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H3B-6527 response in 40 HCC cell lines and 625 cell lines.

Legends describing each of the supplementary figures and tables

RNA-seq analysis of 24 CCLE HCC cell lines.

Crystallographic Data collection and Refinement Statistics.

Body weight data of H3B-6527 as single agent and in combination

RNA-seq analysis of TCGA HCC samples.

H3B-6527 efficacy studies in 30 PDX models show that 10 models are responsive

H3B-6527 effects in a HCC cell line Hep3B orthotopic xenografts in female nude mice.

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1–3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999–7013. ©2017 AACR.

Purpose The purpose of this study is to inquire into the effectiveness of authentic writing instruction embedded in a critical service-learning project in a middle school English Language Arts curriculum. Design/methodology/approach This paper analyzes middle school students’ survey responses before and after their participation in a critical service-learning project designed to engage students in authentic writing. Specifically, the paper considers students’ perspectives of community and writing as a result of their participation in the project. Findings Participants’ perspectives fell into three categories: audience influence, empowerment or personal knowledge to act and confidence in ideas. Originality/value These perspectives suggest a deviation from common findings regarding the benefits of authentic writing instruction, as the presence of an audience in this study often hindered student confidence in their abilities as writers and community change agents. Authors draw from the findings to offer recommendations to support teachers in effectively incorporating authentic writing practices and audiences into their instruction.

This is the introduction to the Yearbook on Critical Social Justice Across the Spectrum of Teaching and Learning: Theory and Practice in Communities and Classrooms.

Background American students represent diverse life experiences, languages, cultures, and community memberships. Given the relatively unchanged demographics of U.S. teachers (primarily middle-class, white females), it is important that teachers engage in culturally proactive pedagogy and design curriculum that both reflects their students’ culture and engages them in developing skills to be participants in a larger society. Purpose This chapter explores how three veteran eighth-grade English language arts teachers in a large middle school in the southeastern United States navigated Youth Participatory Action Research (YPAR) as a culturally proactive and socially just pedagogy and encouraged students to examine power, privilege, and oppression in literature, in informational texts, and in their local communities to identify ways they might change inequities. Research Design Findings from this qualitative study suggest that even veteran teachers often struggle to implement social justice and culturally proactive pedagogies. Findings These teachers wobbled with their own uncertainty about the differences between a more traditional pedagogy, where they drive the learning, and a critical pedagogy that places the students in charge of the direction of their learning. Conclusion/Recommendations From the findings, recommendations are made to teachers who grapple with incorporating socially just and culturally proactive pedagogies into their teaching.

This work explores the potential of using a critical service-learning project with middle grades English language arts students to facilitate development of a social justice mindset. Through The Re...

The effects of professional teacher dispositions on student development have been widely documented. Yet there is limited discussion of the impact of socially just dispositions. The present study critically examines the relationship between justice-oriented mind-sets in preservice teachers and their perceptions of teaching in urban schools. Using critical interpretive case study, we analyze a series of journal reflections from a diverse group of prospective teachers to determine whether exposure to service-learning opportunities within an urban school influenced their views about urban schools and students. As a result of the findings from the study, recommendations for teacher education are addressed.

Drawing on a theory of program coherence, the establishment of an educational third space, and intentional clinical experience, the authors created a unique entry point in a teacher education program. The authors developed the Onsite Secondary Education Project (OSSEP) to connect relevant educational theory and discipline-specific pedagogy through intentional clinical placements for first-semester preservice teachers. Results from this exploratory research demonstrate that program coherence and structured clinical experiences can help preservice teachers orient themselves to the teaching profession and connect educational theory and practice. However, unintentional experiences were identified, suggesting that increased exposure to the classroom helped shape participants’ views toward the teaching profession. Findings offer evidence of a teacher education that balances the idealism of teacher education with the practicalities of the PK-12 classroom.

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1–3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999–7013. ©2017 AACR.

School districts in the U.S. are increasingly calling on content area and English as a Second Language (ESL) teachers to work together to plan and deliver instruction in classrooms with linguistica...

