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Context Thyroid-stimulating hormone (or thyrotropin) receptor (TSHR) could be a selective target for small molecule ligands to treat thyroid cancer (TC). Objective We report a novel, orally efficacious ligand for TSHR that exhibits proliferation inhibitory activity against human TC in vitro and in vivo, and inhibition of metastasis in vivo. Methods A35 (NCATS-SM4420; NCGC00241808) was selected from a sublibrary of >200 TSHR ligands. Cell proliferation assays including BrdU incorporation and WST-1, along with molecular docking studies were done. In vivo activity of A35 was assessed in TC cell–derived xenograft (CDX) models with immunocompromised (NSG) mice. Formalin-fixed, paraffin-embedded sections of tumor and lung tissues were observed for the extent of cell death and metastasis. Results A35 was shown to stimulate cAMP production in some cell types by activating TSHR but not in TC cells, MDA-T32, and MDA-T85. A35 inhibited proliferation of MDA-T32 and MDA-T85 in vitro and in vivo, and pulmonary metastasis of MDA-T85F1 in mice. In vitro, A35 inhibition of proliferation was reduced by a selective TSHR antagonist. Inhibition of CDX tumor growth without decreases in mouse weights and liver function showed A35 to be efficacious without apparent toxicity. Lastly, A35 reduced levels of Ki67 in the tumors and metastatic markers in lung tissues. Conclusion We conclude that A35 is a TSHR-selective inhibitor of TC cell proliferation and metastasis, and suggest that A35 may be a promising lead drug candidate for the treatment of differentiated TC in humans. [ABSTRACT FROM AUTHOR]

Educators are exploiting the advantages of advanced web-based collaboration technologies and massive online interactions. Interactions between learners and human or nonhuman resources therefore play an increasingly important pedagogical role, and the way these interactions are expressed in the user interface of virtual learning environments is assumed to greatly impact the learning process. This paper presents an evaluation of how interactions for learning are expressed in the user interface of an IMS Learning Design (LD) runtime environment. Specifically, we selected Reigeluth and Moore's set of interactions for learning was selected and tested how these interactions are visually expressed and supported in the user interface of the Service Based Learning Design (SLeD) player. The findings show several drawbacks in the current way of visualizing units of learning during runtime. For instance, the synchronization of participants in corresponding learning and support activities is not clearly expressed, the current role remains unclear in multi-role settings, and the nested display of unit-of-learning contents impedes navigation. Drawing from these findings, the paper offers recommendations regarding future development of IMS LD runtime user interfaces.

Although the term "radiation" has a fixed place in everyday life as well as in the media, there is very little empirical research on students' conceptions about this topic. In our study we wanted to find out what students associate with this term. In 2009, we asked 509 students (between grade 4 and grade 6) from seven different schools to draw pictures related to "radiation". This method of children's drawings was supported by short interviews (n?=?74). The motifs appearing in the drawings were analysed, and we investigated whether or not the age and the sex of the children had any influence on the choice of motifs. One major result was that the older the students were, the more likely they were to choose sources of invisible radiation (nuclear power plants, mobile phones) as their motifs. Nine months after the tragic events in Fukushima (and at the same time 2 years after the 2009 data collection), we replicated the study. This time, we received 516 drawings from the same schools as in the 2009 study (supported by 33 interviews). This replicative trend study made it possible to compare the choice of motifs and discover possible differences. The results of this analysis showed that the drawings of 2011 included significantly more motifs related to radioactivity. This difference was prevalent in the drawings regardless of sex or age differences. Direct references to the Fukushima accident could be found in both the drawings and interviews.

One basis of good teaching is to know about your students' preconceptions. Studies about typical ideas that students bring to the science classroom have been and continue to be a major field in science education research. This study aims to explore associations and ideas that students have regarding "radiation", a term widely used in various fields and necessary to understand fundamental ideas in science. In an explorative study, the perceptions of 50 high school students were examined using semi-structured interviews. The students were 14-16 years old and were chosen from 7 different high schools in an urban area in Austria. Following an interview guideline, students were asked about their general associations with the term "radiation" as well as about their general understanding of different types of radiation. A qualitative analysis of these interviews following the method of Flick (2009) revealed that the students' associations were, to a great extent, very different from the scientific use of the term. Several conceptions that could inhibit students' learning processes could be identified. Consequences for the teaching of the topic "radiation" in science lessons, which are based on these preconceptions, are presented in the conclusion.

Following publications emphasizing the need of a taxonomy for instructional methods, this article presents a literature review on classifications for learning and teaching in order to identify possible classifications for instructional methods. Data was collected for 37 classifications capturing the origins, theoretical underpinnings, purposes and uses, as well as degrees of documentation of these classifications. Using cluster analysis, the classifications were first grouped into three clusters according to their characteristics. A discriminant analysis identified three foci: narrow focus, holistic focus and versatile focus. Second, classifications were estimated whether they fulfill taxonomy validation criteria, which are used to judge classifications' internal consistency, meaningfulness to users, ease of navigation, and comprehensible content division. Only a small number of the reviewed classifications fulfilled more than one of the criteria, with the most criteria fulfilled being three. The article concludes that a classification of instructional methods is still needed as the reviewed classifications do not provide sufficient quality, purpose-related setup, or user orientation. Future classification efforts should involve the users in the development to ensure appropriate language and task orientation of the classification. An approach for performing user-driven development is outlined, and applications in a higher education setting and instructional design software are demonstrated. (Contains 4 tables.)

Context: We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza). Objective: To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED. Design: We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher potency phase dependent on TSHR/IGF1R crosstalk and the lower potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of teprotumumab biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR. Results: We show: (1) Tepro dose-dependently inhibits stimulation by TED-Igs; (2) Tepro does not bind to TSHRs; (3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and (4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk and prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs. Conclusion: We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/ IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED. [ABSTRACT FROM AUTHOR]