STAT3 is activated in a subset of the Ewing sarcoma family of tumours.

STAT3 is an oncogene that regulates critical cellular processes and whose constitutive activation has been demonstrated to correlate with biological and clinical features in many types of human malignancy. In this study, STAT3 activation was assessed in the Ewing sarcoma family of tumours (ESFT), which is characterized by fusion of the EWS gene with one of several Ets transcription factors, most commonly EWS-FLI1. STAT3 activation was assessed by immunohistochemistry using a monoclonal antibody specific for tyrosine(705)-phosphorylated STAT3 (pSTAT3(tyr705)) and a tissue microarray containing 49 paraffin-embedded ESFT tumours with known EWS translocations. Twenty-five (51%) tumours were pSTAT3(tyr705)-positive, as defined by more than 10% tumour cell immunostaining. STAT3 activation correlated with tumour site at presentation, with pSTAT3(tyr705)-negative ESFT involving axial sites predominantly (p = 0.008). Notably, among 31 patients who presented with localized disease, high-level STAT3 activation correlated with better overall survival (p = 0.02). STAT3 activation was not directly related to EWS-FLI1 expression, since EWS-FLI1 transfection did not result in STAT3 activation. Furthermore, detailed molecular analysis indicated that STAT3 activation may be seen with EWS-FLI1 or EWS-ERG and appears to be independent of EWS-FLI1 fusion type. In conclusion, STAT3 activation is present in approximately half of ESFT and correlates with clinical features. The role of STAT3 activation in ESFT pathogenesis seems to be independent of the type of EWS/Ets translocation.

Spatiotemporal analysis of the late ERP responses to deviant stimuli.

We used a novel application of principal components analysis (spatiotemporal PCA) to decompose the event-related brain potentials (ERPs) obtained with a dense electrode array, with the purpose of elucidating the late ERP components elicited by deviant stimuli under "attend" and "ignore" conditions. First, a "spatial" PCA was performed to identify a set of scalp distributions (spatial factors or "virtual electrodes") that accounted for the spatial variance in the data set. The data were expressed as spatial factor scores or "virtual ERPs" measured at each of the virtual electrodes. These virtual ERPs were submitted to a "temporal" PCA, yielding a set of temporal factors or "virtual epochs." Statistical analyses of the temporal factor scores found that (1) attended deviant stimuli elicited the P300 and Novelty P3 components, the latter being largest for highly salient nontargets: (2) "ignored" deviants elicited a small Novelty P3, and depending on the primary task, a small P300: and (3) the classical Slow Wave consisted of separate frontal-negative and posterior-positive components.

A cortical potential imaging analysis of the P300 and novelty P3 components.

The P300 and Novelty P3 are positive components of the event related brain potential (ERP) with a latency of at least 300 ms, which are manifestations of brain activity evoked by deviant events. Spencer et al. [1999, 2001] demonstrated that these are two distinct components, both of which may be elicited, with different amplitudes, by both rare and novel events. However, the locations of the intracranial sources of the components remain unknown. We describe the application of cortical potential imaging (CPI) analysis to the data described by Spencer et al. [1999]. The ERPs were recorded from 15 healthy subjects presented with auditory oddball sequences. Cortical potential maps (CPMs) were reconstructed from the scalp potential maps (SPMs) corresponding to the P300 and Novelty P3 components by deblurring the smoothing effect of the head volume conductor. The reconstructed CPMs, derived from the SPMs by means of the CPI, showed localized areas of activity distributed in both the frontal and parietal lobes; the parietal region was active throughout the period of the late positivities. The reconstructed CPMs associated with novel events showed prominent activity at the frontal lobe (Novelty P3) followed by progressively pronounced parietal lobe activity (P300), and these two components can be well separated by the CPMs. These analyses show how the CPI can be used to relate the scalp electrical recordings to the underlying brain activity.

Differentiating the N3 and N4 electrophysiological semantic incongruity effects.

An event-related potential termed the N4 has been widely studied due to its sensitivity to semantic incongruity. A recent report (Nobre & McCarthy, 1994) indicates there is also an N3 component that is sensitive to semantic incongruity. To differentiate these two components, an existing data set with 65 electrode sites, 78 subjects, and 120 sentences was examined. Instead of the usual procedure of averaging over the stimuli within distinct categories for each subject, a new approach--averaging over subjects--was employed. In this item average approach, 120 averages (one per sentence) were produced. Correlational analyses indicate that the N3 is equally sensitive to cloze probability and sentential constraint. The N4, by contrast, is more sensitive to sentential constraint and less to cloze probability; it is also correlated with familiarity. We interpret these results as evidence that the N3 is more responsive to semantic fit whereas the N4 is more responsive to semantic expectancy.

A componential analysis of the ERP elicited by novel events using a dense electrode array.

