Shelley Wang

The discovery of oxysterols as the endogenous liver X receptor (LXR) ligands and subsequent gene targeting studies in mice provided strong evidence that LXR plays a central role in cholesterol metabolism. The identification here of a synthetic, nonsteroidal LXR-selective agonist series represented by T0314407 and T0901317 revealed a novel physiological role of LXR. Oral administration of T0901317 to mice and hamsters showed that LXR activated the coordinate expression of major fatty acid biosynthetic genes (lipogenesis) and increased plasma triglyceride and phospholipid levels in both species. Complementary studies in cell culture and animals suggested that the increase in plasma lipids occurs via LXR-mediated induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program.

BACKGROUND: Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach. METHODS: We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day). RESULTS: The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500-5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects. CONCLUSIONS: This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.

LV electromechanical delay results in asynchronized contraction. However, it is not known if the presence of cardiac diseases without QRS prolongation may result in inter- or intraventricular asynchrony. This study investigated the occurrence of systolic mechanical delay in different regions of the LV in patients with underlying heart diseases and normal QRS duration. Tissue Doppler imaging (TDI) was performed in 141 patients (age 63.7 +/- 11.5 years) with underlying heart diseases (82% had ischemic heart disease) and 92 normal healthy volunteers (age 63.9 +/- 9.8 years) based on the four-basal and four-mid-segment model by apical views. Of these, 124 patients had normal QRS duration (< or = 120 ms) while 17 were prolonged due to LBBB or intraventricular conduction defect. Patients with normal QRS duration had significantly lower peak myocardial isovolumic contraction velocity (IVCM), sustained systolic velocity (SM), and prolonged time to peak IVCM and SM in almost all myocardial segments when compared to controls. The time to peak IVCM (basal lateral vs basal septal segment: 61.0 +/- 29.4 vs 53.3 +/- 24.1 ms, P < 0.005) and SM (basal lateral vs basal septal segment: 174 +/- 44 vs 154 +/- 36 ms, P < 0.001) was further delayed in the LV free-wall segments. Mechanical delay was also evident in the LV free-wall segments in patients with preserved or impaired systolic function, in patients with or without previous myocardial infarction, and in patients with prolonged QRS duration. Patients with prolonged QRS had a higher prevalence of LV free-wall delay of > 50 ms (47 vs 24%, chi-square = 4.6, P < 0.05). In conclusion, the presence of cardiac diseases was characterized by LV global mechanical delay; and, intraventricular asynchronized contraction characterized mostly by further mechanical delay in the free-wall region. These changes occur even in those with normal QRS duration.

EmotiSphere is an interactive sensor-based musical instrument that generates music based on a user's current emotional state. Interactions with EmotiSphere draw upon everyday interactions with physical spherical objects, as well as on familiar interactions with music players. EmotiSphere offers a novel way to understand the relationship between emotion and music, and is aimed at people who want to create music and express themselves but do not necessarily possess skills in music composition. We describe the conceptualization and context of EmotiSphere, as well as its technical implementation.