Schwannoma Gene Therapy via Adeno-Associated Viral Vector Delivery of Apoptosis-Associated Speck-like Protein Containing CARD (ASC): Preclinical Efficacy and Safety

Schwannomas are tumors derived from Schwann-lineage cells, cells that protect and support myelinated nerves in the peripheral nervous system. They are typically slow-growing, encapsulated and benign. These tumors develop along peripheral, spinal and cranial nerves causing pain, sensory-motor dysfunction and death. Primary treatment for schwannoma is operative resection which can be associated with significant morbidity. Pharmacotherapy is largely restricted to bevacizumab, which has minimal or no efficacy for many patients and can be associated with treatment-limiting adverse effects. Given the suffering and morbidity associated with schwannoma and the paucity of therapeutic options, there is an urgent need for safe and effective therapies for schwannomas. We previously demonstrated that adeno-associated virus serotype 1 (AAV1) vector mediated delivery of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter, produced a prolonged reduction in tumor volume and tumor-associated pain in human xenograft and mouse syngeneic schwannoma models. Here, we present data essential for the translation of our AAV1-P0-ASC schwannoma gene therapy to clinical trials. We determine the minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect in the xenograft human-schwannoma model. We also show that the presence of preexisting AAV1 immunity does not alter the antitumor efficacy of AAV-P0-mASC in a syngeneic mouse schwannoma model. Furthermore, the maximum deliverable intratumoral dose of AAV1-P0-ASC was not associated with neuronal toxicity in immunocompetent mice. Taken together, these safety and efficacy data support the translation of the AAV1-P0-ASC schwannoma gene therapy strategy to clinical trials.     

Evaluating the performance of paper people.

111 studies published, 1975–1984, were grouped into 5 major substantive categories, and a comparative meta-analysis was used to contrast the outcomes of paper people studies (i.e., raters read performance vignettes and then rated the performance of several hypothetical ratees) to those of similar studies in which ratings were based on the direct or indirect observation (e.g., via videotape) of ratee behavior. Effect sizes were found to be significantly larger in paper people studies, although this difference was not uniform across all research areas. Results are discussed in terms of differences in signal-to-noise ratios across the 2 methods. (101 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cytokine profile in chronic cardiac failure

Elevated tumour necrosis factor alpha (TNF-alpha) has been demonstrated in chronic cardiac failure (CCF) and may relate to severity of CCF and development of cachexia. We measured TNF receptor p55 in addition to TNF-alpha in an attempt to improve the detection rate of TNF-alpha activation, and simultaneously measured interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein. Thirty-four patients with CCF and 24 control subjects were studied. Only TNF receptor p55 [6.95 (0.77-42.3) vs. 5.52 (1.50-13.36) ng mL-1 (median (range)] and IL-6 [0.335 (0-9.79) vs. 0(0-14.71) pg mL-1) were significantly elevated in patients compared with control subjects (both P < 0.05). All inflammatory markers were more frequently elevated in patients, but none correlated with any of the clinical parameters studied. Reasons for inflammatory marker elevation in CCF are uncertain, but future studies should measure the p55 TNF receptor and IL-6 in addition to TNF-alpha, to improve detection of cytokine activity.     

Software technology for wireless mobile computing

Some of the possibilities and requirements for mobile computing on wireless local area networks (LANs) are discussed from the systems software viewpoint. The design of the Student Electronic Notebook (SEN) is sketched to provide a partial catalog of problems in building a real system for wireless mobile computing. This project was initiated to investigate the potential of wireless mobile computing to reshape education. Some of the key directions for research in software technology for wireless, mobile computing are examined. Some of the authors' experience with wireless LANs is related     

Failure effects on outerdirectedness: a failure to replicate

A replication was conducted of part of Turnure and Zigler's (1964) experiment in which they assessed whether outerdirectedness was a function of failure experiences. Thirty nonretarded and 30 retarded children, matched on MA, experienced either failure games administered with positive or negative comments followed by an imitative assessment task or received only the imitation task. The results did not support Zigler's hypothesis concerning the antecedents of outerdirectedness, as no short-term effects of failure were found. The findings refuted Turnure and Zigler's hypothesis that outerdirectedness is a function of situational social reinforcement. Differences in tasks presented, methods of analysis, and/or school populations may have contributed to the lack of correspondence with the Turnure and Zigler findings.     

Modified super pass gate for multiple-valued logic circuits

A model of a super pass gate (SPG) is adapted to allow multiple-valued logic circuit connections and designs that are normally prohibited by the formal synthesis and minimisation technique for the device. The modification of the SPG allows more efficient circuit minimisation to be achieved for functions that do not readily reduce under the formal synthesis technique     

Making sense of surprise: An investigation of the factors influencing surprise judgments.

Surprise is often defined in terms of disconfirmed expectations, whereby the surprisingness of an event is thought to be dependent on the degree to which it contrasts with a more likely, or expected, outcome. The authors investigated the alternative hypothesis that surprise is more accurately modeled as a manifestation of an ongoing sense-making process. In a series of experiments, participants were given a number of scenarios and rated surprise and probability for various hypothetical outcomes that either confirmed or disconfirmed an expectation. Experiment 1 demonstrated that representational specificity influences the relationship that holds between surprise and probability ratings. Experiment 2 demonstrated that the inclusion of an enabling event lowers surprise ratings for disconfirming outcomes. Experiment 3 explored the reason for this effect, revealing that enabling events lower surprise by reducing uncertainty, thus enhancing ease of integration. Experiment 4 evaluated the contrast hypothesis directly, showing that differences in contrast are not correlated with differences in surprise. These results provide converging support for the view that the level of surprise experienced for an event is related to the difficulty of integrating that event with an existing representation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)