Histon-Lysin-Demethylase 1A (KDM1A)-unabhängige Wirkung des KDM1A- Inhibitors SP2509 auf akute myeloische Leukämie-, Ewing-Sarkom- und Prostatakarzinomzellen

Epigenetische Veränderungen spielen einen wesentlichen Anteil an neoplastischen Transformationen. Die Histon-Lysin-Demethylase 1A (KDM1A) bewirkt solche und stellt somit einen Angriffspunkt in der Tumortherapie dar. Inhibitoren der KDM1A sind u. a. SP2509, Tranylcypromin (TCP), ORY-1001 und GSK2879552. Bei der Anwendung der Inhibitoren in vitro wurden allerdings auffällige Inkongruenzen bezüglich deren Wirkung verzeichnet: ORY-1001, GSK2879552 und TCP zeigten fast keine Wirkung auf die Zelltodrate und den Verlust des mitochondrialen Membranpotentials m während bei der Anwendung von SP2509 ein starker zytotoxischer Effekt beobachtet wurde. Hier kamen erste Zweifel daran auf, dass dieser Effekt von SP2509 aus der KDM1A-Hemmung resultiert. Zur genaueren Untersuchung dieser Diskrepanz wurden in dieser Arbeit die vier Inhibitoren an AML- (MOLM-13, THP-1), Ewing-Sarkomzellen (SK-ES-1, A673), Prostatakarzinomzellen (DU-145, PC-3) sowie einer KDM1A-Knockout-Zelllinie hinsichtlich ihrer Wirkung auf den Zelltod und den Verlust von m durchflusszytometrisch untersucht, sowie die Zellviabilität mittels einem Zytotoxizitätsassay bestimmt. Es konnte nach Behandlung mit SP2509 eine Induktion von Zelltod, dem Verlust von m und der Veränderung der Zellviabilität an AML- und Ewing-Sarkomzellen gezeigt werden. Im Gegensatz dazu zeigten GSK2879552 und TCP keine Wirkung, ORY-1001 nur bei der höchsten eingesetzten Konzentration an THP-1- und A673-Zellen. Die Wirkung aller verwendeten KDM1A-Inhibitoren auf Prostatakarzinomzellen war gering. Zur weiteren Evaluierung wurden Versuche mit KDM1A-Knockout- und deren parentalen Zellen durchgeführt. Hierbei zeigten beide Zelllinien nach der Behandlung mit SP2509 beinah identische Ergebnisse bezüglich Zelltod, Verlust von m und Zellviabilität. Dies bestätigt, dass die zytotoxische Wirkung von SP2509 nicht aus der KDM1A-Hemmung resultiert, sondern der Wirkstoff noch andere zytotoxische Effekte haben muss

Physical activity levels and determinants of change in young adults: a longitudinal panel study

Background: There is growing concern about physical inactivity in adolescents and young adults. Identifying determinants that are associated with low levels of physical activity and with changes in physical activity levels will help to develop specific prevention strategies. The present study describes the prevalence and potential determinants of physical activity behavior and behavior changes of young adults. The study is based on the Swiss Household Panel (SHP), a longitudinal study assessing social changes in a representative sample of Swiss households since 1999. Methods: Data is collected yearly using computer-assisted telephone interviews. Information is obtained from each household member over 14 years of age. Participants between 14 and 24 years entering the SHP between 1999 and 2006 were included (N = 3,068). “Inactive” was defined as less than 1 day/week of at least 30 minutes of moderate physical activity, “no sport” as exercising less than once a week. Age, gender, nationality, linguistic region, household income, education, membership in a sport club, reading, and Internet use were included as potential determinants of physical activity behavior and behavior change. Results: In both young men and young women, the prevalence of inactivity, “no sport”, and non-membership in a sport club was increasing with age. Women were less active than men of the same age. From one wave to the following, 11.1% of young men and 12.1% of young women became active, and 11.9% of men and 13.7% of women became inactive, respectively (pooled data over all eight waves). Non-membership in a sport club was the strongest predictor for “no sport” (ORmen 6.7 [4.9-8.9]; ORwomen 8.1 [5.7-11.4]), but also for being inactive (OR 4.6 [3.5-6.0]; 4.6 [3.3-6.4]). Leaving a sport club (OR 7.8 [4.4-14.0]; 11.9 [5.9-24.1]) and remaining non-member (OR 7.8 [4.7-12.9]; 12.4 [6.4-24.1]) were the strongest predictors of becoming “no sport”. Effects for becoming inactive were similar, though smaller (OR 5.9 [3.4-10.5] and 5.1 [2.7-9.6] for leaving a club, OR 5.1 [3.1-8.4] and 6.9 [4.0-11.8] for remaining non-member). Conclusions: The most important findings were the strong effects of sport club membership on general physical activity. The correlation between sport club membership and exercise was not surprising in its nature, but in its strength

