Synthesis and Pro-Apoptotic Effects of Nitrovinylanthracenes and Related Compounds in Chronic Lymphocytic Leukaemia (CLL) and Burkitt's Lymphoma (BL).

Chronic lymphocytic leukaemia (CLL) is a malignancy of the immune B lymphocyte cells and is the most common leukaemia diagnosed in developed countries. In this paper, we report the synthesis and antiproliferative effects of a series of (E)-9-(2-nitrovinyl)anthracenes and related nitrostyrene compounds in CLL cell lines and also in Burkitt's lymphoma (BL) cell lines, a rare form of non-Hodgkin's immune B-cell lymphoma. The nitrostyrene scaffold was identified as a lead structure for the development of effective compounds targeting BL and CLL. The series of structurally diverse nitrostyrenes was synthesised via Henry-Knoevenagel condensation reactions. Single-crystal X-ray analysis confirmed the structure of (E)-9-chloro-10-(2-nitrobut-1-en-1-yl)anthracene (19f) and the related 4-(anthracen-9-yl)-1H-1,2,3-triazole (30a). The (E)-9-(2-nitrovinyl)anthracenes 19a, 19g and 19i-19m were found to elicit potent antiproliferative effects in both BL cell lines EBV-MUTU-1 (chemosensitive) and EBV+ DG-75 (chemoresistant) with >90% inhibition at 10 µM. Selected (E)-9-(2-nitrovinyl)anthracenes demonstrated potent antiproliferative activity in CLL cell lines, with IC50 values of 0.17 µM (HG-3) and 1.3 µM (PGA-1) for compound 19g. The pro-apoptotic effects of the most potent compounds 19a, 19g, 19i, 19l and 19m were demonstrated in both CLL cell lines HG-3 and PGA-1. The (E)-nitrostyrene and (E)-9-(2-nitrovinyl)anthracene series of compounds offer potential for further development as novel chemotherapeutics for CLL.

Individual differences in speech-on-speech masking are correlated with cognitive and visual task performance.

Individual differences in spatial tuning for masked target speech identification were determined using maskers that varied in type and proximity to the target source. The maskers were chosen to produce three strengths of informational masking (IM): high [same-gender, speech-on-speech (SOS) masking], intermediate (the same masker speech time-reversed), and low (speech-shaped, speech-envelope-modulated noise). Typical for this task, individual differences increased as IM increased, while overall performance decreased. To determine the extent to which auditory performance might generalize to another sensory modality, a comparison visual task was also implemented. Visual search time was measured for identifying a cued object among "clouds" of distractors that were varied symmetrically in proximity to the target. The visual maskers also were chosen to produce three strengths of an analog of IM based on feature similarities between the target and maskers. Significant correlations were found for overall auditory and visual task performance, and both of these measures were correlated with an index of general cognitive reasoning. Overall, the findings provide qualified support for the proposition that the ability of an individual to solve IM-dominated tasks depends on cognitive mechanisms that operate in common across sensory modalities.

Forward masking of spectrotemporal modulation detection.

Recent work has suggested that there may be specialized mechanisms in the auditory system for coding spectrotemporal modulations (STMs), tuned to different combinations of spectral modulation frequency, temporal modulation frequency, and STM sweep direction. The current study sought evidence of such mechanisms using a psychophysical forward masking paradigm. The detectability of a target comprising upward sweeping STMs was measured following the presentation of modulated maskers applied to the same carrier. Four maskers were tested, which had either (1) the same spectral modulation frequency as the target but a flat temporal envelope, (2) the same temporal modulation frequency as the target but a flat spectral envelope, (3) the same spectral and temporal modulation frequencies as the target but the opposite sweep direction (downward sweeping STMs), or (4) the same spectral and temporal modulation frequencies as the target and the same sweep direction (upward sweeping STMs). Forward masking was greatest for the masker fully matched to the target (4), intermediate for the masker with the opposite sweep direction (3), and negligible for the other two (1, 2). These findings are consistent with the suggestion that the detectability of the target was mediated by an STM-specific coding mechanism with sweep-direction selectivity.

The Effects of Uncertainty in Level on Speech-on-Speech Masking.

