Identification of odontogenic ameloblast associated as a novel target gene of the Wnt/ß-catenin signaling pathway.

The Wnt/ß-catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH-7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant ß-catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant ß-catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the ß-catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers.

Direct hyperbilirubinemia in infants with congenital heart disease.

BACKGROUND: The association between congenital heart disease (CHD) and infantile cholestasis, a key finding for the diagnosis of biliary atresia (BA), has not been previously investigated. The aim of this study was therefore to investigate the characteristics of direct hyperbilirubinemia (D-HB) in infants with CHD. METHODS: All neonates admitted to the present hospital and diagnosed with CHD in 2015 and 2016 were included. D-HB (direct bilirubin ≥ 2.0 mg/dL) at ≤60 days of age and other clinical parameters were retrospectively reviewed. Statistical analysis according to presence of D-HB was performed using chi-squared test or Wilcoxon rank sum test. RESULTS: Seventy-six patients (M:F, 36:40) were included in this study. CHD consisted of ventricular septal defect in 17, patent ductus arteriosus in 10, and other in 49. Thirteen patients (17.1%) had D-HB at ≤60 days of age. Resolution of D-HB (DB < 2.0 mg/dL) occurred in 10 of the 13 patients during the hospital stay, and this occurred in ≤7 days in eight of the 10 patients. Sex, gestational age, birthweight, chromosomal anomalies, need for Fontan operation for CHD repair, and/or cardiac operation were not associated with D-HB at ≤60 days of age. CONCLUSION: While D-HB was frequently observed in infants with CHD, the majority of D-HB cases resolved spontaneously in ≤1 week. Neonatal clinical parameters or CHD status was not predictive of D-HB. D-HB lasting >1 week in infants with CHD should be evaluated for the cause.

Tailor-made treatment combined with proton beam therapy for children with genitourinary/pelvic rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas among children. Patients who developed genitourinary/pelvic rhabdomyosarcoma (GU/P-RMS) have a higher complication ratio and relatively poorer event free survival, with local therapy being very important. While proton beam therapy (PBT) is expected to reduce co-morbidity, especially for children, this lacks firm evidence and analysis. We analyzed GU/P-RMS children who had undergone multimodal therapy combined with PBT at a single institution. METHOD: We retrospectively reviewed charts of children with GU/P-RMS treated from January 2007 to May 2013 at the University of Tsukuba Hospital who had undergone multimodal therapy with PBT. RESULTS: There were 5 children and their median age at diagnosis was 2.8 years (0.6-4.4 years). Primary sites were the bladder (2) and the prostate (3). All received neo-adjuvant chemotherapy and 3 underwent chemotherapy during PBT (Group Cx). All patients of Group Cx developed leukocytopenia (WBC <1000/µL). The median dose of PBT was 47.7 GyE (41.4-50.4 GyE). All patients survived by their last hospital visit (median, 36 months). CONCLUSIONS: We analyzed multimodal treatment combined with PBT applied for GU/P-RMS. PBT was well tolerated and could be a plausible choice instead of photon therapy for this population.

Genome-wide approach to identify second gene targets for malignant rhabdoid tumors using high-density oligonucleotide microarrays.

Malignant rhabdoid tumor (MRT) is a rare and highly lethal cancer that mainly affects infants and young children. The majority of MRT are characterized by loss of function of SMARCB1 on chromosome 22q11.2. However, little is known about genetic changes other than SMARCB1 alterations that are responsible for the development and/or progression of MRT. To explore additional gene targets in MRT, we analyzed 21 MRT specimens (12 fresh tumors and 9 MRT-derived cell lines) using high-density single nucleotide polymorphism genotyping microarrays. Although MRT genomes are characterized by common 22q11.2 deletions, affecting the SMARCB1 locus with a frequency of 95.2% (20/21 specimens), other genetic changes have been less frequent. Of the 20 specimens with deletions of 22q11.2, eight specimens showed uniparental disomy of the SMARCB1 locus with homozygous deletions or gene mutations. High-resolution analysis also disclosed the recurrent hemizygous/homozygous deletions of 7q35-q36.1, involving the CNTNAP2 locus in three specimens. Mutations analysis of CNTNAP2 showed a novel R157C missense mutation in a primary case, and methylation analysis showed recurrent hypermethylation of CNTNAP2 in three of nine cell lines. These results demonstrated that CNTNAP2 is one of the additional gene targets, other than SMARCB1, in MRT.

Management of cervicomediastinal neuroblastoma presenting with life-threatening tracheal obstruction in infancy.

The authors report on 3 infants below 6 months of age at diagnosis, with cervicomediastinal neuroblastoma who presented with life-threatening tracheal obstruction as an oncologic emergency. These neuroblastomas were characterized by favorable biology and chemoresistance. All initially grew rapidly before spontaneously regressing. Nerve injuries occurred in all patients as a result of tumor location. Maintenance of the airway until the expected spontaneous regression was a critical component in the management of these patients.

Bilingualism Alters the Neural Correlates of Sustained Attention.

The present study examined whether monolingual and bilingual language experience -- including first and second language proficiency, exposure, and age of acquisition -- modify the neural mechanisms of attention during nonverbal sound discrimination. English monolinguals and Korean-English bilinguals performed an auditory two-stimulus oddball task while their EEG was recorded. Participants heard a series of two different tones (high pitch tone versus low pitch tone), one of which occurred less frequently (deviant trials) than the other (standard trials), and were asked to mentally count the number of infrequent tones. We found that in the early time window, bilinguals had larger amplitudes than monolinguals in response to both standard and deviant trials, suggesting that bilinguals initially increased attention to identify which of the two tones they heard. In the later time window, however, bilinguals had a smaller ERP effect (deviant minus standard trials) relative to monolinguals, suggesting that bilinguals used fewer cognitive resources for the infrequent stimuli at later stages of processing. Furthermore, across the entire sample, increased exposure to the native language led to larger early, middle, and late ERP effects. These results suggest that native language exposure shapes perceptual processes involved in detection and monitoring. Knowing more than one language may alter sustained attentional processes, with implications for perception and learning.

Do Cross-Language Script Differences Enable Bilinguals to Function Selectively When Speaking in One Language Alone?

The present study examined the role of script in bilingual speech planning by comparing the performance of same and different-script bilinguals. Spanish-English bilinguals (Experiment 1) and Japanese-English bilinguals (Experiment 2) performed a picture-word interference task in which they were asked to name a picture of an object in English, their second language, while ignoring a visual distractor word in Spanish or Japanese, their first language. Results replicated the general pattern seen in previous bilingual picture-word interference studies for the same-script, Spanish-English bilinguals but not for the different-script, Japanese-English bilinguals. Both groups showed translation facilitation, whereas only Spanish-English bilinguals demonstrated semantic interference, phonological facilitation, and phono-translation facilitation. These results suggest that when the script of the language not in use is present in the task, bilinguals appear to exploit the perceptual difference as a language cue to direct lexical access to the intended language earlier in the process of speech planning.

Optimal treatment of pneumothorax in adolescents with Marfan syndrome.

PURPOSE: Pneumothorax often develops in patients with Marfan syndrome (MFS). Here, we examined the effects of conservative and surgical pneumothorax treatments in children with MFS. METHODS: In this study, 23 patients, less than 20 years old, diagnosed with both MFS and pneumothorax between 1999 and 2019 were included. All data were collected retrospectively from patients' medical records. RESULTS: In total, 18 of 23 patients (78%) had relapsed pneumothorax either on the ipsilateral or contralateral side. Among these 18 patients, 6 (26%) patients had multiple relapses. Conservative and surgical treatments of pneumothorax were attempted in 33 and 29 lungs, respectively. The conservative treatment was attempted as a definitive therapy in 21 lungs. Twelve conservative treatments (57%) failed, which required surgical intervention. In 9 lungs (43%) with successful conservative treatment, 6 (67%) had ipsilateral relapses. In contrast to the above findings, only 4 (13%) ipsilateral relapses were observed in 29 surgical treatments. CONCLUSIONS: Our study revealed a low response and high relapse rate when MFS adolescents who diagnosed pneumothorax were subjected to the conservative treatment modality. Thus, we recommend surgical intervention as the first line of therapy to treat pneumothorax in adolescents diagnosed with MFS. LEVEL OF EVIDENCE: Ⅲ (Treatment Study).

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism.

Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.

Switchmate! An Electrophysiological Attempt to Adjudicate Between Competing Accounts of Adjective-Noun Code-Switching.

Here, we used event-related potentials to test the predictions of two prominent accounts of code-switching in bilinguals: The Matrix Language Framework (MLF; Myers-Scotton, 1993) and an application of the Minimalist Programme (MP; Cantone and MacSwan, 2009). We focused on the relative order of the noun with respect to the adjective in mixed Welsh-English nominal constructions given the clear contrast between pre- and post-nominal adjective position between Welsh and English. MP would predict that the language of the adjective should determine felicitous word order (i.e., English adjectives should appear pre-nominally and Welsh adjectives post-nominally). In contrast, MLF contends that it is the language of the finite verb inflexion rather than that of a particular word that governs felicitous word order. To assess the predictions of the two models, we constructed sentences featuring a code-switch between the adjective and the noun, that complied with either English or Welsh word-order. Highly proficient Welsh-English bilinguals made semantic acceptability judgements upon reading the last word of sentences which could violate MP assumptions, MLF assumptions, both assumptions, or neither. Behaviourally, MP violations had no significant effect, whereas MLF violations induced an average drop of 11% in acceptability judgements. Neurophysiologically, MP violations elicited a significant Left Anterior Negativity (LAN) modulation, whereas MLF violations modulated both P600 and LAN mean amplitudes. In addition, there was a significant interaction between MP and MLF status in the P600 range: When MP was violated, MLF status did not matter, and when MP criteria were met, MLF violations resulted in a P600 modulation. This interaction possibly reflects a general preference for noun over adjective insertions, and may provide support for MLF over MP at a global sentence processing level. Model predictions also manifested differently in each of the matrix languages (MLs): When the ML was Welsh, MP and MLF violations elicited greater P600 mean amplitudes than MP and MLF adherences, however, this pattern was not observed when the ML was English. We discuss methodological considerations relating to the neuroscientific study of code-switching, and the extent to which our results shed light on adjective-noun code-switching beyond findings from production and experimental-behavioural studies.

Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets.

Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.

Cognate effects in picture naming: does cross-language activation survive a change of script?

Bilinguals are faster to name a picture in one language when the picture's name is a cognate in the other language. We asked whether cognate facilitation in picture naming would be obtained for bilinguals whose two languages differ in script. Spanish-English and Japanese-English bilinguals named cognate and noncognate pictures in English, their second language (L2). Cognate facilitation was observed for both groups. The results suggest that there is cross-language activation of phonology even for different-script bilinguals.

The effect of amitriptyline, gabapentin, and carbamazepine on morphine-induced hypercarbia in rabbits.

BACKGROUND: Severe exacerbation of chronic neuropathic pain often requires morphine in patients already treated with drugs such as tricyclic antidepressants, carbamazepine and gabapentin. However, it is unclear if a combination of these drugs intensifies the effects of morphine on the respiratory system and, if so, whether these effects are due to pharmacokinetic or pharmacodynamic interaction. METHODS: We gave rabbits (n=6 per group) the following drugs daily for 4 days: subcutaneous normal saline 1 mL (control); amitriptyline subcutaneously 7 mg/kg; carbamazepine orally 100 mg/kg; gabapentin subcutaneously 25 mg/kg; and all three drugs concurrently (combination). On the fifth day, morphine 5 mg/kg was given IV, and Paco2, Pao2 and pH were measured. Morphine, morphine 3-glucoronide and morphine 6-glucoronide concentrations were measured in the plasma over the 4 h period after morphine injection. RESULTS: Compared with controls, premorphine baseline Paco2 was significantly higher (P<0.05) in the amitriptyline group. Postmorphine Paco2 was significantly higher in the amitriptyline and combination groups at all time points over the 240 min, and in the gabapentin group at 10 and 30 min after morphine injection (P<0.05). Peak Paco2 was significantly higher in the amitriptyline group (58.4+/-1.6 mm Hg; mean SD, P<0.005) and in the combination group (57.4+/-1.0 mm Hg, P<0.02) than in the control group (50.2+/-5.2 mm Hg). Similarly, the area under the curve of Paco2 from zero to 240 min was significantly higher in the amitriptyline and combination groups than in the control (P<0.001). There were no significant differences among the groups in plasma concentrations of morphine and its metabolites. CONCLUSIONS: We conclude that pretreatment with amitriptyline increases morphine- induced hypercarbia through pharmacodynamic processes. The effects of carbamazepine or gabapentin were not obvious in this model.

Neural signatures of language co-activation and control in bilingual spoken word comprehension.

To examine the neural signatures of language co-activation and control during bilingual spoken word comprehension, Korean-English bilinguals and English monolinguals were asked to make overt or covert semantic relatedness judgments on auditorily-presented English word pairs. In two critical conditions, participants heard word pairs consisting of an English-Korean interlingual homophone (e.g., the sound /mu:n/ means "moon" in English and "door" in Korean) as the prime and an English word as the target. In the homophone-related condition, the target (e.g., "lock") was related to the homophone's Korean meaning, but not related to the homophone's English meaning. In the homophone-unrelated condition, the target was unrelated to either the homophone's Korean meaning or the homophone's English meaning. In overtly responded situations, ERP results revealed that the reduced N400 effect in bilinguals for homophone-related word pairs correlated positively with the amount of their daily exposure to Korean. In covertly responded situations, ERP results showed a reduced late positive component for homophone-related word pairs in the right hemisphere, and this late positive effect was related to the neural efficiency of suppressing interference in a non-linguistic task. Together, these findings suggest 1) that the degree of language co-activation in bilingual spoken word comprehension is modulated by the amount of daily exposure to the non-target language; and 2) that bilinguals who are less influenced by cross-language activation may also have greater efficiency in suppressing interference in a non-linguistic task.

Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.

