Correcting Memory Improves Accuracy of Predicted Task Duration

People are often inaccurate in predicting task duration. The memory bias explanation holds that this error is due to people having incorrect memories of how long previous tasks have taken, and these biased memories cause biased predictions. Therefore, the authors examined the effect on increasing predictive accuracy of correcting memory through supplying feedback for actual task duration. For Experiments 1 (paper-counting task) and 2 (essay-writing task), college students were supplied with duration information about their previous performance on a similar task before predicting task duration. For Experiment 3, participants were recruited at various locations, such as fast food restaurants and video arcades, and supplied with average task duration for others before predicting how long the task would take. In all 3 experiments, supplying feedback increased predictive accuracy. Overall, results indicate that, when predicting duration, people do well when they rely not on memory of past task duration but instead on measures of actual duration, whether their own or that of others. © 2008 American Psychological Association

Longitudinal scaling of VECSEL output power maintaining narrow linewidth

Output power of VECSELs had been scaled by lateral scaling to tens of watts and beyond. Longitudinal scaling, employing multiple VECSEL devices in a single resonator, has the potential to scale up the power as well. However, some of the devices need to be placed at a fold of the resonator and inherently suffers from the spectral instability. The standing wave pattern created at a fold of a standing wave cavity exhibits that of 4-wave interference, and the resulting pattern shows high contrast modulation in the plane of the quantum well. The phase of that modulation depends on the phase relationship between the forward and backward beams, which differs for different longitudinal modes. This results in a situation similar to the special hole burning effect in solid-state lasers in which case the standing wave pattern is in the longitudinal direction. Because of the resonant periodic gain structure, VECSELs do not suffer from spatial hole burning if the device is placed at the end of the standing-wave cavity and single-frequency operation can be obtained relatively simply. This no longer holds when the VECSEL device is placed at the fold of a standing wave cavity. Twisted-mode configuration addresses this and allows narrow-linewidth or single-frequency operation of multi-device VECSELs. By having forward and backward modes in oppositely rotating circular polarization, the standing wave pattern does not show modulation in the planes of quantum wells, recovering the advantage of resonant periodic gain.Immediate accessThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Practical Preclinical Model for Assessing the Potential for Unconjugated Hyperbilirubinemia Produced by Human Immunodeficiency Virus Protease Inhibitors

A practical preclinical model for the hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors has been developed. Indinavir and atazanavir produced significant hyperbilirubinemia, whereas amprenavir, the negative control, was indistinguishable from the ritonavir booster dose. This model was used to disqualify an exploratory protease inhibitor from development

The Volume of Three-Dimensional Cultures of Cancer Cells In Vitro Influences Transcriptional Profile Differences and Similarities with Monolayer Cultures and Xenografted Tumors

Improving the congruity of preclinical models with cancer as it is manifested in humans is a potential way to mitigate the high attrition rate of new cancer therapies in the clinic. In this regard, three-dimensional (3D) tumor cultures in vitro have recently regained interest as they have been acclaimed to have higher similarity to tumors in vivo than to cells grown in monolayers (2D). To identify cancer functions that are active in 3D rather than in 2D cultures, we compared the transcriptional profiles (TPs) of two non-small cell lung carcinoma cell lines, NCI-H1650 and EBC-1 grown in both conditions to the TP of xenografted tumors. Because confluence, diameter or volume can hypothetically alter TPs, we made intra- and inter-culture comparisons using samples with defined dimensions. As projected by Ingenuity Pathway Analysis (IPA), a limited number of signal transduction pathways operational in vivo were better represented by 3D than by 2D cultures in vitro. Growth of 2D and 3D cultures as well as xenografts induced major changes in the TPs of these 3 modes of culturing. Alterations of transcriptional network activation that were predicted to evolve similarly during progression of 3D cultures and xenografts involved the following functions: hypoxia, proliferation, cell cycle progression, angiogenesis, cell adhesion, and interleukin activation. Direct comparison of TPs of 3D cultures and xenografts to monolayer cultures yielded up-regulation of networks involved in hypoxia, TGF and Wnt signaling as well as regulation of epithelial mesenchymal transition. Differences in TP of 2D and 3D cancer cell cultures are subject to progression of the cultures. The emulation of the predicted cell functions in vivo is therefore not only determined by the type of culture in vitro but also by the confluence or diameter of the 2D or 3D cultures, respectively. Consequently, the successful implementation of 3D models will require phenotypic characterization to verify the relevance of applying these models for drug development

ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope.

Targeting tumor-overexpressed EGFR with an antibody-drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations, including activating mutations and those with the exon 2-7 deletion [EGFR variant III (EGFRvIII)], commonly found in glioblastoma multiforme. ABT-414 exhibits potent cytotoxicity against glioblastoma multiforme patient-derived xenograft models expressing either wild-type EGFR or EGFRvIII, with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard-of-care treatment of radiation and temozolomide, providing significant therapeutic benefit in a glioblastoma multiforme xenograft model. On the basis of these results, ABT-414 has advanced to phase I/II clinical trials, and objective responses have been observed in patients with both amplified wild-type and EGFRvIII-expressing tumors. Mol Cancer Ther; 15(4); 661-9. ©2016 AACR. Mol Cancer Ther 2016 Apr; 15(4): 661-

Expression Profile of BCL-2, BCL-X L , and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models

International audienceBCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-X L (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/vene-toclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-X L also affects antitumor responses to venetoclax in multiple myeloma. In multiple mye-loma cell lines (n ¼ 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-X L or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-X L were resistant to venetoclax but sensitive to a BCL-X L – selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-X L or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coex-pressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xeno-grafts that expressed BCL-X L , MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-X L selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n ¼ 95) revealed high levels of BCL-2 and BCL-X L in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2 High /BCL-X L Low. In addition to MCL-1, our data suggest that BCL-X L may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1–13. Ó2016 AACR