Attention, the prioritization of goal-relevant stimuli, and expectation, the modulation of stimulus processing by probabilistic context, represent the two main endogenous determinants of visual cognition. Neural selectivity in visual cortex is enhanced for both attended and expected stimuli, but the functional relationship between these mechanisms is poorly understood. Here, we adjudicated between two current hypotheses of how attention relates to predictive processing, namely, that attention either enhances or filters out perceptual prediction errors (PEs), the PE-promotion model versus the PE-suppression model. We acquired fMRI data from category-selective visual regions while human subjects viewed expected and unexpected stimuli that were either attended or unattended. Then, we trained multivariate neural pattern classifiers to discriminate expected from unexpected stimuli, depending on whether these stimuli had been attended or unattended. If attention promotes PEs, then this should increase the disparity of neural patterns associated with expected and unexpected stimuli, thus enhancing the classifier's ability to distinguish between the two. In contrast, if attention suppresses PEs, then this should reduce the disparity between neural signals for expected and unexpected percepts, thus impairing classifier performance. We demonstrate that attention greatly enhances a neural pattern classifier's ability to discriminate between expected and unexpected stimuli in a region- and stimulus category-specific fashion. These findings are incompatible with the PE-suppression model, but they strongly support the PE-promotion model, whereby attention increases the precision of prediction errors. Our results clarify the relationship between attention and expectation, casting attention as a mechanism for accelerating online error correction in predicting task-relevant visual inputs.
The role of the thalamus in high-level cognition—attention, working memory (WM), rule-based learning, and decision making—remains poorly understood, especially in comparison to that of cortical frontoparietal networks [1–3]. Studies of visual thalamus have revealed important roles for pulvinar and lateral geniculate nucleus in visuospatial perception and attention [4–10] and for mediodorsal thalamus in oculomotor control . Ventrolateral thalamus contains subdivisions devoted to action control as part of a circuit involving the basal ganglia [12, 13] and motor, premotor, and prefrontal cortices , whereas anterior thalamus forms a memory network in connection with the hippocampus . This connectivity profile suggests that ventrolateral and anterior thalamus may represent a nexus between mnemonic and control functions, such as action or attentional selection. Here, we characterize the role of thalamus in the interplay between memory and visual attention. We show that ventrolateral lesions impair the influence of WM representations on attentional deployment. A subsequent fMRI study in healthy volunteers demonstrates involvement of ventrolateral and, notably, anterior thalamus in biasing attention through WM contents. To further characterize the memory types used by the thalamus to bias attention, we performed a second fMRI study that involved learning of stimulus-stimulus associations and their retrieval from long-term memory to optimize attention in search. Responses in ventrolateral and anterior thalamic nuclei tracked learning of the predictiveness of these abstract associations and their use in directing attention. These findings demonstrate a key role for human thalamus in higher-level cognition, notably, in mnemonic biasing of attention.
•Pivotal role of human thalamus in linking memory and attention in vision•Thalamus lesions disrupted attention biases by working memory contents•Ventrolateral (VL) thalamic lesions reversed the normal direction of these biases•Flexible scope of memory types biasing attention through VL and anterior thalamus
de Bourbon-Teles et al. present causal evidence from focal brain lesions and fMRI evidence from healthy participants showing that ventrolateral and anterior thalamic nuclei play a pivotal role in linking mnemonic and attention control functions in human vision.
