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Background-The endomyocardial biopsy (EMB) is considered the gold standard in rejection surveillance post cardiac transplant, but is invasive, with risk of complications. A previous trial suggested that the gene expression profiling (GEP) blood test was noninferior to EMB between 6 and 60 months post transplant. As most rejections occur in the first 6 months, we conducted a single-center randomized trial of GEP versus EMB starting at 55 days post transplant (when GEP is valid). Methods and Results-Sixty heart transplant patients meeting inclusion criteria were randomized beginning at 55 days post transplant to either GEP or EMB arms. A positive GEP ≥30 between 2 and 6 months, or ≥34 after 6 months, prompted a follow-up biopsy. The primary end point included a composite of death/retransplant, rejection with hemodynamic compromise or graft dysfunction at 18 months post transplant. A coprimary end point included change in first-year maximal intimal thickness by intravascular ultrasound, a recognized surrogate for long-term outcome. Corticosteroid weaning was assessed in both the groups. The composite end point was similar between the GEP and EMB groups (10% versus 17%; log-rank P=0.44). The coprimary end point of first-year intravascular ultrasound change demonstrated no difference in mean maximal intimal thickness (0.35±0.36 versus 0.36±0.26 mm; P=0.944). Steroid weaning was successful in both the groups (91% versus 95%). Conclusions-In this pilot study, GEP starting at 55 days post transplant seems comparable with EMB for rejection surveillance in selected heart transplant patients and does not result in increased adverse outcomes. GEP also seems useful to guide corticosteroid weaning. Larger randomized trials are required to confirm these findings. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962377.

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder. HD is caused by polyglutamine expansions in the huntingtin (htt) protein that result in neuronal loss and contribute to HD pathology. The mechanisms of neuronal loss in HD are elusive, and there is no therapy to alleviate HD. To find small molecules that slow neuronal loss in HD, we screened 1,040 biologically active molecules to identify suppressors of cell death in a neuronal cell culture model of HD. We found that inhibitors of mitochondrial function or glycolysis rescued cell death in this cell culture and in in vivo HD models. These inhibitors prevented cell death by activating prosurvival ERK and AKT signaling but without altering cellular ATP levels. ERK and AKT inhibition through the use of specific chemical inhibitors abrogated the rescue, whereas their activation through the use of growth factors rescued cell death, suggesting that this activation could explain the protective effect of metabolic inhibitors. Both ERK and AKT signaling are disrupted in HD, and activating these pathways is protective in several HD models. Our results reveal a mechanism for activating prosurvival signaling that could be exploited for treating HD and possibly other neurodegenerative disorders.caspase ͉ ERK ͉ survival signaling ͉ drugs ͉ neurodegeneration H untington's disease (HD) is an inherited, adult onset, progressive neurodegenerative disorder (1). HD is caused by a polyglutamine expansion (Ͼ36 glutamine repeats) in the huntingtin protein (htt) that leads to neuronal dysfunction and death (1, 2). The mechanism(s) by which the polyglutamine expansion in htt leads to HD pathology remain elusive. Numerous mechanisms including transcriptional dysregulation, altered intracellular trafficking, sequestration of critical cellular proteins in aggregates, aberrant caspase activation, and altered energy metabolism have been implicated in HD (2).HD is a fatal disease with no therapy. To identify potential compounds for development as drugs and to use these compounds to gain mechanistic understanding of HD, we used a screening approach to identify small molecule suppressors of cell death in a cell culture model of HD. In this model, rat striatal neurons that were immortalized by expression of a temperaturesensitive large T antigen were engineered to express a mutant N-terminal, 548-aa fragment of human htt with 120 glutamine repeats to generate the N548 mutant cell line (3). Serum deprivation and a change to the nonpermissive temperature (39°C) causes T antigen degradation and N548 mutant cell death (3). Cell death can be used as an indicator of mutant htt toxicity because the cells expressing mutant htt die faster than parental cells (3). By using a previously described high-throughput assay (4), we discovered that metabolic inhibitors rescued cell death in this cell culture model and in two in vivo HD models. These compounds activated ERK and AKT prosurvival signaling. Furthermore, growth-factor-induced activation of ERK and AKT rescued cell death, thus el...

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