ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Hydridotris(thioxotriazolyl)borate (Tt), an ambidentate (N(3)/S(3)) tripodal ligand. X-ray crystal structures of sodium, bismuth(III), tin(IV), and manganese(I) complexes.

Treatment of the heterocycle 5-thioxo-4,5-dihydro-3,4-dimethyl-1,2,4-triazole (thioxotriazole) with sodium tetrahydroborate at 210 degrees C provides the new [N(3)/S(3)] ambidentate tripod ligand hydridotris(thioxotriazolyl)borate (Tt) as its sodium complex salt. Complexes of this ligand with sodium, bismuth(III), tin(IV), and manganese(I) have been synthesized and characterized by X-ray crystallography. The structures of these complexes illustrate the ambidentate character of the ligand with the softer metals bismuth and tin exhibiting sulfur coordination, while sodium and manganese(I) bond via the ligand nitrogen donors. In the [S(3)] coordination mode the ligand creates eight-membered chelate rings with the metal with the consequence that the metal ligand unit adopts a propeller-type conformation with C(3)-symmetry. However, in the [N(3)] mode six-membered chelate rings are formed analogous to the familiar hydrotris(pyrazolyl)borate (Tp) ligand.

Rapid auditory processing and phonological ability in normal readers and readers with dyslexia.

According to a prominent theory, the phonological difficulties in dyslexia are caused by an underlying general impairment in the ability to process sequences of rapidly presented, brief sounds. Two studies examined this theory by exploring the relationships between rapid auditory processing and phonological processing in a sample of 82 normally reading children (Study 1) and by comparing 17 children with dyslexia to chronological-age and reading-age control participants on these tasks (Study 2). In the normal readers, moderate correlations were found between the measure of rapid auditory processing (Auditory Repetition Task, or ART) and phonological ability. On the ART, the dyslexia group performed at a level similar to that of the reading-age control group but obtained scores that were significantly below those of the chronological-age control group. This difference was due to a subgroup of 4 children in the dyslexia group who had particular difficulty with the ART. The phonological skills of these individuals were not worse than those of the children in the dyslexia group who were unimpaired on the ART. The discussion argues that there is no evidence that phonoogical difficulties are secondary to impairments of rapid auditory processing, as measured by the ART, and highlights the need to examine the strategic and cognitive demands involved in tasks of rapid auditory processing.

A dynamic role for HDAC7 in MEF2-mediated muscle differentiation.

The overlapping expression profile of MEF2 and the class-II histone deacetylase, HDAC7, led us to investigate the functional interaction and relationship between these regulatory proteins. HDAC7 expression inhibits the activity of MEF2 (-A, -C, and -D), and in contrast MyoD and Myogenin activities are not affected. Glutathione S-transferase pulldown and immunoprecipitation demonstrate that the repression mechanism involves direct interactions between MEF2 proteins and HDAC7 and is associated with the ability of MEF2 to interact with the N-terminal 121 amino acids of HDAC7 that encode repression domain 1. The MADS domain of MEF2 mediates the direct interaction of MEF2 with HDAC7. MEF2 inhibition by HDAC7 is dependent on the N-terminal repression domain and surprisingly does not involve the C-terminal deacetylase domain. HDAC7 interacts with CtBP and other class-I and -II HDACs suggesting that silencing of MEF2 activity involves corepressor recruitment. Furthermore, we show that induction of muscle differentiation by serum withdrawal leads to the translocation of HDAC7 from the nucleus into the cytoplasm. This work demonstrates that HDAC7 regulates the function of MEF2 proteins and suggests that this class-II HDAC regulates this important transcriptional (and pathophysiological) target in heart and muscle tissue. The nucleocytoplasmic trafficking of HDAC7 and other class-II HDACs during myogenesis provides an ideal mechanism for the regulation of HDAC targets during mammalian development and differentiation.

A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group.

Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.

Auditory spatial attention using interaural time differences.

Previous probe-signal studies of auditory spatial attention have shown faster responses to sounds at an expected versus an unexpected location, making no distinction between the use of interaural time difference (ITD) cues and interaural-level difference cues. In 5 experiments, performance on a same-different spatial discrimination task was used in place of the reaction time metric, and sounds, presented over headphones, were lateralized only by an ITD. In all experiments, performance was better for signals lateralized on the expected side of the head, supporting the conclusion that ITDs can be used as a basis for covert orienting. The performance advantage generalized to all sounds within the spatial focus and was not dissipated by a trial-by-trial rove in frequency or by a rove in spectral profile. Successful use by the listeners of a cross-modal, centrally positioned visual cue provided evidence for top-down attentional control.