Cognitive control requires a fine balance between stability, the protection of an on-going task-set, and flexibility, the ability to update a task-set in line with changing contingencies. It is thought that emotional processing modulates this balance, but results have been equivocal regarding the direction of this modulation. Here, we tested the hypothesis that a crucial determinant of this modulation is whether affective stimuli represent performance-contingent or task-irrelevant signals. Combining functional magnetic resonance imaging with a conflict task-switching paradigm, we contrasted the effects of presenting negative- and positive-valence pictures on the stability/flexibility trade-off in humans, depending on whether picture presentation was contingent on behavioral performance. Both the behavioral and neural expressions of cognitive control were modulated by stimulus valence and performance contingency: in the performance-contingent condition, cognitive flexibility was enhanced following positive pictures, whereas in the nonperformance-contingent condition, positive stimuli promoted cognitive stability. The imaging data showed that, as anticipated, the stability/flexibility trade-off per se was reflected in differential recruitment of dorsolateral frontoparietal and striatal regions. In contrast, the affective modulation of stability/flexibility shifts was mirrored, unexpectedly, by neural responses in ventromedial prefrontal and posterior cingulate cortices, core nodes of the “default mode” network. Our results demonstrate that the affective modulation of cognitive control depends on the performance contingency of the affect-inducing stimuli, and they document medial default mode regions to mediate the flexibility-promoting effects of performance-contingent positive affect, thus extending recent work that recasts these regions as serving a key role in on-task control processes.
Visual cortex is traditionally viewed as a hierarchy of neural feature detectors, with neural population responses being driven by bottom-up stimulus features. Conversely, “predictive coding” models propose that each stage of the visual hierarchy harbors two computationally distinct classes of processing unit: representational units that encode the conditional probability of a stimulus and provide predictions to the next lower level; and error units that encode the mismatch between predictions and bottom-up evidence, and forward prediction error to the next higher level. Predictive coding therefore suggests that neural population responses in category-selective visual regions, like the fusiform face area (FFA), reflect a summation of activity related to prediction (“face expectation”) and prediction error (“face surprise”), rather than a homogenous feature detection response. We tested the rival hypotheses of the feature detection and predictive coding models by collecting functional magnetic resonance imaging data from the FFA while independently varying both stimulus features (faces vs houses) and subjects’ perceptual expectations regarding those features (low vs medium vs high face expectation). The effects of stimulus and expectation factors interacted, whereby FFA activity elicited by face and house stimuli was indistinguishable under high face expectation and maximally differentiated under low face expectation. Using computational modeling, we show that these data can be explained by predictive coding but not by feature detection models, even when the latter are augmented with attentional mechanisms. Thus, population responses in the ventral visual stream appear to be determined by feature expectation and surprise rather than by stimulus features per se.
Working memory (WM) and attention have been studied as separate cognitive constructs, although it has long been acknowledged that attention plays an important role in controlling the activation, maintenance, and manipulation of representations in WM. WM has, conversely, been thought of as a means of maintaining representations to voluntarily guide perceptual selective attention. It has more recently been observed, however, that the contents of WM can capture visual attention, even when such internally maintained representations are irrelevant, and often disruptive, to the immediate external task. Thus the precise relationship between WM and attention remains unclear, but it appears that they may bi-directionally impact one another, whether or not internal representations are consistent with external perceptual goals. This reciprocal relationship seems, further, to be constrained by limited cognitive resources to handle demands in either maintenance or selection. We propose here that the close relationship between WM and attention may be best described as a give-and-take interdependence between attention directed toward actively maintained internal representations (traditionally considered WM) versus external perceptual stimuli (traditionally considered selective attention), underpinned by their shared reliance on a common cognitive resource. Put simply, we argue that WM and attention should no longer be considered as separate systems or concepts, but as competing and impacting one another because they rely on the same limited resource. This framework can offer an explanation for the capture of visual attention by irrelevant WM contents, as well as a straightforward account of the underspecified relationship between WM and attention.
