Establishment and characterization of TK-ALCL1: a novel NPM-ALK-positive anaplastic large-cell lymphoma cell line.

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK+ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2-/-/Jak3-/- (BRJ) mice, it formed tumor masses within 4-6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK+ ALCL and of novel therapeutic approaches targeting ALK.

Hyperthymic temperament predicts neural responsiveness for monetary reward.

BACKGROUND: Hyperthymic temperament is cheerful action orientation, and is suggested to have a protective effect on depressive symptoms. Responsiveness for reward, which is diminished in depressive patients, is suggested to be related to hyperthymic temperament. Moreover, neural hypoactivation in the reward system in depressive patients is well known. However, only a few previous studies have investigated the neurobiological substrate of hyperthymic temperament. We investigated the relationship between hyperthymic temperament and responsiveness to monetary rewards at the neural level. METHODS: Healthy participants performed a modified version of the monetary incentive delay task in a functional magnetic resonance imaging scanner. We explored the brain regions where neural responsiveness for monetary reward was predicted by hyperthymic temperament. RESULTS: Brain areas in the reward system were widely activated for reward anticipation. Activation in the left thalamus and left putamen was positively predicted by hyperthymic temperament. Conversely, activation in the ventral striatum and right insula was not modulated by hyperthymic temperament. No region activated for reward outcome was not modulated by hyperthymic temperament. LIMITATIONS: Behavioral responsiveness to reward was not predicted by hyperthymic temperament or neural activity. Moreover, we did not correct P values for multiple regression analysis, considering that this was an exploratory study. CONCLUSIONS: We found a neurobiological foundation for the protective aspect of hyperthymic temperament against depression in the reward system. Our findings suggest that the hyperthymic temperament may modulate attentional or motor responses or optimal selection of behavior based on reward, rather than value representation.

Hyperthymic temperament predicts neural responsiveness for nonmonetary reward.

Aim: Hyperthymic temperament is a cheerful action orientation that is suggested to have a protective effect on depressive symptoms. We recently reported that hyperthymic temperament can positively predict activation of reward-related brain areas in anticipation of monetary rewards, which could serve as a biomarker of hyperthymic temperament. However, the relationship between hyperthymic temperament and neural responsiveness to nonmonetary rewards (i.e., feedback indicating success in a task) remains unclear. Methods: Healthy participants performed a modified monetary incentive delay task inside a functional magnetic resonance imaging scanner. To examine the effect of nonmonetary positive feedback, the participants performed feedback and no-feedback trials. We explored brain regions whose neural responsiveness to nonmonetary rewards was predicted by hyperthymic temperament. Results: There was premotor area activation in anticipation of a nonmonetary reward, which was negatively predicted by hyperthymic temperament. Moreover, brain areas located mainly in the primary somatosensory area and somatosensory association area were activated by performance feedback, which was positively predicted by hyperthymic temperament. Conclusion: We found that hyperthymic temperament is related to neural responsiveness to both monetary and nonmonetary rewards. This may be related to the process of affective regulation in the somatosensory area.

Behavioral and neuro-cognitive bases for emergence of norms and socially shared realities via dynamic interaction.

In the digital era, new socially shared realities and norms emerge rapidly, whether they are beneficial or harmful to our societies. Although these are emerging properties from dynamic interaction, most research has centered on static situations where isolated individuals face extant norms. We investigated how perceptual norms emerge endogenously as shared realities through interaction, using behavioral and fMRI experiments coupled with computational modeling. Social interactions fostered convergence of perceptual responses among people, not only overtly but also at the covert psychophysical level that generates overt responses. Reciprocity played a critical role in increasing the stability (reliability) of the psychophysical function within each individual, modulated by neural activity in the mentalizing network during interaction. These results imply that bilateral influence promotes mutual cognitive anchoring of individual views, producing shared generative models at the collective level that enable endogenous agreement on totally new targets-one of the key functions of social norms.

Subjects with bipolar disorder showed different reward system activation than subjects with major depressive disorder in the monetary incentive delay task.

