Expression Signature of IFN/STAT1 Signaling Genes Predicts Poor Survival Outcome in Glioblastoma Multiforme in a Subtype-Specific Manner

Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype-dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes. We developed a specific multi-gene survival model for the Proneural subtype in the TCGA (the Cancer Genome Atlas) discovery set which we have validated in the TCGA validation set. In addition, we have performed network analysis in the form of Bayesian Network discovery and Ingenuity Pathway Analysis to further dissect the underlying biology of this gene signature in the etiology of GBM. We theorize that the strong predictive value of the IFN/STAT1 gene signature in the Proneural subtype may be due to chemotherapy and/or radiation resistance induced through prolonged constitutive signaling of these genes during the course of the illness. The results of this study have implications both for better prediction models for survival outcome in GBM and for improved understanding of the underlying subtype-specific molecular mechanisms for GBM tumor progression and treatment response

Lipopolysaccharide Renders Transgenic Mice Expressing Human Serum Amyloid P Component Sensitive to Shiga Toxin 2

Transgenic C57BL/6 mice expressing human serum amyloid P component (HuSAP) are resistant to Shiga toxin 2 (Stx2) at dosages that are lethal in HuSAP-negative wild-type mice. However, it is well established that Stx2 initiates extra-intestinal complications such as the haemolytic-uremic syndrome despite the presence of HuSAP in human sera. We now demonstrate that co-administering purified Escherichia coli O55 lipopolysaccharide (LPS), at a dosage of 300 ng/g body weight, to HuSAP-transgenic mice increases their susceptibility to the lethal effects of Stx2. The enhanced susceptibility to Stx2 correlated with an increased expression of genes encoding the pro-inflammatory cytokine TNFα and chemokines of the CXC and CC families in the kidneys of LPS-treated mice, 48 hours after the Stx2/LPS challenge. Co-administering the glucocorticoid dexamethasone, but not the LPS neutralizing cationic peptide LL-37, protected LPS-sensitized HuSAP-transgenic mice from lethal doses of Stx2. Dexamethasone protection was specifically associated with decreased expression of the same inflammatory mediators (CXC and CC-type chemokines and TNFα) linked to enhanced susceptibility caused by LPS. The studies reveal further details about the complex cascade of host-related events that are initiated by Stx2 as well as establish a new animal model system in which to investigate strategies for diminishing serious Stx2-mediated complications in humans infected with enterohemorrhagic E. coli strains

A model of contextual effect on reproduced extents in recall tasks: the issue of the imputed motion hypothesis

In this article the fundamental question of space and time dependencies in the reproduction of spatial or temporal extents is studied. The functional dependence of spatial responses on the temporal context and the corresponding dependence of temporal responses on spatial context are reported as the tau and kappa effects, respectively. A common explanation suggested that the participant imputes motion to discontinuous displays. Using a mathematical model we explore the imputed velocity hypothesis and provide a globally fit model that addresses the question of sequences modelling. Our model accounts for observed data in the tau experiment. The accuracy of the model is improved introducing a new hypothesis based on small velocity variations. On the other hand, results show that the imputed velocity hypothesis fails to reproduce the kappa effect. This result definitively shows that both effects are not symmetric.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Electrically Evoked Auditory Steady State Responses in Cochlear Implant Users

Auditory steady state responses are neural potentials in response to repeated auditory stimuli. This study shows that electrically evoked auditory steady state responses (EASSRs) to low-rate pulse trains can be reliably recorded by electrodes placed on the scalp of a cochlear implant (CI) user and separated from the artifacts generated by the electrical stimulation. Response properties are described, and the predictive value of EASSRs for behaviorally hearing thresholds is analyzed. For six users of a Cochlear Nucleus CI, EASSRs to symmetric biphasic pulse trains with rates between 35 and 47 Hz were recorded with seven scalp electrodes. The influence of various stimulus parameters was assessed: pulse rate, stimulus intensity, monopolar or bipolar stimulation mode, and presentation of either one pulse train on one electrode or interleaved pulse trains with different pulse rates on multiple electrodes. To compensate for the electrical artifacts caused by the stimulus pulses and radio frequency transmission, different methods of artifact reduction were employed. The validity of the recorded responses was confirmed by recording on–off responses, determination of response latency across the measured pulse rates, and comparison of amplitude growth of stimulus artifact and response amplitude. For stimulation in the 40 Hz range, response latencies of 35.6 ms (SD = 5.3 ms) were obtained. Responses to multiple simultaneous stimuli on different electrodes can be evoked, and the electrophysiological thresholds determined from EASSR amplitude growth in the 40 Hz range correlate well with behaviorally determined threshold levels for pulse rates of 41 Hz