Sulforaphane is a promising agent under preclinical evaluation in many models of disease prevention. This bioactive phytochemical affects many molecular targets in cellular and animal models; however, amongst the most sensitive is Keap1, a key sensor for the adaptive stress response system regulated through the transcription factor Nrf2. Keap1 is a sulfhydryl-rich protein that represses Nrf2 signaling by facilitating the poly ubiquitination of Nrf2 thereby enabling its subsequent proteasomal degradation. Interaction of sulforaphane with Keap1 disrupts this function and allows for nuclear accumulation of Nrf2 and activation of its transcriptional program. Enhanced transcription of Nrf2 target genes provokes a strong cytoprotective response that enhances resistance to carcinogenesis and other diseases mediated by exposures to electrophiles and oxidants. Clinical evaluation of sulforaphane has been largely conducted by utilizing preparations of broccoli or broccoli sprouts rich in either sulforaphane or its precursor form in plants, a stable β-thioglucose conjugate termed glucoraphanin. We have conducted a series of clinical trials in Qidong, China, a region where exposures to food- and air-borne carcinogens has been considerable, to evaluate the suitability of broccoli sprout beverages, rich in either glucoraphanin (GRR) or sulforaphane SFR or both for their bioavailability, tolerability and pharmacodynamic action in population-based interventions. Results from these clinical trials indicate that interventions with well characterized preparations of broccoli sprouts may enhance the detoxication of aflatoxins and air-borne toxins, which may in turn attenuate their associated health risks, including cancer, in exposed individuals.
The efficiency with which the brain resolves conflict in information processing is determined by contextual factors that modulate internal control states, such as the recent (local) and longer-term (global) occurrence of conflict. Local “control context” effects can be observed in trial-by-trial adjustments to conflict (congruency sequence effects: less interference following incongruent trials), whereas global control context effects are reflected in adjustments to the frequency of conflict encountered over longer sequences of trials (“proportion congruent effects”: less interference when incongruent trials are frequent). Previous neuroimaging and lesion studies suggest that the modulation of conflict-control processes by local control context relies on partly dissociable neural circuits for cognitive (non-emotional) vs. emotional conflicts. By contrast, emotional and non-emotional conflict-control processes have not been contrasted with respect to their modulation by global control context. We addressed this aim in a functional magnetic resonance imaging (fMRI) study that varied the proportion of congruent trials in emotional vs. non-emotional conflict tasks across blocks. We observed domain-general conflict-related signals in the dorsal anterior cingulate cortex (dACC) and pre-supplementary motor area and, more importantly, task-domain also interacted with global control context effects: specifically, the dorsal striatum and anterior insula tracked control-modulated conflict effects exclusively in the emotional domain. These results suggest that, similar to the neural mechanisms of local control context effects, there are both overlapping as well as distinct neural substrates involved in the modulation of emotional and non-emotional conflict-control by global control context.
cognitive control; control context; congruency sequence effects; proportion congruent effects; emotional conflict; non-emotional conflict; fMRI
The reduction of the aflatoxin B1 (AFB1) dialdehyde metabolite to its corresponding mono and dialcohols, catalyzed by aflatoxin B1-aldehyde reductase (AFAR; rat AKR7A1 and human AKR7A3), is greatly increased in livers of rats treated with numerous chemoprotective agents. Recombinant human AKR7A3 has been shown to reduce the AFB1 dialdehyde at rates greater than those of the rat AKR7A1. The activity of AKR7A1 or AKR7A3 may detoxify the AFB1-dialdehyde which reacts with proteins and thereby inhibit AFB1-induced toxicity; however, direct experimental evidence of this hypothesis was lacking. Two human B lymphoblastoid cell lines, designated pMF6/1A2/AKR7A1 and pMF6/1A2, were genetically engineered to stably express AKR7A1 and/or cytochrome P4501A2 (1A2). The pMF6/1A2/AKR7A1 cells were refractory to the cytotoxic effects of 3 ng/mL AFB1, in comparison to pM6/1A2 cells which were more sensitive. Diminished protection occurred at higher concentrations of AFB1 in pMF6/1A2/AKR7A1 cells suggesting that additional factors were influencing cell survival. COS-7 cells were transfected with either vector control, rat AKR7A1, or human AKR7A3, and the cells were treated with AFB1 dialdehyde. There was a 6-fold increase in the dialdehyde LC50, from 66 μM in vector-transfected cells to 400 μM in AKR7A1-transfected cells, and an 8.5-fold increase from 35 μM in vector-transfected cells to 300 μM in AKR7A3-transfected cells. In both cases, this protective effect of the AFAR enzyme was accompanied by a marked decrease in protein adducts. Fractionation of the cellular protein showed that the mitochondria/nuclei and microsomal fractions contained the highest concentration of protein adducts. The levels of human AKR7A3 and AKR7A2 were measured in 12 human liver samples. The expression of AKR7A3 was detectable in all livers and lower than those of AKR7A2 in 11 of the 12 samples. Overall, these results provide the first direct evidence of a role for rat AKR7A1 and human AKR7A3 in protection against AFB1-induced cytotoxicity and protein adduct formation.