Identification of speech from a "target" talker was measured in a speech-on-speech masking task with two simultaneous "masker" talkers. The overall level of each talker was either fixed or randomized throughout each stimulus presentation to investigate the effectiveness of level as a cue for segregating competing talkers and attending to the target. Experimental manipulations included varying the level difference between talkers and imposing three types of target level uncertainty: 1) fixed target level across trials, 2) random target level across trials, or 3) random target levels on a word-by-word basis within a trial. When the target level was predictable performance was better than corresponding conditions when the target level was uncertain. Masker confusions were consistent with a high degree of informational masking (IM). Furthermore, evidence was found for "tuning" in level and a level "release" from IM. These findings suggest that conforming to listener expectation about relative level, in addition to cues signaling talker identity, facilitates segregation of, and maintaining focus of attention on, a specific talker in multiple-talker communication situations.

Distinct and interacting impacts of trait anxiety and a state anxiety manipulation on attentional switching.

BACKGROUND AND OBJECTIVES: According to the Attentional Control Theory, individuals with high levels of anxiety often shift their attention inefficiently due to increased effort to meet task demands. However, literature on the effects of anxiety on shifting performance is discrepant. This study examined the impacts of trait and state anxiety on attentional shifting and whether worry or depression explained variance in shifting. DESIGN AND METHODS: One-hundred thirty-eight undergraduate psychology students were randomized to the Trier Social Stress Test (TSST) or control TSST. Subjects completed measures of state/trait anxiety, worry, and depression and a computerized attention task. Statistical analyses included linear mixed modelling (LMM), t-tests, and ANOVAs. RESULTS: Results revealed significant effects of state and trait anxiety and worry, but not depression. Type (location/direction) and presentation (switch/repeat) of trials also affected response times. Trait anxiety significantly related to trial presentation but did not interact with trial type. State anxiety did not significantly relate to either trial index. State and trait anxiety significantly impacted overall response time. Results revealed variations in cognitive flexibility, but no interactions between state and trait anxiety in predicting task switching. CONCLUSION: These findings are discussed in the context of Attentional Control Theory and relevant empirical research.

Enhancing the perceptual segregation and localization of sound sources with a triple beamformer.

A triple beamformer was developed to exploit the capabilities of the binaural auditory system. The goal was to enhance the perceptual segregation of spatially separated sound sources while preserving source localization. The triple beamformer comprised a variant of a standard single-channel beamformer that routes the primary beam output focused on the target source location to both ears. The triple beam algorithm adds two supplementary beams with the left-focused beam routed only to the left ear and the right-focused beam routed only to the right ear. The rationale for the approach is that the triple beam processing exploits sound source segregation in high informational masking (IM) conditions. Furthermore, the exaggerated interaural level differences produced by the triple beam are well-suited for categories of listeners (e.g., bilateral cochlear implant users) who receive limited benefit from interaural time differences. The performance with the triple beamformer was compared to normal binaural hearing (simulated using a Knowles Electronic Manikin for Auditory Research, G.R.A.S. Sound and Vibration, Holte, DK) and to that obtained from a single-channel beamformer. Source localization in azimuth and masked speech identification for multiple masker locations were measured for all three algorithms. Taking both localization and speech intelligibility into account, the triple beam algorithm was considered to be advantageous under high IM listening conditions.

Design, Synthesis and Biochemical Evaluation of Novel Ethanoanthracenes and Related Compounds to Target Burkitt's Lymphoma.

Lymphomas (cancers of the lymphatic system) account for 12% of malignant diseases worldwide. Burkitt's lymphoma (BL) is a rare form of non-Hodgkin's lymphoma in which the cancer starts in the immune B-cells. We report the synthesis and preliminary studies on the antiproliferative activity of a library of 9,10-dihydro-9,10-ethanoanthracene based compounds structurally related to the antidepressant drug maprotiline against BL cell lines MUTU-1 and DG-75. Structural modifications were achieved by Diels-Alder reaction of the core 9-(2-nitrovinyl)anthracene with number of dienophiles including maleic anhydride, maleimides, acrylonitrile and benzyne. The antiproliferative activity of these compounds was evaluated in BL cell lines EBV- MUTU-1 and EBV+ DG-75 (chemoresistant). The most potent compounds 13j, 15, 16a, 16b, 16c, 16d and 19a displayed IC50 values in the range 0.17-0.38 µM against the BL cell line EBV- MUTU-1 and IC50 values in the range 0.45-0.78 µM against the chemoresistant BL cell line EBV+ DG-75. Compounds 15, 16b and 16c demonstrated potent ROS dependent apoptotic effects on the BL cell lines which were superior to the control drug taxol and showed minimal cytotoxicity to peripheral blood mononuclear cells (PBMCs). The results suggest that this class of compounds merits further investigation as antiproliferative agents for BL.