Repression of basal transcription by vitamin D receptor: evidence for interaction of unliganded vitamin D receptor with two receptor interaction domains in RIP13delta1.

Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression. This VDR isoform lacked sequence in the hinge- and ligand-binding domains implicating one or both of these domains in basal repression. It is well known that thyroid hormone and retinoic acid receptors silence basal transcription of target genes in the absence of ligands and this repressor function can be mediated by the nuclear receptor corepressor N-CoR. Two variants of N-CoR have been described, RIP13a and RIP13delta1. N-CoR and the variants contain two receptor interaction domains, ID-I and ID-II, which are identical except region ID-II in RIP13delta1 has an internal deletion. We have used the mammalian two hybrid system to investigate whether VDR, in the absence of ligand 1,25-(OH)2D3, can interact with these domains. The data showed that unliganded VDR does not interact with either ID-I or ID-II from RIP13a and RIP13delta1, but does interact strongly with a composite domain of ID-I and ID-II from RIP13delta1 (but not from RIP13a) and this strong interaction is abrogated in the presence of ligand. This finding implicates RIP13delta1 in VDR-dependent basal repression of the promoter constructs under investigation. However, over-expression of RIP13delta1 in kidney cell lines did not alter basal expression of the CYP24 promoter construct. It is concluded that either the level of endogenous RIP13delta1 in these kidney cells permits maximal repression or that repression occurs by a mechanism that is independent of RIP13delta1. Alternatively, repression may be dependent on RIP13delta1 but requires an additional cofactor that is limiting in these cells.

Across-channel intensity discrimination in the presence of an interferer.

Listeners' thresholds for discriminating changes in the relative intensities of two octave-spaced pure tones were measured in three conditions using a 2AFC procedure. In the baseline condition the tone pair was presented alone, while in the two interference conditions the tone pair was accompanied by four additional tones, with the frequency separation between adjacent components of the resultant six-component complex being one octave. In the interference conditions the flanking components were either gated synchronously with the target pair, or began 200 ms ahead. The level of the flanking components relative to the target was randomized on each presentation. The overall stimulus level was also randomized on each presentation to reduce the effectiveness of within-channel comparisons. Threshold elevations in the synchronous condition relative to the baseline ranged from approximately 5 to 17 decibels. By contrast, in the asynchronous condition only one listener showed significant (although substantially reduced) interference. The results complement previous observations that across-channel intensity comparisons are poorer between components that begin or end at different times, and are qualitatively consistent with the hypothesis that temporal misalignment promotes the perceptual segregation of simultaneous frequency components.

Relative intensity comparisons between a tone and spectrally remote noise: effects of onset asynchrony.

The present experiment investigated the effect of onset asynchrony on listeners' ability to make relative intensity comparisons between a 1-kHz tone and a band of noise high-pass filtered at 3 kHz. In the synchronous condition, the tone and noise were gated on and off simultaneously. In the two asynchronous conditions, either the tone was gated on before the noise or vice versa, both stimuli terminating simultaneously. In the sequential condition, the offset of the tone coincided with the onset of the noise. The task of the six listeners was to indicate in which of the two presentation intervals the level of the tone was incremented relative to that of the noise. To deter the use of strategies based on successive, within-channel level comparisons, the overall level of the stimuli was randomized on each presentation. For all listeners thresholds were lowest in the synchronous condition, and highest in the sequential condition, the difference ranging from approximately 7 to 18 dB (signal re: pedestal amplitude). Furthermore, five of the six listeners had significantly lower thresholds in the noise-leading condition than in the tone-leading condition, the average difference across listeners being approximately 5 dB. The results are discussed in terms of auditory grouping and the possible strategies available to the listeners.

Profile analysis with an asynchronous target: evidence for auditory grouping.