Few effective options are available for the treatment of unresectable hepatocellular carcinoma (HCC). Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel.
Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m2 (later reduced to 30 mg/m2) and gemcitabine 800 mg/m2 on days 1, 8 every 3 weeks. Twenty-five patients were enrolled in 26 months. Median age was 64 (range 27-78), 17 were male, 14 had liver-only disease and, 11 had extrahepatic disease.
Of 25 patients evaluable for the primary endpoint (response), 2 (8%) have a confirmed partial response. The median TTP is 2.76 months (95% CI 1.84-6.64 months). Median survival was 12.8 months (95% CI: 5.26-28.00). Two patients died on-study due to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. Twenty patients (81%) have experienced grade 3+ adverse events, including 11 with grade 4+ adverse events, primarily neutropenia, thrombocytopenia, diarrhea, and fatigue.
While this combination appears to have potential benefit, as measured by overall survival, its toxicity and the recent introduction of sorafenib has further limited the use of chemotherapy. Approaches other than chemotherapy are likely to be of the greatest potential benefit.
A novel acetylenic tricyclic bis-(cyano enone), TBE-31, is a lead compound in a series of tricyclic compounds with enone functionalities in rings A and C. Nanomolar concentrations of this potent multifunctional molecule suppress the induction of the inflammatory protein, iNOS; activate phase 2 cytoprotective enzymes in vitro and in vivo; block cell proliferation; and induce differentiation and apoptosis of leukemia cells. Oral administration of TBE-31 also significantly reduces formation of aflatoxin-DNA adducts and decreases size and number of aflatoxin-induced pre-neoplastic hepatic lesions in rats by more than 90%. Because of the two cyano enones in rings A and C, TBE-31 may directly interact with dithiothreitol and protein targets such as Keap1 that contain reactive cysteine residues. The above findings suggest that TBE-31 should also be tested for chemoprevention and chemotherapy in relevant models of cancer and against other chronic, degenerative diseases in which inflammation and oxidative stress contribute to disease pathogenesis.
Chemoprevention; aflatoxin; Nrf2; triterpenoid; tricyclic bis-enone; TBE-31
Many studies have found that representations in working memory (WM) can guide visual attention towards items that match the features of the WM contents. While some researchers contend that this occurs involuntarily, others suggest that the impact of WM content on attention can be strategically controlled. Here, we varied the probability that WM items would coincide with either targets or distracters in a visual search task to examine (i) whether participants could intentionally enhance or inhibit the influence of WM items on attention, and (ii) whether cognitive control over WM biases would also affect access to the memory content in a surprise recognition test. We found visual search to be faster when the WM item coincided with the search target, and this effect was enhanced when the memory item reliably predicted the location of the target. Conversely, visual search was slowed when the memory item coincided with a search distracter, and this effect was diminished, but not abolished, when the memory item was reliably associated with distracters. This strategic dampening of the influence of WM items on attention came at a price to memory, however, as participants were slowest to perform WM recognition tests on blocks when the WM content was consistently invalid. These results document that attentional capture by WM contents is partly, but not fully, malleable by top-down control, which appears to adjust the state of the WM content to optimize search behavior. These data illustrate the role of cognitive control in modulating the strength of WM biases of selection, and support a tight coupling between WM and attention.
