The epigenetically regulated miR-494 associates with stem-cell phenotype and induces sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, especially in patients not amenable for curative treatments. The multi-kinase inhibitor sorafenib represents the first-line treatment option for advanced HCC; nevertheless, its effectiveness is limited due to tumor heterogeneity as well as innate or acquired drug resistance, raising the need for new therapeutic strategies. MicroRNAs (miRNAs) involvement in treatment response as well as their safety and efficacy in preclinical models and clinical trials have been widely documented in the oncologic field, including HCC. Here, we identified miR-494 upregulation in a subgroup of human and rat HCCs with stem cell-like characteristics, as well as multiple epigenetic mechanisms involved in its aberrant expression in HCC cell lines and patients. Moreover, we identified p27, puma and pten among miR-494 targets, contributing to speed up cell cycle progression, enhance survival potential in stressful conditions and increase invasive and clonogenic capabilities. MiR-494 overexpression increased sorafenib resistance via mTOR pathway activation in HCC cell lines and, in line, high miR-494 levels associated with decreased sorafenib response in two HCC animal models. A sorafenib-combined anti-miR-494-based strategy revealed an enhanced anti-tumor potential with respect to sorafenib-only treatment in our HCC rat model. In conclusion, our findings suggested miR-494 as a possible therapeutic target as well as a candidate biomarker for patient stratification in advanced HCC.

A parallel rule activation and rule synthesis model for generalization in category learning.

This paper proposes a distinction between primary generalization (transfer from stored exemplars to perceived targets) and secondary generalization (transfer from inferred abstractions to perceived targets). This distinction is embodied in the parallel rule activation and rule synthesis (PRAS) model, a production model capable of exemplar-based and abstraction-based categorization. As an exemplar model, the PRAS model is related to the generalized context model (Nosofsky, 1984). Exemplars are stored in memory encoded as condition-action rules. Working as an exemplar-based model, rules are activated on the basis of their strength and their similarity to the current to-be-categorized instance. Similarity between a target and a stored exemplar is weighted for attention to the dimensions of the psychological space. Depending on the value of a special parameter, the PRAS model is also able to operate as an abstraction model. In the latter case, it attempts to construct generalizing productions, which are activated according to the same rules as the exemplar-specific rules. The model is described in detail. It is applied to a number of important observations described in the research literature, and an experiment is reported that tested the usefulness of the proposed secondary-generalization mechanism. Finally, the discussion elaborates on the implications of the present study for further research.

The effect of cognitive load on saccadic eye movements.

The present study tested the hypothesis that, unlike prosaccades, antisaccades require controlled processing, due to the prepotent response that needs to be inhibited. The effect of the Random time Interval Generation (RIG) task (Vandierendonck, A., De Vooght, G., & Van der Goten, K. (1998). European Journal of Cognitive Psychology, 10, 413-444) on these saccade latencies and errors was studied. This task has the advantage that it loads executive processes, with only minimal interference with verbal or visuo-spatial components. A first experiment compared saccade performance within the prosaccade and the antisaccade task, executed alone and in combination with the RIG task and fixed tapping (added to exclude possible motor component interference explanations). A second experiment investigated the influence of task characteristics on the effects found. Although it was shown that antisaccades are more prone to interference of an executive interference task, it seems that prosaccades are also vulnerable. Interference on prosaccades could originate from a controlled execution of these saccades. A third experiment confirmed that endogenously generated prosaccades are susceptible to dual-task interference and showed that controlled saccade execution, without the need to inhibit a prepotent response, is sufficient to produce interference.

Sensation of resistor-induced warmth in blind persons.

It is commonly believed that the human sense of warmth is inferior in spatiotemporal acuity to the tactile senses. However, little or no evidence is available about the active feeling of warmth. We investigated the ability of people to detect in an active way small changes of warmth on very small areas (2-mm x 2-mm resistors). To that end, a new procedure was developed to measure perception of warmth. The results indicate that people who are able to detect the warmth stimuli perceive small incremental changes and that detection performance improves as stimulus intensity increases. Male subjects seem to be less sensitive than female subjects at lower level of stimulation, but this relationship is reversed at higher levels of stimulation.

Analyzing human random time generation behavior: a methodology and a computer program.