Green and Dai [in Auditory Physiology and Perception, edited by Y. Cazals, L. Demany, and K. Horner (Pergamon, Oxford, 1992)] reported a series of experiments which suggested that listeners' ability to perform simultaneous across-frequency comparisons of intensity is severely impaired when the target and flanking components begin or end at different times. The present experiment sought to replicate the effect of onset asynchrony and included an additional condition in which the leading portion, of the asynchronous target component was accompanied by a pair of "captor" tones. The intended purpose of the captor tones was to promote a perceptual organization in which the leading and synchronous portions of the asynchronous target component were grouped with different auditory objects. For all six listeners an asynchrony of 320 ms raised thresholds substantially relative to the synchronous onset condition, the magnitude of the increase ranging between 6 and 16 dB. By contrast, the mean elevation of threshold in the presence of the captor was only 3 dB, although for all listeners thresholds were still greater than for the synchronous onset condition. The results support the view that the deleterious effect of onset asynchrony on profile analysis performance is due to the operation of auditory grouping principles.

A probe-signal study of auditory discrimination of complex tones.

The present experiments used an analogue of the probe-signal method of Greenberg and Larkin [J. Acoust. Soc. Am. 44, 1513-1523 (1968)] to investigate the extent to which listeners direct attention to a particular spectral region when discriminating complex tones. The listeners' task was to discriminate between two seven-component complex tones on the basis of an increment in the level of a single component. On two-thirds of trials the increment was achieved by adding a fixed primary signal to one component of the complex. The primary-signal trials were relatively easy and were intended to cue listeners to attend to the component to which the primary was added. On the remaining trials a smaller probe signal was added either to the cued component, or to one of three other components. The results of the first experiment, in which the complex tones had a flat spectrum, showed significantly better performance for probe signals applied to the cued component compared to the other three components. To control for the possibility that the observed pattern of results was due to the use of timbral cues, a second experiment was conducted in which the spectral profile of the tones was randomized between trials. The results for the second experiment were similar to those of the first experiment and are consistent with the idea that listeners were focusing attention on the spectral region defined by the primary signal.

Transcriptional repression by COUP-TF II is dependent on the C-terminal domain and involves the N-CoR variant, RIP13delta1.

COUP-TF II/ARP-1 is an 'orphan' steroid receptor that inhibits basal transcription, and represses trans-activation by the vitamin D, thyroid hormone and retinoid receptors. The molecular basis of repression by COUP-TF II remains obscure. In this study we utilized the GAL4 hybrid system to demonstrate that COUP-TF II contains sequences within the C-terminal region that encode a dominant transcriptional repressor that inhibits the ability of the potent chimeric transactivator GAL4VP16 to induce transcription. Mammalian two hybrid analysis demonstrated that COUP-TF II did not efficiently interact with either interaction domains I or II from N-CoR and RIP13. However, COUP-TF II efficiently interacts with a region comprised of interaction domains I + II from the corepressor, RIP13delta1. Efficient interaction of the orphan receptor with the corepressor was critically dependent on a large region comprised of the C, D and E domains of COUP-TF II, which correlated with the domain that maximally represses transcription. This investigation suggested that the N-CoR variant, RIP13delta1 interacts with a region of COUP-TF II that functions as a dominant transcriptional repressor.

Two receptor interaction domains in the corepressor, N-CoR/RIP13, are required for an efficient interaction with Rev-erbA alpha and RVR: physical association is dependent on the E region of the orphan receptors.

Rev-erbA alpha and RVR/Rev-erb beta/BD73 are orphan steroid receptors that have no known ligands in the 'classical sense'. These 'orphans' do not activate transcription, but function as dominant transcriptional silencers. The thyroid hormone receptor (TR) and the retinoic acid receptor (RAR) act as transcriptional silencers by binding corepressors (e.g. N-CoR/RIP13 and SMRT/TRAC-2) in the absence of ligands. The molecular basis of repression by orphan receptors, however, remains obscure, and it is unclear whether these corepressors mediate transcriptional silencing by Rev-erbA alpha and RVR. Recently, two new variants of N-CoR have been described, RIP13a and RIP13delta1. The characterisation of these splice variants has identified a second receptor interaction domain (ID-II), in addition to the previously characterised interaction domain (ID-I). This investigation utilised the mammalian two hybrid system and transfection analysis to demonstrate that Rev-erbA alpha and RVR will not efficiently interact with either ID-I or ID-II separately from RIP13a or RIP13delta1. However, they interact efficiently with a domain composed of ID-I and ID-II from RIP13a. Interestingly, the interaction of Rev-erbA alpha and RVR is strongest with ID-I and ID-II from RIP13delta1. Detailed deletion analysis of the orphan receptor interaction with RIP13/N-CoR rigorously demonstrated that the physical association was critically dependent on an intact E region of Rev-erbA alpha and RVR. Over-expression of the corepressor interaction domains (i.e. dominant negative forms of N-CoR/RIP13) could alleviate orphan receptor-mediated repression of transactivation by GALVP16. This demonstrated that these regions could function as anti-repressors. In conclusion, these data from two independent approaches demonstrate that repression by Rev-erbA alpha and RVR is mediated by an interaction of ID-I and ID-II of N-CoR, RIP13a and delta1 with the putative ligand binding domain of the orphan receptors.