Two languages in mind: Bilingualism as a tool to investigate language, cognition, and the brain.

A series of discoveries in the last two decades has changed the way we think about bilingualism and its implications for language and cognition. One is that both languages are always active. The parallel activation of the two languages is thought to give rise to competition that imposes demands on the bilingual to control the language not in use to achieve fluency in the target language. The second is that there are consequences of bilingualism that affect the native as well as the second language. The native language changes in response to second language use. The third is that the consequences of bilingualism are not limited to language but appear to reflect a reorganization of brain networks that hold implications for the ways in which bilinguals negotiate cognitive competition more generally. The focus of recent research on bilingualism has been to understand the relation between these discoveries and the implications they hold for language, cognition, and the brain across the lifespan.

Speaking two languages at once: unconscious native word form access in second language production.

Bilingualism research has established language non-selective lexical access in comprehension. However, the evidence for such an effect in production remains sparse and its neural time-course has not yet been investigated. We demonstrate that German-English bilinguals performing a simple picture-naming task exclusively in English spontaneously access the phonological form of -unproduced- German words. Participants were asked to produce English adjective-noun sequences describing the colour and identity of familiar objects presented as line drawings. We associated adjective and picture names such that their onsets phonologically overlapped in English (e.g., green goat), in German through translation (e.g., blue flower - 'blaue Blume'), or in neither language. As expected, phonological priming in English modulated event-related brain potentials over the frontocentral scalp region from around 440ms after picture onset. Phonological priming in German was detectable even earlier, from 300ms, even though German was never produced and in the absence of an interaction between language and phonological repetition priming at any point in time. Overall, these results establish the existence of non-selective access to phonological representations of the two languages in the domain of speech production.

Do Spanish-English Bilinguals have Their Fingers in Two Pies - or is It Their Toes? An Electrophysiological Investigation of Semantic Access in Bilinguals.

We examined the time course of cross-language activation during word recognition in the context of semantic priming with interlingual homographs. Spanish-English bilinguals were presented pairs of English words visually one word at a time and judged whether the two words were related in meaning while recording event-related potentials. Interlingual homographs (e.g., "pie": "Pie" in Spanish is a foot.) appeared in the target position and were preceded by primes that were either related to the English meaning (e.g., "apple"), related to the Spanish meaning of interlingual homographs (e.g., "toe") or totally unrelated (e.g., "floor"/"bed"). Spanish-English bilinguals showed semantic priming not only when interlingual homographs were related to the English meaning but also to the Spanish meaning of the prime. These priming effects were detectable in the mean amplitude of the N400 (350-500 ms) even when the target word was related to the prime in Spanish and the context of the experiment was English. However, the relatedness effect was found in the window of a late positive component (LPC; 550-700 ms) only for stimulus pairs related in English. To verify that the observed pattern of the results was due to participants' bilingualism, we also tested a group of English monolinguals. The monolinguals showed a semantic priming effect for the N400 and LPC time windows only when interlingual homographs were related to the English meaning. These results suggest that both languages are activated in the classical time frame of semantic activation indexed by N400 modulations, but that semantic activation in the non-target language failed to be explicitly processed.

Effects of speed of word processing on semantic access: the case of bilingualism.

Bilingual speakers generally manifest slower word recognition than monolinguals. We investigated the consequences of the word processing speed on semantic access in bilinguals. The paradigm involved a stream of English words and pseudowords presented in succession at a constant rate. English-Welsh bilinguals and English monolinguals were asked to count the number of letters in pseudowords and actively disregard words. They were not explicitly told that pairs of words in immediate succession were embedded and could either be semantically related or not. We expected that slower word processing in bilinguals would result in semantic access indexed by semantic priming. As expected, bilinguals showed significant semantic priming, indexed by an N400 modulation, whilst monolinguals did not. Moreover, bilinguals were slower in performing the task. The results suggest that bilinguals cannot discriminate between pseudowords and words without accessing semantic information whereas monolinguals can dismiss English words on the basis of subsemantic information.

Language selection in bilingual word production: electrophysiological evidence for cross-language competition.

Previous research has demonstrated that cross-language activation is present even when proficient bilinguals perform a task only in one language. The present study investigated the time-course of cross-language activation during word production in a second language (L2) by using a picture-word interference paradigm with event-related potentials (ERPs). Spanish-English bilinguals living in an L2 environment named pictures in their L2 English while ignoring L2 English distractor words that were visually presented with the pictures. Participants named pictures more slowly when distractors were semantically related or phonologically related to either the English name of the picture or the Spanish name of the picture than when picture and distractor word were unrelated. Interference was also detectable in the mean amplitude of the N2 peak (200-260 ms) and the N3 range (350-400 ms). The results suggest that lexical alternatives from both languages compete for selection in the process of L2 speech planning in a predominantly L2 context.