domain of polypharmacy, including an overview of the evidence base and definitions of each indicator. � Client focus: Clients who are prescribed multiple psychotropic medications � Project goal: Simplification of medication regimen if clinically feasible following clinical evaluation, for each client

al., 2014). The multitude of phenotypes, which could be at-tained by a developing or activated naive T cell, suggests the existence of gene regulatory mech-anisms that enable the highly calibrated yet swift conversion of multiple signaling events into a definitive transcriptional state of genes

only, but nonetheless cures up to 70 % of de novo pa-tients. Combined treatment with RA and arse-nic definitively cures all mice and over 90% of patients (Lallemand-Breitenbach et al., 1999;

The initial event in multiple sclerosis (MS) is commonly an acute neurological attack caused by inflammation in one or more sites in the cen-tral nervous system (CNS), a presentation re-ferred to as a clinically isolated syndrome (CIS). Approximately 80 % of CIS patients develop clinically definite

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Although much effort in the field of oncology has focused on canonical oncogenes and tumor suppressor genes, the importance of cancer cell metabolism is growing in appreciation (DeBerardinis et al., 2008; Vander Heiden et al., 2009). Known as the Warburg effect (Warburg 1956), this reprogramming of gene expression that alters glucose metabolism enables cells to suppress apoptotic signaling, to grow in hypoxic environments, and to use more glucose for anabolic processes rather than oxidative phos-phorylation, even when oxygen is not limiting (Ferguson and Rathmell, 2008). Pyruvate kinase (PK) catalyzes the conver-sion of phosphoenolpyruvate (PEP) and ADP to

Runx family transcription factors are essential for embryonic development and have key roles in hematopoiesis. They bind DNA through the conserved Runt domain and can activate or re-press transcription by cooperating with other sequence-specific transcription factors, coactiva-tors, and corepressors (Durst and Hiebert, 2004; Taniuchi and Littman, 2004). Runx1 (AML1) and Runx3 (AML2) are intimately linked to T cell fate choice and function by regulating tar-get genes that specify CD4/CD8 development in the thymus and the postthymic differentiation of Th1, Th2, and Th17 cells. Runx1 and Runx3 sequentially interact with the Cd4 silencer to block CD4 expression in double-negative and CD8 single-positive thymocytes (Taniuchi et al., 2002). Runx3 facilitates CD8 T cell lineage choice by repressing Zbtb7b, the gene encoding the CD4 lineage signature transcription factor Th-POK (Egawa and Littman, 2008; Setoguchi et al., 2008) and also plays a role in mature cyto-toxic T cells (Cruz-Guilloty et al., 2009). Runx1 is predominant in naive CD4 T cells and tran-siently down-regulated in response to activa-tion. Runx1 is reexpressed under Th2 culture conditions (Naoe et al., 2007), whereas Th1 cells express Runx3 (Djuretic et al., 2007; Naoe et al., 2007), which cooperates with T-bet to silence Il4 and activates Ifng expression (Djuretic et al., 2007). Runx1 promotes Th17 cell differ-entiation by up-regulating Rorc, the gene en-coding the Th17 signature transcription factor Ror-t, and II17 (Zhang et al., 2008). In T reg cells, Runx1 and the T reg signature transcrip-tion factor Foxp3 cooperate at the protein level to regulate downstream target genes (Ono et al., 2007), but the transcriptional regulation of T reg cell determinants by Runx proteins remains to be investigated.

Molecular signaling pathways are promising targets in cancer therapy, but resistance often thwarts clinical success. Acquired mutations of drug targets, feedback activation of oncogenic signals, and redundant signaling pathways are important causes of resistance, and cocktails of multiple inhibitors are considered one potential solution (Sawyers, 2007). For example, the rapa mycin analogues (rapalogs) are potent inhibi tors of mTORC1 with promising antitumor activity against some cancers (Dancey, 2010). mTORC1 blockade by rapamycin interferes with the activation of capdependent transla tion and exploits a cancer cell’s dependence on increased translation of certain oncoproteins (Wendel et al., 2007; Sonenberg and Hinnebusch, 2009). In animal models, rapamycin dramatically enhances the effectiveness of DNAdamaging chemotherapy (Wendel et al., 2004). However, in clinical trials in nonHodgkin’s lymphoma (NHL), rapalogs have failed to show durable clinical benefit for most patients (Dancey et al., 2009; Hess et al., 2009; Smith et al., 2010). The causes are illunderstood, and new insight should enable better therapies.

The germinal center (GC) reaction is an es-sential step in the development of humoral immunity, in which B cells undergo affinity maturation and differentiation into memory cells and long-lived plasma cells (Gatto and Brink, 2010). Follicular helper T cells (TFH cells) are CD4+ T cells that migrate into B cell follicles and provide specialized help to GC B cells (Crotty, 2011). Impaired TFH cell differentia-tion results in a loss of GCs and T-dependent antibody responses (Johnston et al., 2009; Nurieva et al., 2009; Yu et al., 2009). Con-versely, excessive TFH cell differentiation can drive the production of autoantibodies and is associated with several autoimmune diseases (Hu et al., 2009; Linterman et al., 2009). Recent studies have investigated the signals that regulate TFH cell differentiation. TFH cells possess a distinctive gene program (Crotty, 2011), and the transcription factor Bcl6 is necessary for TFH cell differentiation in vivo (Johnston et al., 2009; Nurieva et al., 2009; Yu et al., 2009). Multiple rounds of interaction with antigen-presenting cells are necessary for TFH cell differentiation (Johnston et al., 2009; Deenick et al., 2010; Choi et al., 2011; Goenka et al., 2011), and multiple signals are involved. In particular, ICOS–ICOSL interaction (Akiba

bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells