Maximizing efficacy of the hypomethylating drug 5-aza-2'-deoxycytidine in human leukemia

5-aza-2'-deoxycytidine (DAC) is a cytidine analogue that strongly inhibits DNA methylation, and was recently approved for the treatment of myelodysplastic syndromes (MDS). To maximize clinical results with DAC, we investigated its use as an anti-cancer drug. We also investigated mechanisms of resistance to DAC in vitro in cancer cell lines and in vivo in MDS patients after relapse. We found DAC sensitized cells to the effect of 1-β-D-Arabinofuranosylcytosine (Ara-C). The combination of DAC and Ara-C or Ara-C following DAC showed additive or synergistic effects on cell death in four human leukemia cell lines in vitro, but antagonism in terms of global methylation. RIL gene activation and H3 lys-9 acetylation of short interspersed elements (Alu). One possible explanation is that hypomethylated cells are sensitized to cell killing by Ara-C. Turning to resistance, we found that the IC50 of DAC differed 1000 fold among and was correlated with the dose of DAC that induced peak hypomethylation of long interspersed nuclear elements (LINE) (r=0.94, P<0.001), but not with LINE methylation at baseline (r=0.05, P=0.97). Sensitivity to DAC did not significantly correlate with sensitivity to another hypomethylating agent 5-azacytidine (AZA) (r=0.44, P=0.11). The cell lines most resistant to DAC had low dCK, hENT1, and hENT2 transporters and high cytosine deaminase (CDA). In an HL60 leukemia cell line, resistance to DAC could be rapidly induced by drug exposure, and was related to a switch from monoallelic to biallelic mutation of dCK or a loss of wild type DCK allele. Furthermore, we showed that DAC induced DNA breaks evidenced by histone H2AX phosphorylation and increased homologous recombination rates 7-10 folds. Finally, we found there were no dCK mutations in MDS patients after relapse. Cytogenetics showed that three of the patients acquired new abnormalities at relapse. These data suggest that in vitro spontaneous and acquired resistance to DAC can be explained by insufficient incorporation of drug into DNA. In vivo resistance to DAC is likely due to methylation-independent pathways such as chromosome changes. The lack of cross resistance between DAC and AZA is of potential clinical relevance, as is the combination of DAC and Ara-C. ^

Maximizing the number of polychronous groups in spiking networks

In this paper we investigate the effect of biasing the axonal connection delay values in the number of polychronous groups produced for a spiking neuron network model. We use an estimation of distribution algorithm (EDA) that learns tree models to search for optimal delay configurations. Our results indicate that the introduced approach can be used to considerably increase the number of such groups.

Europe as International Actor: Maximizing Nation-State Sovereignty. CES Germany & Europe Working Papers, No. 06.3, 1996

The continually increasing literature on foreign- and security-policy dimensions of the European Union (EU) has provided no remedy for the widespread helplessness in gaining a purchase on Europe as an international actor. The basic hindrance to understanding this policy comes from an all-too-literal interpretation of the acronym involved: the CFSP is understood as a total or partial replacement of the nation-states' foreign and security policy. This article aims to point the way to a new understanding of the CFSP in which this policy is not based on the integration of nation­ state foreign and security policy. I suggest that the proper way to grasp the phenomenon of the CFSP is to describe it as an international regime whose goal is to administer links between economic integration and foreign- and security­ policy cooperation in the sense of maximizing the sovereignty of member states. This requires, on the one hand, the prevention of "spillovers" from the economic area that could interfere with the foreign- and security-policy indepen­ dence of member states. On the other hand, it demands applying the EU's economic potential to reinforce the foreign- and security-policy range of member states. Due to the logic of this policy, CFSP priorities and fields of ac­ tion differ profoundly from those of a national foreign and security policy. Expectations on the evolution of the CFSP must be aware of these basic characteristics of this policy.

Educational Systems for Maximizing Learning Online and in the Classroom

Thesis (Ph.D.)--University of Washington, 2016-06

Coloring random graphs and maximizing local diversity

We study a variation of the graph coloring problem on random graphs of finite average connectivity. Given the number of colors, we aim to maximize the number of different colors at neighboring vertices (i.e. one edge distance) of any vertex. Two efficient algorithms, belief propagation and Walksat are adapted to carry out this task. We present experimental results based on two types of random graphs for different system sizes and identify the critical value of the connectivity for the algorithms to find a perfect solution. The problem and the suggested algorithms have practical relevance since various applications, such as distributed storage, can be mapped onto this problem.

DFIG machine design for maximizing power output based on surrogate optimization algorithm

This paper presents a surrogate-model-based optimization of a doubly-fed induction generator (DFIG) machine winding design for maximizing power yield. Based on site-specific wind profile data and the machine's previous operational performance, the DFIG's stator and rotor windings are optimized to match the maximum efficiency with operating conditions for rewinding purposes. The particle swarm optimization-based surrogate optimization techniques are used in conjunction with the finite element method to optimize the machine design utilizing the limited available information for the site-specific wind profile and generator operating conditions. A response surface method in the surrogate model is developed to formulate the design objectives and constraints. Besides, the machine tests and efficiency calculations follow IEEE standard 112-B. Numerical and experimental results validate the effectiveness of the proposed technologies.

