This dissertation studies Ovid’s Fasti and contemporary Augustan Rome. In this poem, Ovid provides explanations for Rome’s religious festivals, featuring numerous stories of Rome’s mythic ...foundations. These tales were newly prominent in Ovid’s time: Augustus used foundational legends to showcase his relationship to Rome’s founders and to assert divine authority for his rule. In art, architecture, law, and his public calendar, he promoted a narrative of Rome’s origins in which men supervised state and religion, while women acted chiefly in the domestic sphere. In the Fasti, by contrast, Ovid examines the female experience: multiple voices and perspectives offer a complex picture that challenges the imperial vision. By allowing women to articulate the sexual violence beneath many of Rome’s rituals (e.g., the Matronalia and the Compitalia), Ovid highlights female experience as foundational to Roman religion and identity. He vividly illustrates the agency of women in bringing peace and prosperity to the state by depicting women such as Lucretia, the Sabine women, and Claudia Quinta as speaking or acting decisively and taking control of their circumstances. Where male behavior is often impulsive (e.g., Mars) or ineffectual (e.g., Numa), women (e.g., Carmentis, Rhea Silvia) predict the future, behave rationally, and even redeem male disorder. Chapter 1 provides a background of Augustan thought on women. Chapter 2 reviews Ovid’s works from the Heroides to the Fasti, tracing his representation of the female voice and experience of sexual violence. Chapter 3 treats Fasti 2: studying two themes male vis and the silencing of women. Women’s voices, ultimately stolen, represent contradictory or alternative accounts of Roman ritual erased by powerful male figures. Chapter 4 studies Fasti 3, highlighting the persistent juxtaposition between the foolish or destructive male figures (Mars, Romulus, Bacchus, Aeneas) and the rational, productive female characters (Rhea Silvia, Sabine Women, Ariadne, Anna Perenna). Chapter 5 examines Fasti 4, which features numerous festivals of production (Fordacidia, Parilia, Vinalia) with special emphasis on the role of mothers in the Megalensia and the Cerealia. Ovid consistently obscures distinguishing markers between matronae and meretrices, suggesting that the state necessarily incorporates and relies upon women of all classes.
"Effective Research Data Management (RDM) is a key component of research integrity and reproducible research, and its importance is increasingly emphasised by funding bodies, governments, and ...research institutions around the world. However, many researchers are unfamiliar with RDM best practices, and research support staff are faced with the difficult task of delivering support to researchers across different disciplines and career stages. What strategies can institutions use to solve these problems? Engaging Researchers with Data Management is an invaluable collection of 24 case studies, drawn from institutions across the globe, that demonstrate clearly and practically how to engage the research community with RDM. These case studies together illustrate the variety of innovative strategies research institutions have developed to engage with their researchers about managing research data. Each study is presented concisely and clearly, highlighting the essential ingredients that led to its success and challenges encountered along the way. By interviewing key staff about their experiences and the organisational context, the authors of this book have created an essential resource for organisations looking to increase engagement with their research communities. This handbook is a collaboration by research institutions, for research institutions. It aims not only to inspire and engage, but also to help drive cultural change towards better data management. It has been written for anyone interested in RDM, or simply, good research practice.
Micronutrient research typically focuses on analyzing the effects of single or a few nutrients on health by analyzing a limited number of biomarkers. The observational study described here analyzed ...micronutrients, plasma proteins, dietary intakes, and genotype using a systems approach. Participants attended a community-based summer day program for 6–14 year old in 2 years. Genetic makeup, blood metabolite and protein levels, and dietary differences were measured in each individual. Twenty-four-hour dietary intakes, eight micronutrients (vitamins A, D, E, thiamin, folic acid, riboflavin, pyridoxal, and pyridoxine) and 3 one-carbon metabolites homocysteine (Hcy), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), and 1,129 plasma proteins were analyzed as a function of diet at metabolite level, plasma protein level, age, and sex. Cluster analysis identified two groups differing in SAM/SAH and differing in dietary intake patterns indicating that SAM/SAH was a potential marker of nutritional status. The approach used to analyze genetic association with the SAM/SAH metabolites is called middle-out: SNPs in 275 genes involved in the one-carbon pathway (folate, pyridoxal/pyridoxine, thiamin) or were correlated with SAM/SAH (vitamin A, E, Hcy) were analyzed instead of the entire 1M SNP data set. This procedure identified 46 SNPs in 25 genes associated with SAM/SAH demonstrating a genetic contribution to the methylation potential. Individual plasma metabolites correlated with 99 plasma proteins. Fourteen proteins correlated with body mass index, 49 with group age, and 30 with sex. The analytical strategy described here identified subgroups for targeted nutritional interventions.