1 (AFB1) is a risk factor for hepatocellular carcinoma in humans. Infant, but not adult, mice are sensitive to AFB1-induced liver carcinogenesis; a single dose during the neonatal period leads to hepatocellular carcinoma in adulthood. Earlier work defined the mutational spectrum in the gpt gene of gpt delta B6C3F1 mice 3 weeks after exposure to aflatoxin. In the present study, we examined the gpt spectrum 10 weeks postdosing and expanded the study to examine, at 3 and 10 weeks, the spectrum at a second locus, the red/gam genes of the mouse λEG10 transgene. Whereas the gpt locus is typically used to define local base changes, the red/gam genes, via the Spi– assay, often are used to detect more global mutations such as large deletions and rearrangements. Three weeks after dosing with AFB1, there was a 10-fold increase over the control in the Spi– mutant fraction (MF) in liver DNA; after 10 weeks, a further increase was observed. The MF in the gpt gene was also increased at 10 weeks compared with the MF at 3 weeks. No gender-specific differences were found in the Spi– or gpt MFs. Whereas Spi– mutations often signal large genetic changes, they did not in this specific case. The Spi– spectrum was dominated by GC to TA transversions, with one exceptionally strong hotspot at position 314. Using two genetic loci, the data show a strong preference for the induction of GC to TA mutations in mice, which is the dominant mutation seen in people exposed to aflatoxin.
aflatoxin B1; hepatocellular carcinoma;; mutation; infant mouse.
Attention is attracted exogenously by physically salient stimuli, but this effect can be dampened by endogenous attention settings, a phenomenon called “contingent capture”. Emotionally salient stimuli are also thought to exert a strong exogenous influence on attention, especially in anxious individuals, but whether and how top-down attention can ameliorate bottom-up capture by affective stimuli is currently unknown. Here, we paired a novel spatial cueing task with functional magnetic resonance imaging (fMRI) in order to investigate contingent capture as a function of the affective salience of bottom-up cues (face stimuli) and individual differences in trait anxiety. In the absence of top-down cues, exogenous stimuli validly cueing targets facilitated attention in low anxious participants, regardless of affective salience. However, while high anxious participants exhibited similar facilitation following neutral exogenous cues, this facilitation was completely absent following affectively negative exogenous cues. Critically, these effects were contingent on endogenous attentional settings, such that explicit top-down cues presented prior to the appearance of exogenous stimuli removed anxious individuals’ sensitivity to affectively salient stimuli. FMRI analyses revealed a network of brain regions underlying this variability in affective contingent capture across individuals, including the fusiform face area (FFA), posterior ventrolateral frontal cortex, and supplementary motor area. Importantly, activation in the posterior ventrolateral frontal cortex and the supplementary motor area fully mediated the effects observed in FFA, demonstrating a critical role for these frontal regions in mediating attentional orienting and interference resolution processes when engaged by affectively salient stimuli.
Attention; Posner cueing paradigm; ventral attention network; contingent capture; emotion; fear
Epidemiological evidence has suggested that consumption of a diet rich in cruciferous vegetables reduces the risk of several types of cancers and chronic degenerative diseases. In particular, broccoli sprouts are a convenient and rich source of the glucosinolate, glucoraphanin, which can release the chemopreventive agent, sulforaphane, an inducer of glutathione S-transferases. Two broccoli sprout-derived beverages, one sulforaphane-rich (SFR) and the other glucoraphanin-rich (GRR), were evaluated for pharmacodynamic action in a crossover clinical trial design. Study participants were recruited from the farming community of He Zuo Township, Qidong, China, previously documented to have a high incidence of hepatocellular carcinoma with concomitant exposures to aflatoxin and more recently characterized with exposures to substantive levels of airborne pollutants. Fifty healthy participants were randomized into two treatment arms. The study protocol was as follows: a 5 days run-in period, a 7 days administration of beverage, a 5 days washout period and a 7 days administration of the opposite beverage. Urinary excretion of the mercapturic acids of acrolein, crotonaldehyde, ethylene oxide and benzene were measured both pre- and postinterventions using liquid chromatography tandem mass spectrometry. Statistically significant increases of 20–50% in the levels of excretion of glutathione-derived conjugates of acrolein, crotonaldehyde and benzene were seen in individuals receiving SFR, GRR or both compared with their preintervention baseline values. No significant differences were seen between the effects of SFR versus GRR. Intervention with broccoli sprouts may enhance detoxication of airborne pollutants and attenuate their associated health risks.