Maximizing the Efficiency of Greenhouse Gas Related Consumer Policy

Consumer policy approaches regarding green products and solutions can be differentiated by their main focus. “Green positioning” is basically targeted at environmentally aware consumers, while “efficiency-focused positioning” concentrates on the efficiency gain of the product or solution, targeting the whole society, regardless of consumers' environmental awareness. The paper argues that the scope and total environmental benefit can be increased if green products or solutions are promoted in different ways, not only as “green” but also based on other arguments (like cost-efficiency, return on investment, etc.). The paper suggests a model for improving the efficiency of greenhouse gas (GHG)-related consumer policy. Based on the marginal social cost curve and the marginal private cost curve, different (green, yellow, and red) zones of action are identified. GHG mitigation options chosen from those zones are then evaluated with the help of profiling method, addressing the barriers to implementation. Profiling may help design an implementation strategy for the selected options and make consumer policy more effective and acceptable for mass market. Case study results show three different ways of positioning of GHG-related consumer policy in Hungary from 2000 and give practical examples of profiling, based on the latest marginal social cost curve and the contemporary energy saving policy of the state regarding the residential sector.

Maximizing the Efficiency of Greenhouse Gas Related Consumer Policy

Consumer policy approaches regarding green products and solutions can be differentiated by their main focus. “Green positioning” is basically targeted at environmentally aware consumers, while “efficiency-focused positioning” concentrates on the efficiency gain of the product or solution, targeting the whole society, regardless of consumers' environmental awareness. The paper argues that the scope and total environmental benefit can be increased if green products or solutions are promoted in different ways, not only as “green” but also based on other arguments (like cost-efficiency, return on investment, etc.). The paper suggests a model for improving the efficiency of greenhouse gas (GHG)-related consumer policy. Based on the marginal social cost curve and the marginal private cost curve, different (green, yellow, and red) zones of action are identified. GHG mitigation options chosen from those zones are then evaluated with the help of profiling method, addressing the barriers to implementation. Profiling may help design an implementation strategy for the selected options and make consumer policy more effective and acceptable for mass market. Case study results show three different ways of positioning of GHG-related consumer policy in Hungary from 2000 and give practical examples of profiling, based on the latest marginal social cost curve and the contemporary energy saving policy of the state regarding the residential sector.

Maximizing Hospitality Learning Outcomes: An Integrated Experiential In-Class Approach

This study explored the influence of an experiential, in-class approach to the hospitality curriculum as a means of increasing its efficiency and effectiveness. Specifically, the study provides an example of how hospitality faculty might utilize an experiential, in-class approach to integrate additional hospitality-specific content along with process and content issues for working in teams and team decision-making. The results of this study support the efficient and effective use of an experiential inclass teaching method. The value of this study is twofold: (1) it provides an initial test of this approach’s usefulness and (2) it provides a forum for continued conversations of how experiential approaches can be utilized to enhance and reinforce other hospitality content and managerial skills and to bridge the gap between vocational and liberal education outcomes.

MAXIMIZING LANDSCAPE PERFORMANCE AT ADVENTIST HOSPITAL: HEALING THE PEOPLE, HEALING SLIGO CREEK

This paper answers the question of whether a design intervention on Washington Adventist Hospital’s Takoma Park campus can combine stormwater Best Management Practices with outdoor healing spaces, to improve the health of the local creek (Sligo Creek) while creating a restorative environment for the hospital community. To improve the health of Sligo Creek, a campus-wide stormwater analysis was undertaken, in addition to an intervention-site-specific stormwater analysis, and a literature review of stormwater best management practices. To create a restorative environment, a literature review of healing gardens was undertaken, in addition to a campus-wide site analysis, to uncover the most ideally suited site to create a restorative environment.

Maximizing HIV partner notification opportunities for index patients and their sexual partners in Malawi

Introduction HIV testing and counselling (HTC) is important to effect positive sexual behaviour change and is an entry point to treatment, care, and psychosocial support. One of the most practical initiatives to increase HTC is to encourage sexual partners of HIV-infected persons to test for HIV. However, partner notification strategies must be feasible in the healthcare setting and acceptable to the population. Methods We conducted a qualitative study during the pilot phase of an HIV partner notification trial to complement its assessment of feasibility and acceptability of methods of partner notification. We performed in-depth interviews with 16 consecutive HIV-positive index participants who consented and their 12 identifiable sexual partners. We also conducted two focus group discussions with healthcare workers to supplement the patient perspectives. In the main study, newly diagnosed HIV cases (index cases) were randomized to one of three methods of partner notification: passive, contract, and provider referral. Clients in the passive referral group were responsible for notifying their sexual partners themselves. Individuals in the contract referral group were given seven days to notify their partners, after which a healthcare provider contacted partners who had not reported for counselling and testing. In the provider group, a healthcare provider notified partners directly. Results Although most index participants and partners expressed a preference for passive notification, they also highlighted benefits for provider-assisted notification and the universal right for all HIV-exposed persons to know their HIV exposure and benefit from HIV testing and access antiretroviral treatment. Several participants mentioned couples counselling as a way to diffuse tension and get accurate information. All mentioned benefits to HIV testing, including the opportunity to change behaviour. Conclusions Provider-assisted partner notification is not preferred, but it is acceptable and may complement the passive method of notification. Couples counselling should also be encouraged.