Objective. We reviewed cases of placental site trophoblastic tumors from the New England Trophoblastic Disease Center (NETDC) database from 1982–1999 in an effort to identify prognostic factors for ...recurrent disease.
Methods. A chart review was performed utilizing patients identified from the NETDC database. Data obtained included patient age at diagnosis, antecedent pregnancy, duration and extent of disease, presenting symptoms, pre- and posttreatment hCG levels, diagnostic and therapeutic procedures, treatment and outcome of patients. Statistical analysis was performed using Student's t test and χ2 test when appropriate.
Results. Thirteen patients were identified. All ultimately underwent hysterectomy although initial treatment of 1 patient was uterine resection. There were 5 recurrences (43%)—3 among the 9 patients who had no metastases on presentation (33%) and 2 of 3 patients who presented with metastases (66%). The 5 patients who recurred were among 8 who had received peri- or postoperative chemotherapy (62.5%). Treatment of recurrences included continued or alternate chemotherapy, radiotherapy, and/or excision of locally recurrent disease. Follow up time averaged 56.2 months (range 12–182 months). One of the 4 patients receiving chemotherapy ≤1 week after hysterectomy recurred, whereas all 4 patients who received chemotherapy 3 weeks or more after hysterectomy recurred. Uterine tumor volume was significantly greater, 154.1 cm3, in patients with initial metastases versus 42.3 cm3 in patients without initial metastases (P = 0.04). Mitotic index (P = 0.04) was significantly increased in patients who developed recurrent disease.
Conclusion. High mitotic index appears to be an adverse prognostic indicator for recurrence. Hysterectomy remains the mainstay of treatment. Chemotherapy is indicated for patients with metastases and may be indicated when the mitotic index is >5 mitoses/10 HPF. Radiation treatment may play a role in recurrent disease but must be evaluated on a case-by-case basis.
Abstract 2611
Approximately 30% of acute myeloid leukemia (AML) patients have activating mutations in FLT3, commonly internal tandem duplication (ITD) mutations, which are associated with poor ...survival. Although FLT3 tyrosine kinase inhibitors (TKI) such as AC220 can induce remissions, resistance-causing mutations in FLT3-ITD are known to impair the in vitro activity of first and second generation FLT3 TKIs. DCC2036 is a unique switch-pocket, non-ATP competitive (allosteric) inhibitor with low nanomolar inhibitory concentration 50 (IC50) activity against a number of tyrosine kinases including FLT3 (1.7 nM), TRKA (7.0 nM), TIE-2 (2.7 nM) and BCR-ABL (2.0 nM). DCC2036 has shown promising activity in a phase I/II clinical trial in chronic myeloid leukemia (CML), where plasma concentrations of 350 nM of DCC2036 have been safely achieved. DCC-2036 has induced clinical and molecular remissions in patients with TKI-resistant CML expressing the ‘gate-keeper' T315I BCR-ABL mutation, as well as demonstrated activity against mutations that cause BCR-ABL conformational escape resistant (Cancer Cell. 2011;19:556). Here, we evaluated the in vitro activity of DCC2036 against FLT3-ITD in cell line model systems. In the FLT3-ITD expressing human leukemia MV4-11 and MOLM-13 cells, treatment with DCC2036 (20 to 500 nM for 24 hours) dose-dependently induced cell cycle G1-phase accumulation with decline in the S and G2/M phases. Exposure to 50 to 500 nM DCC2036 for 48 to 72 hours also dose-dependently induced apoptosis of 30 to 80 % of MV4-11 and MOLM-13, as well as induced 30 to 50% apoptosis of patient-derived primary AML cells with FLT3-ITD (n =4). This was associated with dose-dependent decline in the levels of p-FLT3, p-STAT5, p-AKT, p-ERK1/2 and Bcl-xL levels but increase in the levels of BIM and p27. In contrast, treatment