BACKGROUND: Differentiating between bipolar disorder (BD) and major depressive disorder (MDD) during the depressive episode is an important clinical challenge. Reward system abnormalities have received much attention as one of the biological underpinnings of BD and MDD, but few studies have directly compared these abnormalities in remitted and depressed states. METHODS: This was a functional MRI study using the Monetary Incentive Delay task in 65 patients (BD [n = 33], MDD [n = 32]) and 33 healthy controls (HC). Regions of interest (ROI) analysis with 21 ROIs related to reward anticipation and 17 ROIs related to gain outcome were implemented, as well as whole-brain analysis. The difference in the dimensional effect of depression on brain activation was also examined. RESULTS: Relative to the HC group, BD patients showed significantly decreased activation during reward anticipation in the anterior cingulate cortex, anterior insula (AI), and putamen, and MDD patients showed significantly decreased activation in the AI and brainstem. The dimensional effect of depression severity showed a trend-level difference between BD and MDD in the right brainstem and left AI. CONCLUSIONS: The current study showed a possible differential effect of depression on the reward system between MDD and BD. Further studies on reward systems might offer reliable markers to distinguish between MDD and BD patients in the depressive phase.

Fetal blockade of nicotinic acetylcholine transmission causes autism-like impairment of biological motion preference in the neonatal chick.

Several environmental chemicals are suspected risk factors for autism spectrum disorder (ASD), including valproic acid (VPA) and pesticides acting on nicotinic acetylcholine receptors (nAChRs), if administered during pregnancy. However, their target processes in fetal neuro-development are unknown. We report that the injection of VPA into the fetus impaired imprinting to an artificial object in neonatal chicks, while a predisposed preference for biological motion (BM) remained intact. Blockade of nAChRs acted oppositely, sparing imprinting and impairing BM preference. Beside ketamine and tubocurarine, significant effects of imidacloprid (a neonicotinoid insecticide) appeared at a dose ≤1 ppm. In accord with the behavioral dissociations, VPA enhanced histone acetylation in the primary cell culture of fetal telencephalon, whereas ketamine did not. VPA reduced the brain weight and the ratio of NeuN-positive cells (matured neurons) in the telencephalon of hatchlings, whereas ketamine/tubocurarine did not. Despite the distinct underlying mechanisms, both VPA and nAChR blockade similarly impaired imprinting to biological image composed of point-light animations. Furthermore, both impairments were abolished by postnatal bumetanide treatment, suggesting a common pathology underlying the social attachment malformation. Neurotransmission via nAChR is thus critical for the early social bond formation, which is hindered by ambient neonicotinoids through impaired visual predispositions for animate objects.

Construction of Roman roads toward neuroeconomics.

Neuroeconomics is still "under construction." To be a leading discipline, it needs firm ecological rationale and neurobiological bases. "Vigor" supplies this infrastructure through the mathematics of the foraging theory and system-neuroscience evidence on utility and motor control. It will prepare us for the future neuroeconomics, if studied appropriately in the light of evolution.

Mere presence of co-eater automatically shifts foraging tactics toward 'Fast and Easy' food in humans.

Competition for food resources is widespread in nature. The foraging behaviour of social animals should thus be adapted to potential food competition. We conjectured that in the presence of co-foragers, animals would shift their tactics to forage more frequently for smaller food. Because smaller foods are more abundant in nature and allow faster consumption, such tactics should allow animals to consume food more securely against scrounging. We experimentally tested whether such a shift would be triggered automatically in human eating behaviour, even when there was no rivalry about food consumption. To prevent subjects from having rivalry, they were instructed to engage in a 'taste test' in a laboratory, alone or in pairs. Even though the other subject was merely present and there was no real competition for food, subjects in pairs immediately exhibited a systematic behavioural shift to reaching for smaller food amounts more frequently, which was clearly distinct from their reaching patterns both when eating alone and when simply weighing the same food without eating any. These patterns suggest that behavioural shifts in the presence of others may be built-in tactics in humans (and possibly in other gregarious animals as well) to adapt to potential food competition in social foraging.

Complex social ecology needs complex machineries of foraging.

Uncertainty is caused not only by environmental changes, but also by social interference resulting from competition over food resources. Actually, foraging effort is socially facilitated, which, however, does not require incentive control by the dopamine system; Zajonc's "drive" theory is thus questionable. Instead, social adjustments may be pre-embedded in the limbic network responsible for decisions of appropriate effort-cost investment.

Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers.