Cognitive models have long distinguished between “automatic” associative processes that can be triggered in a bottom-up fashion, and “controlled” processes, where internal goals guide information processing in a deliberate, top-down manner. However, recent behavioral studies have cast doubt on the validity of this dichotomy, showing that implicit contextual cues can modulate performance in a way suggestive of an associative triggering of specific top-down control states. Here, we harnessed functional magnetic resonance imaging (fMRI) in humans to test whether these behavioral findings truly reflect online, bottom-up priming of top-down attentional control settings. Using a flanker interference task where stimulus location cued the likelihood of incongruent trials, we found that the behavioral phenomenon of implicit, context-specific improvements in interference resolution was mirrored in hemodynamic activity in the medial superior parietal lobule (mSPL), previously implicated in voluntary (as opposed to primed) attention shifts. Moreover, the mSPL displayed context-specific functional coupling with visual regions involved in processing the flanker stimuli, and the modulation of the latter was predictive of the behavioral effects. Finally, the implementation of this contextual control was “on the fly”, that is, it was primed online by a switch to the context associated with high conflict. These results suggest that top-down control states can be bound into episodic event representations and can subsequently be primed by other features of those representations. Together, our findings illustrate a more intimate link between associative and controlled processing than is traditionally assumed, and place the neural substrate of that linkage in the posterior parietal cortex.
Interference resolution is improved for stimuli presented in contexts (e.g., locations) associated with frequent conflict. This phenomenon, the context-specific proportion congruent (CSPC) effect, has challenged the traditional juxtaposition of “automatic” and “controlled” processing because it suggests that contextual cues can prime top-down control settings in a bottom-up manner. We recently obtained support for this “priming of control” hypothesis with functional magnetic resonance imaging by showing that CSPC effects are mediated by contextually cued adjustments in processing selectivity. However, an equally plausible explanation is that CSPC effects reflect adjustments in response caution triggered by expectancy violations (i.e., prediction errors) when encountering rare events as compared to common ones (e.g., incongruent trials in a task context associated with infrequent conflict). Here, we applied a quantitative model of choice, the linear ballistic accumulator (LBA), to distil the reaction time and accuracy data from four independent samples that performed a modified flanker task into latent variables representing the psychological processes underlying task-related decision making. We contrasted models which differentially accounted for CSPC effects as arising either from contextually cued shifts in the rate of sensory evidence accumulation (“drift” models) or in the amount of evidence required to reach a decision (“threshold” models). For the majority of the participants, the LBA ascribed CSPC effects to increases in response threshold for contextually infrequent trial types (e.g., congruent trials in the frequent conflict context), suggesting that the phenomenon may reflect more a prediction error-triggered shift in decision criterion rather than enhanced sensory evidence accumulation under conditions of frequent conflict.
cognitive control; conflict; evidence accumulation models; interference; mathematical modeling; priming; prediction error; response threshold
Visual cortical responses are usually attenuated by repetition, a phenomenon known as repetition suppression (RS). Here, we use multivoxel pattern analyses of functional magnetic resonance imaging (fMRI) data to show that RS co-occurs with the converse phenomenon (repetition enhancement, RE) in a single cortical region. We presented human volunteers with short sequences of repeated faces and measured brain activity using fMRI. In an independently defined face-responsive extrastriate region, the response of each voxel to repetition (RS vs. RE) was consistent across scanner runs, and multivoxel patterns for both RS and RE voxels were stable. Moreover, RS and RE voxels responded to repetition with dissociable latencies and exhibited different patterns of connectivity with lower and higher visual regions. Computational simulations demonstrated that these effects must be due to differences in repetition sensitivity, and not feature selectivity. These findings establish that 2 classes of repetition responses coexist within 1 visual region and support models acknowledging this distinction, such as predictive coding models where perception requires the computation of both predictions (which are enhanced by repetition) and prediction errors (which are suppressed by repetition).
