The Role of GLI-1 in Endocrine Resistant Breast Cancer

Estrogen receptor positive (ER+) and estrogen receptor negative (ER-) are two major types of breast cancer. For women with ER+ positive breast cancer, patients are treated with the antiestrogenic compounds, tamoxifen or faslodex for five years, immediately after surgical resection of tumors. Unfortunately, 30-40% of these patients will develop resistance to endocrine therapy. Our recent study has shown that the Hedgehog (Hhg) signaling pathway plays a significant role in endocrine resistance and that the aberrantly activated transcription factor, GLI-1, is vital to the development of resistance. However, not much is known about the GLI-1 target genes that might contribute to endocrine resistance. Our goal is to determine novel target genes of GLI-1 and determine how these genes promote endocrine therapy resistance.PelotoniaA five-year embargo was granted for this item.Academic Major: Biomedical Scienc

A New Monster

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Robust and Flexible Estimation of Stochastic Mediation Effects: A Proposed Method and Example in a Randomized Trial Setting

Causal mediation analysis can improve understanding of the mechanisms underlying epidemiologic associations. However, the utility of natural direct and indirect effect estimation has been limited by the assumption of no confounder of the mediator-outcome relationship that is affected by prior exposure---an assumption frequently violated in practice. We build on recent work that identified alternative estimands that do not require this assumption and propose a flexible and double robust semiparametric targeted minimum loss-based estimator for data-dependent stochastic direct and indirect effects. The proposed method treats the intermediate confounder affected by prior exposure as a time-varying confounder and intervenes stochastically on the mediator using a distribution which conditions on baseline covariates and marginalizes over the intermediate confounder. In addition, we assume the stochastic intervention is given, conditional on observed data, which results in a simpler estimator and weaker identification assumptions. We demonstrate the estimator's finite sample and robustness properties in a simple simulation study. We apply the method to an example from the Moving to Opportunity experiment. In this application, randomization to receive a housing voucher is the treatment/instrument that influenced moving to a low-poverty neighborhood, which is the intermediate confounder. We estimate the data-dependent stochastic direct effect of randomization to the voucher group on adolescent marijuana use not mediated by change in school district and the stochastic indirect effect mediated by change in school district. We find no evidence of mediation. Our estimator is easy to implement in standard statistical software, and we provide annotated R code to further lower implementation barriers.Comment: 24 pages, 2 tables, 2 figure

Die Republik Kalmückien (Chalmg Tangtsch): das 'Unternehmen Iljumzinov'

