8 research outputs found
One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression
No full textEwing sarcoma is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long-term survival rates of less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between Ewing sarcoma and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in patients with Ewing sarcoma. We show that both genetic inhibition and pharmacologic inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2, lead to substantial inhibition of Ewing sarcoma cell proliferation and colony-forming ability and that this effect is primarily caused by depletion of glycine and one-carbon units required for the synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor pralatrexate, similarly yields profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of serine hydroxymethyltransferase 2 dramatically impairs tumor growth in a xenograft model of Ewing sarcoma. Together, these data establish dependence on one-carbon metabolism as a novel and targetable vulnerability of Ewing sarcoma cells, which can be exploited for therapy. Significance: Using both genetic and pharmacologic approaches, this study identifies Ewing sarcoma’s dependence on one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy
Recommended from our members
A comprehensive assessment of children's activity-travel patterns with implications for activity-based travel demand modeling
No full texttextChildren are an often overlooked and understudied population group, whose travel needs are responsible for a significant number of trips made by a household. In addition, children’s travel and activity participation have direct implication for adults’ activity-travel patterns. A better understanding of children’s activity-travel patterns and the linkages between parents and children’s activity-travel needs is necessary for accurate prediction and forecasting of activity-based travel demand modeling systems. In contrast to the need to examine and model children’s activity-travel patterns, existing activity-based research and modeling systems have almost exclusively focused their attention on the activity-travel patterns of adults. Therefore, the goal of this research effort is to contribute to the area of activity-based travel demand analysis by comprehensively examining children’s activity-travel patterns, and by developing a framework for incorporating children within activity-based travel demand modeling systems. This dissertation provides a comprehensive review of previous research on children’s activity engagement and travel by focusing on the dimensions characterizing children’s activity-travel patterns and the factors affecting these dimensions. Further, an exploratory analysis examines the weekday and weekend activity participation characteristics of school-going children. The study focuses on the overall time-use of children in different types of activities, as well as on several dimensions characterizing the context of participation in activities. In addition, the dissertation discusses the treatment of children within current activity-based travel demand modeling systems and conceptualizes an alternative framework for simulating the daily activity-travel patterns of children. An empirical analysis is undertaken of the post-school out-of-home activity-location engagement patterns of children aged 5 to 17 years. Specifically, this research effort utilizes a multinomial logit model to analyze children’s post-school location patterns, and employs a multiple discrete-continuous extreme value (MDCEV) model to study the propensity of children to participate in, and allocate time to, multiple activity episode purpose-location types during the after-school period. Finally, the paper identifies the need and opportunities for further research in the field of children’s travel behavior analysis.Civil, Architectural, and Environmental Engineerin
Developing a digital library of computer science teaching resources: Report of the ITiCSE\u2798 working group on the online computer science teaching center
No full textWe describe recommendations for how to plan and develop a web-based digital library to support computer science education, i.e., the online Computer Science Teaching Center (CSTC) . This report details three facets: The identification of appropriate resources for inclusion in the CSTC, the review process for submissions, and the development and promotion of CSTC. A taxonomy of teaching resources is provided, and includes. This material is based upon work partially supported by the National Science Foundation under Grant No. DUE-9752190 and by the Association for Computing Machinery Education Board. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the Association for Computing Machinery Education Board
Treatment of obesity in children a study on the efficacy of a family-based group program compared with routine counselling
No full textFrom the geopolitical to the everyday : 'home' for Muslim women in London and Bristol.
No full textPhDMy thesis examines ideas of home, identity and belonging for Muslim women within the context of the domestic ‘War on Terror’. My project has two main strands. My research is framed by a discursive examination of both the mobilization of ideas of home and the positioning of Muslim women within imaginative geographies of the domestic War on Terror. I focus upon media coverage of terror plot home raids (beginning with the 7/7 bombings) and subsequent socio-political debates concerning the ‘veil’. The second strand of my research concentrates upon exploring the lived experience and emotional geographies of home, identity and belonging for Muslim women in London and Bristol.
My research addresses several important research agendas. I contribute to and develop contemporary debates concerning geographies of race and racism. I examine both the construction of racialised discourses of national identity, belonging and securitization and how racism is experienced negotiated and resisted. I examine some of the effects that religio-racial profiling has had upon my participants’ everyday lives, geographies of mobility and articulations of belonging/citizenship, particularly in relation to national identity. I argue that covering practices as a marker of religious identity have socio-spatial effects, which inform my participants’ negotiation and inhabitation of the different localities encountered within their everyday geographies. I explore how identity and belonging are experienced through the material and emotional creation of home, particularly in relation to religious practices, arguing that home becomes an important site of identity affirmation in relation to experiences of racism. More broadly my research contributes to debates concerning the increasing prevalence of religion within contemporary community and individual identity politics. Finally, I draw out how my participants’ experiences impact upon their ideas of citizenship and belonging, augmenting theorisations of citizenship which posit citizenship as multiple and rooted in place not nationality