Overexpression of alternative splicing of far upstream element binding protein 1 (FUBP1) interacting repressor (FIR; poly(U) binding splicing factor 60 [PUF60]) and cyclin E were detected in esophageal squamous cell carcinomas (ESCC). Accordingly, the expression of FBW7 was examined by which cyclin E is degraded as a substrate via the proteasome system. Expectedly, FBW7 expression was decreased significantly in ESCC. Conversely, c-myc gene transcriptional repressor FIR (alias PUF60; U2AF-related protein) and its alternative splicing variant form (FIRΔexon2) were overexpressed in ESCC. Further, anticancer drugs (cis-diaminedichloroplatinum/cisplatin [CDDP] or 5-fluorouracil [5-FU]) and knockdown of FIR by small interfering RNA (siRNA) increased cyclin E while knockdown of FIRΔexon2 by siRNA decreased cyclin E expression in ESCC cell lines (TE1, TE2, and T.Tn) or cervical SCC cells (HeLa cells). Especially, knockdown of SAP155 (SF3b1), a splicing factor required for proper alternative splicing of FIR pre-mRNA, decreased cyclin E. Therefore, disturbed alternative splicing of FIR generated FIR/FIRΔexon2 with cyclin E overexpression in esophageal cancers, indicating that SAP155 siRNA potentially rescued FBW7 function by reducing expression of FIR and/or FIRΔexon2. Remarkably, Three-dimensional structure analysis revealed the hypothetical inhibitory mechanism of FBW7 function by FIR/FIRΔexon2, a novel mechanism of cyclin E overexpression by FIR/FIRΔexon2-FBW7 interaction was discussed. Clinically, elevated FIR expression potentially is an indicator of the number of lymph metastases and anti-FIR/FIRΔexon2 antibodies in sera as cancer diagnosis, indicating chemical inhibitors of FIR/FIRΔexon2-FBW7 interaction could be potential candidate drugs for cancer therapy. In conclusion, elevated cyclin E expression was, in part, induced owing to potential FIR/FIRΔexon2-FBW7 interaction in ESCC.

Four eyes match better than two: Sharing of precise patch-use time among socially foraging domestic chicks.

To examine how resource competition contributes to patch-use behaviour, we examined domestic chicks foraging in an I-shaped maze equipped with two terminal feeders. In a variable interval schedule, one feeder supplied grains three times more frequently than the other, and the sides were reversed midway through the experiment. The maze was partitioned into two lanes by a transparent wall, so that chicks fictitiously competed without actual interference. Stay time at feeders was compared among three groups. The "single" group contained control chicks; the "pair" group comprised the pairs of chicks tested in the fictitious competition; "mirror" included single chicks accompanied by their respective mirror images. Both "pair" and "mirror" chicks showed facilitated running. In terms of the patch-use ratio, "pair" chicks showed precise matching at approximately 3:1 with significant mutual dependence, whereas "single" and "mirror" chicks showed a comparable under-matching. The facilitated running increased visits to feeders, but failed to predict the patch-use ratio of the subject. At the reversal, quick switching occurred similarly in all groups, but the "pair" chicks revealed a stronger memory-based matching. Perceived competition therefore contributes to precise matching and lasting memory of the better feeder, in a manner dissociated from socially facilitated food search.

Drill needle aspiration biopsy for submucosal tumors in an experimental study.

BACKGROUND AND AIMS: EUS-guided FNA biopsy has been widely performed to aid in the diagnosis of submucosal tumors (SMTs). However, in cases of small tumors, the diagnostic yield of EUS-FNA is poor. Therefore, it is necessary to develop a new needle for the diagnosis. We developed a device with a new mechanism that we refer to as a drill needle aspiration biopsy (DNAB). The aim of this study was to evaluate the use of DNAB in resected gastric SMT specimens. METHODS: A drill needle with a sharp tip and wide ditch was inserted into a catheter for angiography. Continuous suction is enabled through the catheter at the tip. DNAB was performed with one pass and one stroke in 13 gastric SMTs resected by operation. Similarly, FNA was performed by one pass and ten strokes. These gastric tumors included nine diagnosed gastrointestinal stromal tumors and four undiagnosed SMTs by preoperative examinations. The tissue quantity between DNAB and FNA was macroscopically and microscopically examined. RESULTS: All 13 drill biopsy specimens were obtained. Additionally, all 13 gastric SMTs, including 4 undiagnosed tumors, could be diagnosed by DNAB. The quantity of each specimen obtained by DNAB was macroscopically and microscopically much greater than that by FNA. In particular, for tumors <25 mm in the longer axis, the ratio of microscopic diagnosable cases was 100 % (7/7) for DNAB and 42.9 % (3/7) for FNA. CONCLUSIONS: DNAB is a novel method that can obtain more tissue than FNA for small gastric SMT.