Spectral regularity as a factor distinct from harmonic relations in auditory grouping.

When the regular spectral pattern formed by an odd-harmonic complex (the base) is disrupted by an added even harmonic, the added component is judged as more salient than its neighbors. This study considered whether the effects of spectral pattern on perceptual segregation are restricted to harmonic stimuli. Participants either rated the clarity or judged the relative pitch of a cued component in a series of complex tones. The difference in clarity between added and base components found for the harmonic complexes was not reduced when the complexes were made inharmonic either by a frequency shift or by spectral stretch or compression. However, the added-base difference could be abolished for an inharmonic complex when the distribution of components across frequency was made uniform. These findings suggest that spectral regularity is a factor distinct from harmonic relations in auditory grouping.

Regularity of spectral pattern and its effects on the perceptual fusion of harmonics.

A single even harmonic added to an odd-harmonic complex may be judged as perceptually more salient than the odd harmonics themselves (Roberts & Bregman, 1991). It is proposed that this effect occurs because the even harmonic is inconsistent with the regular spectral pattern formed by the odd-harmonic complex (the base). Therefore, a reduction in the regularity of the base spectrum should reduce the even-odd difference. Spectral regularity was reduced either by removing base components, or by including components in the base that were inconsistent with its original pattern. Subjects listened to (primarily) harmonic complex tones and rated the clarity of one of the harmonics, cued by a preceding pure tone. Both removing components from the base and including extraneous components in the base reduced the even-odd difference. The results suggest that it is easier to segregate a harmonic from a periodic complex tone when it does not form part of the regular pattern of spectral spacing defined by the other harmonics.

An examination of attentional control in the auditory modality: further evidence for auditory orienting.

Four experiments are reported that examine attentional control in the auditory modality. In Experiment 1, the subjects made detection responses to the onset of a monaurally presented pure tone that was preceded by a pure-tone cue. On a valid trial, the cue was presented in the same ear as the target; on an invalid trial, it was presented in the contralateral ear to the target; and on a neutral trial, it was presented in both ears. Overall performance was facilitated on valid trials in comparison with invalid trials. In later experiments, the subjects made choice decisions about the location of the target, and significant cuing effects were found relative to the neutral condition. Finally, performance was assessed in the presence of central (spoken) word cues. Here, the content of the cue specified the likely location of the target. Under these conditions, costs and benefits were found over a range of cue-target stimulus onset asynchronies. The results are discussed in terms of automatic and controlled attentional processes.

Spectral pattern and the perceptual fusion of harmonics. II. A special status for added components?

A single even-numbered harmonic can be segregated from an odd-harmonic complex more easily than its odd-numbered neighbors, for low fundamentals [Roberts and Bregman, J.Acoust. Soc. Am. 90, 3050-3060 (1991)]. It has been proposed that this effect occurs because the even harmonic is inconsistent with the regular spectral pattern formed by the odd harmonics. However, in this study we evaluate some alternative accounts of the effect. The stimuli were harmonic complex tones for which one of the components was cued by a preceding pure tone. Subjects were required to listen for the cued component and either to rate its clarity (experiments 1 and 3) or to judge its pitch in relation to the preceding tone (experiment 2). It is argued that the weaker fusion of an added even harmonic depends on its status as an added component rather than as an even harmonic (experiment 1), and on its immediate perceptual salience rather than on auditory learning. An even-odd difference was also found when even and odd harmonics were tested in an identical spectral context (experiment 2), and when one of the neighboring odd harmonics was removed (experiment 3). These results are consistent with the proposal that it is easier to segregate a harmonic from a periodic complex tone when it does not form part of the regular pattern of spectral spacing defined by the other harmonics.