face perception; fMRI; predictive coding; repetition enhancement; repetition suppression
Exposure to genotoxic chemicals at a young age increases cancer incidence later in life. Aflatoxin B1 (AFB1) is a potent genotoxin that induces hepatocellular carcinoma (HCC) in many animal species and in humans. Whereas adult mice are insensitive to aflatoxin-induced carcinogenesis, mice treated with AFB1 shortly after birth develop a high incidence of HCC in adulthood. Furthermore, the incidence of HCC in adult male mice treated as infants is much greater than in females, reasons for which are unclear. In this study, treatment with AFB1 produced similar levels of DNA damage and mutations in the liver of newborn male and female gpt delta B6C3F1 mice. Twenty-four hours after dosing with AFB1 (6 mg/kg), the highly mutagenic AFB1-FAPY adduct was present at twice the level of AFB1-N7-guanine in liver DNA of males and females. A multiple dose regimen (3 × 2 mg/kg), while delivering the same total dose, resulted in lower AFB1 adduct levels. Mutation frequencies in the gpt transgene in liver were increased by 20- to 30-fold. The most prominent mutations in AFB1-treated mice were G:C to T:A transversions and G:C to A:T transitions. At this 21-day time point, no significant differences were found in mutation frequency or types of mutations between males and females. These results show that infant male and female B6C3F1 mice experience similar amounts of DNA damage and mutation from AFB1 that may initiate the neoplastic process. The gender difference in the subsequent development of HCC highlights the importance of elucidating additional factors that modulate HCC development.
aflatoxin; neonatal mouse; hepatocarcinoma; mutation; gpt delta mouse
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with nearly 700 000 deaths occurring annually. Hepatitis B virus (HBV) is a major contributor to HCC and acquired mutations in the HBV genome may accelerate its pathogenesis. In this study, a matched case–control investigation of 345 men who died of HCC and 625 controls were nested within a cohort of male hepatitis B surface antigen (HBsAg) carriers from Qidong, China. Matched preserving odds ratios (ORs) were used as a measure of association and 95% confidence intervals (CIs) as a measure of precision. Real-time polymerase chain reaction allowed for a quantitative comparison of the levels of the HBV 1762T/1764A mutation in cases and controls. A total of 278 (81%) of the cases were positive for the HBV 1762T/1764A mutation compared with 250 (40%) of the controls. The matched preserving OR of 6.72 (95% CI: 4.66 to 9.68) strongly indicated that cases were significantly more probably than controls to have the mutation. Plasma levels of DNA harboring the HBV mutation were on average 15-fold higher in cases compared with controls (P < 0.001). Most strikingly, the level of the mutation in the 20 controls who later developed and died of HCC were on average 274-fold higher than controls who did not develop HCC. Thus, within this cohort of HBsAg carriers at high risk of developing HCC, individuals positive for the HBV 1762T/1764A mutation at enrollment were substantially more probably to subsequently develop HCC, with a higher concentration of the mutation in plasma enhancing predisposition for cancer development.
Aflatoxin B1 (AFB1) is a DNA-binding toxin that contributes to the burden of liver cancer in tropical areas. AFB1-DNA adducts are powerful biomarkers that discern individual and population risk from exposure to this carcinogen. The discovery of concordance between the metabolic pathways of the male Fischer rat and humans allowed data from rats to guide the development of chemoprevention strategies employed in clinical trials in high-risk regions. In this study, the variables of strain and sex are studied in the rat model, as a step toward understanding how ethnic differences and sex influence DNA adduct formation and the induction of enzymes by chemoprotective agents. Sulforaphane (SF), which induces phase II enzymes including glutathione S-transferases (GSTs), was evaluated for its ability to induce GST activity and reduce the AFB1-DNA adducts in livers of both sexes of two rat strains that differ in susceptibility to AFB1 hepatocarcinogenesis. A dose-dependent relationship was found for SF for both induction of GST and reduction in of AFB1-N7-guanine in both Fischer (sensitive to AFB1) and Sprague-Dawley rats (relatively resistant). Sprague-Dawley rats exhibited the greatest increase in GST levels and the largest reduction in AFB1-N7-guanine in liver DNA. Males and females of each strain were also compared to determine if the ability of SF to induce GST and reduce AFB1-N7-guanine correlated with gender differences in sensitivity to AFB1 carcinogenesis. No gender-specific responses to SF were observed. These results support the view that SF induction of liver GST activity may play a role in its chemoprotective activity.