This exploratory case study examines the experiences of one first-year, Black female English language arts teacher and her Advanced Placement Language and Composition students. Through an exploration of her relationship with her Black students, the data reveal how she faced challenges when finding balance in her classroom management style, encountered cultural dissonance, developed teacher-student relationships, and struggled with how White, middle-class values may have shaped her classroom interactions with her students. The results of this study inform the field of teacher education and have potential implications for pre-service and inservice teachers worldwide working with students from diverse racial/ethnic backgrounds.

Through course readings, museum visits, focus group discussions, and reflections on clinical observation experiences, preservice teachers developed a fictitious educational setting (Courage High School) that incorporates critical, social justice practices and privileges the experiences and cultural backgrounds of all K-12 students. Participants presented a model for this school and how it would benefit specific student needs. From our classroom experiences, the authors developed recommendations for how future educators problematized ideas of courage, race, and diversity in developing Courage High School. The authors suggest that using museums as experiential pedagogical tools and offering authentic learning opportunities can encourage a critical, social justice orientation to teaching and may inspire future teachers to enact courage in their teaching practice.

Using case study method, this project examines the perceptions and practices related to development of self and cultural awareness among a cohort of 104 (n=104) first-year students, all aspiring to become future teachers. Over the course of one academic semester, first year students who planned to enter the teacher education program participated in readings, activities, assignments, field based observations, and discussions developed to facilitate self and cultural awareness. The findings from analyses of these artifacts indicate that pre-service teachers began to demonstrate deeper awareness of how personal opinions and biases influenced their interactions with others and the types of characteristics related to appreciating diversity in urban classrooms. This study has implications for engaging first year students in early field-based clinical experiences in order to develop self and cultural awareness in preparation for teaching.

In this chapter, the authors discuss the outcomes of a program evaluation of a university-middle school service-learning partnership. The initial goal was to evaluate the extent to which three middle school teachers, our community partners, were satisfied with the volunteer experience their seventh grade students had with first-year university students. The evaluation came after a three-year partnership between undergraduates enrolled in a liberal studies course focused on citizenship and education and a team of middle school students and their teachers. Interviews revealed that this partnership enabled teachers to view their students through a different lens than they had prior to the partnership. Further, teachers suggested that the service-learning activities facilitated a deeper understanding of students' funds-of-knowledge and talents. This research supports the possibility that there are valuable unintended outcomes of service-learning partnerships between universities and public schools.

Service-learning is commonly employed in teacher preparation within the bounds of discipline-specific methods courses. This chapter presents an overview of the Civic Minor in Urban Youth and Communities program, which takes an interdisciplinary approach to service-learning as an ethos rather than a limited experience bounded by content area or grade level. In this three-course sequence, students examine the relationship between education and citizenship, design and implement their own service-learning projects, and learn how to implement service-learning in their future classrooms. This immersive experience provides students with a de-centering experience that promotes an asset-based, service-oriented approach to diverse communities.

Whether it is in the sciences or humanities, inquiry is a valued pedagogy for teaching and learning. Teacher candidates often enter into their teacher preparations programs with limited experience and understanding of the process of inquiry. The chapter's purpose is to introduce and discuss the Inquiry Processing Cycle, which is a theoretical model for engaging in inquiry. The chapter explains how the Inquiry Processing Cycle emerged from Grounded Theory (Glaser & Strauss, 1967) from an on-going qualitative study of first-year undergraduate students (n=110) in a College of Education first-year class called Prepared for Success. The study found that the participants perceived that the process of inquiry was a fundamental part of being a successful college student as well as being an effective teacher. Yet, the participants were unclear about how to actually proceed with an inquiry. From these findings, the chapter illustrates how to engage in the inquiry process using the Inquiry Processing Cycle.

English language learners (ELLs) are the fastest growing population in the US schools (National Center for Education Statistics (NCES), 2011); these students are consistently outperformed by their White counterparts on the National Assessment of Educational Progress data (NCES, 2011). While traditional English as a second language (ESL) classes emphasize building students’ knowledge of spoken and written aspects of the English language, focusing on vocabulary and grammar instruction, we propose that ESL instruction might also include a focus on more nuanced elements of the language such as dialect and register and the relation between power and language, which is critical literacy. This article defines critical literacy in working with ELLs, explores the potential benefit of understanding language/power relationships, and provides one unit plan that will enable teachers to facilitate this development of knowledge.