'Die kleine Republik Kalmückien nimmt in vielerlei Hinsicht einen besonderen Platz unter den 89 Subjekten Rußlands ein. Sie ist eine der 21 Republiken, die neben einem autonomen Gebiet und zehn autonomen Kreisen die nationalen Gebietskörperschaften bilden und zusammen mit den übrigen Verwaltungsterritorien die Rußländische Föderation konstituieren. Kalmückien gehörte zu den am wenigsten entwickelten Regionen der Sowjetunion wie der RSFSR, und nach dem Untergang der UdSSR schien wenig dafür zu sprechen, daß sich daran viel ändern würde. In das Licht der Öffentlichkeit rückte die Republik 1993, als bei den damals anstehenden Präsidentschaftswahlen Kirsan Iljumzinov für das höchste Staatsamt Kalmückiens kandidierte. Er war eine bis dahin außerhalb seines Heimatgebietes kaum bekannte politische Figur, einer jener nicht wenigen jungen Leute, die nach dem Ende der Sowjetherrschaft in Politik und Wirtschaft nach oben strebten. Was ihn aus deren Reihe hervorhob, war seine 'exotische', kalmückische Herkunft, die er publikumswirksam zu nutzen verstand, sowie sein offen demonstrierter Reichtum, über dessen legalen Erwerb jedoch schon bald rufschädigende Versionen umliefen. Es war von Unterschlagung und krimineller Bereicherung die Rede gewesen, Vorwürfe, die Iljumzinov stets geschickt parierte, ohne jedoch letzte Zweifel ganz aus der Welt schaffen zu können. Seinem Image als einem erfolgreichen 'Businessman' taten sie kaum Abbruch, erhöhten eher sein Ansehen unter einer rasch anwachsenden kalmückischen Gefolgschaft, die ihn dann auch zum Präsidenten in Elista wählte. Iljumzinov hat auch deshalb geraume Zeit die Schlagzeilen beherrscht, weil er mit Visionen von einer modernen, kapitalistischen Welt auftrat, die er den Kalmücken bringen wollte und in rosigen Farben seinen gebannten Zuhörern zu schildern verstand. Es war die Rede von einem zukünftigen 'zweiten Kuweit', von einer Verzehnfachung des Lebensstandards und anderen kühnen Visionen, was ihm den Spott nicht nur der internationalen Presse eingebracht hat. Inzwischen ist es um ihn wie um sein Land etwas stiller geworden. Gegenstand der vorliegenden Darstellung ist die Entwicklung der 'Republik Chalmg Tangtsch' (so die Bezeichnung in der Landesprache) unter ihrem jungen Präsidenten. Sie beruht unter anderem auf Beobachtungen und Erfahrungen, die der Verfasser im September 1997 in Kalmückien gemacht hat.' (Textauszug)'In many respects the small republic of Kalmykia occupies a special place among the eighty-nine subjects of the Russian Federation. It is one of the twenty-one republics, one autonomous territory and ten autonomous areas that form Russia s national territorial entities and together with the other administrative territories constitute the Russian Federation. Kalmykia was one of the least developed regions of both the Soviet Union and the RSFSR and it seemed unlikely that this situation would change following the demise of the USSR. Kalmykia became the focus of public attention in 1993, when Kirsan Ilyumzhinov stood for Kalmykia s highest state office in the presidential elections. Until then he had been little known outside his home territory and was one of a large number of young people who, following the end of Soviet rule, tried to make a career in politics or in the economy. What made Ilyumzhinov stand out were his 'exotic' Kalmyk origins, which he knew how to exploit to gain public support, and his conspicuous wealth, the origin of which soon became the subject of damaging rumours of embezzlement and criminal connections. Although Ilyumzhinov showed great skill in countering such speculation, there were still some lingering doubts. His image as a successful 'businessman' remained largely unscathed, however; if anything, it served to increase his popularity among a swiftly growing Kalmyk following, which duly elected him as president in Elista. Another reason why Ilyumzhinov dominated the headlines for quite some time was his vision of a modern, capitalist future for Kalmykia, which he presented in glowing terms to his spellbound listeners. There was talk of a 'second Kuwait', of a ten-fold increase in living standards and other extravagant visions. For this he was ridiculed both in the international press and elsewhere. In the meantime, interest in both Ilyumzhinov and Kalmykia has subsided. The subject of the present report is the development of the Republic of Xhalmg Tangsh, as it is called in the local language, under its new young president. It is based in part on the author's observations and experiences during a trip to Kalmykia in September 1997.' (extract

Relative multiplexing for minimizing switching in linear-optical quantum computing

Many existing schemes for linear-optical quantum computing (LOQC) depend on multiplexing (MUX), which uses dynamic routing to enable near-deterministic gates and sources to be constructed using heralded, probabilistic primitives. MUXing accounts for the overwhelming majority of active switching demands in current LOQC architectures. In this manuscript, we introduce relative multiplexing (RMUX), a general-purpose optimization which can dramatically reduce the active switching requirements for MUX in LOQC, and thereby reduce hardware complexity and energy consumption, as well as relaxing demands on performance for various photonic components. We discuss the application of RMUX to the generation of entangled states from probabilistic single-photon sources, and argue that an order of magnitude improvement in the rate of generation of Bell states can be achieved. In addition, we apply RMUX to the proposal for percolation of a 3D cluster state in [PRL 115, 020502 (2015)], and we find that RMUX allows a 2.4x increase in loss tolerance for this architecture.Comment: Published version, New Journal of Physics, Volume 19, June 201