Selective contribution of the telencephalic arcopallium to the social facilitation of foraging efforts in the domestic chick.

To investigate the neural basis of socio-economic behaviors in birds, we examined the effects of bilateral electrolytic lesions of arcopallium (Arco, the major descending pallial area of the avian telencephalon) and the surrounding nuclei in domestic chicks. We tested foraging effort (running distance) in an I-shaped maze with two food patches that delivered food in a biased manner according to a variable interval schedule. Normally, chicks run back and forth between the patches, and the patch use time matches the respective food delivery rate. In the paired phase, even without actual interference of food, chicks showed social facilitation of running effort compared with the single phase. Chicks with lesions in the Arco and lateral Arco showed significant reductions in social facilitation. The lesion effects of the lateral Arco were particularly selective, as it was not accompanied by changes in running distance in the single phase. Lesions of the nidopallium and nucleus taeniae of the amygdala produced no changes in foraging behavior. On the other hand, the Arco lesion did not impair social facilitation of operant peck latency. In accordance with this, anterograde tracing revealed characteristic projections from the lateral Arco to the extended amygdala, hippocampus, and septum, as well as wide areas of limbic nuclei in the hypothalamus and medial areas of the striatum including the nucleus accumbens. Pathways from the lateral Arco could enable chicks to overcome the extra effort investment of social foraging, suggesting functional and anatomical analogies to the anterior cingulate cortex and basolateral amygdala in mammals.

Striatal and Tegmental Neurons Code Critical Signals for Temporal-Difference Learning of State Value in Domestic Chicks.

To ensure survival, animals must update the internal representations of their environment in a trial-and-error fashion. Psychological studies of associative learning and neurophysiological analyses of dopaminergic neurons have suggested that this updating process involves the temporal-difference (TD) method in the basal ganglia network. However, the way in which the component variables of the TD method are implemented at the neuronal level is unclear. To investigate the underlying neural mechanisms, we trained domestic chicks to associate color cues with food rewards. We recorded neuronal activities from the medial striatum or tegmentum in a freely behaving condition and examined how reward omission changed neuronal firing. To compare neuronal activities with the signals assumed in the TD method, we simulated the behavioral task in the form of a finite sequence composed of discrete steps of time. The three signals assumed in the simulated task were the prediction signal, the target signal for updating, and the TD-error signal. In both the medial striatum and tegmentum, the majority of recorded neurons were categorized into three types according to their fitness for three models, though these neurons tended to form a continuum spectrum without distinct differences in the firing rate. Specifically, two types of striatal neurons successfully mimicked the target signal and the prediction signal. A linear summation of these two types of striatum neurons was a good fit for the activity of one type of tegmental neurons mimicking the TD-error signal. The present study thus demonstrates that the striatum and tegmentum can convey the signals critically required for the TD method. Based on the theoretical and neurophysiological studies, together with tract-tracing data, we propose a novel model to explain how the convergence of signals represented in the striatum could lead to the computation of TD error in tegmental dopaminergic neurons.

Dissociation of the neural substrates of foraging effort and its social facilitation in the domestic chick.

The frequency or intensity of behavior is often facilitated by the presence of others. This social facilitation has been reported in a variety of animals, including birds and humans. Based on Zajonc's "drive theory," we hypothesized that facilitation and drive have shared neural mechanisms, and that dopaminergic projections from the midbrain to striatum are involved. As the ascending dopaminergic projections include the mesolimbic and nigrostriatal pathways, we targeted our lesions at the medial striatum (MSt) and substantia nigra (SN). We found that a bilateral electrolytic lesion of the MSt suppressed baseline foraging effort, but social facilitation was intact. Conversely, an electrolytic lesion targeted at the unilateral SN (on the right side) partially suppressed social facilitation, while baseline foraging effort remained unaffected. However, selective depletion of catecholaminergic (thyrosine hydroxylase immunoreactive) terminals by micro-infusion of 6-hydroxydopamine (6-OHDA) to bilateral MSt had no significant effects on foraging behavior, whereas it impaired formation of the association memory reinforced by water reward. Neurochemical assay by high-perfromance liquid chromatography also revealed a significant decrease in the dopamine and noradrenaline contents in MSt after 6-OHDA micro-infusion compared with intact control chicks. Thus, we conclude that the neural substrate of social facilitation can be dissociated from that responsible for reward-based foraging effort, and that ascending dopaminergic pathways do not appear to contribute to social facilitation. Based on our detailed analysis of the lesion areas, we discuss fiber tracts or neural components of the midbrain tegmental area that may be responsible for social facilitation.