In the present article, it is argued that in addition to the traditional random generation tasks discussed by Towse and Neil (1998), random time interval generation tasks should be considered as useful alternatives, because they allow a better empirical control of the executive task component in dual-task situations. First, a framework for discussing randomness over time is presented. Then, the article goes on to present three methods for the analysis of such tasks. A first method is based on the correlation between the intervals produced. The second method calculates the approximate entropy, and the third method converts the time sequences into binary sequences and estimates the statistical properties of the sequence on the basis of these binary data. A principal components analysis on 19 different measures based on 1,381 sequences produced in a number of single-task and dual-task experiments shows that the proposed measures form two general clusters, one related to output probability, perseveration, and alternation, and one related to sequential commonalities. The article also briefly describes a computer program that implements these methodologies.

Is judgment of random time intervals biased and capacity-limited?

Recently, random generation of time intervals has been proposed as a procedure to impair executive processing in a dual-task paradigm without substantial interference with phonological and visuo-spatial working memory resources. A fundamental assumption of this procedure is that humans are able to distinguish time sequences on their degree of randomness. The present study tests this assumption. To this end, non-biased, repetition-biased, alternation-biased sequences and repetitive rhythms were judged under conditions of higher or lower executive load. In Exp. 1, load depended on the presentation speed, while in Exp. 2, a dual-task condition was used with either a concurrent number-copying task or an arithmetic task. It was found that the participants could distinguish repetitive rhythms from more or less random sequences, and that both accuracy of this judgment and latency were affected by the concurrent load. The findings are taken as a first indication that random time judgment is capacity-limited.

Working memory constraints on linear reasoning with spatial and temporal contents.

The present article reports two experiments testing the use of working memory components during reasoning with temporal and spatial relations in four-term series problems. In the first experiment four groups of subjects performed reasoning tasks with temporal and with spatial contents either without (control) or with a secondary task (articulatory suppression, visuo-spatial suppression or central executive suppression). The second experiment tested the secondary task effects in a within-subjects design either on problems with a spatial content or on problems with a temporal content, and within each content domain either under conditions of self-paced or of fixed presentation of the premises. Both experiments found effects of all three secondary tasks on reasoning accuracy. This supports the hypothesis that the subjects construct spatial representations of the premise information with the support of visuo-spatial resources of working memory. The second experiment also showed that during premise intake, only visuo-spatial and central executive secondary tasks had an effect. The implications of the data for the working memory requirements of reasoning and for theories of linear reasoning are discussed.

Interfering with the central executive by means of a random interval repetition task.

Four dual-task experiments are reported in which a short-term memory task is performed concurrently with a random interval repetition task, which was designed to interfere with functions normally attributed to the central executive in the working memory model of Baddeley and Hitch (1974). The task was found to interfere with supra-span serial recall and with backward memory span, but did not disrupt performance on a forward-memory-span task. The effects were observed in dissociation with effects of articulatory suppression and matrix tapping, so that the locus of the effects of the new task is not due to the slave systems. In addition, single-task random-interval repetition performance was sampled and compared to performance in the dual-task conditions of all four experiments. Although quality of tapping performance differed between the single-task and the dual-task conditions, it was not related to recall performance. All the results are discussed with reference to the working memory model.

Verifying simple arithmetic sums and products: are the phonological loop and the central executive involved?

In two experiments, we investigated the role of the phonological loop and the central executive in the verification of the complete set of one-digit addition (Experiment 1) and multiplication (Experiment 2) problems. The focus of the present study was on the contradictory results concerning the contribution of the phonological loop in the verification of true problems (e.g., 8 + 4 = 12 or 4 x 6 = 24) reported until now. The results revealed that this slave system is not involved in verifying simple arithmetic problems, in contrast to the central executive. Furthermore, our results indicated that the split effect is due to the use of two different arithmetic strategies.

Parallel visual and memory processes.

We studied parallel processes: visual processes with the prosaccade, the no-saccade and the antisaccade task on the one hand and memory processes with the random tap task on the other hand. The random tap task is believed to be a pure interference task for the central executive component of working memory. The number of saccadic errors was found not to be influenced by taxing the central executive, while the latency times were significantly increased both in the prosaccade and in the antisaccade task. The effect seen in the antisaccade task was expected since it is a non-automatic activity under central executive control. Because the prosaccade task is an automatic activity, an effect of central executive load was not expected. As an explanation for our findings, we postulate that the prosaccade task is brought under willed control of the central executive.

Labor induction with prostaglandin F2alpha. Influence on psychomotor evolution of the child in the first 30 months.

The long-term effects of elective induction of labor at term by amniotomy and the intravenous infusion of prostaglandin F2alpha were studied in 40 children. No untoward effect of this procedure on the psychomotor development of the children during the first 30 months could be demonstrated.