In this study, we examined the relationship between the novelty P3 and the P300 components of the brain event-related potential (ERP). Fifteen subjects responded manually to the rare stimuli embedded either in a classical auditory oddball series or in a series in which "novel" stimuli were inserted. The electroencephalogram (EEG) was recorded with a dense array of 129 electrodes. The data were analyzed by using spatial Principal Components Analysis (PCA) to identify a set of orthogonal scalp distributions, "virtual electrodes" that account for the spatial variance. The data were then expressed as ERPs measured at each of the virtual electrodes. These ERPs were analyzed using temporal PCA, yielding a set of "virtual epochs." Most of the temporal variance of the rare events was associated with a virtual electrode with a posterior topography, that is, with a classical P300, which was active during the virtual epoch associated with the P300. The novel stimuli were found to elicit both a classical P300 and a component focused on a virtual electrode with a frontal topography. We propose that the term Novelty P3 should be restricted to this frontal component.

Addressing misallocation of variance in principal components analysis of event-related potentials.

Interpretation of evoked response potentials is complicated by the extensive superposition of multiple electrical events. The most common approach to disentangling these features is principal components analysis (PCA). Critics have demonstrated a number of caveats that complicate interpretation, notably misallocation of variance and latency jitter. This paper describes some further caveats to PCA as well as using simulations to evaluate three potential methods for addressing them: parallel analysis, oblique rotations, and spatial PCA. An improved simulation model is introduced for examining these issues. It is concluded that PCA is an essential statistical tool for event-related potential analysis, but only if applied appropriately.

Dense sensor array topography of the event-related potential to task-relevant auditory stimuli.

High spatial density recording and better topographic mapping algorithms have improved the spatial resolving power of the event-related potential (ERP), adding to its already excellent temporal resolution. This study used a 64 channel recording array and spherical spline interpolation to create topographic descriptions of the voltage and current density scalp distributions of the ERP in an auditory oddball paradigm. Frequent (standard) and infrequent (target) tones were presented at a rate of one every approximately 2500 ms to a group of 20 college undergraduates in passive listening and active (count the infrequent tones) task blocks. ANOVAs and topographic analyses were performed on the primary deflections in the 'late' portion of the ERP: the P1, N1, P2, N2 and P3. A target minus standard difference wave was also created for each task. The difference wave contained a mismatch negativity (MMN), an N2b and a P3d. The MMN did not differ between the passive and active tasks and had a topography similar to the N1; also the difference wave P3d was topographically similar to the target P3. The N2b, which occurred only to targets in the active condition, and was the first index of target detection, had a scalp distribution consistent with generation in frontal and superior temporal cortex, suggesting activity in cortical areas of selective attention and auditory stimulus representation.

Error-related scalp potentials elicited by hand and foot movements: evidence for an output-independent error-processing system in humans.

The error-related negativity (ERN) is a fronto-centrally distributed component of the event-related brain potential (ERP) that occurs when human subjects make errors in a variety of experimental tasks. In the present study, we recorded ERPs from 128 scalp electrodes while subjects performed a choice reaction time task using either their hands or feet. We applied the brain electric source analysis technique to compare ERNs elicited by hand and foot errors. The scalp distributions of these error potentials suggest that they share the same neural generator and, therefore, that the ERN process is output-independent. Together with other findings, the results are consistent with the hypothesis that the ERN is generated within the anterior cingulate cortex and is elicited by the activation of a generic error-processing system.

Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p.

Autosomal dominant familial spastic paraplegia (AD-FSP) is a degenerative disorder of the central motor system characterised by progressive spasticity of the lower limbs. AD-FSP has been divided into pure and complicated forms. Pure AD-FSP is genetically heterogeneous; three loci have been mapped to chromosomes 14q (SPG3), 2p (SPG4), and 15q (SPG6), whereas no loci responsible for complicated forms have been identified to date. Here we report linkage to the SPG4 locus in a three generation family with AD-FSP complicated by dementia and epilepsy. Assuming that both forms of AD-FSP are caused by mutations involving the same FSP gene, analysis of recombination events in this family positions the SPG4 gene within a 0 cM interval flanked by loci D2S2255 and D2S2347.

Localization of auditory evoked potentials related to selective intermodal attention.

A long-standing question in attention research is the extent to which selection involves gates in the sensory stream and the extent to which they involve added secondary processes. Intermodal attention paradigms are useful for examining this issue since different modalities involve readily distinguished cortical regions. Evoked potential studies have identified an attention-related frontal negativity labeled the Nd in auditory attention studies. It has been suggested that it arises from modulation of the auditory cortex (compatible with gating mechanisms) or of the frontal cortex (compatible with secondary processes such as short-term memory buffers). Efforts to localize the Nd have been impaired by the finding that the Nd comprises multiple components. Some novel procedures utilizing principal components analysis, in conjunction with high-density 64-channel recordings, were used to address this issue. Results suggest that the major source of the early Nd (the portion of most interest) resides in the frontal cortex, supporting the secondary process view for this particular mechanism.