Advances in Preventive Therapy for Estrogen-Receptor-Negative Breast Cancer.

Preventing breast cancer is an effective strategy for reducing breast cancer deaths. The purpose of chemoprevention (also termed preventive therapy) is to reduce cancer incidence by use of natural, synthetic, or biological agents. The efficacy of tamoxifen, raloxifene, and exemestane as preventive therapy against estrogen-receptor (ER)-positive breast cancer is well established for women at increased risk for breast cancer. However, because breast cancer is a heterogeneous disease, distinct preventive approaches may be required for effective prevention of each subtype. Current research is, therefore, focused on identifying alternative mechanisms by which biologically active compounds can reduce the risk of all breast cancer subtypes including ER-negative breast cancer. Promising agents are currently being developed for prevention of HER2-positive and triple-negative breast cancer (TNBC) and include inhibitors of the ErbB family receptors, COX-2 inhibitors, metformin, retinoids, statins, poly(ADP-ribose) polymerase inhibitors, and natural compounds. This review focuses on recent progress in research to develop more effective preventive agents, in particular for prevention of ER-negative breast cancer

Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs).

Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

Hierarchical Knowledge-Gradient for Sequential Sampling

We consider the problem of selecting the best of a finite but very large set of alternatives. Each alternative may be characterized by a multi-dimensional vector and has independent normal rewards. This problem arises in various settings such as (i) ranking and selection, (ii) simulation optimization where the unknown mean of each alternative is estimated with stochastic simulation output, and (iii) approximate dynamic programming where we need to estimate values based on Monte-Carlo simulation. We use a Bayesian probability model for the unknown reward of each alternative and follow a fully sequential sampling policy called the knowledge-gradient policy. This policy myopically optimizes the expected increment in the value of sampling information in each time period. Because the number of alternatives is large, we propose a hierarchical aggregation technique that uses the common features shared by alternatives to learn about many alternatives from even a single measurement, thus greatly reducing the measurement effort required. We demonstrate how this hierarchical knowledge-gradient policy can be applied to efficiently maximize a continuous function and prove that this policy finds a globally optimal alternative in the limit

UNAIDS 90‐90‐90 Campaign to End the AIDS Epidemic in Historic Perspective

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137622/1/milq12265.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137622/2/milq12265_am.pd

Targeted therapy for breast cancer prevention.

With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer

Alien Registration- Ozometz, Powel (Bangor, Penobscot County)

https://digitalmaine.com/alien_docs/11586/thumbnail.jp

The soldier’s tale: Problematising Foucault’s military foundations

This is the author accepted manuscript. The final version is available from Cambridge University Press (CUP) via the DOI in this record.The popularity of Foucauldian understandings of government in International Relations (IR) has led to a vibrant debate over the utility of Foucault’s work for the discipline, especially over its applicability outside Western liberal societies. By concentrating on governmentality’s international applicability, however, IR scholarship has neglected Foucault’s account of the foundations of modern social mentalities, apparatuses, and techniques. Foucault frequently based his ideas on historical research, with warfare and military affairs featuring prominently in his accounts of discipline and governmentality. Based on a problematisation of the military aspects of Foucault’s thought, this article challenges Foucauldian IR scholarship to revisit governmentality’s foundations and reconsider the contemporary relevance of Foucault’s account of government. Foucault neglected the heterogeneity of European militaries, such as their reliance on impermanent, auxiliary, and non-Western forces. He thereby missed the opportunity to develop a more sophisticated account of the relationship between force, the military, government, discipline, and biopolitics. Moreover, this article challengesFoucauldian IR scholarship to revisit the empirical foundations of Foucault’s work and reconsider the geographical and temporal extent of the relevance of Foucault’s account of government as a result