Synthesis, Antiproliferative and Pro-Apoptotic Effects of Nitrostyrenes and Related Compounds in Burkitt's Lymphoma.

BACKGROUND: Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide. The nitrostyrene scaffold is identified as a lead target structure for the development of particularly effective compounds targeting Burkitt's lymphoma (BL). OBJECTIVES: The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt's lymphoma (BL). METHODS: A panel of structurally varied compounds were designed and synthesised using Henry Knoevenagel condensation reactions. Single crystal X-Ray analysis confirmed the E configuration for six examples of these novel structures. A number of nitrostyrene-related compounds were also investigated including 1,3-bis(aryl)-2-nitropropenes together with heterocyclic scaffolds containing the nitrovinyl pharmacophore such as 3-nitro-2-phenyl-2H-chromenes. The antiproliferative activities of the compounds were evaluated using the BL cell lines EBV- MUTU-1 and EBV+ DG- 75 (chemoresistant) to establish preliminary structure-activity relationships. RESULTS: Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2Hchromene structures were successfully established with typical IC50 values of 0.45 µM and 0.47 µM in MUTU-1 cells and 1.41 µM and 1.92 µM, respectively, in DG-75 cells. The mechanism of cell death was identified as apoptotic and the lead compound was found to elicit comparable apoptotic effects to Taxol in Burkitt's lymphoma cell lines MUTU-1 and DG-75. CONCLUSION: This class of pharmaceutically active compounds with potential for the treatment of Burkitt`s lymphoma suggest a potential role for nitrostyrene based agents in chemotherapy.

Discrimination of frequency variance for tonal sequences.

Real-world auditory stimuli are highly variable across occurrences and sources. The present study examined the sensitivity of human listeners to differences in global stimulus variability. In a two-interval, forced-choice task, variance discrimination was measured using sequences of five 100-ms tone pulses. The frequency of each pulse was sampled randomly from a distribution that was Gaussian in logarithmic frequency. In the non-signal interval, the sampled distribution had a variance of σSTAN (2), while in the signal interval, the variance of the sequence was σSIG (2) (with σSIG (2) > σSTAN (2)). The listener's task was to choose the interval with the larger variance. To constrain possible decision strategies, the mean frequency of the sampling distribution of each interval was randomly chosen for each presentation. Psychometric functions were measured for various values of σSTAN (2). Although the performance was remarkably similar across listeners, overall performance was poorer than that of an ideal observer (IO) which perfectly compares interval variances. However, like the IO, Weber's Law behavior was observed, with a constant ratio of ( σSIG (2)- σSTAN (2)) to σSTAN (2) yielding similar performance. A model which degraded the IO with a frequency-resolution noise and a computational noise provided a reasonable fit to the real data.

The salience of enhanced components within inharmonic complexes.

A subjective listening task was used to measure the salience of enhanced components using typical intensity-enhancement stimuli, time-reversed versions of those stimuli, and stimuli which contained a frequency shift of the target component. Twenty-five listeners judged whether or not a pitch "stood out" within an inharmonic complex. For comparison, judgments also were made for stimuli with a single segment that consisted of a simultaneously masked target. The results indicate that the perceived salience of enhanced components is greater than might be predicted by the effective magnitude of those components, and that informational masking is likely involved.

Spectral and level effects in auditory signal enhancement.

Auditory enhancement refers generally to the increased perceptual salience of a spectral region when that region is preceded by its spectral complement, e.g., reinserting a missing component in a harmonic complex makes that component "pop out." One manifestation of enhancement is the increased detectability of a signal in certain spectro-temporal configurations. In the present experiments, detection thresholds were measured for a 2-kHz signal that was masked by an inharmonic complex with a spectral notch centered at 2-kHz. When the masker was preceded by a precursor/adaptor with a spectral gap identical to that of the masker, detection thresholds were lowest when the gap width was 0.6 octave. The amount of signal enhancement, the difference in thresholds between the no-precursor and precursor -conditions, decreased for smaller and larger gap widths. In addition, this general result was robust for precursors such as band-reject noise and harmonic complexes that were different in perceptual quality from the masker. This suggests that grouping/segregation processes do not mediate enhancement as assessed here. Similarly, significant enhancement was observed with precursor-masker level differences over a 40-dB range. Overall, these results further indicate that frequency resolution is a dynamic process that depends on spectro-temporal context. They also are consistent with a mechanism involving adaptation of inhibition that likely occurs at low levels in the auditory system.

