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"Farrell, Amy"
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Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer
The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50–60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.
Journal Article
Fat Shame
To be fat hasn't always occasioned the level of hysteria that this condition receives today and indeed was once considered an admirable trait. Fat Shame: Stigma and the Fat Body in American Culture explores this arc, from veneration to shame, examining the historic roots of our contemporary anxiety about fatness. Tracing the cultural denigration of fatness to the mid 19th century, Amy Farrell argues that the stigma associated with a fat body preceded any health concerns about a large body size. Firmly in place by the time the diet industry began to flourish in the 1920s, the development of fat stigma was related not only to cultural anxieties that emerged during the modern period related to consumer excess, but, even more profoundly, to prevailing ideas about race, civilization and evolution. For 19th and early 20th century thinkers, fatness was a key marker of inferiority, of an uncivilized, barbaric, and primitive body. This idea--that fatness is a sign of a primitive person--endures today, fueling both our $60 billion war on fat and our cultural distress over the obesity epidemic. Farrell draws on a wide array of sources, including political cartoons, popular literature, postcards, advertisements, and physicians' manuals, to explore the link between our historic denigration of fatness and our contemporary concern over obesity. Her work sheds particular light on feminisms' fraught relationship to fatness. From the white suffragists of the early 20th century to contemporary public figures like Oprah Winfrey, Monica Lewinsky, and even the Obama family, Farrell explores the ways that those who seek to shed stigmatized identities--whether of gender, race, ethnicity or class--often take part in weight reduction schemes and fat mockery in order to validate themselves as civilized. In sharp contrast to these narratives of fat shame are the ideas of contemporary fat activists, whose articulation of a new vision of the body Farrell explores in depth. This book is significant for anyone concerned about the contemporary war on fat and the ways that notions of the civilized body continue to legitimate discrimination and cultural oppression.
eBook
A spectrum of inclusion : Strategies for students with ASD
As teachers we all experience students with autism spectrum disorder (ASD). These students are unique, insightful and bring a distinct dynamic to your classroom. Throughout my teaching career, these students have taught me to be flexible, innovative and to plan lessons that are creative and 'out of the box.' There are many resources to help support us as we strive to ensure that our classrooms are safe and inclusive places for all our students, including those with ASD. In this article, I outline some of the starting points and key resources that can help you make your classroom ASD-friendly [Author abstract]
Journal Article
MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance
Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.
Neuroendocrine differentiation of epithelial tumor cells can contribute to cancer cell resistance and survival. Here, the authors show that dysregulated c-Myc promotes neuroendocrine differentiation in pancreatic ductal adenocarcinoma, leading to poor survival and chemoresistance.
Journal Article
Enhancing detection of labor violations in the agricultural sector: A multilevel generalized linear regression model of H-2A violation counts
Agricultural workers are essential to the supply chain for our daily food, and yet, many face harmful work conditions, including garnished wages, and other labor violations. Workers on H-2A visas are particularly vulnerable due to the precarity of their immigration status being tied to their employer. Although worksite inspections are one mechanism to detect such violations, many labor violations affecting agricultural workers go undetected due to limited inspection resources. In this study, we identify multiple state and industry level factors that correlate with H-2A violations identified by the U.S. Department of Labor’s Wage and Hour Division using a multilevel zero-inflated negative binomial model. We find that three state-level factors (average farm acreage size, the number of agricultural establishments with less than 20 employees, and higher poverty rates) are correlated with H-2A violations. These findings offer valuable insights into where H-2A violations are being detected at the state and industry levels.
Journal Article
Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression
High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer.
Journal Article
Comparing different domains of analysis for the characterisation of N-glycans on monoclonal antibodies
With the size of the biopharmaceutical market exponentially increasing, there is an aligned growth in the importance of data-rich analyses, not only to assess drug product safety but also to assist drug development driven by the deeper understanding of structure/function relationships. In monoclonal antibodies, many functions are regulated by N-glycans present in the constant region of the heavy chains and their mechanisms of action are not completely known. The importance of their function focuses analytical research efforts on the development of robust, accurate and fast methods to support drug development and quality control. Released N-glycan analysis is considered as the gold standard for glycosylation characterisation; however, it is not the only method for quantitative analysis of glycoform heterogeneity. In this study, ten different analytical workflows for N-glycan analysis were compared using four monoclonal antibodies. While observing good comparability between the quantitative results generated, it was possible to appreciate the advantages and disadvantages of each technique and to summarise all the observations to guide the choice of the most appropriate analytical workflow according to application and the desired depth of data generated.
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•Comparative analysis of N-glycans present on four monoclonal antibodies using ten analytical methods reported.•Data presented to allow for impartial selection of appropriate analytical strategy depending on depth of information desired and ease of approach.•Methods included intact and subunit strategies and glycopeptide characterisation compared to released N-glycan as the current gold standard.
Journal Article
Not Guilty
A brilliant book that masterfully debunks the conventional wisdom that those who are charged with crimes in our criminal justice system, even when they are acquitted at trial, are almost certainly guilty. It is a data-driven tour de force. --Richard A. Leo, author of Police Interrogation and American Justice. Givelber and Farrell make a persuasive case that most jury acquittals are based on evidence not emotion, and that acquittals should be taken to mean what they say: that the defendant is Not Guilty. --Samuel Gross, co-author of A Modern Approach to Evidence: Text, Problems, Transcripts, and Cases. As scores of death row inmates are exonerated by DNA evidence and innocence commissions are set up across the country, conviction of the innocent has become a well-recognized problem. But our justice system makes both kinds of errors - we acquit the guilty and convict the innocent - and exploring the reasons why people are acquitted can help us to evaluate the efficiency and fairness of our criminal justice system. Not Guilty provides a sustained examination and analysis of the factors that lead juries to find defendants not guilty, as well as the connection between those factors and the possibility of factual innocence, examining why some criminal trials result in not guilty verdicts and what those verdicts suggest about the accuracy of our criminal process.
eBook