No abstract

A core deficit in drug addiction is the inability to inhibit maladaptive drug-seeking behavior. Consistent with this deficit, drug-addicted individuals show reliable cross-sectional differences from healthy non-addicted controls during tasks of response inhibition accompanied by brain activation abnormalities as revealed by functional neuroimaging. However, it is less clear whether inhibition-related deficits predate the transition to problematic use, and, in turn, whether these deficits predict the transition out of problematic substance use. Here, we review longitudinal studies of response inhibition in children/adolescents with little substance experience and longitudinal studies of already-addicted individuals attempting to sustain abstinence. Results show that response inhibition, and its underlying neural correlates, predict both substance use outcomes (onset and abstinence). Neurally, key roles were observed for multiple regions of the frontal cortex (e.g., inferior frontal gyrus, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex). In general, less activation of these regions during response inhibition predicted not only the onset of substance use, but interestingly, also better abstinence-related outcomes among individuals already addicted. The role of subcortical areas, although potentially important, is less clear because of inconsistent results and because these regions are less classically reported in studies of healthy response inhibition. Overall, this review indicates that response inhibition is not simply a manifestation of current drug addiction, but rather a core neurocognitive dimension that predicts key substance use outcomes. Early intervention in inhibitory deficits could have high clinical and public health relevance.

The prognosis of patients with human high-grade gliomas (HGGs) remains dismal despite major advances in their management, due mainly to the high resistance of these infiltrative tumor cells to programmed cell death (PCD). Most therapeutic strategies for HGGs are aimed to maximize PCD type I, apoptosis or type II, autophagy. These are predominantly distinctive processes, but many studies suggest a cross-talk between the two. A better understanding of the link between PCD types I and II might allow development of more effective therapies for HGGs. In this study, we examined whether there is a common upstream signaling event responsible for both apoptotic and autophagic PCD using 3 chemotherapeutic agents in human HGG cells. Our study shows that each agent caused a significant decrease in cell viability in each of the HGG cell lines tested. The increase rate of apoptosis and autophagy varied among cell lines and chemotherapeutic agents used. Increased expression of cytidine-cytidine-adenosine-adenosine-thymidine (C)/ enhancer binding protein (EBP) homologous transcription factor C/EBP homologous protein (CHOP)/ growth arrest and DNA damage-inducible gene 153 (GADD153) was documented after use of either proautophagic or pro-apoptotic agents. The involvement of CHOP/GADD153 in both type I and type II PCD was confirmed by overexpression and gene-silencing studies. Gene silencing by small-interfering RNAmediated CHOP/GADD153 resulted in increased cell viability, decreased upregulation of microtubule-associated protein light-chain 3 ′ type II (LC3II) and cleaved caspase-3, and inhibition of apoptosis and autophagy. Exogenous expression of CHOP/GADD153 triggered apoptosis and autophagy in the absence of other stimuli. The clinical significance of these findings was supported by the evidence that celecoxib, a nonsteroidal anti-inflammatory drug known to induce GADD153-mediated apoptosis, strongly increases both type I and type II PCD in HGG cells when combined with another inducer of GADD153. These data suggest that CHOP/ GADD153 should be investigated as a novel targetable signaling step to improve therapies for HGGs.Keywords: apoptosis, autophagy, CHOP/GADD153, cell viability, gliomas. High-grade gliomas (HGGs), the most frequent types of gliomas, are associated with poor prognosis. Among these, glioblastoma multiforme (GBM), accounting for 50% of gliomas, is associated with a 5-year survival rate of less than 5% and a median survival rate of approximately 14 months, even after use of aggressive surgical tumor resection and postoperative radiation therapy combined with temozolomide (TMZ) chemotherapy is used.2 This is due mainly to high resistance of these infiltrative tumor cells to programmed cell death (PCD).HGG cells show only partial sensitivity to therapies that induce apoptosis, i.e., PCD type I.3 -6 Recent studies indicate that HGG cells are more sensitive to treatments that induce autophagy, i.e., PCD type II. pro-apoptotic and pro-autophagic actions. In particular, TMZ, the oral alkylating agent currently con...

No abstract