In an era marked by major political and social change, teachers of urban students must be prepared to engage and appreciate an ever-changing demographic of learners who come from backgrounds different from their own. In this chapter, we discuss the need for professional development embedded in culturally responsive teaching, multicultural education, and critical literacy, all of which have the power to incite social action. We posit that social action has the potential to empower and engage urban learners in meaningful ways. We believe this work fills the gap that exists in the literature regarding urban education and social and political movements

Research in teacher education suggests that field experiences in community settings can offer pre-service teachers a context for understanding the link between theory and practice. This paper documents the experiences of pre-service educators participating in a service-learning experience at a Children's Defense Fund Freedom School in the south-eastern United States. Pre-service teachers engaged in critical reflection, online journals, and daily debriefing sessions and praised the benefits of a service experience in an urban context and explained how interactions within the programme gave them the insight into the teaching profession. The author argues that this project successfully bridged the gap between teacher education theory and practice.

Within social studies, researchers note limited attention has been given to examining gender differences associated with technology integration, and have called for increased dialogue regarding gender-related technology issues (Crocco, 2006, 2008; Crocco, Cramer, & Meier, 2008; Friedman & Hicks, 2006; Marri, 2007; Mason, Manfra, & Siko, 2005; Sanders, 2006). In response, this chapter explores the gender divide in secondary teachers' perceptions of effective technology integration. Using a qualitative research design, this chapter provides insight into social studies teachers' perceptions of their pedagogical practices and technology integration. The purpose of this study is to develop an understanding of the differences in male and female teachers' use of technology to teach and support student learning. Consideration of how technology is associated with gender-sensitive pedagogical thinking and practice may address the aforementioned gap in technology usage in social studies. Patterns uncovered in data analysis suggest that gender plays a critical role in social studies technology integration. The results from this study can inform methods in which technology is integrated into future social studies classrooms, particularly in emerging areas such as online courses.

Hepatocellular carcinoma (HCC) has limited treatment options and generally poor prognosis. Recent genomic studies have identified FGF19 as a driver oncogene in HCC. FGF19 is a gut secreted hormone that acts in the liver through FGFR4 to regulate bile acid synthesis. Consistent with the notion that FGF19 is a driver oncogene in HCC, transgenic mice overexpressing FGF19 form liver tumors and genetic ablation of FGFR4 prevented tumor formation. These data suggest targeting FGFR4 would have therapeutic benefit in HCC with altered FGF19 signaling. While a number of Pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by their FGFR1-3 related dose limiting toxicities. Using structure guided drug design, we have generated a highly selective covalent FGFR4 inhibitor, H3B-6527. Biochemical and cellular selectivity assays showed that H3B-6527 is >300 fold selective towards FGFR4 compared to other FGFR isoforms. Addition of H3B-6527 to FGF19 amplified HCC cell lines led to dose dependent inhibition of FGF19/FGFR4 signaling and concomitant reduction in cell viability. In a panel of 40 HCC cell lines, H3B-6527 selectively reduced the viability of cells that harbor FGF19 amplification and showed no effect in FGF19 non-amplified HCC cell line models. Oral dosing of H3B-6527 to mice led to dose-dependent pharmacodynamic modulation of FGFR4 signaling and tumor regression in FGF19 altered HCC cell line derived xenograft models. H3B-6527 demonstrated inhibition of tumor growth in an orthotopic liver xenograft model of FGF19 altered HCC grown in nude mice. Importantly, the inhibition of tumor growth occurred at doses that were well tolerated in mice and no evidence of FGFR1-3 related toxicities were observed at efficacious doses. In a panel of 30 HCC patient-derived xenograft (PDX) models, H3B-6527 demonstrated tumor regressions in the context of FGF19-amplified tumors. In addition, H3B-6527 showed antitumor activity and tumor regressions in PDX models with high FGF19 expression but no FGF19 amplification. The mechanism for FGF19 overexpression in the absence of gene amplification is under investigation. In conclusion, our preclinical studies demonstrate that FGF19 expression is a predictive biomarker for response to FGFR4 inhibitor therapy. Genomic analysis of public and proprietary data sets indicates that at least approximately 30% of HCC patients exhibit altered FGF19 expression and could potentially benefit from H3B-6527 monotherapy treatment. Citation Format: Anand Selvaraj, Erik Corcoran, Heather Coffey, Sudeep Prajapati, Ming-Hong Hao, Nicholas Larsen, Jennifer Tsai, Takashi Satoh, Kana Ichikawa, Julie Jaya Joshi, Raelene Hurley, Jeremy Wu, Chia-Ling Huang, Suzanna Bailey, Craig Karr, Pavan Kumar, Victoria Rimkunas, Crystal Mackenzie, Nathalie Rioux, Amy Kim, Sandeep Akare, George Lai, Lihua Yu, Peter Fekkes, John Wang, Markus Warmuth, Peter Smith, Dominic Reynolds. H3B6527, a selective and potent FGFR4 inhibitor for FGF19-driven hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3126. doi:10.1158/1538-7445.AM2017-3126