Master of Arts

thesisHugo Arce, a polemic Guatemalan writer/journalist, wrote what could be termed transitional resistance literature. Both his journalism and his literary works are marked by a discourse of opposition to the staggering violence and impunity that Guatemala faced during the periods in which Arce wrote. Resistance literature has often been theorized in terms of movements for national liberation and revolutionary movements. Nevertheless, resistance literature as a struggle over the cultural/historical also plays a particularly important role during periods of transition to democracy and out of civil war. This thesis focuses on two cuentos from ¿Y Maura?, the final work of Guatemalan author Hugo Arce. The thesis consists of an introduction and four chapters. The introduction briefly presents the background to the study, the professional significance of the study, and the delimitations of the study. The first chapter provides a general introduction to Hugo Arce's literary and journalistic work. It also places that work within the social and historical context and includes a literature review touching on the historical circumstances during which he wrote and briefly discusses the body of his literary work. The introductory chapter also serves the purpose of potentially being useful to those approaching the subject with an eye towards journalism or history. The second chapter discusses the literary theory that will be applied in the close reading and introduces the work of ¿Y Maura? as a whole. In particular, that chapter explores the ways the ambiguous zone created by a state of emergency may be exploited to eliminate opposition groups. The chapter ties this idea to the specific history of Guatemala. In Chapter III and IV, the thesis looks at Arce's literature against this backdrop. The framework of resistance literature is augmented by looking at specific cuentos through the lens of Giorgio Agamben's State of Exception and Victor Perera's The Unfinished Conquest. The third chapter is a close reading of the cuento, La Transfiguración. The fourth presents a close reading of the cuento El Delator. Finally, the conclusion ties the four chapters together, arguing that Arce's work is an example of transitional resistance literature

Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data.

Breast cancer is one of the most commonly diagnosed cancers in women. While there are several effective therapies for breast cancer and important single gene prognostic/predictive markers, more than 40,000 women die from this disease every year. The increasing availability of large-scale genomic datasets provides opportunities for identifying factors that influence breast cancer survival in smaller, well-defined subsets. The purpose of this study was to investigate the genomic landscape of various breast cancer subtypes and its potential associations with clinical outcomes. We used statistical analysis of sequence data generated by the Cancer Genome Atlas initiative including somatic mutation load (SML) analysis, Kaplan-Meier survival curves, gene mutational frequency, and mutational enrichment evaluation to study the genomic landscape of breast cancer. We show that ER(+), but not ER(-), tumors with high SML associate with poor overall survival (HR = 2.02). Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes. While it is known that somatic mutations in specific genes affect breast cancer survival, this study is the first to identify that SML may constitute an important global signature for a subset of ER(+) tumors prone to high mortality. Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival. Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies

From Democracy to Stability: European Union Democracy Promotion in Tunisia 1995-2007

Very little scholarship has been published on politics in Tunisia in the last two decades, resulting in scant coverage of the country’s political relations with the European Union (EU). Likewise, few studies of the EU’s democracy promotion and Mediterranean policies have provided any in-depth analysis of Tunisia. Meanwhile, much has been made by scholars of role played by democracy promotion in the EU’s foreign policy, particularly focusing on understandings of the Union as a ‘normative power’ or as an advocate of the ‘democratic peace theory’. By assessing EU democracy promotion in Tunisia, this thesis argues that democracy promotion has become a predominantly functional part of this foreign policy; its principal role being a means of realising the Union’s principal objectives of achieving security and stability for Europeans. By analysing the discourse of actors involved with the EU’s democracy promotion, the thesis traces a shift in EU policy from a more normative position in the mid-1990s to a more realist and securitised one since the turn of the twenty-first century. Tunisia has evolved over the last two centuries as a state strongly committed to European-influenced socio-economic reforms, but reforms which have led to little political contestability and few changes in government. However, as the EU forged a new approach to its Mediterranean neighbours, it established the promotion of democracy in its neighbours as an integral part of its foreign and security policies. Democracy was to be promoted in Tunisia within multilateral and holistic policy frameworks, such as the Euro-Mediterranean Partnership, and by a range of methods that encourage reform of many levels of the region’s societies. Yet it appears that these reforms are failing to deliver the political reforms they once promised. Furthermore, democracy is gradually slipping off the EU’s agenda, and its policy objectives converge with those of the Tunisian government as security concerns come to dominate its policy discourses. In the Tunisian context at least, democracy is a purely utilitarian device used to achieve security. When that security already exists, democracy loses its utility, and fades from its once prominent place in the EU policy in Tunisia