Lymphoepithelioma-like esophageal carcinoma with macroscopic reduction.

Esophageal lymphoepithelioma-like carcinoma (LELC) is extremely rare. We report the first case of esophageal LELC showing macroscopic reduction. A 67-year-old male presented with dysphagia and, by endoscopic examination, was found to have a significantly raised tumor of 10 mm in diameter in the thoracic esophagus. The biopsied material showed esophageal cancer. We performed endoscopic submucosal dissection. However, the tumor became flattened, similar to a scar, in only 2 mo. Histologically, the carcinoma cells had infiltrated the submucosal layer. Prominent infiltration of T lymphoid cells that stained positive for CD8 was observed around the carcinoma cells. Therefore, this lesion was considered to be an LELC with poorly differentiated squamous cells. Because the margin was positive, an esophagectomy was performed. Carcinoma cells were detected in the neck in one lymph node. The staging was T1N0M1b. However, the patient has been well, without adjuvant therapy or recurrence, for more than 5 years.

Behavioural and pharmacological effects of fluvoxamine on decision-making in food patches and the inter-temporal choices of domestic chicks.

Behavioural effects of fluvoxamine (FLV, selective serotonin reuptake inhibitor) were examined in 1-2 week old domestic chicks. Chicks were tested in an I-shaped maze equipped with a feeder (ON feeder) that served 1 or 2 grains of millet at gradually increasing intervals, so that a depleting food patch was mimicked. By leaving the feeder, the food delivery program was reset, and chicks gained food at short intervals only after a travel to a dummy feeder (OFF feeder) placed on the opposite side of the maze. Chicks quickly learned to actively shuttle between the ON and the OFF feeders. FLV (intra-peritoneal injection, 20 mg/kg BW) acutely caused chicks to stay longer at the gradually depleting ON feeder. Inter-temporal choices were also tested, whereby two coloured beads were simultaneously presented, each associated with a small/short-delay reward or a large/long-delay alternative. FLV suppressed the choice of the short-delay option. It is suggested that an enhanced level of serotonin (5-HT) makes chicks more tolerant of the delayed food item in both behavioural paradigms. Furthermore, the decision to leave a depleting patch cannot be equated to choosing the long-delay option of the choice paradigm. Furthermore, FLV suppressed work efforts (velocity and running distance) in uncued shuttle and number of distress calls. In vivo microdialysis experiments revealed that FLV enhanced the extracellular concentration of 5-HT as well as dopamine (DA) locally in the medial striatum/nucleus accumbens. Underlying neuromodulatory mechanisms of behavioural control are examined in relation to locomotion, behavioural tolerance and interval timing.

Social facilitation revisited: increase in foraging efforts and synchronization of running in domestic chicks.

Social influences on foraging efforts were examined in domestic chicks by investigating the frequency of runs made to feeders and the amount of pecking to gain food. Single or paired chicks foraged in an I-shaped maze equipped with a millet feeder on each end, that distributed one or two grains at variable intervals. Regardless of when the grain(s) were dispensed, chicks ran back and forth between the feeders. Analyses of their movement patterns revealed: (1) running patterns were not directly synchronized with the dispensing of grain(s), (2) running distance was longer in paired chicks than in single chicks, (3) paired chicks partially synchronized their runs between feeders, and (4) social effects were immediate but cumulative after repeated blocks. We further examined the social effects on running by dividing the I-maze into two parallel lanes separated by a transparent wall, so that kleptoparasitic interference of food did not occur. Again, the chicks increased their running speed and were even more synchronized with their partner's movements, indicating that food competition alone was not responsible for increased foraging effort. The number of pecks to get grains was also assessed under conditions where the food tray was gradually replaced, from an easy one to more difficult ones. When tested in the separated I-maze, paired chicks pecked more in the difficult food situation without increase in the number of gained grains. Results suggest that (i) social facilitation leads to increased foraging efforts and (ii) the presence of a conspecific is alone may lead to enhanced foraging efforts in chicks. These findings are discussed in terms of possible ecological background of social facilitation.