The effects of unmodulated carrier fringes on the detection of frequency modulation.

Detection thresholds for 100 ms of either 5- or 20-Hz frequency modulation (FM) were measured at various temporal positions within a 600-ms, 4-kHz pure-tone carrier. The results indicated that the temporal position of the signal relative to the fringe influences detection thresholds, including an effect that is reminiscent of auditory backward recognition masking. A task involving frequency increments, rather than sinusoidal FM, yielded similar results. Additional manipulation of total carrier duration indicated that FM detection thresholds improve as the duration of the forward fringe increases, while a backward fringe only degrades performance in the absence of any forward fringe. The results suggest that listeners are insensitive to subtle frequency changes that occur at the onset of a longer stimulus and that the interaction between the opposing effects of the forward and backward fringes is not additive.

The effects of marker-related temporal cues on auditory gap-duration discrimination.

In three experiments, we examined the ability of listeners to discriminate the duration of temporal gaps (silent intervals) and the influence of other temporal stimulus properties on their performance. In the first experiment, gap-duration discrimination thresholds were measured either in continuous noise or with noise markers with durations of 3 and 300 ms. Thresholds measured with 300-ms markers differed from those measured in continuous noise or with 3-ms markers. In the second experiment, stimuli consisting of a gap between two discrete markers were generated such that the gap duration, the onset-to-onset duration between markers, and the duration of the first marker were pseudorandomized across trials. Listeners' responses generally were consistent with the cue that was identified as the target cue from among the three cues in each block of trials, but the data suggested that the onset-to-onset cue was particularly salient in all conditions. Using a modified method-of-adjustment procedure in the third experiment, subjects were instructed to discriminate between the durations of gaps in discrete markers of different durations in two intervals, where the gap duration in one interval was adapted to measure the point of subjective equality. Without feedback, listeners tended to equate the onset-to-onset times of the markers rather than the gap durations. Overall, the results indicated that listeners' judgments of silent gaps between two discrete markers are strongly influenced by the onset-to-onset time, or rhythm, of the markers.

Forward masking of frequency modulation.

Forward masking of sinusoidal frequency modulation (FM) was measured with three types of maskers: FM, amplitude modulation (AM), and a masker created by combining the magnitude spectrum of an FM tone with random component phases. For the signal FM rates used (5, 20, and 40 Hz), an FM masker raised detection thresholds in terms of frequency deviation by a factor of about 5 relative to without a masker. The AM masker produced a much smaller effect, suggesting that FM-to-AM conversion did not contribute substantially to the FM forward masking. The modulation depth of an FM masker had a nonmonotonic effect, with maximal masking observed at an intermediate value within the range of possible depths, while the random-phase FM masker produced less masking, arguing against a spectrally-based explanation for FM forward masking. Broad FM-rate selectivity for forward masking was observed for both 4-kHz and 500-Hz carriers. Thresholds measured as a function of the masker-signal delay showed slow recovery from FM forward masking, with residual masking for delays up to 500 ms. The FM forward-masking effect resembles that observed for AM [Wojtczak and Viemeister (2005). J. Acoust. Soc. Am. 188, 3198-3210] and may reflect modulation-rate selective neural adaptation to FM.

The enhancement effect: evidence for adaptation of inhibition using a binaural centering task.

The enhancement effect is consistently shown when simultaneously masked stimuli are preceded by the masker alone, with a reduction in the amount of masking relative to when that precursor is absent. One explanation for this effect proposed by Viemeister and Bacon [(1982). J. Acoust. Soc. Am. 71, 1502-1507] is the adaptation of inhibition, which predicts that an enhanced component (the "target") will be effectively more intense within the auditory system than one that has not been enhanced. Forward masking studies have indicated this effect of increased gain; however, other explanations of the enhancement effect have also been suggested. In order to provide an alternative measure of the amount of effective gain for an enhanced target, a subjective binaural centering task was used in which listeners matched the intensities of enhanced and unenhanced 2-kHz tones presented to opposite ears to produce a centered stimulus. The results showed that the enhancement effect produces an effective 4-5 dB increase in the level of the enhanced target. The enhancement effect was also measured using other enhancement paradigms which yielded similar results over a range of levels for the target, supporting an account based on adaptation of inhibition.

Discrimination of temporally asymmetric modulation with triangular envelopes on a broadband-noise carrier (L).