with DCC2036 induced significantly lower level of apoptosis (<15%) in either normal CD34+ progenitor cells or AML cells without FLT3-ITD. We next evaluated the in vitro activity of DCC2036 against AC220-resistant mutations in FLT3-ITD (F691L, D835V/Y and Y842C/H) that we identified in a pre-clinical screen and in patients with loss of response to AC220 (Smith et al, ASH 2011, submitted), as well as against FLT3-ITD/F691I, analogous to the BCR-ABL/T315I mutation. DCC2036 potently inhibited proliferation of FLT3-ITD transduced Ba/F3 cells with an IC50 of 14.5 nM (IC50 of parental Ba/F3 cells in the presence of IL-3 >1000nM). DCC2036 retained some activity against the clinically relevant FLT3-ITD gatekeeper mutation F691L and F691I (IC50 49 nM and 34 nM), and was similarly active against the activation loop mutations Y842C and Y842H (IC50 26–28 nM). The activation loop mutations D835V and D835Y, which are commonly detected in patients with loss of response to AC220 and are hypothesized to destabilize the kinase inactive “DFG-out” conformation, were substantially less sensitive to DCC2036 (IC50 233 nM and 196 nM, respectively). Based on our previous findings (Blood. 2005;105:1768) that FLT3-ITD is a heat shock protein (hsp) 90 client oncoprotein, we also determined the effect of co-treatment with the non-geldanamycin hsp90 inhibitor AUY922 (5 to 10 nM) (Novartis Pharmaceuticals) against the cultured and primary FLT3-ITD expressing AML cells. Co-treatment with AUY922 significantly improved the activity of DCC2036 against primary AML cells (p < .05). These findings demonstrate that DCC2036 exhibits potent activity against cultured and primary AML cells with FLT-3-ITD, as well as against cellular models of FLT3-ITD with AC220-resistant gatekeeper and select activation loop mutations. The molecular basis of resistance to DCC2036 conferred by activation loop mutations at D835 is under investigation. Co-treatment with DCC-2036 and the hsp90 inhibitor AUY922 exerted higher lethal activity against cultured and primary AML cells with FLT3-ITD.
Wise:Deciphera Pharmaceuticals LLC: Employment. Reyes:Millennium, Sanofi Aventis: Consultancy. Berger:Deciphera Pharmaceuticals: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment.
Ultrafaint dwarf galaxies (UFDs) are typically assumed to have simple, stellar populations with star formation ending at reionization. Yet as the observations of these galaxies continue to improve, ...their star formation histories (SFHs) are revealed to be more complicated than previously thought. In this paper, we study how star formation, chemical enrichment, and mixing proceed in small, dark matter halos at early times using a high-resolution, cosmological, hydrodynamical simulation. The goals are to inform the future use of analytic models and to explore observable properties of the simulated halos in the context of UFD data. Specifically, we look at analytic approaches that might inform metal enrichment within and beyond small galaxies in the early Universe. We find that simple assumptions for modeling the extent of supernova-driven winds agree with the simulation on average whereas inhomogeneous mixing and gas flows have a large effect on the spread in simulated stellar metallicities. In the context of the UFDs, this work demonstrates that simulations can form halos with a complex SFH and a large spread in the metallicity distribution function within a few hundred Myr in the early Universe. In particular, bursty and continuous star formation are seen in the simulation and both scenarios have been argued from the data. Spreads in the simulated metallicities, however remain too narrow and too metal-rich when compared to the UFDs. Future work is needed to help reduce these discrepancies and advance our interpretation of the data.
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