic-100 decreased 3-D growth of cells. Conclusion: Hypoxia, in part via suppression of miR-100, induces FGFR3 expression in bladder cancer, both of which have an important role in maintaining cell viability under conditions of stress

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy

Who I Am: The Meaning of Early Adolescents’ Most Valued Activities and Relationships, and Implications for Self-Concept Research

Self-concept research in early adolescence typically measures young people’s self-perceptions of competence in specific, adult-defined domains. However, studies have rarely explored young people’s own views of valued self-concept factors and their meanings. For two major self domains, the active and the social self, this mixed-methods study identified factors valued most by 526 young people from socioeconomically diverse backgrounds in Ireland (10-12 years), and explored the meanings associated with these in a stratified subsample (n = 99). Findings indicate that self-concept scales for early adolescence omit active and social self factors and meanings valued by young people, raising questions about content validity of scales in these domains. Findings also suggest scales may under-represent girls’ active and social selves; focus too much on some school-based competencies; and, in omitting intrinsically salient self domains and meanings, may focus more on contingent (extrinsic) rather than true (intrinsic) self-esteem

Control-Value Appraisals, Enjoyment, and Boredom in Mathematics:A Longitudinal Latent Interaction Analysis

Based on the control-value theory of achievement emotions, this longitudinal study examined students' control-value appraisals as antecedents of their enjoyment and boredom in mathematics. Self-report data for appraisals and emotions were collected from 579 students in their final year of primary schooling over three waves. Data were analyzed using latent interaction structural equation modeling. Control-value appraisals predicted emotions interactively depending on which specific subjective value was paired with perceived control. Achievement value amplified the positive relation between perceived control and enjoyment, and intrinsic value reduced the negative relation between perceived control and boredom. These longitudinal findings demonstrate that control and value appraisals, and their interaction, are critically important for the development of students' enjoyment and boredom over time

Latina and European American Girls’ Experiences with Academic Sexism and their Self-Concepts in Mathematics and Science During Adolescence

The study investigated Latina and European American adolescent girls’ (N = 345, M = 15.2 years, range = 13 to 18) experiences with academic sexism in mathematics and science (M/S) and their M/S perceived competence and M/S value (liking and importance). M/S academic sexism was based on girls’ reported experiences hearing sexist comments about girls’ abilities in math and science. Older European American adolescents, and both younger and older Latina adolescents, who experienced several instances of academic sexism felt less competent in M/S than girls who experienced less sexism (controlling for M/S grades). In addition, among older girls (regardless of ethnicity), those who experienced several instances of academic sexism valued M/S less than girls who experienced less sexism

Children reading to dogs: a systematic review of the literature

Background Despite growing interest in the value of human-animal interactions (HAI) to human mental and physical health the quality of the evidence on which postulated benefits from animals to human psychological health are based is often unclear. To date there exist no systematic reviews on the effects of HAI in educational settings specifically focussing on the perceived benefits to children of reading to dogs. With rising popularity and implementation of these programmes in schools, it is essential that the evidence base exploring the pedagogic value of these initiatives is well documented. Methods Using PRISMA guidelines we systematically investigated the literature reporting the pedagogic effects of reading to dogs. Because research in this area is in the early stages of scientific enquiry we adopted broad inclusion criteria, accepting all reports which discussed measurable effects related to the topic that were written in English. Multiple online databases were searched during January-March 2015; grey literature searches were also conducted. The search results which met the inclusion criteria were evaluated, and discussed, in relation to the Oxford Centre for Evidence Based Medicine levels of evidence; 27 papers were classified as Level 5, 13 as Level 4, 7 as Level 2c and 1 as Level 2b. Conclusion The evidence suggests that reading to a dog may have a beneficial effect on a number of behavioural processes which contribute to a positive effect on the environment in which reading is practiced, leading to improved reading performance. However, the evidence base on which these inferences are made is of low quality. There is a clear need for the use of higher quality research methodologies and the inclusion of appropriate controls in order to draw causal inferences on whether or how reading to dogs may benefit children’s reading practices. The mechanisms for any effect remain a matter of conjectur

Identification of a hypoxia-regulated miRNA signature in bladder cancer and a role for miR-145 in hypoxia-dependent apoptosis

Background: Hypoxia leads to the stabilisation of the hypoxia-inducible factor (HIF) transcription factor that drives the expression of target genes including microRNAs (miRNAs). MicroRNAs are known to regulate many genes involved in tumourigenesis. The aim of this study was to identify hypoxia-regulated miRNAs (HRMs) in bladder cancer and investigate their functional significance. Methods: Bladder cancer cell lines were exposed to normoxic and hypoxic conditions and interrogated for the expression of 384 miRNAs by qPCR. Functional studies were carried out using siRNA-mediated gene knockdown and chromatin immunoprecipitations. Apoptosis was quantified by annexin V staining and flow cytometry. Results: The HRM signature for NMI bladder cancer lines includes miR-210, miR-193b, miR-145, miR-125-3p, miR-708 and miR-517a. The most hypoxia-upregulated miRNA was miR-145. The miR-145 was a direct target of HIF-1a and two hypoxia response elements were identified within the promoter region of the gene. Finally, the hypoxic upregulation of miR-145 contributed to increased apoptosis in RT4 cells. Conclusions: We have demonstrated the hypoxic regulation of a number of miRNAs in bladder cancer. We have shown that miR- 145 is a novel, robust and direct HIF target gene that in turn leads to increased cell death in NMI bladder cancer cell lines

Relationships between students' conceptions of constructivist learning and their regulation and processing strategies

The present study investigated relationships between students' conceptions of constructivist learning on the one hand, and their regulation and processing strategies on the other hand. Students in a constructivist, problem-based learning curriculum were questioned about their conceptions of knowledge construction and self-regulated learning, as well as their beliefs regarding their own (in)ability to learn and motivation to learn. Two hypothesized models were tested within 98 psychology students, using a structural equation modelling approach: The first model implemented regulation and processing variables of the Inventory of Learning Styles [ILS, Vermunt (Learning styles and regulation of learning in higher education - towards process-oriented instruction in autonomous thinking, 1992)], the second model of the Motivated Strategies for Learning Questionnaire [MSLQ, Pintrich and de Groot (Journal of Educational Psychology, 82, 33-40, 1990)]. Results showed that structural relations exist between conceptions of constructivist learning and regulation and processing strategies. Furthermore, students who express doubt with regard to their own learning capacities are at risk for adopting an inadequate regulation strategy. A three-tiered structure of conceptual, controlling, and operational level appeared valid for the MSLQ variables, but not entirely for those of the ILS