Research has indicated a major role of dopamine in decision-making processes, but the underlying mechanisms remain largely unknown due to inconsistency in effects of dopaminergic drugs. To clarify the impact of dopamine on impulsive choice, we administered 150 mg L-DOPA to 87 healthy adults in a randomized, placebo-controlled, double-blind, crossover study, evaluating performance in four value-based decision-making tasks. We predicted that baseline impulsivity would moderate L-DOPA effects. In support of our hypothesis, L-DOPA had no main effect on impulsive choice, but reduced risk-seeking for gains in more-impulsive subjects. Because L-DOPA effects may be influenced by body weight, we repeated our analyses on data from half of the sample (n = 44) with lower weight, anticipating a stronger effect. In addition to the effect on risk-seeking for gains, low-weight participants also exhibited baseline-dependent effects of L-DOPA on loss aversion and delay discounting. Our results are consistent with the hypothesis of an inverted U-shaped dopamine function in which both low and high extremes of dopamine signaling are associated with high-impulsive choice. Consideration of differential baseline impulsivity and body weight may resolve previous seemingly paradoxical pharmacological results and might deepen our understanding of dopaminergic mechanisms underlying impulsivity.

Overexpression of the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2/IGF2BP2) has been described in different cancer types. Gallbladder carcinoma (GBC) is a rare but highly aggressive cancer entity with late clinical detection and poor prognosis.The aim of this study was to investigate the role of IMP2 in human GBC.Tissue microarrays (TMAs) of an international multi-center GBC sample collection from n = 483 patients were analyzed by immunohistochemistry. IMP2 immunoreactivity was found in 74.3% of the tumor samples on TMA, of which 14.0% showed strong and 86.0% low staining intensity. 72.4% of the tumor samples were IMP1 positive, but IMP1 showed lower expression in tumor tissue compared to control tissues. IMP3 immunoreactivity was observed in 92.7% of all tumors, of which 53.6% revealed strong IMP3 expression. Kaplan-Meier analysis linked high IMP2 expression to shorter survival time (p = 0.033), whereas neither IMP1 nor IMP3 expression was linked to a decreased survival time. Eight different human biliary tract cancer (BTC) cell lines were evaluated for tumor growth kinetics in mouse xenografts. Cell lines with high IMP2 expression levels showed the fastest increase in tumor volumes in murine xenografts. Furthermore, IMP2 expression in these cells correlated with the generation of reactive oxygen species (ROS) and RAC1 expression in BTC cells, suggesting RAC1-induced ROS generation as a potential mechanism of IMP2-promoted progression of GBC.In conclusion, IMP2 is frequently overexpressed in GBC and significantly associated with poor prognosis and growth rates in vivo. IMP2 might therefore represent a new target for the treatment of advanced GBC.

BackgroundGallbladder cancer (GBC) is a rare neoplasia of the biliary tract with high mortality rates and poor prognosis. Signs and symptoms of GBC are not specific and often arise at late stage of disease. For this reason, diagnosis is typically made when the cancer is already in advanced stages, and prognosis for survival is less than 5 years in 90% of cases. Biomarkers to monitor disease progression and novel therapeutic alternative targets for these tumors are strongly required. Commonly, dysregulated protein synthesis contributes to carcinogenesis and cancer progression. In this case, protein synthesis directs translation of specific mRNAs, and, in turn, promotes cell survival, invasion, angiogenesis, and metastasis of tumors. In eukaryotes, protein synthesis is regulated at its initiation, which is a rate-limiting step involving eukaryotic translation initiation factors (eIFs). We hypothesize that eIFs represent crossroads in the development of GBC, and might serve as potential biomarkers. The study focus was the role of eIF6 (an anti-association factor for the ribosomal subunits) in GBC.MethodsIn human GBC samples, the expression of eIF6 was analyzed biochemically at the protein (immunohistochemistry, immunoblot analyses) and mRNA levels (qRT-PCR).ResultsHigh levels of eIF6 correlated with shorter overall survival in biliary tract cancer (BTC) patients (n = 28). Immunohistochemical data from tissue microarrays (n = 114) demonstrated significantly higher expression levels of eIF6 in GBC compared to non-neoplastic tissue. Higher eIF6 expression on protein (immunoblot) and mRNA (qRT-PCR) level was confirmed by analyzing fresh frozen GBC patient samples (n = 14). Depletion of eIF6 (using specific siRNA-mediated knockdown) in Mz-ChA-2 and TFK-1 cell lines inhibited cell proliferation and induced apoptosis.ConclusionOur data indicates that eIF6 overexpression plays a major role in the translational control of GBC, and indicates its potential as a new biomarker and therapeutic target in GBC.Electronic supplementary materialThe online version of this article (10.1007/s00432-019-03030-x) contains supplementary material, which is available to authorized users.

We previously reported that L-DOPA effects on reward-based decision-making in a randomized, placebo-controlled, double-blind, crossover study were consistent with an inverted U-shaped function whereby both low and high extremes of dopamine signaling are associated with high-impulsive choice. To test this hypothesis, we performed [18F]DOPA positron emission tomography in 60 of the 87 participants in that study, and measured the effective distribution volume ratio (EDVR) of [18F]DOPA influx rate to [18F]dopamine washout rate, an index of presynaptic dopaminergic function. Participants with higher baseline EDVR self-reported lower impulsivity, and discounted rewards as a function of delay more strongly after receiving L-DOPA, whereas the opposite was detected for those with lower baseline EDVR. Our findings support a relationship of striatal dopaminergic activity to trait impulsivity, and the view that there is a non-linear, possibly inverted U-shaped relationship of striatal dopaminergic function with delay discounting. Individuals with optimal dopamine signaling would become more impulsive when receiving dopamine-enhancing drugs, whereas those with suboptimal dopaminergic signaling would benefit and exhibit less impulsive choice. Consideration of differences in endogenous dopamine signaling and possibly also other neurotransmitter activity may be crucial to advance understanding of the neurobiochemical mechanisms of impulsive decision-making and related mental disorders.

Methamphetamine use disorder (MUD) is increasing worldwide and commonly associated with learning deficits. Little is known the about underlying trajectories, i.e., how the affected higher-order cognitive functions develop over time and with respect to abstinence and relapse. A probabilistic reversal learning (PRL) paradigm was implemented to uncover the microstructure of impulsive choice and maladaptive learning strategies in 23 patients with MUD in comparison with 24 controls. Baseline data revealed fewer optimal choices and a pattern of altered learning behavior from negative and positive feedback in patients suggesting impairments in flexibly-adapting behavior to changes of reward contingencies. Integrating longitudinal data from a follow-up assessment after 3 months of specific treatment revealed a group-by-time interaction indicating a normalization of these cognitive impairments in patients with MUD. In summary, our study demonstrates behavioral correlates of maladaptive decision-making processes in patients with MUD, which may recover after 3 months of MUD-specific therapy paving the way for further learning-based interventions. Limited by a small sample size, the results of this pilot study warrant replication in larger populations.