Highly detectable, time-reversed triangular amplitude modulation, with linear increases and decreases in amplitude, was used in an adaptive task to measure just-noticeable differences for changes in the direction of envelope temporal asymmetry for different modulation depths (m = 1.0 and 0.5) and rates (8, 16, and 32 Hz). Thresholds were analyzed using three different measures of the modulator's shape based on (1) the change in the position of the peak within a cycle, (2) the change in the slope of the modulator's increasing amplitude portion, and (3) the change in slope measured in units of amplitude per unit cycle rather than amplitude per unit time. The amplitude per unit cycle measure resulted in the best fit to all the data, and predicted additional data that were gathered with roved modulation frequency. The results suggest that a time normalization process may be involved in the perception and discrimination of envelope shape.

Detection of modulation of a 4-kHz carrier.

To better understand the processing of complex high-frequency sounds, modulation-detection thresholds were measured for sinusoidal frequency modulation (SFM), quasi-frequency modulation (QFM), sinusoidal amplitude modulation (SAM), and random-phase FM (RPFM). At the lowest modulation frequency (5 Hz) modulation thresholds expressed as AM depth were similar for RPFM, SAM and QFM suggesting the predominance of envelope cues. At the higher modulation frequencies (20 and 40 Hz) thresholds expressed as total frequency excursions were similar for SFM and QFM suggesting a common mechanism, one perhaps based on single-channel FM-to-AM conversion or on a multi-channel place mechanism. The fact that the nominal envelopes of SFM and QFM are different (SFM has a flat envelope), seems to preclude processing based on the envelope of the external stimulus. Also, given the 4-kHz carrier and the similarity to previously published results obtained with a 1-kHz carrier, processing based on temporally-coded fine structure for all four types of modulation appears unlikely.

Extracting binaural information from simultaneous targets and distractors: effects of amplitude modulation and asynchronous envelopes.

When different components of a stimulus carry different binaural information, processing of binaural information in a target component is often affected. The present experiments examine whether such interference is affected by amplitude modulation and the relative phase of modulation of the target and distractors. In all experiments, listeners attempted to discriminate interaural time differences of a target stimulus in the presence of distractor stimuli with ITD=0. In Experiment 1, modulation of the distractors but not the target reduced interference between components. In Experiment 2, synthesized musical notes exhibited little binaural interference when there were slight asynchronies between different streams of notes (31 or 62 ms). The remaining experiments suggested that the reduction in binaural interference in the previous experiments was due neither to the complex spectra of the synthesized notes nor to greater detectability of the target in the presence of modulated distractors. These data suggest that this interference is reduced when components are modulated in ways that result in the target appearing briefly in isolation, not because of segregation cues. These data also suggest that modulation and asynchronies between modulators that might be encountered in real-world listening situations are adequate to reduce binaural interference to inconsequential levels.

Forward-masked monaural and interaural intensity discrimination.

Intensity-discrimination thresholds were measured for a 25-ms, 6-kHz pure tone for pedestal levels from 40 to 90 dB sound pressure level (SPL) with and without a forward masker (100-ms narrowband Gaussian noise, N(0)=70 dB). When the masker was present, the masker and probe were separated by 100 ms of silence. Unmasked and masked thresholds were measured in a two-interval monaural procedure and, separately, in a single-interval interaural procedure in which the pedestal and incremented pedestals were presented simultaneously to opposite ears. While the monaural thresholds were elevated markedly by the forward masker for mid-level pedestals, interaural thresholds were nearly unaffected by the masker across pedestal levels. The results argue against the notion that the monaural elevation in forward-masked thresholds is due to degraded encoding of intensity information at early stages of auditory processing.

Discrimination of depth of sinusoidal amplitude modulation with and without roved carrier levels.

Thresholds for the discrimination of the depth of sinusoidal amplitude modulation with a broadband noise carrier were measured for three listeners in a two-alternative, forced-choice task for modulation frequencies of 8, 32, and 128 Hz. Thresholds were measured with the spectrum level of the carrier fixed at 20 dB across all trials and, separately, with the carrier spectrum level roved randomly over a 20-dB range (10-30 dB) in each interval. Mean thresholds were equal or slightly lower (but not significantly so) for the fixed conditions relative to the roved conditions, and the differences between thresholds were too small to be explained by assuming that listeners compared instantaneous intensity at corresponding phases of the modulation cycle (for example, in the troughs). Rather, it appears that listeners discriminated modulation depth by extracting an estimate of the modulation depth within each interval that was independent of the overall level. Consequently, models of envelope extraction must include normalization of the envelope fluctuations to the envelope dc.