Student's vocal participation trajectories in whole-class discussions during teacher professional development

Research studies have long shown that dialogic classroom interactions can have a positive impact on student learning. Despite this, in practice, monologic classroom discussions still predominate. This comparative scarcity of dialogic classroom discussions is linked to the considerable challenges inherent in cultivating them, both for teachers and their students. The aim of this paper is to demonstrate the extent to which, during a one-year teacher professional development program, students' vocal participation in whole-class discussions can be successfully fostered. As data material, we used videotaped classroom discussions of six classes (three mathematics and three history classes) from pre-, post-, and delayed post-test intervention lessons, as well as from three practice phases of the training. The discussions were evaluated using quantitative analyses and content analysis. In all six classes, the pre-post-test comparison revealed an increase in students' talk share. In four of the six classes, more students participated after the intervention than before. The type of student contributions changed in all classes: The students more often justified their contributions and referred to other students' contributions. The insights gained regarding the mostly non-linear progression of individual developments, and regarding subject-based differences, yield useful hints for the design of professional development formats

Teste com cartões de Teller e avaliação da visão funcional em crianças com baixa visão

To know the effectiveness of Teller card test along with the functional vision evaluation in low vision preschool children presenting normal or delayed development. Methods: Transversal study comprising patients from the children visual stimulation Ambulatory Service of the Faculty of Medical Sciences, University of Campinas Teaching Hospital, Campinas (SP)(FCM/HC/ Unicamp). The best corrected visual acuity was obtained using Teller cards and functional vision evaluation, independent from the child development. Results: From a total of 143 evaluated children, 65% did not respond to the Teller card test, only to, the functional vision evaluation. Among 143 children, 99 (70%) presented development delay and 44 (30%), normal development. Conclusion: The Teller card test was not enough to evaluate the children visual acuity with development delays, since more than half of them were not responsive to it, making it necessary that they were submitted to a complementary functional visual evaluation746362365Conhecer a eficácia do teste com Cartões de Teller em complemento a avaliação da visão funcional em crianças préescolares com baixa visão e desenvolvimento normal ou atrasado. Métodos: Estudo transversal em pacientes do ambulatório de estimulação visual infantil do Hospital de Clínicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas (HC/ FCM/Unicamp). A acuidade visual com a melhor correção óptica foi medida com Cartões de Teller e avaliação da visão funcional, independente do desenvolvimento da criança. Resultados: De um total de 143 crianças avaliadas 65% não responderam ao teste de Teller, porém, em complemento à avaliação da visão funcional pôde ser conhecida a acuidade visual das mesmas. Dentre as 143 crianças, 99 (70%) apresentaram atraso no desenvolvimento e 44 (30%) desenvolvimento normal. Conclusão: O Teste com Cartões de Teller para se conhecer a acuidade visual de crianças com atraso em seu desenvolvimento não se apresentou suficiente, pois mais da metade das crianças avaliadas não foi responsiva ao mesmo, necessitando de complementação de avaliação da visão funcional para a medida da acuidade visua

