OBJECTIVES/GOALS: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is the standard of care treatment for non-metastatic prostate cancer (NMPC). Despite the efficacy, treatment-related symptoms including fatigue greatly reduce the quality of life of cancer patients. The goal of the study is to examine the influence of combined ADT/RT on fatigue and understand its underlying mechanisms. METHODS/STUDY POPULATION: Sixty-four participants with NMPC were enrolled. Fatigue was assessed using the Functional Assessment of Cancer Therapy–Fatigue. Mitochondrial function parameters were measured as oxygen consumption from peripheral blood mononuclear cells (PBMCs) extracted from participants’ whole blood. An ADT/RT-induced fatigue mouse model was developed with fatigue measured as a reduction in voluntary wheel-running activity (VWRA) in 54 mice. Mitochondrial function was assessed in the ADT/RT mouse brains using Western blot analysis of Glucose transporter 4 (GLUT4) and transcription factor A, mitochondrial (TFAM). RESULTS/ANTICIPATED RESULTS: Fatigue in the ADT group was exacerbated during RT compared to the non-ADT group. This effect was specific to fatigue, as depressive symptoms were unaffected. PBMCs of fatigued subjects exhibited decreased ATP coupling efficiency compared to non-fatigued subjects, indicative of mitochondrial dysfunction. The ADT/RT mice demonstrated a synergistic effect of ADT and RT in decreasing VWRA. Brain tissues of ADT/RT mice exhibited decreased levels of GLUT4 and TFAM suggesting that impaired neuronal metabolic homeostasis may contribute to fatigue pathogenesis. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that fatigue induced by ADT/RT may be attributable to mitochondrial dysfunction both peripherally and in the central nervous system (CNS). The synergistic effect of ADT/RT is behaviorally reproducible in a mouse model, and its mechanism may be related to bioenergetics in the CNS.

OBJECTIVES/GOALS: Fatigue is a distressing side effect of cancer and its treatment. It is a subjective symptom that can include mental, physical, emotional, and motivational components. We sought to determine whether preventing inflammation affects fatigue-like behavior in a mouse model of radiation therapy. METHODS/STUDY POPULATION: C57BL/6 mice received three consecutive 8 gray doses of daily peripheral irradiation. We used voluntary wheel running activity to measure fatigue-like behavior before and after this period. Minocycline, an antibiotic with anti-inflammatory effects, was administered beginning a week before irradiation and continued throughout the experiment. We also tested mice lacking the toll-like receptor adaptor protein, MyD88. Cognitive abilities were tested using spontaneous alternation in a Y-maze. RESULTS/ANTICIPATED RESULTS: We found that minocycline reduces fatigue-like behavior exhibited after irradiation, but had no effect on pre-irradiation activity levels. Similarly, fatigue-like behavior after radiation was partially reversed by genetic loss of MyD88. Y-maze spontaneous alternation performance remained similar in all groups. DISCUSSION/SIGNIFICANCE OF IMPACT: Both pharmacological and genetic anti-inflammatory manipulations increased voluntary activity levels after irradiation. Our results suggest that inflammation is an important factor in the development of fatigue-like behavior. Modulators of inflammatory processes hold potential for alleviating fatigue.

Most of the research on the rule of law in the European Union focuses on its external dimension. However, to be a credible rule of law promoter abroad, rule of law standards at home need to match what the EU preaches abroad. This article assesses developments regarding the strengthening of the rule of law in the Area of Freedom, Security and Justice heralded in 2009 as one of the objectives of the Stockholm Programme. Two mechanisms had been envisaged. First, a new peer-review mechanism, based on a Dutch initiative, would be introduced. Second, ambitions to improve the monitoring culture of Justice and Home Affairs instruments found some support in the strengthening of the relationship between the Council of Europe and the European Union. Not only the negotiations on the EU's accession to the European Convention on Human Rights should improve the rule of law and mutual trust, but the EU could also better make use of the existing monitoring instruments of the Council of Europe. Inter-institutional tensions over the implementation of JHA policies, as well as turbulences surrounding the EU's accession to the ECHR have nonetheless come to light and are explored in this article.

On 21 September 1792, at Danton's proposal, the French National Assembly declared that ‘there can be no constitution but one approved by the people’. In France, the idea of direct democracy dates back to the Revolution. However, due to the Terror and the practice under Napoleonic Empires, in which they were turned into plebiscites, referendums acquired a negative connotation. Under the Vth Republic, De Gaulle turned referendums into an instrument of personalisation and presidentialisation, and since his day, there have been few referendums staged. In 10 years of office, President Jacques Chirac only used it twice with much less success and political courage.

Much of the drug testing available today is able to determine the presence or absence of a variety of psychoactive substances in a range of body fluids and tissues. For the results of such tests to be confidently interpreted, additional information is required, including general assessment and history-taking. In a wide range of large psychiatric surveys, substance dependence emerges as one of the most common mental health-related disorders, and it is also the one that is least likely to be treated. The range of available tests can be best considered as acting to support and complement a broader assessment and diagnostic procedure.