aflatoxin B1; chemoprevention; liver cancer; sulforaphane; DNA adducts; glutathione S-Transferase
Emotional arousal at encoding is known to facilitate later memory recall. In the present study, we asked whether this emotion-modulation of episodic memory is also evident at very short time scales, as measured by “feature integration effects,” the moment-by-moment binding of relevant stimulus and response features in episodic memory. This question was motivated by recent findings that negative emotion appears to potentiate first-order trial sequence effects in classic conflict tasks, which has been attributed to emotion-modulation of conflict-driven cognitive control processes. However, these effects could equally well have been carried by emotion-modulation of mnemonic feature binding processes, which were perfectly confounded with putative control processes in these studies. In the present experiments, we tried to shed light on this question by testing explicitly whether feature integration processes, assessed in isolation of conflict–control, are in fact susceptible to negative emotion-modulation. For this purpose, we adopted a standard protocol for assessing the rapid binding of stimulus and response features in episodic memory (Experiment 1) and paired it with the presentation of either neutral or fearful background face stimuli, shown either at encoding only (Experiment 2), or at both encoding and retrieval (Experiment 3). Whereas reliable feature integration effects were observed in all three experiments, no evidence for emotion-modulation of these effects was detected, in spite of significant effects of emotion on response times. These findings suggest that rapid feature integration of foreground stimulus and response features is not subject to modulation by negative emotional background stimuli and further suggest that previous reports of emotion-modulated trial–transition effects are likely attributable to the effects of emotion on cognitive control processes.
feature integration; emotion; cognitive control; event files; binding
The increasing prevalence of obesity has become one of the most challenging problems facing healthcare providers. Despite recommendations from the U.S. Preventive Services Task Force many health professionals fail to discuss obesity with their patients. This study sought to identify terms that individuals with obesity and being treated in primary care find the most and least acceptable for describing their excess weight. Three-hundred ninety obese adult primary care patients in the Philadelphia area were administered the Weight Preferences Questionnaire from January 2008 through February 2009. Ratings of 11 terms used to describe excess weight were transformed to a five-point scale, ranging from “very desirable” (+2) to neutral (0) to “very undesirable” (-2). The term “fatness” (mean score -1.1 ± 1.3) was rated as significantly more undesirable than all other descriptors (p < 0.001). The terms “excess fat” (-0.6 ± 1.3), “large size” (-0.6 ± 1.3), “obesity” (-0.5 ± 1.4), and “heaviness” (-0.4 ± 1.2) were rated as significantly more undesirable then the remaining terms, which included weight problem, body mass index (BMI), and excess weight (p<0.001). In contrast, the term “weight” was viewed as the most desirable term for characterizing excess weight. Patients' preferences for terms were not significantly influenced by gender, race/ethnicity, or a BMI ≥ 40 kg/m2. Practitioners who treat obesity are encouraged to avoid undesirable terms when discussing this condition with their patients. Instead practitioners may want to consider broaching the topic using more patient-friendly term such as “weight,” “BMI,” “weight problem,” or excess weight.”
obesity; preferred terms
One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout-derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12 hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than GRR beverage. Elimination rates were considerably slower with GRR allowing for achievement of steady state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane.
sulforaphane; glucoraphanin; broccoli sprouts; clinical trial