Teste com Cartões de Teller e avaliação da visão funcional em crianças com baixa visão

To know the effectiveness of Teller card test along with the functional vision evaluation in low vision preschool children presenting normal or delayed development.v. 74n.636236

A multimodal neuroimaging classifier for alcohol dependence

With progress in magnetic resonance imaging technology and a broader dissemination of state-of-the-art imaging facilities, the acquisition of multiple neuroimaging modalities is becoming increasingly feasible. One particular hope associated with multimodal neuroimaging is the development of reliable data-driven diagnostic classifiers for psychiatric disorders, yet previous studies have often failed to find a benefit of combining multiple modalities. As a psychiatric disorder with established neurobiological effects at several levels of description, alcohol dependence is particularly well-suited for multimodal classification. To this aim, we developed a multimodal classification scheme and applied it to a rich neuroimaging battery (structural, functional task-based and functional resting-state data) collected in a matched sample of alcohol-dependent patients (N = 119) and controls (N = 97). We found that our classification scheme yielded 79.3% diagnostic accuracy, which outperformed the strongest individual modality - grey-matter density - by 2.7%. We found that this moderate benefit of multimodal classification depended on a number of critical design choices: a procedure to select optimal modality-specific classifiers, a fine-grained ensemble prediction based on cross-modal weight matrices and continuous classifier decision values. We conclude that the combination of multiple neuroimaging modalities is able to moderately improve the accuracy of machine-learning-based diagnostic classification in alcohol dependence

A multimodal neuroimaging classifier for alcohol dependence

With progress in magnetic resonance imaging technology and a broader dissemination of state-of-the-art imaging facilities, the acquisition of multiple neuroimaging modalities is becoming increasingly feasible. One particular hope associated with multimodal neuroimaging is the development of reliable data-driven diagnostic classifiers for psychiatric disorders, yet previous studies have often failed to find a benefit of combining multiple modalities. As a psychiatric disorder with established neurobiological effects at several levels of description, alcohol dependence is particularly well-suited for multimodal classification. To this aim, we developed a multimodal classification scheme and applied it to a rich neuroimaging battery (structural, functional task-based and functional resting-state data) collected in a matched sample of alcohol-dependent patients (N = 119) and controls (N = 97). We found that our classification scheme yielded 79.3% diagnostic accuracy, which outperformed the strongest individual modality - grey-matter density - by 2.7%. We found that this moderate benefit of multimodal classification depended on a number of critical design choices: a procedure to select optimal modality-specific classifiers, a fine-grained ensemble prediction based on cross-modal weight matrices and continuous classifier decision values. We conclude that the combination of multiple neuroimaging modalities is able to moderately improve the accuracy of machine-learning-based diagnostic classification in alcohol dependence

Klassengespräche im Fachunterricht lernförderlich gestalten lernen: Entwicklung von Strategien für die Analyse von Unterrichtsgesprächen im Kontext einer Interventionsstudie mit Geschichts- und Mathematiklehrpersonen

In diesem Beitrag stellen wir dar, wie fachübergreifende und fachspezifische Anforderungen an eine dialogische Klassengesprächsführung im Fachunterricht (a) bei der Gestaltung einer Fortbildung für Mathematik- und Geschichtslehrpersonen und (b) bei der Analyse von videografierten Klassengesprächen aus beiden Fächern ineinandergreifen. Um mögliche Veränderungen des Gesprächsverhaltens (Lehrperson, Lernende) im Laufe dieser Fortbildung (1 Jahr) zu erfassen, werden unterschiedliche Analysemethoden verwendet, die unterschiedliche Perspektiven repräsentieren (allgemein- und fachdidaktische), unterschiedliche Aspekte der Gespräche fokussieren und quantifizierende mit qualitativen Verfahren kombinieren. Das Potenzial dieses Vorgehens wird anhand von zwei Beispielen – Videodaten einer Geschichts- und einer Mathematiklehrperson – illustriert und diskutiert, in denen je unterschiedliche Analyseverfahren zur Anwendung kommen

Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation

There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available threedimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed. To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)- mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)g inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease.: We have established and validated a suite of highly reproducible tumor microplate threedimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.This work was funded by The National Centre for the Replacement, Refinement and Reduction of Animals in Research (G1000121 ID no. 94513), Cancer Research UK (grant number C309/A8274), and by Red Tematica de Investigación Cooperativa en Cancer (RD06/0020/1022). We acknowledge NHS funding to the NIHR Biomedical Research Centre. MM is supported by a postdoctoral research contract (FIS, Program ‘Sara Borrell’, Instituto de Salud Carlos III), Ministerio de Ciencia e Innovación, Spain

'E-learning' como um complemento do ensino presencial de prevenção da cegueira: ensaio clínico

OBJECTIVE: To investigate if E-learning material improves the basal student knowledge level before attending the presential class of blindness prevention (BP) and if helps to fix this information one-month after the class. METHODS: Fourth-year medical students were randomly assigned to have a presential class of BP (Traditional group = TG) or to have a presential class of BP plus an additional E-learning material (E-learning group = ELG). This material was e-mailed one week before the presential class. The students were submitted to a multiple-choice test (with three options each) with seven questions immediately before the presential class, immediately after the class, and one-month later. The three tests had the same questions; however, the answers options were distributed in different sequences. The primary outcome was immediate pretest score. The secondary outcomes were immediate posttest score and one-month posttest score. RESULTS: Among the 120 fourth-year medical students, a random sample of 34 students was assigned to the TG and 34 students was assigned to the ELG. The two groups showed similar immediate posttest score (TG=6.8 and ELG=6.9; P<.754), but the differences at the immediate pretest score (TG=3.6 and ELG=4.7; P<.001), and at the one-month posttest score, were significant (TG=6.1 and ELG=6.8; P<.001). CONCLUSIONS: The pretest and the one-month posttest results suggested that the E-learning material acts as an effective complementary tool of the presential class of blindness prevention.OBJETIVO: Avaliar se um material disponibilizado através de E-learning antes de aulas presenciais de prevenção da cegueira (PC) melhora o nível de conhecimento basal dos estudantes, e ajuda a manter esse conteúdo um mês após a aula. MÉTODOS: Estudantes do quarto ano do curso médico foram aleatoriamente sorteados para ter aulas presenciais de PC (grupo tradicional = GT) ou ter aulas presenciais precedidas de material adicional por E-learning (grupo E-learning = GEL). Este material foi enviado por correio eletrônico uma semana antes da aula presencial. Os estudantes foram submetidos a testes de múltipla escolha com sete questões (com três alternativas cada) imediatamente antes da aula presencial, imediatamente após a aula, e um mês após a aula. Os três testes tiveram as mesmas questões: entretanto, as respostas foram distribuídas em sequências diferentes. O desfecho primário foi a nota do pré-teste. Os desfechos secundários foram as notas dos pós-teste imediato e do pós-teste tardio. RESULTADOS: Entre os 120 alunos do quarto ano de medicina, uma amostra aleatória de 34 alunos foi selecionada para o grupo GT e 34 alunos para o grupo GEL. Os dois grupos obtiveram nota similar no pós-teste imediato (GT=6.8 e GEL=6.9; P<.754), porém diferenças estatisticamente significativas no pré-teste (GT=3.6 e GEL=4.7; P<.001), e no pós-teste tardio (GT=6.1 e GEL=6.8; P<.001). CONCLUSÃO: Os resultados do pré-teste e do pós-teste tardio sugerem que o E-learning pode ser um complemento eficiente do ensino presencial de prevenção da cegueira.343