The use of cyclodextrins (CDs) and their derivatives as enantioselective modifiers for chiral discrimination in various capillary electrophoresis (CE) modes has been growing in popularity. The current studies have succesfully applied chiral CE mediated with cyclodextrins for the chiral recognition and racemic resolution of several water-soluble melatonergic drug enantiomers such as BMS-191435, BMS-191602 and BMS-193587. Cyclodextrins including β-cyclodextrin (β-CD) and its derivative heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) were chosen as chiral selectors incorporated in the buffer system. Comparative studies of these two CDs on the chiral recognition of drug enantiomers indicated specific inclusion of the guest molecules in the CD cavity. Optimum chiral capillary electrophoresis conditions such as concentration of chiral selectors and proper choice of pH were studied. Complexation binding constants for the interaction between chiral selectors and drug enantiomers were determined, indicating higher affinity forS enantiomers. Molecular interactions with DM-β-CD were also investigated using a computer modelling approach. Two distinct molecular interactions relating to the inclusion complexes were simulated. Energy minimized structures indicated the interaction differentiation of 1 kcal/mol in favor ofS enantiomer (1cal= 4.184J), which is consistent with chiral CE results. NMR spectroscopy was also utilized to determine the sites of molecular interaction between enantiomers and chiral selectors. These studies provide a structural basis for the understanding and application of CD mediated CE chiral separations in pharmaceutical research.

Elevated levels of potassium (K + ) promote maturation and survival of cerebellar granule neurons in culture. When switched from a culture medium containing high K + (25 mM) to one with low K + (5 mM) mature granule neurons undergo death by apoptosis. The mechanism by which high K + promotes neuronal survival and conversely inhibits apoptosis) is unclear. Several pieces of evidence indicate that an increase in intracellular calcium (Ca 2+ ) resulting from depolarization mediated-influx of extracellular Ca 2+ is necessary. We examined the effect of thapsigargin on granule neuron cultures. Thapsigargin is an inhibitor of the endoplasmic reticular Ca 2+ ATPase causing a depletion of Ca 2+ from internal stores. this treatment would therefore be expected to raise intracellular cytosolic Ca 2+ without membrane depolarization. We find that treatment of mature neurons with thapsigargin at doses ⩾5 nM inhibits death resulting from the lowering of extracellular K + . The survival effect of thapsigargin was not affected by inhibitors of extracellular Ca 2+ influx including nifedipine, verapamil, methoxyverapamil, Mg 2+ , and Ni 2+ , nor was it inhibited by the NMDA receptor antagonist, MK801. We have further examined whether thapsigargin could substitute for elevated K + during the maturation of granule cells. Unexpectedly, treatment of younger (immature) neuronal cultures with the same dose of thapsigargin (5 nM) induced cell death. DNA fragmentation analysis suggested that death was due to apoptosis and not toxicity. As observed with the survival effect on mature neurons, the lethal effect of thapsigargin on immature granule cells was not prevented by inhibitors of Ca 2+ influx.